EAU Guidelines on

Sexual and
Reproductive Health
A. Salonia (Chair), L. Boeri, P. Capogrosso, G. Corona,
M. Dinkelman-Smith, M. Falcone, M. Gül, A. Kadioğlu,
J.I. Martinez-Salamanca, S. Minhas (Vice-chair),
E.C. Serefoğlu, P. Verze
Guidelines Associates: A. Cocci, C. Fuglesang Jensen,
A. Kalkanli, L.A. Morgado, U. Milenkovic, G. Russo
Guidelines Office: E.J. Smith

© European Association of Urology 2025

TABLE OF CONTENTS PAGE
1. INTRODUCTION 12
1.1 Aims and Objectives 12
1.2 Panel Composition 12
1.3 Available Publications 12
1.4 Publication History 12
1.5 Summary of Changes 12

2. METHODOLOGY 12
2.1 Methods 12
2.2 Review 13

3.MALE HYPOGONADISM 13
3.1 Definition, epidemiology and classification of male hypogonadism 13
3.1.1 Definition 13
3.1.2 Epidemiology 13
3.1.3 Classification 14
3.2 Comorbidities associated with male hypogonadism 16
3.2.1 Obesity 16
3.2.2 Metabolic Syndrome/Type 2 Diabetes 16
3.2.3 Sars-CoV-2 / COVID-19 17
3.3 Late-onset hypogonadism 17
3.3.1 Clinical Diagnosis and Evaluation 17
3.3.2 History taking 17
3.3.3 Physical examination 18
3.3.4 Laboratory Diagnostics 18
3.3.5 Summary of evidence and recommendations for the diagnostic evaluation
and screening of LOH 19
3.4 Treatment of Classical and Late-onset Hypogonadism 22
3.4.1 Indications and contraindications for treatment of hypogonadism 22
3.4.2 Testosterone therapy outcomes 22
3.4.2.1 Sexual dysfunction 22
3.4.2.2 Vitality and physical strength 23
3.4.2.3 Mood and cognition 23
3.4.2.4 Body composition and metabolic profile 23
3.4.2.5 Bone 24
3.4.2.6 Summary of evidence and recommendations for testosterone
therapy outcome 24
3.4.3 Choice of treatment 25
3.4.3.1 Lifestyle factors 25
3.4.3.2 Medical preparations 25
3.4.3.2.1 Oral formulations 25
3.4.3.2.2 Parenteral formulations 25
3.4.3.2.3 Transdermal testosterone preparations 26
3.4.3.2.4 Transmucosal formulations 26
3.4.3.2.5 Subdermal depots 26
3.4.3.2.6 Anti-oestrogens 26
3.4.3.2.7 Gonadotropins 27
3.4.3.3 Summary of evidence and recommendations for choice of treatment
for LOH 28

2 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

 3.5 Safety and follow-up in hypogonadism management 29
3.5.1 Hypogonadism and fertility issues 29
3.5.2 Male breast cancer 29
3.5.3 Lower urinary tract symptoms/benign prostatic hyperplasia 29
3.5.4 Prostate cancer (PCa) 29
3.5.5 Cardiovascular Disease 30
3.5.5.1 Cardiac Failure 31
3.5.6 Erythrocytosis 31
3.5.7 Obstructive Sleep Apnoea 32
3.5.8 Follow-up 32
3.5.9 Summary of evidence and recommendations on safety and monitoring in
testosterone treatment 33

4. EPIDEMIOLOGY AND PREVALENCE OF SEXUAL DYSFUNCTION AND DISORDERS OF MALE

REPRODUCTIVE HEALTH 34
4.1 Erectile dysfunction 34
4.2 Premature ejaculation 35
4.3 Other ejaculatory disorders 35
4.3.1 Delayed ejaculation 35
4.3.2 Anejaculation and Anorgasmia 35
4.3.3 Retrograde ejaculation 35
4.3.4 Painful ejaculation 35
4.3.5 Haemospermia 36
4.4 Low sexual desire 36

5.MANAGEMENT OF ERECTILE DYSFUNCTION 36

5.1 Definition and classification 36
5.2 Risk factors 36
5.3 Pathophysiology 36
5.3.1 Pelvic surgery and prostate cancer treatment 38
5.3.2 Summary of evidence on the epidemiology/aetiology/pathophysiology of ED 38
5.4 Diagnostic evaluation (basic work-up) 39
5.4.1 Medical and sexual history 39
5.4.2 Physical examination 39
5.4.3 Laboratory testing 39
5.4.4 Cardiovascular system and sexual activity: the patient at risk 40
5.5 Diagnostic Evaluation (advanced work-up) 44
5.5.1 Nocturnal penile tumescence and rigidity test 44
5.5.2 Intracavernous injection test 44
5.5.3 Dynamic duplex ultrasound of the penis 44
5.5.4 Arteriography and dynamic infusion cavernosometry or cavernosography 44
5.5.5 Psychopathological and psychosocial assessment 44
5.5.6 Summary of evidence and recommendations for diagnostic evaluation of ED 46
5.6 Treatment of erectile dysfunction 46
5.6.1 Patient education 48
5.6.2 Modifiable risk factors 48
5.6.3 Phosphodiesterase type 5 inhibitors 48
5.6.3.1 Sildenafil 48
5.6.3.2 Tadalafil 48
5.6.3.3 Vardenafil 49
5.6.3.4 Avanafil 49
5.6.3.5 Continuous use of PDE5Is 49
5.6.3.6 Safety concerns for PDE5Is 50

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 3

 5.6.3.6.1 Cardiovascular safety 50
5.6.3.6.2 Contraindications for the concomitant use of organic
nitrates and nicorandil 50
5.6.3.6.3 Antihypertensive drugs 50
5.6.3.6.4 Interactions with α-blockers 50
5.6.3.7 Management of non- or poor-responders to PDE5Is 50
5.6.3.8 Topical/Intraurethral alprostadil 51
5.6.4 Psychosocial intervention and therapy 51
5.6.5 Hormonal treatment 51
5.6.6 Vacuum erection devices 51
5.6.7 Intracavernous injections therapy 51
5.6.7.1 Alprostadil 51
5.6.7.2 Other vasoactive intracavernous treatments 52
5.6.8 Innovative treatment modalities 53
5.6.8.1 Regenerative medicine therapies 53
5.6.8.1.1 Shockwave therapy 53
5.6.8.1.2 Platelet-Rich Plasma 53
5.6.8.1.3 Stem-cells 54
5.6.8.2 Botulinum Neurotoxin 54
5.6.9 Herbal medicine and natural supplements 54
5.6.10 Erectile dysfunction after radical prostatectomy 55
5.6.11 Surgical management 55
5.6.11.1 Surgery for post-traumatic arteriogenic ED 55
5.6.11.2 Venous ligation surgery 55
5.6.11.2.1 Penile prostheses 55
5.6.12 Summary of evidence and recommendations for treatment of ED 57
5.7 Follow-up 58

6.DISORDERS OF EJACULATION 58
6.1 Introduction 58
6.2 Premature ejaculation 58
6.2.1 Epidemiology 58
6.2.2 Pathophysiology and risk factors 58
6.2.3 Impact of PE on quality of life 58
6.2.4 Classification 59
6.2.5 Diagnostic evaluation 59
6.2.5.1 Intravaginal ejaculatory latency time (IELT) 59
6.2.5.2 Premature ejaculation assessment questionnaires 59
6.2.5.3 Physical examination and investigations 60
6.2.5.4 Summary of evidence and recommendations for the diagnostic
evaluation of PE 60
6.2.6 Disease management 60
6.2.6.1 Psychological aspects and intervention 61
6.2.6.1.1 Summary of evidence and recommendations for the
assessment and treatment (psychosexual approach)
of PE 62
6.2.6.2 Pharmacotherapy 62
6.2.6.2.1 Dapoxetine 62
6.2.6.2.2 Off-label use of antidepressants 63
6.2.6.2.3 Topical anaesthetic agents 64
6.2.6.2.3.1 Lidocaine/prilocaine cream 64
6.2.6.2.3.2 Lidocaine/prilocaine spray 64
6.2.6.2.4 Tramadol 64
6.2.6.2.5 Phosphodiesterase type 5 inhibitors 64
6.2.6.2.6 Other drugs 65

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 6.2.7 Summary of evidence and recommendations for the treatment of PE 65
6.3 Delayed Ejaculation (DE) 66
6.3.1 Definition and classification 66
6.3.2 Pathophysiology and risk factors 66
6.3.3 Investigation and treatment 67
6.3.3.1 Psychological aspects and intervention 67
6.3.3.2 Pharmacotherapy 67
6.4 Anejaculation 68
6.4.1 Definition and classification 68
6.4.2 Pathophysiology and risk factors 68
6.4.3 Investigation and treatment 68
6.5 Painful Ejaculation 68
6.5.1 Definition and classification 68
6.5.2 Pathophysiology and risk factors 68
6.5.3 Investigation and treatment 68
6.5.3.1 Surgical intervention 68
6.6 Retrograde ejaculation 68
6.6.1 Definition and classification 68
6.6.2 Pathophysiology and risk factors 68
6.6.3 Disease management 69
6.6.3.1 Pharmacological 69
6.6.3.2 Management of infertility 70
6.7 Anorgasmia 70
6.7.1 Definition and classification 70
6.7.2 Pathophysiology and risk factors 70
6.7.3 Disease management 70
6.7.3.1 Psychological/behavioural strategies 71
6.7.3.2 Pharmacotherapy 71
6.7.3.3 Management of infertility 71
6.8 Haemospermia 71
6.8.1 Definition and classification 71
6.8.2 Pathophysiology and risk factors 71
6.8.3 Investigations 71
6.8.4 Disease management 72
6.8.5 Summary of evidence and recommendations for the investigation and
management of haemospermia 74

7.LOW SEXUAL DESIRE AND MALE HYPOACTIVE SEXUAL DESIRE DISORDER 74

7.1 Definition, classification and epidemiology 74
7.2 Pathophysiology and risk factors 74
7.2.1 Psychological aspects 74
7.2.2 Biological aspects 75
7.2.3 Risk factors 75
7.3 Diagnostic work-up 75
7.3.1 Assessment questionnaires 75
7.3.2 Physical examination and investigations 75
7.4 Disease management 75
7.4.1 Psychological intervention 75
7.4.2 Pharmacotherapy 76
7.5 Recommendations for the treatment of low sexual desire 76

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 5

8.PENILE CURVATURE 77
8.1 Congenital penile curvature 77
8.1.1 Epidemiology/aetiology/pathophysiology 77
8.1.2 Diagnostic evaluation 77
8.1.3 Disease management 77
8.1.4 Summary of evidence and recommendation for diagnosis and treatment of
congenital penile curvature 77
8.2 Peyronie’s Disease 77
8.2.1 Epidemiology 77
8.2.2 Diagnostic evaluation 78
8.2.2.1 Summary of evidence and recommendations for diagnosis of
Peyronie’s disease 78
8.2.3 Disease management 79
8.2.3.1 Conservative treatment 79
8.2.3.1.1 Oral treatment 79
8.2.3.1.2 Intralesional treatment 80
8.2.3.1.3 Topical treatments 82
8.2.3.1.4 Other treatments 82
8.2.3.1.5 Summary of evidence and recommendations for
conservative treatment of Peyronie’s disease 83
8.2.3.2 Surgical treatment 84
8.2.3.2.1 Tunical shortening procedures 84
8.2.3.2.2 Tunical lengthening procedures 85
8.2.3.2.3 Penile prosthesis 87
8.2.3.2.4 Summary of evidence and recommendations for
surgical treatment of Peyronie’s disease 88

9.PENILE SIZE ABNORMALITIES AND DYSMORPHOPHOBIA 90

9.1 Definition, epidemiology and classification 90
9.1.1 History 90
9.1.2 Definition 90
9.1.3 Epidemiology and Classification 91
9.1.3.1 False penile shortness - congenital or acquired 92
9.1.3.2 Intrinsic penile shortness – congenital 92
9.1.3.3 Intrinsic penile shortness – acquired 93
9.1.3.4 Body dysmorphic disorder 93
9.1.4 Summary of evidence and recommendations for classification 93
9.2 Diagnosis 94
9.2.1 Medical history, physical examination and psychological assessment 94
9.2.1.1 Medical History 94
9.2.1.2 Sexual history 94
9.2.1.3 Physical examination and penile size measurements 94
9.2.1.4 Psychological assessment 95
9.2.1.5 Counselling and outcomes assessment - Validated questionnaires 95
9.2.2 Imaging 95
9.3 Management 96
9.3.1 Non-surgical Treatments 96
9.3.1.1 Psychotherapy 96
9.3.1.2 Penile traction therapy 96
9.3.1.3 Vacuum erection device 97
9.3.1.4 Endocrinological therapies 97
9.3.1.5 Summary of evidence and recommendations for the non-surgical
management of short penile size 97

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 9.3.2 Surgical Treatments 98
9.3.2.1 Surgical treatment of adult acquired buried penis 98
9.3.2.1.1 Adult acquired buried penis surgical procedures
classification 98
9.3.2.2 Surgical treatment of congenital intrinsic penile shortness 99
9.3.2.2.1 Suspensory ligament release 99
9.3.2.2.2 Ventral phalloplasty/scrotoplasty 99
9.3.2.2.3 Suprapubic lipoplasty/liposuction/lipectomy 99
9.3.2.2.4 Total phallic reconstruction 99
9.3.2.2.5 Summary of evidence and recommendations for surgical
treatment of congenital intrinsic penile shortness 100
9.3.2.3 Surgical treatment of acquired penile shortness 100
9.3.2.3.1 Penile prosthesis implantation (PPI) 100
9.3.2.3.2 Penile disassembly 100
9.3.2.3.3 Lengthening corporal manoeuvres 100
9.3.2.3.4 Total phallic reconstruction (TPR) 101
9.3.2.3.5 Summary of evidence and recommendations for
surgical treatment of acquired penile shortness 101
9.3.2.4 Penile girth enhancement 101
9.3.2.4.1 Penile Girth enhancement history 101
9.3.2.4.2 Injection therapy 101
9.3.2.4.2.1 Soft tissue fillers (Hyaluronic acid and
PMMA) 102
9.3.2.4.2.2 Other Fillers (silicone, paraffin) 102
9.3.2.4.3 Surgical therapy 102
9.3.2.4.3.1 Autologous fat injection 102
9.3.2.4.3.2 Grafting procedures (albugineal and
peri-cavernosal) 102
9.3.2.4.3.3 Biodegradable scaffolds 103
9.3.2.4.3.4 Subcutaneous penile implant (Penuma®) 103
9.3.2.4.4 Summary of evidence and recommendations for penile
girth enhancement 103
9.3.2.5 Functional outcomes: sexual function, sensitivity, impact on quality
of life and emotional adjustment 104
9.3.2.6 Final remarks 105

10.
PRIAPISM 105
10.1 Ischaemic (Low-Flow or Veno-Occlusive) Priapism 105
10.1.1 Epidemiology, aetiology, pathophysiology and Diagnosis 105
10.1.1.1 Summary of evidence on the epidemiology, aetiology and
pathophysiology of ischaemic priapism 107
10.1.2 Diagnostic evaluation 107
10.1.2.1 History 107
10.1.2.2 Physical examination 107
10.1.2.3 Laboratory testing 107
10.1.2.4 Penile imaging 108
10.1.2.5 Summary of evidence and recommendations for the diagnosis of
ischaemic priapism 109
10.1.3 Disease management 110
10.1.3.1 Medical Management – first-line treatment 110
10.1.3.1.1 Penile anaesthesia/analgesia 110
10.1.3.1.2 Aspiration ± irrigation with 0.9% w/v saline solution 110
10.1.3.1.3 Aspiration ± irrigation with 0.9% w/v saline solution
in combination with intracavernous injection of
pharmacological agents. 111

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 10.1.3.1.4 Intracavernosal and oral pharmacological agents 111
10.1.3.1.5 Management of priapism related to sickle cell disease 112
10.1.3.2 Surgical management- second-line treatments 113
10.1.3.2.1 Penile shunt surgery 113
10.1.3.2.2 Immediate penile prosthesis implantation 114
10.1.3.2.3 Surgery for non-acute sequelae after ischaemic
priapism 115
10.1.4 Summary of evidence and recommendations for treatment of ischaemic
priapism 117
10.2 Priapism in Special Situations 118
10.2.1 Stuttering (recurrent or intermittent) priapism 118
10.2.1.1 Diagnostic evaluation 119
10.2.1.2 Disease management 119
10.2.1.2.1 α-Adrenergic agonists 119
10.2.1.2.2 Hormonal manipulations of circulating testosterone 119
10.2.1.2.3 Digoxin 119
10.2.1.2.4 Terbutaline 120
10.2.1.2.5 Gabapentin 120
10.2.1.2.6 Baclofen 120
10.2.1.2.7 Hydroxyurea 120
10.2.1.2.8 Phosphodiesterase type 5 inhibitors 120
10.2.1.2.9 Intracavernosal injections 120
10.2.1.2.10 Penile prosthesis 120
10.2.1.3 Summary of evidence and recommendations for treatment of
stuttering priapism 121
10.2.1.4 Follow-up 121
10.2.2 Priapism in children 121
10.3 Non-ischaemic (high-flow or arterial) priapism 121
10.3.1 Epidemiology/aetiology/pathophysiology 121
10.3.2 Diagnostic evaluation 122
10.3.2.1 History 122
10.3.2.2 Physical examination 122
10.3.2.3 Laboratory testing 122
10.3.2.4 Penile imaging 122
10.3.2.5 Summary of evidence and recommendations for the diagnosis of
non-ischaemic priapism 123
10.3.3 Disease management 123
10.3.3.1 Conservative management 123
10.3.3.2 Selective arterial embolisation 123
10.3.3.3 Surgical management 124
10.3.3.4 Summary of evidence and recommendations for the treatment of
non-ischaemic priapism 124
10.3.3.5 High-flow priapism in children 124
10.3.3.6 Follow-up 125

11.
MALE INFERTILITY 125
11.1 Definition and classification 125
11.2 Epidemiology/aetiology/pathophysiology/risk factors 125
11.2.1 Introduction 125
11.2.2 Summary of evidence and recommendations on epidemiology and aetiology
of male infertility 126

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 11.3 Diagnostic work-up 127
11.3.1 Medical/reproductive history and physical examination 127
11.3.1.1 Medical and reproductive history 127
11.3.1.2 Physical examination 127
11.3.2 Semen analysis 128
11.3.3 Measurement of sperm DNA Fragmentation Index (SDF) 130
11.3.4 Hormonal determinations 131
11.3.5 Genetic testing 131
11.3.5.1 Chromosomal abnormalities 131
11.3.5.1.1 Sex chromosome abnormalities (Klinefelter syndrome
and variants [47,XXY; 46,XY/47, XX mosaicism]) 131
11.3.5.1.2 Autosomal abnormalities 132
11.3.5.2 Cystic fibrosis gene mutations 132
11.3.5.2.1 Unilateral or bilateral absence/abnormality of the vas
and renal anomalies 132
11.3.5.3 Y microdeletions – partial and complete 133
11.3.5.3.1 Clinical implications of Y microdeletions 133
11.3.5.3.1.1 Testing for Y microdeletion 133
11.3.5.4 Exome sequencing 133
11.3.6 Imaging in infertile men 134
11.3.6.1 Scrotal US 134
11.3.6.1.1 Testicular neoplasms 134
11.3.6.1.2 Varicocele 135
11.3.6.1.3 Other 135
11.3.6.2 Transrectal US 135
11.3.7 Summary of evidence and recommendations for the diagnostic work-up of
male infertility 135
11.4 Special Conditions and Relevant Clinical Entities 137
11.4.1 Cryptorchidism 137
11.4.1.1 Classification 137
11.4.1.1.1 Aetiology and pathophysiology 138
11.4.1.1.2 Pathophysiological effects in maldescended testes 138
11.4.1.1.2.1 Degeneration of germ cells 138
11.4.1.1.2.2 Relationship with fertility 138
11.4.1.1.2.3 Germ cell tumours 138
11.4.1.2 Disease management 138
11.4.1.2.1 Hormonal treatment 138
11.4.1.2.2 Surgical treatment 138
11.4.1.3 Summary of evidence recommendations for cryptorchidism 139
11.4.2 Germ cell malignancy and male infertility 139
11.4.2.1 Testicular germ cell cancer and reproductive function 139
11.4.2.2 Testicular microcalcification (TM) 140
11.4.2.3 Summary of evidence and recommendations for germ cell
malignancy and testicular microcalcification 141
11.4.3 Varicocele 142
11.4.3.1 Classification 142
11.4.3.2 Diagnostic evaluation 142
11.4.3.3 Basic considerations 142
11.4.3.3.1 Varicocele and fertility 142
11.4.3.3.2 Varicocelectomy 142
11.4.3.3.3 Prophylactic varicocelectomy 143
11.4.3.3.4 Varicocelectomy for assisted reproductive technology
and raised SDF 144

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 11.4.3.4 Disease management 144
11.4.3.5 Summary of evidence and recommendations for varicocele 146
11.4.4 Male accessory gland infections and infertility 146
11.4.4.1 Introduction 146
11.4.4.2 Diagnostic evaluation 146
11.4.4.2.1 Semen analysis 146
11.4.4.2.2 Microbiological findings 146
11.4.4.2.3 White blood cells 147
11.4.4.2.4 Sperm quality 147
11.4.4.2.5 Seminal plasma alterations 147
11.4.4.2.6 Glandular secretory dysfunction 147
11.4.4.2.7 Reactive oxygen species (ROS) 148
11.4.4.2.8 Disease management 148
11.4.4.3 Epididymitis 148
11.4.4.3.1 Diagnostic evaluation 148
11.4.4.3.1.1 Ejaculate analysis 148
11.4.4.3.1.2 Disease management 148
11.4.4.4 Summary of evidence and recommendation for male accessory
gland infections 148
11.5 Non-Invasive Male Infertility Management 149
11.5.1 Empirical treatments 149
11.5.1.1 Life-style 149
11.5.1.2 Antioxidant treatment 149
11.5.1.3 Probiotic treatment 149
11.5.1.4 Selective oestrogen receptor modulators 150
11.5.1.5 Aromatase inhibitors 150
11.5.2 Summary of evidence and recommendation for Non-Invasive Male Infertility
Management 150
11.5.3 Hormonal therapy 150
11.5.3.1 Secondary hypogonadism 150
11.5.3.1.1 Secondary hypogonadism due to hyperprolactinemia 151
11.5.3.2 Primary Hypogonadism 151
11.5.3.3 Idiopathic Male Factor Infertility 151
11.5.3.4 Anabolic Steroid Abuse 151
11.5.3.5 Summary of evidence and recommendations for treatment of male
infertility with hormonal therapy 151
11.6 Invasive Male Infertility Management 152
11.6.1 Obstructive azoospermia 152
11.6.1.1 Diagnostic evaluation 153
11.6.1.1.1 Clinical examination 153
11.6.1.1.2 Hormone levels 153
11.6.1.1.3 Genetic testing 153
11.6.1.1.4 Testicular biopsy 153
11.6.1.2 Disease management 153
11.6.1.2.1 Sperm retrieval 153
11.6.1.3 Summary of evidence and recommendations for obstructive
azoospermia 154
11.6.2 Non-obstructive azoospermia 155
11.6.2.1 Investigation of non-obstructive azoospermia 155
11.6.2.2 Surgery for non-obstructive azoospermia 155
11.6.2.3 Indications and techniques of sperm retrieval 155
11.6.2.4 Recommendations for Non-Obstructive Azoospermia 158
11.7 Assisted Reproductive Technologies 158
11.8 Psychosocial aspects in men’s infertility 159

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12. LATE EFFECTS, SURVIVORSHIP AND MEN’S HEALTH 159

13. REFERENCES 161

14. CONFLICT OF INTEREST 264

15. CITATION INFORMATION 265

16. COPYRIGHT AND TERMS OF USE 265

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1. INTRODUCTION
1.1 Aims and Objectives
The European Association of Urology (EAU) Sexual and Reproductive Health Guidelines aim to provide a
comprehensive overview of the medical aspects relating to sexual and reproductive health in adult men.
It must be emphasised that guidelines present the best evidence available to the experts. However,
following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace
clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - while
taking personal values and preferences/individual circumstances of patients into account. Guidelines are not
mandates and do not purport to be a legal standard of care.

1.2 Panel Composition

The EAU Sexual and Reproductive Health Guidelines Panel consists of an international multi-disciplinary
group of urologists and endocrinologists. All experts involved in the production of this document have
submitted potential conflict of interest statements which can be viewed on the EAU website:
http://www.uroweb.org/guideline/sexual-and-reproductive-health/.

1.3 Available Publications

A quick reference document, the Pocket Guidelines, is available. This is an abridged versions
that may require consultation together with the full text version. A number of scientific
publications are also available. All documents can be viewed through the EAU website:
http://www.uroweb.org/guideline/sexual-and-reproductive-health/. An EAU Guidelines App for iOS and Android
devices is also available containing the Pocket Guidelines, interactive algorithms and calculators, clinical
decision support tools, guidelines cheat sheets and links to the extended guidelines.

1.4 Publication History

The EAU Sexual and Reproductive Health Guidelines were first published in 2020. This 2025 document presents
a limited update of the 2024 publication.

1.5 Summary of Changes

For the 2025 Sexual and Reproductive Health Guidelines new and relevant evidence was identified, collated
and appraised through a structured assessment of the literature for all sections of the Guidelines. This
resulted in the inclusion of 76 updated studies across the Guidelines. Key changes include:
• Significant changes to section 5.4.4 Cardiovascular system and sexual activity: the patient at risk. This
section has been completely restructured and updated including two new figures 5.2 and 5.3.
• Two new recommendations in section 5.6.12 Summary of evidence and recommendations for treatment
of ED.
• Modification of the recommendation for penile surgery for adult acquired buried penis in section 9.3.2.2.5.
• Addition of a new sections – section 11.3.5.4 Exome sequencing and 11.5.1.3 Probiotic treatment.
• Update of the recommendations in section 11.3.7.

2. METHODOLOGY
2.1 Methods
For the 2025 Sexual and Reproductive Health Guidelines, new and relevant evidence has been identified,
collated, and appraised through a structured assessment of the literature for Sections 5 Management of Erectile
Dysfunction and 11 Male Infertility. Databases searched included Medline, EMBASE, and the Cochrane Libraries,
covering a time frame between the 1st Jan 2023 and 1st May 2024. A total of 1,499 and 2,788 unique records
were identified, retrieved, and screened for relevance for Sections 5 and 11, respectively. Detailed search
strategies are available online: https://uroweb.org/guidelines/sexual-and-reproductive-health/publications-
appendices.

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Recommendations within the Guidelines are developed by the panels to prioritise clinically important care
decisions. The strength of each recommendation is determined by the balance between desirable and
undesirable consequences of alternative management strategies, the quality of the evidence (including certainty
of estimates), and the nature and variability of patient values and preferences. This decision process, which can
be reviewed in the strength rating forms which accompany each guideline statement, addresses a number of
key elements:

1. the overall quality of the evidence which exists for the recommendation [1];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study
related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact and certainty of patient values and preferences on the intervention.

Strong recommendations typically indicate a high degree of evidence quality and / or a favourable balance
of benefit to harm and patient preference. Weak recommendations typically indicate availability of lower
quality evidence, and/or equivocal balance between benefit and harm, and uncertainty or variability of patient
preference [2].

Additional information can be found online at the EAU website: http://www.uroweb.org/guideline/. A list of
associations endorsing the EAU Guidelines can also be viewed online at this address.

2.2 Review
The EAU Sexual and Reproductive Health Guidelines were peer reviewed prior to publication in 2020. The new
priapism section was reviewed prior to publication in 2021. In 2023 the newly added section on penile size
abnormalities and dysmorphophobia was reviewed prior to publication.

3. MALE HYPOGONADISM
3.1 Definition, epidemiology and classification of male hypogonadism
3.1.1 Definition
Male hypogonadism is a clinical syndrome which comprises of symptoms with or without signs and
biochemical evidence of testosterone deficiency. Hypogonadism is associated with decreased testicular
function and production of androgens and/or impaired sperm production [3]. This may be caused by impaired
testicular function (hypergonadotropic hypogonadism or primary hypogonadism) or as a result of inadequate
stimulation of the testes by the hypothalamic-pituitary axis (hypogonadotropic hypogonadism or secondary
hypogonadism) (Table 3.1) or uncommonly by reduced ability of testosterone to stimulate the androgen
receptor at the cellular level. Hypogonadism can adversely affect multiple organ functions and quality of life
(QoL) [3, 4]. This chapter specifically addresses the management of adult male hypogonadism also called
late onset hypogonadism (LOH). Some insights related to congenital or pre-pubertal hypogonadism are also
provided.

3.1.2 Epidemiology
The prevalence of LOH increases with age, with the major causes being obesity, other co-morbidities (e.g.,
diabetes) and overall poor health [5]. The incidence of hypogonadism has been reported to be between 12.3
and 11.7 cases per 1,000 people per year [6, 7]. Aging accounts for a low percentage of hypogonadism, as there
is only a small gradual decline in testosterone, up to the age of 80 years, in healthy aging men [5]. In men aged
40-79 years, the incidence of symptomatic hypogonadism varies between 2.1 and 5.7% [6, 8, 9].
There is a high prevalence of LOH within specific populations, including patients with obesity, type
2 diabetes (T2DM), metabolic syndrome (MetS), cardiovascular diseases (CVD), chronic obstructive pulmonary
disease (COPD), renal disease and cancer [9]. In particular low testosterone levels are relatively common in men
with T2DM [10, 11] and in those with metabolic derangements.
Klinefelter syndrome, a trisomy associated with a 47,XXY karyotype, is the most prevalent genetic
cause of primary hypogonadism, with a global prevalence of 1/500-1,000 live male births [12-15]. However,
< 50% of individuals with Klinefelter syndrome are diagnosed during their lifetime [16].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 13

3.1.3 Classification
Male hypogonadism can be classified according to the aetiology into primary hypogonadism or secondary
hypogonadism (Table 3.1) [3, 17]. A compensated or subclinical form of hypogonadism, characterised by normal
testosterone serum levels and elevated luteinising hormone (LH) production, has also been reported [18]; the
clinical significance of this condition is unclear [18-21].
The classification of hypogonadism has also been divided into two broad categories: ‘Classical/
Organic’ and ‘Functional’, often but not correctly identified as LOH. The clinical effects of testosterone deficiency
are however common to all patients independent of the cause of the hypogonadism; although, they may vary
in severity or as a result of age of onset. Classical hypogonadism includes: congenital or acquired diseases
causing structural and/or irreversible impairment of the pituitary and/or testes. Functional hypogonadism
is diagnosed on the absence of any recognised organic alterations in the HPG axis and it is mainly a
consequence of co-morbidities, affecting the Hypothalamic-Pituitary-Testicular (HPT) axis and should be treated
first by resolving or improving any underlying conditions (e.g., anorexia in younger male subjects). Late onset
hypogonadism represents an even broader clinical entity including adult onset forms which can have an organic
or functional origin and can be primary or secondary [22]. Late onset hypogonadism is frequently diagnosed in
the absence of an identifiable classical cause of hypogonadism, which becomes more prevalent with age. By
definition LOH must comprise both persistent specific symptoms and biochemical evidence of testosterone
deficiency [3, 23].
Finally, hypogonadism can also result from several conditions leading to reduced sensitivity/
insensitivity to testosterone and its metabolites [3].

The current guidelines maintain a classification of Primary and Secondary Hypogonadism, with special
reference to LOH. The classification, based on the aetiology of hypogonadism, allows clinicians to adequately
select appropriate treatment. In patients with secondary hypogonadism, both fertility and testosterone
normalisation can be theoretically achieved with adequate treatment, whereas in primary hypogonadism only
testosterone therapy can be considered, which eventually impairs fertility due to suppression of the HPT axis
[3, 17] (Table 3.1). It should also be recognised that symptoms and signs of hypogonadism can be similarly
independent of the site of origin of the disease. Conversely, the age of onset of hypogonadism can influence
the clinical phenotype [24]. Accordingly, for early onset, such as that occurring during foetal life, the clinical
phenotype can span from an almost complete female phenotype (e.g., complete androgen insensitivity or
enzymatic defects blocking androgen synthesis) to various defects in virilisation. In the case of a pre- or peri-
pubertal appearance of hypogonadism due to a milder central (isolated hypogonadotropic hypogonadism [IHH])
or a peripheral defect (such as in Klinefelter syndrome), there may be delayed puberty with an overall eunuchoid
phenotype. Finally, when hypogonadism develops after puberty and especially with ageing symptoms can be
mild and often confused the with ageing process [3, 24].

Table 3.1: Classification of male hypogonadism

PRIMARY HYPOGONADISM (hypergonadotropic hypogonadism)

Congenital or developmental disorders
Common causes Uncommon causes
• Klinefelter syndrome • Rare chromosomal abnormalities -
(XX male, 47 XYY and 48 XXYY syndrome
• 21 Trisomy (Down syndrome)
• Noonan syndrome
• Autosomal translocations1
• Defects of testosterone biosynthesis
• CAH (testicular adrenal rest tumours)
• Disorders of sex development (gonadal dysgenesis)
• LHR gene mutations
• Myotonic dystrophy (including type I and II)
• Uncorrected cryptorchidism (including INSL3 and LGR8
mutations)
• Bilateral congenital anorchia
• Sickle cell disease
• Adreno-leukodystrophy

14 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Acquired disorders
Drug-induced Localised problems
•  hemotherapy agents
C • Bilateral surgical castration or trauma
• Alkylating agents • Testicular irradiation
• Methotrexate • Orchitis (including mumps orchitis)
• Testosterone synthesis inhibitors - • Autoimmune testicular failure
Ketoconazole, Aminoglutethimide, • Testicular Torsion
Mitotane and Metyrapon • Alcohol/Cirrhosis
• Environmental Toxins
Systemic diseases/conditions with hypothalamus/pituitary impact
• Chronic systemic diseases* • Malignancies – Lymphoma and Testis cancer
• Chronic organ failure* • Spinal cord injury
• Glucocorticoid excess (Cushing • Vasculitis
syndrome)* • Infiltrative diseases (amyloidosis; leukaemia)
• Ageing*
• HIV
SECONDARY HYPOGONADISM (hypogonadotropic hypogonadism)
Congenital or developmental disorders
Common causes Uncommon causes
• Haemochromatosis* • Combined hormone pituitary deficiency
• Idiopathic hypogonadotropic hypogonadism
• IHH with variants: Normosmic IHH, Kallmann syndrome,
isolated LH β gene mutations and Prader-Willi syndrome
Acquired disorders
Drug-induced Localised problems
• Oestrogens • Traumatic brain injury
• Testosterone or androgenic anabolic • Pituitary neoplasm (micro/macro-adenomas)
steroids • Hypothalamus tumours
• Progestogens (including cyproterone • Pituitary stalk diseases
acetate) • Iatrogenic - surgical hypophysectomy and pituitary or
• Hyperprolactinemia-induced drugs cranial irradiation
• Opiates - GnRH agonist or antagonist and • Inflammatory and infectious diseases -lymphocytic
glucocorticoids hypophysitis; pituitary infections; granulomatous
lesions; sarcoidosis; Wegener’s granulomatosis; other
granulomatosis and encephalitis
• Langerhans’ histiocytosis
• Hyperprolactinaemia, as a consequence of localised
problems (hypothalamus-pituitary mass)
Systemic diseases/conditions impacting the hypothalamus/pituitary
• Chronic systemic diseases* - • Spinal cord injury
Type 2 diabetes mellitus/Metabolic • Transfusion-related iron overload (β-thalassemia)
Syndrome/metabolic diseases; HIV • Eating disorders*
infection; chronic organ failure; and • Endurance exercise
chronic Inflammatory Arthritis • Acute and critical illness
• Glucocorticoid excess (Cushing • Ageing*
syndrome)*
ANDROGEN RESISTANCE/DECREASED TESTOSTERONE BIOACTIVITY
Congenital or developmental disorders
• Aromatase deficiency
• Kennedy diseases (spinal and bulbar muscular atrophy) and other extensions of CAG repeats
• Partial or complete androgen insensitivity
• 5α reductase type II (5aR) deficiency

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 15

Acquired disorders
Drug-induced Localised problems
• Drug-induced AR blockage - steroidal • Coeliac disease
antiandrogen, cyproterone acetate and
spironolactone
• Non-steroidal antiandrogen – flutamide,
bicalutamide and nilutamide
• Drug-induced 5α reductase (5aR) activity
blockade – finasteride and dutasteride
• Drug-induced ER blockade – clomiphene,
tamoxifen and raloxifene
• Drug-induced aromatase activity
blockade – letrozole, anastrozole and
exemestane
• Increased Sex Hormone Binding Globulin
(SHBG)
* Conditions acting at central and peripheral levels resulting in either primary and secondary hypogonadism.
1 Different autosomal translocations can cause rare cases of hypogonadism and infertility.

A brief discussion on the physiology of testosterone production can be found in Appendix 1, online supplementary
evidence (https://uroweb.org/guidelines/sexual-and-reproductive-health/publications-appendices).

3.2 Comorbidities associated with male hypogonadism

3.2.1 Obesity
Low testosterone levels are common in men with obesity. Male hypogonadism is associated with a greater
percentage of fat mass and a lower lean mass compared to men with adequate testosterone levels [25-27]. Low
testosterone levels are strongly associated with increased visceral adiposity, but also lead to lipid deposition in
the liver and muscle and is associated with atherosclerosis [25, 26].

3.2.2 Metabolic Syndrome/Type 2 Diabetes

Hypogonadism is frequently associated with MetS or its related components, including central obesity,
hyperglycaemia, insulin resistance, dyslipidaemia and arterial hypertension [28].

Several randomised controlled trials (RCTs) have demonstrated that testosterone therapy may improve insulin
resistance and hyperglycaemia and lower total and low-density protein (LDL)-cholesterol [29-34]. Testosterone
therapy in hypogonadal T2DM improved glycaemic control in some RCTs and registry trials; however, there is no
conclusive evidence [30, 35, 36]. A large placebo-controlled RCT, including 1,007 patients with impaired glucose
tolerance or newly diagnosed T2DM and total testosterone < 14 nmol/L showed that testosterone therapy for
two years reduced the proportion of patients with T2DM regardless of a lifestyle programme [34]. Similarly, a
registry study reported that testosterone therapy was associated in time with remission of T2DM [35]. High-
density lipoprotein (HDL)-cholesterol may decrease, remain unchanged or increase with testosterone therapy.

Testosterone therapy in men with MetS and low testosterone has been shown to reduce mortality compared to
untreated men [37, 38], although no conclusive evidence is available.

Erectile dysfunction (ED) is common in men with MetS and T2DM (up to 70% of patients). The causes of ED
are multi-factorial and 30% of men with ED have co-existing testosterone-deficiency/hypogonadism. Some
evidence has suggested that ED is only found in men with T2DM and clearly reduced testosterone levels (< 8
nmol/L or 2.31 ng/mL) [39]. From a pathophysiological perspective, it has been reported that this is because
ED is predominantly caused by vascular and neuropathic disease, and therefore not likely in men who do not
have established vascular disease. Therefore, men presenting with ED should be screened for MetS. Likewise,
patients with ED and diabetes may be offered testosterone measurement.

Placebo-controlled RCTs of testosterone therapy in T2DM have demonstrated improved sexual desire and
satisfaction, but not erectile function [30, 39]. Similar results were derived from a meta-analysis of published
trials [40]. Accordingly, a large two-year RCT of testosterone undecanoate vs. placebo showed that testosterone
therapy significantly improved sexual function and ED in men with impaired glucose tolerance or newly
diagnosed T2DM low testosterone (< 14 nmol/L) [34].

16 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Testosterone therapy has been associated with a reduced percentage of body fat and increase in lean body
mass [41]. Data from a registry study have suggested that testosterone therapy with long-acting intramuscular
testosterone undecanoate over a period of eleven years was associated with a substantial but gradual loss of
weight, along with a reduction in waist circumference [42]

3.2.3 Sars-CoV-2 / COVID-19

Data suggest that low circulating testosterone levels are more frequently associated with worse clinical
outcomes in men with COVID-19 [43-50]. A cohort study, analysing two large academic health systems
databases, including 723 men with a history of COVID-19 reported that hypogonadal men had a higher risk of
being hospitalised [51]. In addition, a meta-analysis suggested that reduced testosterone levels detected at
hospital admission for COVID-19 are associated with a four- to five-fold increased risk of being admitted to the
Intensive Care Unit (ICU) or dying, after adjustment for potential confounders [52].
Although no information on the role of testosterone therapy in the acute phase of the disease is
currently available, data also showed that the hypogonadal patients under testosterone therapy had a reduced
risk to be hospitalised after SARS-CoV-2 infection [51]. However, whether or not low testosterone can directly
contribute to worse COVID-19 outcomes is still under investigation. The possibility that low testosterone
in the acute phase of COVID-19 infection represents an adaptive response mechanism to dampen non-
essential activities non conducive to recovery (physical and sexual activities) by turning off testosterone-
dependent functions, cannot be excluded [53, 54]. Accordingly, a meta-analysis showed that secondary or mixed
hypogonadism is more frequently observed in the acute phase of the infection [52].
Studies evaluating patients in the recovery phase of COVID-19 have documented either restored [55,
56] or persistently low testosterone levels in the majority of cases [57]. A longitudinal evaluation study showed
that during the recovery phase a further improvement of testosterone levels can be observed up to twelve
months after COVID-19. Male subjects who have recovered from COVID-19 should be accurately followed-up to
exclude any long-term andrological consequences such as impairment in sperm and testosterone production
[52].

3.3 Late-onset hypogonadism

Testosterone production declines with ageing. The European Male Aging Study (EMAS) reported a 0.4% per
annum (log hormone-age) decrease in total testosterone and a 1.3% per annum decline in free testosterone
(fT) [5]. Late onset hypogonadism is the term frequently used to describe this phenomenon and the detection
of hypogonadism in adulthood. Evidence indicates that several associated diseases and chronic comorbidities
can interfere with the HPG axis leading to development of primary hypogonadism or, more frequently,
secondary hypogonadism in adulthood, thus significantly influencing the physiological age-dependent decline
of testosterone. By combining the data from three different waves of the Massachusetts Male Aging Study
(MMAS), demonstrated that associated comorbidity and obesity significantly decreased, whereas smoking
tended to increase total, free and bio-available testosterone concentrations [58]. Data derived from the EMAS
confirmed these findings [5, 19]. Based upon these data and other evidence, the concept of functional and
organic hypogonadism has been more recently introduced (see above) [59]. The diagnosis of functional
hypogonadism is based on the exclusion of a classical (organic) aetiology. The main causes suggested for
functional hypogonadism are obesity, comorbidities and ageing, with the first two accounting for most cases.
Inflammatory cytokines released in chronic inflammation, and adipocytokines and E2 in obesity, can suppress
the HPG axis. The role of ageing up to age 80 years seems relatively small [59]. Considering that suppression
of HPG axis activity is functional, and potentially reversible by empiric measures, such as weight loss, the need
for testosterone therapy has been questioned [59]. The division between functional and organic hypogonadism
is still a matter of debate, since any impairment of the HPT axis which results in symptomatic low testosterone
levels is associated with a disorder, despite the fact it can lack identifiable “pathological” causes.

3.3.1 Clinical Diagnosis and Evaluation

The mainstay of LOH diagnosis includes signs and symptoms consistent with hypogonadism (Table 3.2),
coupled with biochemical evidence of low morning serum total testosterone levels on two or more occasions,
measured with a reliable assay and in fasting conditions.

3.3.2 History taking

Specific symptoms associated with hypogonadism, including LOH, are shown in Table 3.2. These symptoms
are non-specific and need to be recorded and taken in context with the clinical and biochemical state. Several
self-reported questionnaires or structural interviews have been developed for screening of hypogonadism.
Although these case-history tools have demonstrated clinical utility in supporting the biochemical diagnosis of
hypogonadism, or in the assessment of testosterone therapy outcomes, their specificity remains poor and they
should not be used for a systematic screening of hypogonadal men [60]. Headache and/or visual disturbance

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 17

may indicate a pituitary related disorder. History of surgical intervention for cryptorchidism or hypospadias
must be taken into account as possible signs of congenital defects. Chronic and systemic comorbidities must
be comprehensively investigated in every patient. Use of drugs that potentially interfere with the HPG axis
should be excluded (Table 3.1). Acute diseases are associated with development of functional hypogonadism
and determination of serum total testosterone levels should be avoided in these conditions; however, the role
of testosterone in the case of acute illness remains to be clarified [43, 47, 52, 61]. Fertility should always be
discussed.

Table 3.2: Specific symptoms associated with LOH

Sexual symptoms Physical symptoms Psychological symptoms

More specific • Reduced libido • Decreased vigorous • Low mood/mood
• Erectile dysfunction activity deflection
• Decreased • Difficulty walking > 1 km • Decreased motivation
spontaneous/morning • Decreased bending • Fatigue
erections
Less specific • Reduced frequency of • Hot flushes • Concentration or
sexual intercourse • Decreased energy mnemonic difficulties
• Reduced frequency of • Decreased physical • Sleep disturbances
masturbation strength/function/
• Delayed ejaculation activity

3.3.3 Physical examination

Since obesity is frequently associated with hypogonadism (mostly functional), the determination of body
mass index (BMI) and the measurement of waist circumference are strongly recommended in all individuals.
Testicular and penile size, as well the presence of sexual secondary characteristics can provide useful
information regarding overall androgen status. In addition, upper segment/lower segment ratio (n.v. > 0.92) and
arm-span to height ratio (n.v. < 1.0) can be useful to identify a eunochoid body shape, especially in subjects with
pre-pubertal hypogonadism or delayed puberty. Finally, digital rectal examination (DRE) should be performed in
all subjects to exclude prostate abnormalities before testosterone therapy (any type) or to support suspicion of
hypogonadism (in case of reduced volume) [62].

3.3.4 Laboratory Diagnostics

Testosterone levels are produced in a circadian variation, which may persist in ageing men [63, 64].
Testosterone levels are also potentially influenced by food intake [65]; therefore, serum total testosterone
should be measured in fasting conditions and in the morning (between 07.00 and 11.00 hours). A confirmatory
measurement should always be undertaken in the case of a primary pathological value, and before starting any
testosterone therapy.
Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) represents the most accurate
method for sex steroid evaluation; however, standardised automated platform immuno-assays for total
testosterone assessment demonstrate a good correlation with LC-MS/MS [66]. Available immuno-assays
are not able to provide an accurate estimation of fT; therefore, direct fT evaluation with these methods is not
recommended and should be avoided [67]. Equilibrium dialysis is the most accurate method for fT measurement
[68]. Alternatively, fT can be derived from specific mathematical calculations taking into account serum SHBG
and albumin levels [69] (http://www.issam.ch/freetesto.htm). It is clinically relevant to highlight how total
testosterone values may change as a function of corresponding circulating SHBG levels. Table 3.3 lists the
conditions most commonly associated with changes in circulating SHBG levels.
Data from meta-analyses have shown that testosterone therapy is ineffective when baseline levels
are > 12 nmol/L (3.5 ng/mL). Positive outcomes are documented when testosterone levels are < 12 nmol/L,
being higher in symptomatic patients with more severe forms of hypogonadism (< 8 nmol/L). Hence, 12 nmol/L
should be considered as a possible threshold for starting testosterone therapy in the presence of hypogonadal
symptoms [41, 70].
In clinical conditions that may interfere with SHBG levels (Table 3.3), evaluation of fT should be
considered to better estimate actual androgen levels (Figure 3.1). Unfortunately, despite its potential clinical
value [71], no validated thresholds for fT are available from clinical studies and this represents an area of
uncertainty; however, data from the EMAS indicated that fT levels < 220 pmol/L (6.4 ng/dL) increased the
likelihood to correctly identify hypogonadism as compared with total testosterone levels alone, particularly when
total testosterone levels are between 8.0 and 11 nmol/L [8, 72, 73].

18 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

 The determination of LH must be performed along with prolactin (PRL) when pathological total
testosterone levels are detected, in order to correctly define the underlying conditions and exclude possible
organic causes (Figure 3.1). Follicle-stimulating (FSH) and luteinising (LH) hormones determination can
further support the diagnosis of primary or secondary hypogonadism [21, 74]. Due to its negative influence on
libido, PRL can also be considered as first-line screening in patients with reduced sexual desire. In addition,
contrast-enhanced pituitary magnetic resonance imaging (MRI) scanning, as well as other pituitary hormone
evaluations, is required in the presence of specific symptoms such as visual disturbances, headache and when
hyperprolactinemia is confirmed [75, 76]. Limited evidence suggests also performing pituitary MRI in the case of
severe hypogonadism (< 6 nmol/L, 1.75 ng/mL) with inadequate gonadotropin levels (Figure 3.1) [75-77].

Table 3.3: Main factors associated with an increase or reduction of SHBG circulating levels

SHBG increase SHBG decrease

• Drugs: anticonvulsants, oestrogens, thyroid • Drugs: growth hormone (GH), glucocorticoids,
hormone testosterone, anabolic androgenic steroids
• Hyperthyroidism • Hypothyroidism
• Hepatic disease • Obesity
• Ageing • Acromegaly
• Smoking • Cushing’s disease
• AIDS/HIV • Insulin resistance (MetS/T2DM)
• Non-alcoholic fatty liver disease (NAFLD), Nephrotic
syndrome

3.3.5 Summary of evidence and recommendations for the diagnostic evaluation and screening of LOH

Summary of evidence LE
Sexual symptoms are the most specific symptoms associated with LOH. 1a
Diagnosis of LOH should be based on specific signs and symptoms of androgen deficiency, together 1a
with consistently low serum testosterone levels.
Total testosterone 12 nmol/L (3.5 ng/mL) represents a reliable threshold to diagnose LOH. 1a
Functional hypogonadism is a consequence of comorbidity/concomitant drugs, which can impair 4
testosterone production in adulthood. The diagnosis of functional hypogonadism is a diagnosis of
exclusion, after ruling out organic causes of hypogonadism.
Calculated free testosterone of < 220 pmol/L has been suggested as a possible cut-off to diagnose 3
LOH.
Self-reported questionnaires and structural interviews have been developed for screening of 2a
hypogonadism, but their specificity remains poor.

Recommendations Strength rating

Diagnostic evaluation
Check for concomitant diseases, drugs and substances that can interfere with testosterone Strong
production/action.
Measure total testosterone in the morning (07.00 and 11.00 hours) and in the fasting state, Strong
with a reliable laboratory assay.
Repeat total testosterone on at least two separate occasions when < 12 nmol/L and before Strong
starting testosterone therapy.
Use 12 nmol/L total testosterone (3.5 ng/mL) as a reliable threshold to diagnose late onset Strong
hypogonadism (LOH).
Measure sex hormone-binding globulin (SHBG) and free-testosterone calculation when Strong
indicated.
Analyse luteinising hormone (LH) and follicle-stimulating hormone (FSH) serum levels to Strong
differentiate between the different types of hypogonadism.
Measure prolactin (PRL) levels if evidence of low sexual desire (or other suggestive signs/ Strong
symptoms) and secondary hypogonadism is present.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 19

Perform pituitary magnetic resonance imaging (MRI) in secondary hypogonadism, with Strong
elevated PRL or symptoms specific of a pituitary mass and/or presence of other anterior
pituitary hormone deficiency.
Perform pituitary MRI in secondary severe hypogonadism (total testosterone < 6 nmol/L). Weak
Screening
Screen for LOH only in symptomatic men. Strong
Do not use structured interviews and self-reported questionnaires for systematic screening Strong
for LOH as they have a low specificity.

20 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Figure 3.1: Diagnostic evaluation of Late-Onset Hypogonadism

Check symptoms and signs

suggesve for hypogonadism

Check for drugs and substances that can interfere with T producon/acon
Check for concomitant metabolic diseases: obesity/metabolic syndrome/diabetes
Check for potenal testosterone therapy contraindicaons

Measure fasng and morning (7-11 am) total T

(consider PRL measurement if low desire or other suggesve symptoms are present)
(consider SHBG and free-T calculaon when indicated)
(consider LH when T deficiency pathophysiology must be invesgated)

TT > 12 nM/
TT < 12 nM TT > 12 nM
reduced cFT
hypogonadism hypogonadism
hypogonadism
possible unlikely
possible

TT < 12 nM
Repeat TT
(reduced cFT)
measurements
and LH reduced/
along with LH
inappropriate
PRL +/-SHBG cFT
normal

TT < 12 nM
Secondary
(reduced cFT)
hypogonadism
and LH elevated

Primary Check for drugs and

hypogonadism substances that can
interfere with T
producon/acon.
Check for concomitant
metabolic disease:
obesity/metabolic
syndrome/diabetes

TT < 8 nM TT < 6 nM/

Perform
elevated PRL
pituitary
Headache/visual
MRI
disturbances

Invesgate if drugs or substances that may interfere with Possible

hypothalamic-pituitary axis can be eliminated. Ferlity specific
Suggest modifying potenal interfering condions obesity /underweight desired therapy
or other metabolic disturbances

Gonadotropin
Rule out testosterone therapy possible contraindicaons therapy

Testosterone therapy trial Diagnosis Treatment Follow-up

TT = total testosterone; cFT = calculated free testosterone; PRL = prolactin; SHBG = sex hormone-binding globulin;
LH = luteinising hormone; MRI = Magnetic resonance imaging.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 21

3.4 Treatment of Classical and Late-onset Hypogonadism
3.4.1 Indications and contraindications for treatment of hypogonadism
Patients with symptomatic hypogonadism (total testosterone < 12 nmol/L) without specific contraindications
are suitable candidates to receive testosterone therapy (Table 3.4).

Absolute contraindications are untreated breast and prostate cancer (PCa). Similarly conditions such
as cardiovascular events as well as uncontrolled or poorly controlled congestive heart failure should be
considered when prescribing testosterone therapy [78]. Conversely, severe lower urinary tract symptoms
(LUTS) [International Prostate Symptom Score (IPSS) score > 19] represent a relative contraindication, as
there is insufficient data on the long-term effects of testosterone therapy in these patients [66]. A positive
family history for venous thromboembolism requires further analysis to exclude a condition of undiagnosed
thrombophilia-hypofibrinolysis [79]. These patients need to be carefully counselled prior to testosterone
therapy initiation. A haematocrit (HCT) > 54% should require testosterone therapy withdrawal, reduction in
dose, change of formulation and venesection depending on the clinical situation to avoid any potential cardio-
vascular complications. Lower baseline HTC (48-50%) should be carefully evaluated before testosterone therapy
initiation, to avoid pathological increases during treatment, especially in high-risk men such as those with COPD
or Obstructive Sleep Apnoea Syndrome (OSAS), likewise in natives living at high altitudes, since they may suffer
from secondary excessive erythrocytosis [80]. Accordingly, the Framingham Heart Study showed that HCT > 48%
represented a condition associated with increased risk of coronary artery disease (CAD) and mortality and was
associated with cardiovascular disorders [81]. Testosterone therapy suppresses gonadotropin and endogenous
testosterone secretion as well as spermatogenesis [82]; therefore, testosterone therapy is contraindicated in
individuals who desire fertility [83]. Secondary hypogonadism is characterised by low or inappropriately normal
gonadotropin levels; therefore, the rationale is to substitute the gonadotropin deficiency with simultaneously
FSH and LH analogues, if fertility is desired [84].

Table 3.4: Main contraindications of testosterone therapy

Absolute contraindications Locally advanced or metastatic prostate cancer (PCa)

Male breast cancer
Men with an active desire to have children
Haematocrit ≥ 54%
Uncontrolled or poorly controlled congestive heart failure
Relative contraindication IPSS score > 19
Baseline haematocrit 48-50%
Familial history of venous thromboembolism

3.4.2 Testosterone therapy outcomes

3.4.2.1 Sexual dysfunction
Sexual concerns are the main symptoms of hypogonadal patients [3, 8, 85, 86]. A consistent body of evidence
shows that testosterone therapy in hypogonadal men (total testosterone < 12 nmol/L) may have a beneficial
effect on several aspects of sexual life; in contrast, there is no evidence of benefits in using testosterone therapy
for treating sexual dysfunction in eugonadal men [70, 87-89]. The beneficial effect on sexual function seems to
be more related to testosterone level normalisation than the specific testosterone formulations used [89, 90].
A meta-analysis of placebo-controlled RCTs showed that testosterone therapy significantly improves
erectile function (as measured by IIEF-Erectile Function domain score) and that patients with more severe
hypogonadism (i.e., total testosterone < 8 nmol/L) are more likely to achieve better improvement than patients
with milder hypogonadism (i.e., total testosterone < 12 nmol/L) [70]. Similar results were observed for
sexual desire; however, the presence of metabolic comorbidity (such as diabetes and obesity) decreased the
magnitude of these improvements. In particular, testosterone therapy alone resulted in a clinically effective
outcome only in patients with milder ED [70]. Similar results have also been confirmed in an update analysis
[91]. In line with these data, report from the non-inferiority “Testosterone Replacement Therapy for Assessment
of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE)” study, showed that in
middle-aged and older hypogonadal (total testosterone < 10.4 nmol/L) men with pre-existing or a high risk of
CVD, testosterone therapy with gel for two years improved sexual activity, hypogonadal symptoms, and sexual
desire, but not erectile function [92].
Other sexual function parameters, such as intercourse, orgasm and overall satisfaction, were all
improved as compared with placebo [70, 91]. Men with a comorbidity, such as T2DM, usually show modest
improvements in terms of sexual function after testosterone therapy and may potentially require concomitant
phosphodiesterase type 5 inhibitors (PDE5Is) to improve effectiveness [3, 89, 93]. A meta-analysis including 913

22 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

patients derived from eight RCTs suggested that combination therapy (testosterone and PDE5Is) was superior
when compared to PDE5Is alone in improving erectile function [94]. The specific beneficial effect derived from
the combined use of testosterone therapy and PDE5Is is unclear [87]. Similarly, information related to the
combined use of testosterone therapy with other ED drug therapies is lacking [3, 89].

The Sexual Function Trial of the Testosterone Trials (TTrials) (one of the largest placebo-controlled trials on
testosterone therapy) documented consistent improvements in 10 of 12 measures of sexual activities in older
(≥ 65 years) hypogonadal men, particularly in frequency of intercourse, masturbation and nocturnal erections
(as measured by PDQ-Q4) [95]. The magnitude in improvement was shown to be proportional to the increase in
serum total testosterone, fT and E2 levels, it was not possible to demonstrate a threshold level [96]. A study of
220 men with MetS with or without T2DM also found that sexual function improved in men who reported sexual
problems with improvement in IIEF scores, with specific increases in libido and sexual satisfaction [30].

3.4.2.2 Vitality and physical strength

The role of testosterone in stimulating muscle growth and strength is well established. Accordingly, androgenic-
anabolic steroids (AAS) have been used as performance-enhancing agents to increase physical performance
in competitive sport [97]. In this regard, testosterone therapy in hypogonadal men has been shown to increase
muscle mass and reduce fat mass, with limited effects on final weight [41]. Despite this evidence, the role
of testosterone therapy in older men with mobility limitations remains unclear. The National Health and
Nutrition Examination Survey 1999-2004 [98] was unable to detect any association between overall circulating
testosterone levels and the amount of physical activity. However, among non-obese men, those in the highest
physical activity tertile were significantly less likely to have low or low-normal testosterone than those in the
lowest tertile. Data from TTrials indicated that testosterone therapy did not substantially increase the fraction
of men whose 6-minute walking distance increased > 50 m or the absolute increase in the distance walked
by those enrolled in the physical function trial [95]. However, when the whole population of the TTrials was
considered, a significant, although modest, positive effect on these two parameters was reported [95]. Similar
data were derived from the Vitality Trial [95]. As support of the aforementioned considerations, a recent meta-
analysis including 2043 subjects older than 60 years failed to show a significant improvement of muscle
strength of testosterone therapy when compared to placebo [99].

3.4.2.3 Mood and cognition

Several observational studies have documented a relationship between depressive symptoms, reduced QoL
and hypogonadism [100, 101]. However, the specific relationship between hypogonadism and the incidence of
depression is still unclear [101]. Only a few placebo-controlled RCTs have investigated the role of testosterone
therapy in improving depressive symptoms. Data derived from TTrials showed that testosterone therapy
improved mood, and depressive symptoms as continuous measures using several instruments [95]. However,
the final effect was small in magnitude. In line with this data, the largest meta-analysis of available studies,
including 1,890 hypogonadal men (baseline total testosterone < 12 nmol/L or fT < 225 pmol/L) men from 27
RCTs, documented that the positive effect of testosterone therapy was particularly evident in patients with
milder symptoms [102]. The BLAST study of testosterone therapy in T2DM reported that those men with
depression were less likely to respond with regards to symptoms of sexual dysfunction compared to men
without depression [36]. Findings from the TRAVERSE trial [78], showed that testosterone therapy alone did not
appear to represent an effective treatment option for most men with clinical depressive disorders [103].
Robust data on the effect of testosterone therapy on QoL are limited. Although recent meta-analyses
suggest a significant effect of testosterone therapy over placebo, the magnitude is low and the heterogeneity
high, therefore reducing the scientific value of the effect [90, 104].
The role of testosterone therapy in patients with cognitive impairment is even more uncertain. The
TTrials evaluated the effect of testosterone therapy in 493 individuals with age-associated memory impairment
to assess possible improvement of several aspects of cognitive function. However, results failed to demonstrate
any beneficial effect of testosterone therapy in improving cognitive function [95]. Similarly, a meta-analysis
involving 17 studies enrolling 1,438 patients with a mean age of 70.4 years and a mean follow-up of 45.6 weeks
did not find any effect of testosterone therapy on cognitive domains [105].

3.4.2.4 Body composition and metabolic profile

Late onset hypogonadism is associated with a greater percentage of fat mass and a lesser lean mass compared
to testosterone-repleted men [106]. The major effect of low testosterone is to increase visceral adiposity but
it also leads to deposition of lipids in the liver and muscle and is associated with atherosclerosis [25]. Some
published data have suggested that testosterone therapy reduces percentage body fat and increases lean
mass [107]. Testosterone therapy has also been found to decrease waist circumference, body weight and BMI,
with these effects more predominant after twelve months of treatment [107-109]. Over two years, the T4DM

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 23

RCT reported that men on testosterone therapy and a lifestyle programme had a greater reduction in waist
circumference, total and abdominal fat mass and an increase in total and arm muscle mass and an increased
strength in the non-dominant hand compared to a lifestyle programme alone [34]. There was a trend toward
reduction in body weight although this approached significance but did not reach significance. The latter result
is probably compounded by the increase in muscle mass as well as the decrease in fat mass. However, it
should be recognised that the results of previous studies are mainly derived from registry and observational
trials, which have important limitations due to the risk of selection bias for the non-random assignment of
testosterone exposure. Accordingly, data derived from RCTs showed only an improvement of fat mass and lean
mass of the same amount without any modifications in body weight [41]. A meta-analysis including seventeen
RCTs specifically investigated the role of testosterone therapy on several metabolic parameters in patients
with T2DM and/or MetS [40]. In line with what was reported in the general population, testosterone therapy
was associated with an improvement in body composition either in T2DM or MetS without any effects on body
weight. Similarly positive effects were also observed on fasting glycemia and insulin resistance (HOMA index)
whilst more conflicting data were obtained for HbA1c and lipid profile [40]. In line with these data, the results
derived from the T4DM study showed that a combination of lifestyle and testosterone therapy can reduce
the incidence of T2DM at follow-up [40]. However, a subgroup analysis of the TRAVERSE study reported that
testosterone therapy did not improve glycaemic control in men with hypogonadism and prediabetes or diabetes
[110]. The different characteristics of the populations as well as the lack of specific lifestyle program may
partially explain the neutral effects observed in the TRAVERSE study.

3.4.2.5 Bone
Evidence suggests that bone mineralisation requires circulating sex steroids within the normal range [111].
The possible association between mild hypogonadism and osteopenia/osteoporosis is weak, whereas severe
hypogonadism (total testosterone < 3.5 nM) is frequently associated with bone loss and osteoporosis,
independent of patient age [111]. Three independent meta-analyses showed a positive effect of testosterone
therapy on bone mineral density (BMD), with the highest effect at the lumber level [112-114]. Interestingly,
this latter meta-analysis has provided novel evidence that the role of testosterone on BMD was even higher
in patients with diabetes [114], who are themselves at a higher risk of hypogonadism and bone fracture [40,
115, 116]. Similarly, data derived from TTrials and the T4DM studies confirmed that testosterone therapy
increased BMD in hypogonadal ageing men [95, 117]. A subgroup analysis of the TRAVERSE study showed
that the fracture incidence was numerically higher amongst men in the testosterone therapy group vs. placebo;
however, it should be noted that this was not the primary outcome of the study [118]. Furthermore, when the
most clinically important fractures, such as bone and hip fractures, were considered no difference between
testosterone therapy and placebo was observed. Available data are insufficient to determine the effect of
testosterone therapy alone on the risk of fractures [111]. The use of testosterone therapy as an adjunct to anti-
resorptive treatment in hypogonadal patients at high risk of fractures has not been established. Therefore, anti-
resorptive therapy must be the first-choice treatment in hypogonadal men at high risk for bone fractures. The
combination of anti-resorptive treatment and testosterone therapy should be offered only in conjunction with
hypogonadism-related symptoms.

3.4.2.6 Summary of evidence and recommendations for testosterone therapy outcome

Summary of evidence LE
Testosterone therapy can improve:
• Milder forms of ED and libido in hypogonadal men. 1a
• Other sexual symptoms, including intercourse frequency, orgasm and overall satisfaction. 1b
• Body composition and insulin resistance. 1a
• Weight, waist circumference and lipid profile, but the evidence is conflicting. 3
• Mild depressive symptoms in hypogonadal men. 1a
• Bone mineral density, but information related to fracture risk is lacking. 1a

Recommendations Strength rating

Do not use testosterone therapy in eugonadal men. Strong
Use testosterone therapy as first-line treatment in hypogonadal patients with mild erectile Strong
dysfunction (ED).
Use a combination of phosphodiesterase type 5 inhibitors and testosterone therapy in more Weak
severe forms of ED.

24 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Use conventional medical therapies for severe depressive symptoms and osteoporosis. Strong
Do not use testosterone therapy to reduce weight and enhance cardio-metabolic status. Weak
Do not use testosterone therapy to improve cognition vitality and physical strength in ageing Strong
men.

3.4.3 Choice of treatment

3.4.3.1 Lifestyle factors
Functional hypogonadism is frequently associated with obesity and metabolic disorders [119]. Therefore,
weight loss and lifestyle changes should be the first approach for all overweight and obese men with
hypogonadism. A previous meta-analysis documented that a low-calorie diet is able to revert obesity-associated
secondary hypogonadism by increasing total testosterone and fT, reducing oestrogens and restoring normal
gonadotropin circulating levels [120]. This was confirmed in an updated meta-analysis showing that the increase
in testosterone is significantly associated with weight reduction [121]. Similar results can be obtained through
physical activity, which is associated with the duration of scheduled exercise and weight loss obtained [121].
However, it should be recognised that the increase in testosterone levels observed after a low-calorie diet
and physical activity is small (1-2 nmol) [120, 121]. In addition, 60-86% of weight lost is regained after three
years and 75-121% after five years [122]. Lifestyle changes represent an essential part of the management of
obesity; however, some evidence suggests that when compared to lifestyle modifications alone, testosterone
therapy-treated obese men benefit most from relief of their symptoms associated with testosterone deficiency,
whereas those not treated did not benefit [84]. There is limited evidence to suggest that combination of life-style
interventions and testosterone therapy in symptomatic hypogonadal men might result in better outcomes [106].
As described above, the T4DM study has demonstrated that over two years of testosterone therapy with lifestyle
intervention was superior to lifestyle intervention alone in reducing waist circumference and total and abdominal
fat content. There was no significant reduction in body weight when compared to lifestyle intervention alone
[34].

3.4.3.2 Medical preparations

Several testosterone formulations are available (Table 3.5). Direct comparisons among different testosterone
products are still lacking. Candidates for testosterone therapy should be adequately informed about the possible
risks and benefits of all available testosterone preparations. The final choice should be based on the clinical
situation, testosterone formulation availability, and patient needs and expectations [22, 123].

3.4.3.2.1 Oral formulations

An oral formulation has been available in oleic acid since the 1970s, and has been recently reformulated in
a mixture of castor oil and propylene glycol laureate (TU caps), to allow the drug to be maintained at room
temperature without degradation [22, 123]. The main limitation is related to poor bioavailability, which is
strongly dependent on dietary fat content [22, 123]. The US Food and Drug Administration (FDA) approved a
new formulation of oral TU in a liquid-filled soft gel capsule, which improved oral availability [124]. Available
evidence showed that TU capsule formulations can reach steady 24-hour average serum testosterone levels in
more than 80% of hypogonadal men, thus resulting in a significant improvement of all sexual function domains
at all time points when compared to baseline along with an excellent safety profile [124]. More recently, the
FDA has approved a new oral formulation which contains as carriers Vitamin E, phytosterol esters, polyoxyl
40 hydrogenated castor oil and propylene glycol monolaurate [124]. For all new oral TU formulations a mild
increase in arterial blood pressure has been reported. Hence, the FDA has required a black box warning that
these drugs can induce a blood pression increase [124].
Mesterolone is a 5α-DHT derivate available for oral administration. Along with DHT, mesterolone
cannot be converted to oestrogens and can only be used for a limited period and specific indications, such as
the presence of painful gynaecomastia. However, the lack of a full spectrum of testosterone bioactivity strongly
limits its long-term use [22, 123].

3.4.3.2.2 Parenteral formulations

Injectable testosterone preparations can be classified according to their half-lives (Table 3.5). Testosterone
propionate is a short-term ester formulation requiring multiple fractionated doses (usually 50 mg, every two
to three days), thus representing a major limitation for its use [22, 123]. Cypionate and enanthate-T esters are
short-term formulations, requiring administration every two to four weeks. A formulation containing mixed
testosterone esters (TU, isocaproate, phenyl propionate, propionate) which has the benefit of a steady release
of testosterone into the circulation, is available in some countries. The use of these older formulations is
associated with wide fluctuations in plasma testosterone concentrations and is often reported as unpleasant by
patients and potentially resulting in adverse effects, such as polycythaemia [22, 123, 125]. A longer-lasting TU

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 25

injectable formulation is widely available [22, 123], with a good safety/benefit profile allowing the maintenance
of normal stable testosterone levels at a dose of 1,000 mg initially every twelve weeks, following a six-week
loading dose, but can be adjusted to a frequency of ten to fourteen weeks dependent on the trough (pre-injection
level) after three to five injections to maintain levels in the therapeutic range (usually > 12 and < 18 nmol/L) [22,
123, 126].

3.4.3.2.3 Transdermal testosterone preparations

Among the available transdermal formulations, testosterone gels represent the most frequently used preparations.
The gel is quickly absorbed by the stratum corneum, creating a reservoir within the subcutaneous tissues from
where testosterone is continuously delivered for 24 hours, after a single daily application. These formulations have
been shown to normalise serum testosterone levels with an excellent safety profile [22, 123]. The introduction of
specific devices and skin enhancers has resulted in better skin penetration of the drugs, thus reducing potential
adverse effects. Local skin adverse effects are limited when compared to those with traditional testosterone
patches, but they potentially allow transference of testosterone during close contact with the skin surface. The
risk can be reduced by wearing clothing or by applying the gel on skin surfaces not usually touched (e.g., the inner
thigh surface) [22, 123]. To reduce the total amount of gel applied and residual quantities remaining on the skin,
new formulations of testosterone gel have been introduced with a testosterone concentration of 1.62-2% [22,
123]. Another transdermal testosterone formulation includes a topical, alcohol-based testosterone (2%) solution,
which must be applied to the underarm once daily, using a metered dose applicator [22, 123]. This testosterone
formulation is not available in Europe. Testosterone levels should be monitored to optimise the testosterone
dose. Blood collection is best taken at two to four hours after gel application to use the peak level of testosterone
absorbed as a reference for adequate therapeutic levels. Levels of testosterone after application can vary and a
repeat measurement may be indicated especially as sometimes, inadvertently, the skin over the vene-puncture site
can be contaminated by the gel, leading to falsely elevated results.
In some European countries, DHT is available as a hydroalcoholic 2.5% gel. It is rapidly absorbed,
reaching a steady state in two to three days [22, 123]. Similar to that reported for mesterolone, DHT is not
aromatised but can be useful for treating particular conditions, such as gynaecomastia and microphallus [22, 123].

3.4.3.2.4 Transmucosal formulations

A testosterone buccal system is still available in several countries. It consists of a sustained-release muco-
adhesive buccal-testosterone-tablet requiring twice-daily application to the upper gums. The tablet does not
dissolve completely in the mouth and must be removed after 12 hours. This formulation has been proven to
restore testosterone levels within the physiological range with minimal or transient local problems, including
gum oedema, blistering and gingivitis [22, 123].
A gel for intranasal administration is available in some countries, including the USA and Canada. It
requires administration two or three times daily using a specific metered-dose pump. The application is rapid,
non-invasive, convenient, and avoids secondary transference observed with other topical products [22, 123].
Preliminary results suggest that intranasal testosterone is associated with a lower Gn levels suppression and
with a lower risk of haematocrit increases [127].

3.4.3.2.5 Subdermal depots

The implantation of testosterone pellets, available in a limited number of countries, represents the longest
available testosterone formulation lasting from four to seven months. The procedure is invasive and may be
unattractive to patients [22, 123].

3.4.3.2.6 Anti-oestrogens
Anti-oestrogens, including selective oestrogen receptor (ER) modulators (SERMs) and aromatase inhibitors (AI)
have been suggested as off-label treatments to restore testosterone levels and fertility in men with functional
secondary hypogonadism or idiopathic infertility. They work by preventing down-regulation of the HPG axis by
oestrogens and for this reason are particularly useful in men with obesity and metabolic disorders [121, 128].
In the latter case, the hypothesis is that the excess of adipose tissue leads to increased aromatase activity
and oestrogens levels resulting in impairment of the HPG [119]. Due to their putative mechanism of action,
they require an intact HPG axis and cannot work in primary hypogonadism or secondary hypogonadism due
to organic damage of the HPG axis. Both types of SERMs, which bind ERs with an agonist or antagonist effect
depending upon the target tissue, and AIs, which prevent androgens from being converted into oestrogens
by aromatase, have been used in clinical practice [22, 123]. The evidence published so far is poor; all these
products are off-label treatments and SERMs, due to their agonistic effect on venous vessels, could predispose
men to the development of venous thromboembolism [22, 123]. In this context patients should be warned of the
potential increased risk of venous thromboembolism, although data are lacking. Long-term use of these agents
can lead to reduced bone density and development of osteoporosis, potentially increasing fracture risk.

26 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

3.4.3.2.7 Gonadotropins
Gonadotropin therapy should be considered the standard in men with secondary hypogonadism who desire
paternity (Table 3.5) [22, 123]. Recombinant hCG (rhCG) and LH (rLH) formulations offer comparable effects
to urinary-derived preparations [123]. According to a meta-analysis of the available evidence, hCG should
be administered with FSH since combined therapy results in better outcomes. Similar to recombinant hCG,
recombinant FSH (rFSH) offers comparable effects to urinary-derived preparations [126].

Table 3.5: Available preparations for hypogonadism treatment

Formulation Chemical structure t½ Standard Advantages Disadvantages

dosage
GONADOTROPINS
Human chorionic gonadotrophin (HCG)
Extractive HCG purified from NA 1,000-2,000 Low cost Multiple weekly
urine of pregnant IU administration
women 3 times/week
Recombinant Human recombinant NA No data in NA NA
HCG men
Luteotropic hormone (LH)
Recombinant Human recombinant NA No data in NA NA
LH men
Follicle-stimulating hormone (FSH)
Extractive FSH purified from NA 75-150 IU Low cost Multiple weekly
urine of pregnant 3 times/week administration
women
Recombinant Human recombinant NA 75-150 IU NA Multiple weekly
FSH 3 times/week administration
TESTOSTERONE PREPARATIONS
Oral
Testosterone 17-α-hydroxylester 4 hrs 120-240 mg Reduction of liver Unpredictable
undecanoate 2 or 3 times involvement absorption
daily Oral convenience depending on dietary
Modifiable dosage fat content
Must be taken with
meals
Testosterone 17-α-hydroxylester 2-5 100-237 mg 2 Oral convenience Gastrointestinal side
undecanoate hrs times daily Modifiable dosage effects
self-emulsifying Quick reversal Increase in blood
delivery system pressure
Mesterolone 1α-methyl-4, 12 hrs 50-100 mg Oral convenience Not aromatisable
5α-dihydro- 2 or 3 times Modifiable dosage
testosterone daily Useful in
gynaecomastia
Parental
Testosterone 17-α-hydroxylester 4-5 250 mg every Low cost Fluctuations in
enanthate days 2-3 weeks Short-acting circulating
Testosterone 17-α-hydroxylester 8 days 200 mg every preparation allowing testosterone levels
cypionate 2-3 weeks drug withdrawal in Multiple injections
case of adverse Relative risk of
Testosterone 17-α-hydroxylester 20 hrs 100 mg every
effects polycythaemia
propionate 2 days
Testosterone 4-androsten-3-one- 4-5 250 mg every
ester mixture* 17 beta-hydroxy- days 3 weeks
androst-4-en-3-one

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 27

Testosterone 17-α-hydroxylester 34 1,000 mg Steady-state Pain at injection site
undecanoate in days every 10-14 testosterone level Long-acting
castor oil weeks without fluctuation preparation not
750 mg every Long-lasting allowing rapid drug
10 weeks Less frequent withdrawal in case
administration of adverse effects
Surgical implants Native testosterone N/A 4-6 200 mg Long duration and Placement is
implants constant serum invasive
lasting up to 6 testosterone level Risk of extrusion
months and site infections
TRANSDERMAL
Testosterone Native testosterone 10 hrs 50-100 mg/ Steady-state Skin irritation
patches day testosterone level Daily administration
Testosterone gel Native testosterone 6 hrs 50-100 mg/ without fluctuation Possible transfer
1-2% day during intimate
Underarm Native testosterone NA 60-120 mg/ contact
testosterone day Daily administration
(testosterone
solution 2%)
Dihydro- Native dihydro- NA 34-70 mg/day Steady-state Possible transfer
testosterone gel testosterone testosterone level during intimate
2.5% without fluctuation contact
Useful in Daily administration
gynaecomastia Not aromatizable
TRANSMUCOSAL
Testosterone Native testosterone 12 hrs 60 mg Steady-state Possible oral
buccal system 3 times daily testosterone level irritation
without fluctuation Twice-daily dosing
Unpleasant taste
Testosterone Native testosterone 6 hrs 33 mg Nasal irritation
nasal 3 times daily Multiple daily
administration
NA = not applicable.
* Testosterone ester mixture - propionate (30mg), phenylpropionate (60mg), isocaproate (60mg), decanoate
(100mg)

3.4.3.3 Summary of evidence and recommendations for choice of treatment for LOH

Summary of evidence LE
Weight loss obtained through a low-calorie diet and regular physical activity results in a small 1a
improvement in testosterone levels.
Testosterone gels and long-acting injectable TU represent testosterone preparations with the optimal 1a
safety profiles.
Gonadotropins treatment can be used to restore fertility in men with secondary hypogonadism. 1a

Recommendations Strength rating

Treat, when indicated, organic causes of hypogonadism (e.g., pituitary masses, Strong
hyperprolactinemia, etc).
Improve lifestyle and reduce weight (e.g., obesity); withdraw, when possible, concomitant Strong
drugs that can impair testosterone production; treat other co-morbidities, when possible,
before starting testosterone therapy.
Fully inform patients about expected benefits and adverse effects of any treatment option. Strong
Select the testosterone preparation in a joint decision process, and fully informed patients of
the risks and benefits.

28 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Use testosterone gels rather than long-acting depot administration when starting initial Weak
treatment in high-risk men.

3.5 Safety and follow-up in hypogonadism management

3.5.1 Hypogonadism and fertility issues
The aim of pharmacological management of hypogonadism is to increase testosterone levels to normal
levels which resolve or improve symptoms of hypogonadism. The first choice is to administer exogenous
testosterone. However, while exogenous testosterone has a beneficial effect on the clinical symptoms of
hypogonadism, it inhibits gonadotropin secretion by the pituitary gland, resulting in impaired spermatogenesis
and sperm cell maturation [129]. Therefore, testosterone therapy is contraindicated in hypogonadal men seeking
fertility treatment [83]. When secondary hypogonadism is present, gonadotropin therapy may maintain normal
testosterone levels and restore sperm production [3].

3.5.2 Male breast cancer

Studies have clearly documented that breast cancer growth is significantly influenced by testosterone and/or
by its conversion to E2 through different mechanisms and pathways [130]. Accordingly, the use of SERMs still
represents an important therapeutic option in the management of this cancer [130]. No information is available
on the role of testosterone therapy in patients successfully treated for male breast cancer; therefore, treated and
active male breast cancer should be recognised as absolute contraindications for testosterone therapy.

3.5.3 Lower urinary tract symptoms/benign prostatic hyperplasia

A trial of 60 patients undergoing testosterone therapy for six months showed no significant differences on post-
void residual urine and prostate volume, while storage symptoms as measured by IPSS significantly improved,
despite an increase in prostate-specific antigen (PSA) level [131]. A larger pre-treatment prostate volume was a
predictive factor of improvement in LUTS. Similarly, a placebo controlled RCT including 120 hypogonadal (total
testosterone < 12 nmol/L) men with MetS and listed for BPH surgery, showed that testosterone therapy did not
result in a difference in LUTS severity compared to placebo. Conversely, an improvement in ultrasound markers
of inflammation in the expression of several pro-inflammatory genes was found in the treatment active arm
[132]. A long-term study of 428 men undergoing testosterone therapy for eight years demonstrated significant
improvements in IPSS, no changes max flow rate (Qmax) and residual urine volume, but also a significant
increase in prostate volume [133]. Similar data from the Registry of Hypogonadism in Men (RHYME), including
999 patients with a follow-up of three years, did not demonstrate any significant difference in PSA levels or
total IPSS in men undergoing testosterone therapy, compared to untreated patients [134]. Similar results were
reported in an Italian registry (SIAMO-NOI), collecting data from 432 hypogonadal men from fifteen centres
[135]. Meta-analyses have not found significant changes in LUTS between patients treated with testosterone
or placebo [136-142]. According to the most recent literature, there are no grounds to discourage testosterone
therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen
administration. The only concern is related to patients with severe LUTS (IPSS > 19), as they are usually
excluded from RCTs; therefore, limiting the long-term safety data of testosterone therapy in this specific setting
[62].

3.5.4 Prostate cancer (PCa)

A considerable number of observational studies have failed to demonstrate any association between circulating
higher testosterone levels and PCa [143]. In contrast, studies investigating the relationship between low levels
of testosterone and risk of PCa have found that men with very low levels of fT have a reduced risk of developing
low-to-intermediate-grade PCa, but have a non-significantly increased chance of developing high-grade PCa
[143]. This peculiar pattern was also reported in trials such as the Health Professionals Follow-up Study, the
Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE),
with varying magnitudes of significance [144].
A meta-analysis, including 27 placebo-controlled, RCTs, found no evidence of increased PSA levels
following testosterone therapy for one year. When considering 11 studies reporting on the occurrence of PCa,
the meta-analysis found no evidence of increased risk of PCa. However, a one year follow-up may be considered
too short to draw firm conclusions on the risks of developing PCa. Furthermore, the analysis was restricted to
studies with > 1-year follow-up, but no significant changes in PSA levels nor increased risk of PCa were found
[137]. After five years’ median follow-up in three independent registry studies with > 1,000 patients undergoing
testosterone therapy, PCa occurrence remained at all times below the reported incidence rate in the general
population [145]. Similar results were reported by a large observational study including 10,311 men treated
with testosterone therapy and 28,029 controls with a median follow-up of 5.3 years [146]. The same study, also
showed that the risk of PCa was decreased for men in the highest tertile of testosterone therapy cumulative
dose exposure as compared with controls [146].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 29

 The TRAVERSE trial did not show any difference in terms of PCa incidence or high-grade PCa rate
between arms (testosterone therapy vs. placebo) at a mean follow-up was 33.0 ± (SD) 12.1 months. Conversely,
the same trial showed a significantly greater increase from baseline of total PSA in the treatment group as
compared with the placebo arm [78].

With regards to PCa survivors, safety in terms of the risk of recurrence and progression has not yet been
established. Limited data are available in the literature, with most case series not providing sufficient data to
draw definitive conclusions (e.g., insufficient follow-up, small samples, lack of control arms, heterogeneity in
study population and treatment regimen, etc.) [147]. A meta-analysis derived from thirteen studies including
608 patients, of whom 109 had a history of high-risk PCa, with follow-up of 1-189.3 months [148], suggested
that testosterone therapy did not increase the risk of biochemical recurrence, but the available evidence is poor,
limiting data interpretation [148]. Similar considerations can be derived from another, larger meta-analysis of
21 studies [149]. However, it is important to recognise both meta-analyses showed high heterogeneity among
the different studies and included a limited number of subjects. An RCT assessing the safety/benefit ratio of
testosterone therapy in hypogonadal men successfully treated with prostatectomy for non-aggressive PCa is
currently ongoing [150].

In conclusion, recent literature does not support an increased risk of PCa in hypogonadal men undergoing
testosterone therapy. Although it is mandatory to avoid testosterone administration in men with advanced
PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors [149],
should prompt caution in choosing to treat symptomatic hypogonadal men in this setting. Specifically, patients
should be fully counselled that the long-term effects of testosterone therapy in this setting are still unknown
and requires further investigation. Due to the lack of strong evidence-based data on safety, the possible use of
testosterone therapy in symptomatic hypogonadal men previously treated for PCa should be fully discussed
with patients and limited to low-risk individuals.

3.5.5 Cardiovascular Disease

Evidence suggests that hypogonadal men have an increased risk of CVD [151, 152]. Whether or not LOH is
a cause or a consequence of atherosclerosis has not been clearly determined. Late-onset hypogonadism is
associated with CV risk factors, including central obesity, insulin resistance and hyperglycaemia, dyslipidaemia,
pro-thrombotic tendency and chronic inflammatory state [152]. Atherosclerosis is a chronic inflammatory
disease, that releases pro-inflammatory cytokines into the circulation, which are known to suppress testosterone
release from the HPG axis. Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM
demonstrates some benefit in CV risk, including reduced central adiposity, insulin resistance, total cholesterol
and LDL-cholesterol and suppression of circulating cytokines [29-31, 36, 152, 153]. However, due to the
equivocal nature of these studies, testosterone therapy cannot be recommended for use outside of treatment of
specific symptoms.

Published data show that LOH is associated with an increase in all-cause and CVD-related mortality [7, 154-
157]. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for
cardiovascular morbidity [141] and mortality [158]. Importantly, men with low testosterone when compared
to eugonadal men with angiographically proven coronary disease have twice the risk of earlier death [152].
Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal
range have a reduced number of CV events compared to men with testosterone in the lower three quartiles
[154]. Androgen deprivation therapy for PCa is linked to an increased risk of CVD and sudden death [159].
Conversely, two long-term epidemiological studies have reported reduced CV events in men with high normal
serum testosterone levels [160, 161]. Erectile dysfunction is independently associated with CVD and may be the
first clinical presentation in men with atherosclerosis.

The knowledge that men with hypogonadism and/or ED may have underlying CVD should prompt individual
assessment of their CV risk profile. Individual risk factors (e.g., lifestyle, diet, exercise, smoking, hypertension,
diabetes and dyslipidaemia) should be assessed and treated in men with pre-existing CVD and in patients
receiving androgen deprivation therapy. Cardiovascular risk reduction can be managed by primary care
clinicians, but patients should be appropriately counselled by clinicians active in prescribing testosterone
therapy [85]. If appropriate, patients should be referred to cardiologists for risk stratification and treatment of
comorbidity.

No RCTs have provided a clear answer on whether testosterone therapy affects CV outcomes. The TTrial (n=790)
in older men [162], the TIMES2 (n=220) [30] and, the BLAST studies in men with MetS and T2DM and the pre-frail
and frail study in elderly men - all of one year duration and the T4DM 2-year study - did not reveal any increase

30 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

in Major Adverse Cardiovascular Events (MACE) [30, 33, 34, 162, 163]. Randomised controlled trials between
three and twelve months in men with known heart disease treated with testosterone therapy have not found an
increase in MACE, but have reported improvement in cardiac ischaemia, angina and functional exercise capacity
[164-166]. A large cohort study (n=20,4857 men) found that neither transdermal gel or intramuscular testosterone
was associated with an increased risk of composite cardiovascular outcome in men with or without prevalent
CVD (mean follow up 4.3 years) [167]. The European Medicines Agency (EMA) has stated that ‘The Co-ordination
Group for Mutual recognition and Decentralisation Procedures-Human (CMDh), a regulatory body representing
EU Member States, has agreed by consensus that there is no consistent evidence of an increased risk of heart
problems with testosterone in men. However, the product information is to be updated in line with the most
current available evidence on safety, and with warnings that the lack of testosterone should be confirmed by
signs and symptoms and laboratory tests before treating men with these drugs [168].

Data recently released from the TRAVERSE study confirm findings of the EMA [78]. The latter is the first double-
blind, placebo-controlled, noninferiority RCT with primary CV safety as an end point. The results showed that
testosterone therapy was noninferior to placebo with respect to the incidence of MACE. However, a mild higher
incidence of atrial fibrillation, of acute kidney injury, and pulmonary embolism was observed in the testosterone
group [78]. The latter observations, however, need to be confirmed since previous available data do not support
an increased risk of venous thromboembolism [79, 169] or major arrhythmias [170] after testosterone therapy.
Similarly, the long-term follow-up (median of 5.1 years since last injection) of the T4DM study showed no
differences in self-reported rates of new diagnosis of CVD [171].

In conclusion, current available data from interventional studies suggest that there is no increased risk up to
three years of testosterone therapy [172-176]. The currently published evidence has reported that testosterone
therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with
normalised testosterone levels. The findings could be considered sufficiently reliable for at least a three-year
course of testosterone therapy, after which no available study can exclude further or long-term CV events [177,
178].

3.5.5.1 Cardiac Failure

Testosterone therapy is contraindicated in men with severe chronic cardiac failure because fluid retention
may lead to exacerbation of the condition. Some studies have shown that men with moderate chronic cardiac
failure may benefit from low doses of testosterone, which achieve mid-normal range testosterone levels [165,
179, 180]. An interesting observation is that untreated hypogonadism increased the re-admission and mortality
rate in men with heart failure [181]. If a decision is made to treat hypogonadism in men with chronic cardiac
failure, it is essential that the patient is followed up carefully with clinical assessment and both testosterone and
haematocrit measurements on a regular basis.

3.5.6 Erythrocytosis
An elevated haematocrit is the most common adverse effect of testosterone therapy. Stimulation
of erythropoiesis is a normal biological action that enhances delivery of oxygen to testosterone-sensitive
tissues (e.g., striated, smooth and cardiac muscle). Any elevation above the normal range for haematocrit
usually becomes evident between three and twelve months after testosterone therapy initiation. However,
polycythaemia can also occur after any subsequent increase in testosterone dose, switching from topical to
parenteral administration and, development of co-morbidity, which can be linked to an increase in haematocrit
(e.g., respiratory or haematological diseases).
There is no evidence that an increase of haematocrit up to and including 54% causes any adverse
effects. If the haematocrit exceeds 54% there is a testosterone independent but weak associated rise in CV
events and mortality [81, 182-184]. Any relationship is complex as these studies were based on patients with
any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no
specific studies in men with only testosterone-induced erythrocytosis.

As detailed, the TRAVERSE study, which had included symptomatic hypogonadal men aged 45-80 years who
had pre-existing or a high risk of CVD, showed a mild higher incidence of pulmonary embolism, a component
of the adjudicated tertiary end point of venous thromboembolic events, in the testosterone therapy than in the
placebo group (0.9% vs. 0.5%) [78]. However, three previous large studies have not shown any evidence that
testosterone therapy is associated with an increased risk of venous thromboembolism [185, 186]. Of those,
one study showed that an increased risk peaked at six months after initiation of testosterone therapy, then
declined over the subsequent period [187]. In one study venous thromboembolism was reported in 42 cases
and 40 of these had diagnosis of an underlying thrombophilia (including factor V Leiden deficiency, prothrombin
mutations and homocysteinuria) [188]. A meta-analysis of RCTs of testosterone therapy reported that venous

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 31

thromboembolism was frequently related to underlying undiagnosed thrombophilia-hypofibrinolysis disorders
[79]. In a RCT of testosterone therapy in men with chronic stable angina there were no adverse effects on
coagulation, by assessment of tissue plasminogen activator or plasminogen activator inhibitor-1 enzyme
activity or fibrinogen levels [189]. Similarly, another meta-analysis and systematic review of RCTs found that
testosterone therapy was not associated with an increased risk of venous thromboembolism [169]. With
testosterone therapy an elevated haematocrit is more likely to occur if the baseline level is toward the upper
limit of normal prior to initiation. Added risks for raised haematocrit on testosterone therapy include smoking
or respiratory conditions at baseline. Higher haematocrit is more common with parenteral rather than topical
formulations. Accordingly, a large retrospective two-arm open registry, comparing the effects of long-acting
testosterone undecanoate and testosterone gels showed that the former preparation was associated with a
higher risk of haematocrit levels > 50%, when compared to testosterone gels [190]. In men with pre-existing CVD
extra caution is advised with a definitive diagnosis of hypogonadism before initiating testosterone therapy and
monitoring of testosterone as well as haematocrit during treatment.

Elevated haematocrit in the absence of comorbidity or acute CV or venous thromboembolism can be managed
by a reduction in testosterone dose, change in formulation or if the elevated haematocrit is very high by
venesection (500 mL), even repeated if necessary, with usually no need to stop the testosterone therapy.

3.5.7 Obstructive Sleep Apnoea

There is no evidence that testosterone therapy can result in onset or worsening of sleep apnoea. Combined
therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective than CPAP
alone in the treatment of obstructive sleep apnoea [191]. In one RCT, testosterone therapy in men with severe
sleep apnoea reported a reduction in oxygen saturation index and nocturnal hypoxaemia after seven weeks of
therapy compared to placebo, but this change was not evident after eighteen weeks’ treatment and there was no
association with baseline testosterone levels [192].

3.5.8 Follow-up
Testosterone therapy alleviates symptoms and signs of hypogonadism in men in a specific time-dependent
manner. The TTrials clearly showed that testosterone therapy improved sexual symptoms as early as three
months after initiation [95]. Similar results have been derived from meta-analyses [79, 87]. Hence, the first
evaluation should be planned after three months of treatment. Further evaluation may be scheduled at six
months or twelve months, according to patient characteristics, as well as results of biochemical testing (see
below). Patients at high risk of developing elevated haematocrit should be evaluated every three months during
the first year of testosterone therapy and at least every six months thereafter. Accordingly, current guidelines
suggest that haematocrit should be maintained below 45% in patients with polycythaemia vera to avoid
thromboembolism risk [193]. Similarly, data derived using a multi-institutional database including a large cohort
of hypogonadal (total testosterone < 12 nmol/L) men who received testosterone therapy and subsequently
did (n=5,887) or did not (n=4,2784) develop polycythaemia (haematocrit > 52%) showed that men who had an
increased haematocrit had a higher risk of MACE or venous thromboembolism mostly during the first year of
therapy [194]. The risk was even higher when a haematocrit threshold of 54% was considered whilst no risk
was observed when a 50% threshold was applied [194]. Table 3.6 summarises the clinical and biochemical
parameters that should be monitored during testosterone therapy.

TTrials were designed to maintain the serum testosterone concentration within the normal range for young men
(280–873 ng/dL or 9.6-30 nmol/L) [95]. This approach resulted in a good benefit/risk ratio. A similar approach
could be considered during follow-up. The correct timing for evaluation of testosterone levels varies according
to the type of preparation used (Table 3.5). Testosterone is involved in the regulation of erythropoiesis [125]
and prostate growth [62], hence evaluation of PSA and haematocrit should be mandatory before and during
testosterone therapy. However, it is important to recognise that the risk of PCa in men aged < 40 years is low.
Similarly, the mortality risk for PCa in men aged > 70 years has not been considered high enough to warrant
monitoring in the general population [195]. Therefore, any screening for PCa through determination of PSA and
DRE in men aged < 40 or > 70 years during testosterone therapy should be discussed with the patients.

Baseline and, at least, annually glyco-metabolic profile evaluation may be a reasonable consideration,
particularly in the management of functional hypogonadism. Testosterone therapy may be beneficial for
hypogonadal men with low or moderate fracture risk [111]; therefore, dual energy X-ray absorptiometry (DEXA)
bone scan may also be considered at baseline and 18-24 months following testosterone therapy, particularly in
patients with more severe hypogonadism [111].

32 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Digital rectal examination may detect prostate abnormalities that can be present even in men with normal PSA
values. Hence, DRE is mandatory in all men at baseline and is recommended to be performed at least annually
during testosterone therapy, as long as there is no significant increase in PSA velocity.

The decision to stop testosterone therapy or to perform prostate biopsy due to PSA increase or prostate
abnormalities should be based on local PCa guidelines. There is a large consensus that any increase of
haematocrit > 54% during testosterone therapy requires therapy withdrawal and phlebotomy to avoid potential
adverse effects including venous-thromboembolism and CVD, especially in high-risk individuals. In patients
with lower risk of relevant clinical sequelae, the situation can be alternatively managed by reducing testosterone
dose and switching formulation along with venesection. A positive family history of venous-thromboembolism
should be carefully investigated and the patient counselled with regard to testosterone therapy to avoid/prevent
thrombophilia-hypofibrinolysis [79]. Finally, caution should be exercised in men with pre-existing CVD or at
higher risk of CVD [78].

Table 3.6: Clinical and biochemical parameters to be checked during testosterone therapy

Parameters Year 1 of treatment After year 1 of treatment

Baseline 3 months 6 months 12 months Annually 18-24 months
Clinical
Symptoms X X X X X
Body Mass Index X X X
Waist circumference X X X X
Digital rectal examination X X X
Blood pressure X X X X
Biochemistry
PSA (ng/mL) X X X2 X X
Haematocrit (%) X X X1,2 X X
Testosterone X X X X
Lipid and glycaemic profile X X X
Instrumental
DEXA X X
1Population with polycythaemia vera or at high risk of secondary polycythaemia (e.g., sleep apnea, morbid
obesity, heavy smokers, chronic obstructive pulmonary disease); 2Prostate cancer survivors.

3.5.9 Summary of evidence and recommendations on safety and monitoring in testosterone treatment

Summary of evidence LE
Testosterone therapy is contraindicated in men with secondary hypogonadism who desire fertility. 1a
Testosterone therapy is contraindicated in men with active prostate cancer or breast cancer, as these 1a
patients are usually excluded from RCTs.
Testosterone therapy does not increase the risk of prostate cancer, but long-term prospective follow-up 1a
data are required to validate this statement.
The effect of testosterone therapy in men with severe lower-urinary tract symptoms is limited, as these 1a
patients are usually excluded from RCTs.
There is no substantive evidence that testosterone therapy, when replaced to normal levels, results in 1a
the development of major adverse cardiovascular events.
There is no evidence of a relationship between testosterone therapy and mild, moderate or CPAP- 1b
treated severe sleep apnoea.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 33

Recommendations Strength rating
Fully counsel symptomatic hypogonadal men who have been surgically treated for localised Weak
prostate cancer (PCa) and who are currently without evidence of active disease considering
testosterone therapy, emphasising the lack of sufficient safety data on long-term follow-up.
Restrict treatment to patients with a low risk of recurrent PCa*. Treatment should start after Weak
at least one year follow-up with prostate-specific antigen (PSA) level < 0.01 ng/mL.
Advise patients that safety data on the use of testosterone therapy in men treated for breast Strong
cancer are unknown.
Assess cardiovascular risk factors before commencing testosterone therapy. Strong
Assess men with known cardiovascular disease (CVD) for cardiovascular symptoms before Strong
initiating testosterone therapy and monitor these men with close clinical assessment and
evaluation during treatment.
Treat men with hypogonadism and pre-existing CVD, venous-thromboembolism or chronic Weak
cardiac failure, who require testosterone therapy with caution, by careful clinical monitoring
and regular measurement of haematocrit (not exceeding 54%) and testosterone levels.
Exclude a family history of venous-thromboembolism before starting testosterone therapy. Strong
Monitor testosterone, haematocrit at three, six and twelve months after testosterone therapy Strong
initiation, and thereafter annually. A haematocrit > 54% requires testosterone therapy
adjustment or withdrawal and venesection if required. Re-introduce testosterone therapy
at a lower dose once the haematocrit has normalised and consider switching to topical
testosterone preparations.
Evaluate patients with polycythaemia vera and those with a higher risk of developing Strong
elevated haematocrit every three months during the first year of testosterone therapy, and at
least every six months thereafter.
Evaluate total PSA in PCa survivors at three, six and twelve months during the first year of Strong
testosterone therapy, and annually thereafter.
*For EAU risk groups for biochemical recurrence of localised or locally advanced prostate cancer see EAU Prostate
Cancer Guidelines, 2025.

4. EPIDEMIOLOGY AND PREVALENCE OF

SEXUAL DYSFUNCTION AND DISORDERS OF
MALE REPRODUCTIVE HEALTH
4.1 Erectile dysfunction
Epidemiological data have shown a high prevalence and incidence of ED worldwide [196]. Among others,
the Massachusetts Male Aging Study (MMAS) [197] reported an overall prevalence of 52% ED in non-
institutionalised men aged 40-70 years in the Boston area; specific prevalence for minimal, moderate, and
complete ED was 17.2%, 25.2%, and 9.6%, respectively. In the Cologne study of men aged 30-80 years, the
prevalence of ED was 19.2%, with a steep age-related increase from 2.3% to 53.4% [198]. The incidence rate
of ED (new cases per 1,000 men annually) was 26 in the long-term data from the MMAS study [199] and 19.2
(mean follow-up of 4.2 years) in a Dutch study [200]. In a cross-sectional real-life study among men seeking
first medical help for new-onset ED, one in four patients was younger than 40 years, with almost 50% of the
young men complaining of severe ED [201]. Differences among these studies can be explained by differences in
methodology, ages, and socio-economic and cultural status of the populations studied. The prevalence rates of
ED studies are reported in Appendix 2 Table S4.1 online supplementary evidence: https://uroweb.org/guidelines/
sexual-and-reproductive-health/publications-appendices.

34 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

4.2 Premature ejaculation
The highest prevalence rate of 31% (men aged 18-59 years) was found by the National Health and Social Life
Survey (NHSLS), which determines adult sexual behaviour in the USA [202]. Prevalence rates were 30% (18-29
years), 32% (30-39 years), 28% (40-49 years) and 55% (50-59 years), respectively. However, it is unlikely that the
PE prevalence is as high as 20-30% based on the relatively low number of men who seek medical help for PE.
These high prevalence rates may be a result of the dichotomous scale (yes/no) in a single question asking if
ejaculation occurred too early, as the prevalence rates in European studies have been significantly lower [203].
Two separate observational, cross-sectional surveys from different continents found that overall prevalence
of PE was 19.8 and 25.8%, respectively [204, 205]. Further stratifying these complaints into the classifications
defined by Waldinger et al., [206], rates of lifelong PE were 2.3 and 3.18%, acquired PE 3.9 and 4.48%, variable
PE 8.5 and 11.38% and subjective PE 5.1 and 6.4%, respectively [204, 205]. Both studies showed that men
with acquired PE were more likely to seek treatment compared to men with lifelong PE. The prevalence rates
of premature ejaculation as evidenced by the highly discrepant prevalence rates reported in are reported in
Appendix 2 Table S4.2 online supplementary evidence: https://uroweb.org/guidelines/sexual-and-reproductive-
health/publications-appendices.

4.3 Other ejaculatory disorders

4.3.1 Delayed ejaculation
Due to it uncertain definitions, the epidemiology of delayed ejaculation (DE) is not clear [207]. However, several
well-designed epidemiological studies have revealed that its prevalence is around 3% among sexually active
men [202, 208]. According to data from the NHSLS, 7.78% of a national probability sample of 1,246 men aged
18-59 years reported inability achieving climax or ejaculation [202]. In a similar stratified national probability
sample survey completed over six months among 11,161 men and women aged 16-44 years in Britain, 0.7% of
men reported inability to reach orgasm [209]. In an international survey of sexual problems among 13,618 men
aged 40–80 years from 29 countries, 1.1-2.8% of men reported that they frequently experience inability to reach
orgasm [210]. Another study conducted in the USA, in a national probability sample of 1,455 men aged 57-85
years, 20% of men reported inability to climax and 73% reported that they were bothered by this problem. [211].
Similar to PE, there are distinctions among lifelong, acquired and situational DE [212]. Although the evidence is
limited, the prevalence of lifelong and acquired DE is estimated at 1 and 4%, respectively [213].

4.3.2 Anejaculation and Anorgasmia

Establishing the exact prevalence of anejaculation and anorgasmia is difficult since many men cannot
distinguish between ejaculation and orgasm. The rarity of these clinical conditions further hampers the attempts
to conduct epidemiological studies. In a report from the USA, 8% of men reported unsuccessfully achieving
orgasm during the past year [202].
According to Kinsey et al., [214], 0.14% of the general population have anejaculation. The most
common causes of anejaculation were spinal cord injury, diabetes mellitus and multiple sclerosis. Especially
in most cases of spinal cord injury, medical assistance is the only way to ejaculate. While masturbation leads
to the lowest rates of ejaculation, higher response rates can be obtained with penile vibratory stimulation or
acetylcholine esterase inhibitors followed by masturbation in patients with spinal cord injury [215].

4.3.3 Retrograde ejaculation

Similarly to anejaculation, it is difficult to estimate the true incidence of retrograde ejaculation (RE). Although
RE is generally reported in 0.3-2% of patients attending fertility clinics [216], diabetes may increase these rates
by leading to autonomic neuropathy. Autonomic neuropathy results in ED and ejaculatory dysfunctions ranging
from DE to RE and anejaculation, depending on the degree of sympathetic autonomic neuropathy involved [217].
In 54 diabetic patients with sexual dysfunction, RE was observed with a 6% incidence [218]. In a controlled
trial, RE was observed in 34.6% of diabetic men [219]. A trial reported the rate of RE among 57 type-1-diabetes
mellitus patients (aged 18-50 years) was at least 8.8% [220]. Retrograde ejaculation was also reported in
studies of patients who had undergone transurethral resection of prostate (TURP) or open prostatectomy due
to disrupted bladder neck integrity. A study of the effect of prostatectomy on QoL in 5,276 men after TURP,
found that 68% reported post-surgical RE [221]. However, with the development of less invasive techniques, the
incidence of RE decreases following the surgical treatment of LUTS [222-226].

4.3.4 Painful ejaculation

Painful ejaculation is a common but poorly understood clinical phenomenon, which is associated with sexual
dysfunction. Several studies demonstrated its prevalence to range between 1-10% in the general population
[227-229]; however, it may increase to 30-75% among men with chronic prostatitis/chronic pelvic pain syndrome
(CP/CPPS) [230-234]. It should be noted that the design of most of these studies was not scientifically sound
and the condition was probably under-reported due to the lack of an evidence-based definition and well-defined
prognostic criteria.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 35

4.3.5 Haemospermia
The exact incidence and prevalence of haemospermia are difficult to elucidate due to a number of factors
including its covert presentation, usually self-limiting nature and patient embarrassment. The symptoms
represent 1-1.5% of all urological referrals and occurs in all age groups, with a mean age of 37 years [235, 236].
In a PCa screening study of 26,126 men, aged > 50 years or older than 40 with a history of PCa or of black
ethnicity, haemospermia was found in 0.5% on entry to the trial [237].

4.4 Low sexual desire

The global prevalence of low sexual desire in men is 3-28% [210, 238, 239]. Low solitary and dyadic sexual
desires have been reported in 68% and 14% of men, respectively [240]. Also, low sexual desire has been
observed as a common complaint in gay men, with a prevalence of 19-57% [241, 242]. Despite its relationship
with age, low sexual desire has also been reported among young men (18-29 years), with a prevalence of 6-19%
[202, 243, 244].

5. MANAGEMENT OF ERECTILE DYSFUNCTION

5.1 Definition and classification
Erectile dysfunction is defined as the persistent inability to attain and maintain an erection sufficient to
permit satisfactory sexual performance [245]. Erectile dysfunction may affect psychosocial health and have a
significant impact on the QoL of patients and their partner’s [197, 246-248]. Erectile dysfunction is commonly
classified into three groups based on aetiology: organic, psychogenic and mixed ED. However, this classification
should be used with caution as most cases are actually of mixed aetiology. Therefore, it has been suggested to
use the terms “primary organic” or “primary psychogenic”.

5.2 Risk factors

Erectile dysfunction is a complex medical issue with several known causes, including vascular, hormonal,
neurologic, and psychological dysfunctions and is associated with chronic health conditions [249]. An
association with numerous risk factors including age, diabetes mellitus, dyslipidaemia, hypertension, CVD,
obesity, MetS, hyperhomocysteinemia, lack of exercise, smoking and drug use has been reported [247, 250-
261]. In addition, a number of therapeutic agents for CVD have been shown to have a detrimental effect on
erectile function (EF), whereas newer drugs have exhibited a neutral or even beneficial effect [253, 262, 263].
Other reported risk factors include atrial fibrillation, hyperthyroidism, vitamin D and folic acid deficiency,
hyperuricemia, depression and anxiety disorders, chronic kidney and rheumatic disease, COPD, migraine,
inflammatory bowel disease, osteoporosis and sleep disorders [258, 264-277]. In addition, a growing body of
evidence has demonstrated an association between the onset of new ED in men who have had COVID-19 [278-
281].

Erectile dysfunction is also frequently associated with other urological conditions and procedures including
LUTS/BPH and surgery for LUTS/BPH [282-284], chronic pelvic pain syndrome (CPPS) and chronic prostatitis
[285], bladder pain syndrome/interstitial cystitis [286], premature ejaculation [287] and urethroplasty surgery for
posterior urethral strictures [288].

5.3 Pathophysiology
The pathophysiology of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or
psychogenic (Table 5.1) [289]. In most cases, numerous pathophysiological pathways can co-exist and may all
negatively impact EF.

Table 5.1: Pathophysiology of ED [289]

Vasculogenic
Recreational habits (i.e., cigarette smoking)
Lack of regular physical exercise
Obesity
Cardiovascular diseases (e.g., hypertension, coronary artery disease, peripheral vasculopathy)
Type 1 and 2 diabetes mellitus; hyperlipidaemia; metabolic syndrome; hyperhomocysteinemia
Major pelvic surgery (e.g., radical prostatectomy) or radiotherapy (pelvis or retroperitoneum)

36 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Neurogenic
Central causes
Degenerative disorders (e.g., multiple sclerosis, Parkinson’s disease, multiple atrophy, etc.)
Spinal cord trauma or diseases
Stroke
Central nervous system tumours
Peripheral causes
Type 1 and 2 diabetes mellitus
Chronic renal failure, chronic liver failure
Polyneuropathy
Surgery (major surgery of pelvis/retroperitoneum) or radiotherapy (pelvis or retroperitoneum)
Surgery of the urethra (urethral stricture, open urethroplasty, etc.)
Anatomical or structural
Hypospadias, epispadias; micropenis
Phimosis
Peyronie’s disease
Penile cancer (other tumours of the external genitalia)
Hormonal
Diabetes mellitus; Metabolic Syndrome
Hypogonadism (any type)
Hyperthyroidism
Hyper- and hypocortisolism (Cushing’s disease, etc.)
Panhypopituitarism and multiple endocrine disorders
Mixed pathophysiological pathways
Chronic systemic diseases (e.g., diabetes mellitus, hypertension, metabolic syndrome, chronic kidney disease,
chronic liver disorders, hyperhomocysteinemia, hyperuricemia, chronic obstructive pulmonary disease,
rheumatic disease)
Psoriasis, gouty arthritis, ankylosing spondylitis, non-alcoholic fatty liver disease, chronic periodontitis, open-
angle glaucoma, inflammatory bowel disease, chronic fatigue syndrome, allergic rhinitis, obstructive sleep
apnoea, depression
Iatrogenic causes (e.g., TRUS-guided prostate biopsy)
Drug-induced
Antihypertensives (i.e., thiazidediuretics, beta-blockers)*
Antidepressants (e.g., selective serotonin reuptake inhibitors, tricyclics)
Antipsychotics
Antiandrogens (GnRH analogues and antagonists; 5-ARIs)
Recreational drugs (e.g., heroin, cocaine, marijuana, methadone, synthetic drugs, anabolic steroids, excessive
alcohol intake)
Psychogenic
Generalised type (e.g., lack of arousability and disorders of sexual intimacy)
Situational type (e.g., partner-related, performance-related issues or due to distress)
Trauma
Penile fracture
Pelvic fracture
GnRH = gonadotropin-releasing hormone; 5-ARIs = 5α-reductase inhibitors.
*A symmetry analysis showed that cardiovascular drugs do not strongly affect the risk of subsequently being
prescribed anti-erectogenic drug. The analysis only assessed the short-term risk [290].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 37

5.3.1 Pelvic surgery and prostate cancer treatment
Pelvic surgery, especially for oncological disease (e.g., radical prostatectomy (RP) [291], radical cystectomy
[292] and colorectal surgery [293]), may have a negative impact on EF and overall sexual health. Surgery
resulting in damage of the neurovascular bundles, that control the complex mechanism of the cavernous
erectile response, may result in ED, although nerve-sparing approaches have been adopted over the last
few decades. To date only the surgical treatment of PCa has enough scientific evidence supporting its
potential pathophysiological association with ED [294-296]. However, even non-surgical treatments of PCa (i.e.,
radiotherapy, or brachytherapy) can be associated with ED [294, 297, 298].

The ProtecT trial randomised 1,643 patients to active treatment (RP or RT) or active monitoring for localised
PCa and assessed sexual function, including EF, using the EPIC-26 instrument [278]. At baseline, 67% of men
reported erections firm enough for sexual intercourse. At six-year follow-up assessment this fell to 30% in the
active monitoring group, 27%% in the RT group and 17% in the RP group, respectively. In a RCT comparing low-
to intermediate-risk PCa patients treated with either surgery or RT (without ADT), the sexual function scores of
EPIC-26 were significantly higher for men receiving RT at two years post-treatment [299].

Radical prostatectomy for the treatment of clinically localised intermediate- or high-risk PCa is a widely
performed procedure. Research has shown that 25-75% of men experience post-RP ED [279, 280, 295].
Conversely, the rate of unassisted post-operative EF recovery ranges between 20 and 25% in most studies.
These rates have not substantially improved or changed over the past two decades, despite growing attention
to post-surgical rehabilitation protocols and refinement of surgical techniques [280, 281, 300]. Overall, patient
age, baseline EF and surgical volume, with the subsequent ability to preserve the neurovascular bundles, are the
main factors in promoting the highest rates of post-operative EF [279, 296, 301, 302]. Regardless of the surgical
technique, surgeons’ experience clearly impacts on post-operative EF outcome [303]. Surgical approach may
also affect post-RP EF, but the current evidence is conflicting with one systematic review reporting a significant
advantage in favour of RARP compared to open retropubic RP for twelve-month potency rates [304] and two
RCTs reporting only a small improvement in EF for RARP or no different in EF between techniques [305, 306].

Erectile dysfunction is also a common problem after both external beam radiation therapy (EBRT) and
brachytherapy for PCa. A systematic review and meta-analysis including men treated with EBRT (65%),
brachytherapy (31%) or both (4%) showed that the post-treatment prevalence of ED was 34% at one year and
57% at 5.5 years, respectively [307, 308]. Similar findings have been reported for stereotactic radiotherapy with
26-55% of previously sexually functioning patients reporting ED at five years [309].

Recently other modalities have emerged as potential therapeutic options in patients with clinically-localised
PCa, including high-intensity focused US (HIFU), cryo-therapeutic ablation of the prostate (cryotherapy), focal
padeliporfin-based vascular-targeted photodynamic therapy and focal RT by brachytherapy or CyberKnife®.
All these approaches have been reported to have a less-negative impact on EF with many studies reporting a
complete recovery at one-year follow-up [310].

5.3.2 Summary of evidence on the epidemiology/aetiology/pathophysiology of ED

Summary of evidence LE
Erectile dysfunction is common worldwide. 2b
Erectile dysfunction shares common risk factors with cardiovascular disease. 2b
Lifestyle modification (regular exercise and decrease in BMI) can improve erectile function. 1b
Erectile dysfunction is a symptom, not a disease. Some patients may not be properly evaluated or 4
receive treatment for an underlying disease or condition that may be causing ED.
Erectile dysfunction is common after RP, irrespective of the surgical technique used. 2b
Erectile dysfunction is common after external radiotherapy and brachytherapy. 2b
Erectile dysfunction is less common after cryotherapy and high-intensity focused US. 2b

38 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

5.4 Diagnostic evaluation (basic work-up)
5.4.1 Medical and sexual history
The first step in evaluating ED is always a detailed medical and sexual history of patients and, when available,
their partners [311]. Figure 5.1 lists the minimal diagnostic evaluation (basic work-up) in patients with ED.

A detailed description should be made of the rigidity and duration of both sexually stimulated and morning
erections and of problems with sexual desire, arousal, ejaculation, and orgasm [312-314]. Validated
questionnaires, such as the IIEF [315] or its short version (i.e., Sexual Health Inventory for Men; SHIM) [316],
help to assess the different sexual function domains (i.e., sexual desire, EF, orgasmic function, intercourse
satisfaction, and overall satisfaction), as well as the potential impact of a specific treatment modality. Similarly,
structured interviews allow the identification and quantification of the different underlying factors affecting EF
[317].
Psychometric analyses also support the use of the Erectile Hardness Score (EHS) for the
assessment of penile rigidity in practice and in clinical trials research [318]. Patients should always be screened
for symptoms of possible hypogonadism, including decreased libido and energy, and fatigue (see Table 3.3:
Specific symptoms associated with LOH).

5.4.2 Physical examination

Every patient must be given a physical examination focused on the genitourinary, endocrine, vascular and
neurological systems [319, 320]. A physical examination may reveal unsuspected diagnoses, such as Peyronie’s
disease, pre-malignant or malignant genital lesions, prostatic enlargement or irregularity/nodularity, or signs and
symptoms suggestive of hypogonadism (see Table 3.3: Specific symptoms associated with LOH).
Blood pressure and heart rate should be measured if they have not been assessed in the previous
three to six months. Likewise, either BMI calculation or waist circumference measurement should be undertaken
to assess patients for comorbid conditions (e.g., MetS).

5.4.3 Laboratory testing

Patients should undergo a fasting blood glucose or haemoglobin A1c and lipid profile measurement if they
have not been assessed in the previous twelve months. Hormonal tests should include early morning total
testosterone in a fasting state. The bio-available or calculated-free testosterone values may sometimes be
needed to corroborate total testosterone measurements (see sections 3.2.1 and 3.4.1) [321]. Additional
laboratory tests may be considered in selected patients with specific signs and associated symptoms (e.g.,
total PSA [322], PRL and LH [323]). Although physical examination and laboratory evaluation of most men with
ED may not reveal the exact diagnosis, clinical and biochemical evaluation presents an opportunity to identify
comorbid conditions [320].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 39

Figure 5.1: Minimal diagnostic evaluation (basic work-up) in patients with ED

Patient with ED (self-reported)

Medical and psychosexual history (use of validated instruments, e.g. IIEF)

Idenfy other sexual Idenfy common Idenfy reversible Assess psychosocial

problems, (not ED) causes of ED risk factors for ED status

Focused physical examinaon

Signs of Cardiovascular and

Penile deformies Prostac disease
hypogonadism neurological status

Laboratory tests

Total testosterone (morning sample)

Glucose-lipid profile
if indicated, bio-available or free
(if not assessed in the last 12 months)
testosterone

Diagnosis Treatment Follow-up

ED = erectile dysfunction; IIEF = International Index of Erectile Function.

5.4.4 Cardiovascular system and sexual activity: the patient at risk

Patients who seek treatment for sexual dysfunction have a high prevalence of CVDs. Erectile dysfunction
significantly increases the risk of CVD, coronary heart disease, stroke, atrial fibrillation, cardiovascular and
all-cause mortality [324]. Longitudinal data from an observational population-based study of 965 men without
CVD showed that younger men (especially those < 50 years) with transient and persistent ED have an increased
Framingham CVD risk [325]. Therefore, ED should be considered a precursor of CVD, and more severe and
longer standing ED yields greater risk. Erectile dysfunction can improve the sensitivity of screening for
asymptomatic CVD in men with or without diabetes [326-328].

Over time, the Princeton Consensus (Expert Panel) Conferences were dedicated to optimising sexual function
and preserving cardiovascular health [329-333]. The current EAU Guidelines on the diagnosis and treatment of
men with ED have been adapted from the recommendations from the Princeton Consensus conferences on
sexual dysfunction and cardiac risk published in 2024 [334].

The Princeton Consensus Conference IV aimed to critically evaluate the current evidence for the relationship
between ED and CV health, to update the CV work-up in the ED patient, to reassess when and how to treat ED
patients with known CVD, and to reassess the accuracy and relevance of previous Princeton management
algorithms [334, 335]. Accordingly, the Princeton Consensus Conference IV recommended the use of the 2019
American College of Cardiology/American Heart Association atherosclerotic CVD (ASCVD) risk score for all
men undergoing evaluation for predominantly vasculogenic ED [336]. As a whole, the ASCVD risk assessment

40 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

score utilises the Pooled Cohort Equations (PCE), which is based on age; sex; ethnicity; total cholesterol and
HDL-cholesterol concentrations; systolic blood pressure; and whether the patient is receiving treatment for
hypertension, has diabetes, or smokes [336]. The ASCVD provides an estimate of the patient’s risk of a major CV
event within the next 10 years categorised as follows: low risk < 5%; borderline risk 5% to < 7.5%; intermediate
risk ≥ 7.5% to < 20%; and high risk ≥ 20% [334, 337].
In this context, since men aged 40 to 60 years can have their cardiac risk significantly
underestimated with this tool alone, the Expert Panel Consensus from the Princeton Conference IV
recommended to use the widely available non-contrast-enhanced cardiac computed tomography to measure
coronary artery calcium (CAC) scores for all men in the borderline to intermediate ASCVD risk category as the
most sensitive and specific marker of subclinical CAD [334]. Therefore, the Princeton Consensus Conference
IV ended using the CAC score as the single strongest predictor of CVD risk and the concept of it being ideal to
guide clinical recommendations.
Accordingly, the proposed cardiovascular work-up for patients presenting with ED now relies on a
flowchart which largely considers the 10-year ASCVD risk calculation (Figure 5.2). Moreover, a specific flowchart
is also dedicated to ED patients with overt CV symptoms and/or CVD (Figure 5.3). This algorithm aims to
estimate the CV risk associated with sexual activity in patients with ED and known CVD (i.e., the full range
of CV disorders, including but not limited to ischemic disorders, arrhythmias, and cardiac output pathology).
The goal is to identify the risks related to the likelihood of mortal or morbid events during or shortly after
sex. The updated recommendations from the Princeton Consensus Conference IV also extend to include the
appropriateness of treatment with PDE5Is among low-risk patients currently using or who have easy access to
nitrates that they might use [334].
Overall, the flowcharts proposed by the Princeton Consensus Panel IV, including the CAC scoring,
should always be considered taking into account local expertise, availability of test and cost effectiveness. They
should be adapted to the European context and tailored to account for the heterogeneity of patients' clinical
profiles.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 41

c suggesons:
nd expectaons
-making
o-sexual and
treatment
Figure 5.2: Cardiovascular risk assessment of ED patient with no overt disease or cardiac symptoms (based on
IV Princeton Consensus) [334]
nges Provide educaon
or and counselling to
ns paent (and their Ask for ED symptoms
partner, where as part of the initial assessment
appropriate)

Standard CVD
YES NO
risk assessment

Topical/ Suspected vasculogenic mechanism?

y Intra-urethral
alprostadil Vasculogenic
s ED only YES

Calculate 10-year ASCVD risk, assess risk enhancing factors, patient-clinician risk discussion

es in terms of:
eatment invasiveness LI-SWT
mprovement of erecle (with/without
Low risk PDE5Is) Borderline to intermediate risk High risk
effects
asfacon
(<5%) (5-20%) (>20%)

Re-evaluate ED
CAC testing
pathophysiology:
Definitive
vasculogenic YES CAC = O CAC 1 to 100 CAC > 100
reatment opons mechanism?
and counselling

sfacon NO
nave or combined

Lifestyle modification
High intensity statin,
+ moderate to high
Emphasise LDL goal < 70 mg/dL,
ment outcome Standard ED intensity statin to
lifestyle consider aspirin, refer
management bring LDL < 70 mg/dL
interventions to preventive
+ consider preventive
cardiology
ses implant cardiology

Diagnosis Treatment Follow-up

Reproduced with permission from Kloner et al., 2024

ED = erectile dysfunction; CVD = cardiovascular disease; ASCVD = Atherosclerotic Cardiovascular Disease;
CAC = coronary artery calcium.

42 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

 paent needs and expectaons
Shared decision-making
r conjoint psycho-sexual and
medical/physical treatment

Lifestyle changes Figure 5.3. Management

Provide educaonof ED in men with overt CV symptoms and/or CVD (based on IV Princeton Consensus)
and risk factor [334] and counselling to
modificaons paent (and their
partner, where
Sexual inquiry of all men
appropriate)

ED confirmed CVD risk factor and

CVD w/o if suspected
Oral Topical/ vasculogenic ED
therapy (see figure 3)
Intra-urethral
with alprostadil Vasculogenic
Exercise ability for age
PDE5Is ED only

Intermediate or
Low risk indeterminable High risk
apeuc outcomes in terms of: risk
self-perceived treatment invasiveness LI-SWT
ent-associated improvement of erecle (with/without
Elective risk
n PDE5Is)
assessment
ent-related side effects Stress test
ent-associated sasfacon

PASS FAIL
Advise, treat ED Cardiologist referral
(Low risk) (High risk)

dequate use of treatment opons

new instrucons and counselling On nitrates/
YES Are nitrates necessary
On riociguat
nt-associated sasfacon
r treatment alternave or combined
s
NO NO YES

adequate treatment outcome Consider stopping

PDE5Is
nitrates

Penile prostheses implant

If off nitrates, Non-PDE5Is
Diagnosis Treatment Follow-up PDE5Is RX for ED

Reproduced with permission from Kloner et al., 2024

*Low-risk patients: Patients for whom sexual activity does not represent significant cardiac risk. These patients
can generally perform exercise of modest intensity without symptoms and include successfully revascularized
individuals, patients with asymptomatic controlled hypertension, those with mild valvular disease, and patients
with left ventricular dysfunction/heart failure (NYHA classes I and II) who achieved 5 METS without ischemia on
recent exercise testing.
**Intermediate-risk or indeterminable (or indeterminate) risk patients: Patients with mild or moderate stable angina
pectoris, past myocardial infarction (MI) (2-8 weeks) without intervention awaiting exercise electrocardiography,
congestive heart failure patients (NYHA class III), and noncardiac sequelae of atherosclerotic disease (e.g.,
peripheral arterial disease, history of stroke or transient ischemic attack). In this setting, further examination
using exercise stress testing is required for indeterminate-risk patients before resuming sexual activity. If patients
cannot complete a standard exercise test (owing to a disabling condition such as arthritis), a chemical stress test
with echocardiography or nuclear imaging can be performed. Moreover, patients with suspected atherosclerotic
disease may need additional testing using CAC, carotid intima-media thickness or the ankle-brachial index that
may be helpful in reclassifying to high- or low-risk categories.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 43

***High-risk patients: Patients with severe cardiac conditions or unstable enough to pose a significant risk with
sexual activity. Overall, most men are moderately or severely symptomatic. Common high-risk profiles include
unstable or refractory angina pectoris, uncontrolled hypertension, congestive heart failure (NYHA class IV), recent
MI without intervention (< 2 weeks), high-risk arrhythmia (exercise-induced ventricular tachycardia, implantable
cardioverter-defibrillator with frequent shocks, and poorly controlled atrial fibrillation).
ED = erectile dysfunction; PDE5Is = Phosphodiesterase 5 Inhibitors.

5.5 Diagnostic Evaluation (advanced work-up)

Most patients with ED can be managed based on their medical and sexual history; conversely, some patients
may need specific diagnostic tests (Table 5.2).

5.5.1 Nocturnal penile tumescence and rigidity test

The nocturnal penile tumescence and rigidity (NPTR) test applies nocturnal monitoring devices that measure
the number of erectile episodes, tumescence (circumference change by strain gauges), maximal penile rigidity,
and duration of nocturnal erections. The NPTR assessment should be performed on at least two separate
nights. A functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on
the tip of the penis that lasts for ≥ 10 minutes [338]. Nocturnal penile tumescence and rigidity monitoring is
an approach for objectively differentiating between organic and psychogenic ED (patients with psychogenic
ED usually have normal findings in the NPTR test). However, there are still limitations to NPTR namely the true
correlation between NPTR and a sex-related erection, the definition used to establish ED as well as the many
potential confounding factors (e.g., situational, age, depression, sleep-related content) may limit its routine use
for diagnostic purposes [338, 339].

5.5.2 Intracavernous injection test

The intracavernous injection test gives limited information about vascular status. A positive test is a rigid
erectile response (unable to bend the penis) that appears within 10 minutes after the intracavernous injection
and lasts for 30 minutes [340]. Overall, the test per se is inconclusive as a diagnostic procedure and a duplex
Doppler study of the penis should be requested, if clinically warranted.

5.5.3 Dynamic duplex ultrasound of the penis

Dynamic duplex ultrasound (US) of the penis is a second-level diagnostic test that specifically studies the
haemodynamic pathophysiology of EF. Therefore, in clinical practice, it is usually applied in those conditions
in which a potential vasculogenic aetiology of ED (e.g., diabetes mellitus, multiple concomitant CV risk
factors and/or overt peripheral vascular disease, renal transplantation and poor responders to oral therapy)
is suspected. Peak systolic blood flow > 30 cm/s, end-diastolic velocity < 3 cm/s and resistance index > 0.8
are considered normal [341, 342]. Recent data suggest that duplex scanning as a haemodynamic study may
be better at tailoring therapy for ED, such as for low-intensity shock wave treatment (LI-SWT) in men with
vasculogenic ED [343]. Further vascular investigation is unnecessary if a duplex US examination is normal.
However, it has limitations with regards to the standardised metrics for the haemodynamic parameters utilised,
its diagnostic accuracy is challenged by false positive diagnosis due to confounding factors (e.g. anxiety, low
vasoactive agent dosage) and its added value to the intracavernous injection test is still unclear [344-347].
Measures such as audiovisual sexual stimulation, high-dosage alprostadil or combination of vasoactive and/or
oral agents can help improve its accuracy [348-350].

5.5.4 Arteriography and dynamic infusion cavernosometry or cavernosography

Pudendal arteriography should be performed only in patients who are being considered for penile
revascularisation [351]. Currently, dynamic infusion cavernosometry or cavernosography are infrequently used
diagnostic modalities for the assessment of venogenic ED and the concept of venogenic ED has been
questioned. Computed tomography cavernosography is an emerging diagnostic modality providing detailed
anatomical information that may aid in diagnosing and planning treatment for ED [352].

5.5.5 Psychopathological and psychosocial assessment

Mental health issues and psychological distress are frequently comorbid with ED [353]. This is most evident
for depression and anxiety related disorders, but may also include transitory states of altered mood (i.e.,
dysfunctional affective states resulting from a specific life stressor or crisis) [270, 354, 355]. Relationship
factors, including lack of satisfaction with the partner, poor sexual relationships, length of the relationship,
or feeling emotionally disconnected from the partner during sex, have been related to erectile difficulties
and dysfunction [354, 356, 357]. In contrast, intimacy was found to be a protective factor in ED [259, 358].
Additionally, the cognitive factors underpinning organic and non-organic ED (i.e., all dysfunctional thinking styles
and expectations about sexuality, poor self-esteem and cognitive distraction from erotic cues) must also be
assessed.

44 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Psychosexual assessment in ED cases include a clinical interview considering all the previous topics [359].
Also, self-reported measures are frequently used within the psychosocial context [360]. A growing amount of
data suggests that men who have sex with men (MSM) presenting specific psychological risks associated with
erectile capability regarding anal sex [361]. Therefore, professionals must tailor their assessment in the context
of sexual minorities.

Figure 5.4: Psychopathological and psychosocial assessment

Collect evidence for Evaluate psychosexual history and

specific life stressors relaonship factors

Evaluate dysfunconal thinking

Consider role of Consider cultural
style and expectaons regarding
partner background
sexuality and erecle funcon

Decide on referral to (sexual)

psychotherapy

Include psychosexual aspects as

outcomes for treatment efficacy
- relationship/intimacy
- sexual satisfaction
- well-being
- flexible thinking style and
expectations

Table 5.2: Indications for specific diagnostic tests for ED and the specific diagnostic tests

Indications for specific diagnostic tests for ED

Primary ED (not caused by acquired organic disease or psychogenic disorder).
Young patients with a history of pelvic or perineal trauma, who could benefit from potentially curative
revascularisation surgery or angioplasty.
Patients with penile deformities that might require surgical correction (e.g., Peyronie’s disease and congenital
penile curvature).
Patients with complex psychiatric or psychosexual disorders.
Patients with complex endocrine disorders.
Specific tests may be indicated at the request of the patient or their partner.
Medico-legal reasons (e.g., implantation of penile prosthesis to document end-stage ED, and sexual abuse).

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 45

Specific diagnostic tests for ED
Nocturnal Penile Tumescence and Rigidity (NTPR) using Rigiscan®
Vascular studies
• Intracavernous vasoactive drug injection
• Penile dynamic duplex ultrasonography
• Penile dynamic infusion cavernosometry and cavernosography
• Internal pudendal arteriography
Specialised endocrinological studies
Specialised psycho-diagnostic evaluation

5.5.6 Summary of evidence and recommendations for diagnostic evaluation of ED

Summary of evidence LE
Medical and sexual history, physical examination and laboratory testing including metabolic and 3
hormonal profile may identify risk factors for ED and may help in defining the ED aetiology.
Validated psychometric questionnaires (e.g. IIEF; EHS) are reliable tools to assess ED severity. 3
Specific diagnostic tests could be of help in discerning between vasculogenic, hormonal or 3
psychogenic causes of ED.

Recommendations Strength rating

Take a comprehensive medical and sexual history in every patient presenting with erectile Strong
dysfunction (ED). Take a targeted psychosexual history, including life stressors, cultural
aspects, and cognitive factors regarding patient sexual performance.
Use a validated questionnaire related to ED to assess all sexual function domains (e.g., Strong
International Index of Erectile Function) and the effect of a specific treatment modality.
Include a focused physical examination in the initial assessment of men with ED to identify Strong
underlying medical conditions and comorbid genital disorders that may be associated with ED.
Evaluate laboratory tests, including glucose and lipid profile and total testosterone, to identify Strong
and treat any reversible risk factors and lifestyle factors that can be modified.
Include specific diagnostic tests in the initial evaluation of ED in the presence of the Strong
conditions presented in Table 5.2.

5.6 Treatment of erectile dysfunction

The Guidelines Panel have developed a comprehensive therapeutic and decision-making algorithm (Figure 5.5)
for treating ED. The treatment algorithm was developed as an alternative to the traditional three-tier concept,
to support personalised treatment tailored to individual patients, according to invasiveness, tolerability and
effectiveness of the different therapeutic options and patients’ expectations. In this context, patients should be
fully counselled with respect to all available treatment modalities.

The majority of men with ED are not treated with cause-specific therapeutic options. This results in a tailored
treatment strategy that depends on invasiveness, efficacy, safety and costs, as well as patient preference
[362]; therefore, physician-patient dialogue is essential throughout the management of ED. A systematic
review has shown a consistent discontinuation rate for all available ED treatment options [363]. This highlights
the importance of clinicians understanding patient’s beliefs about ED treatment, therapeutic ineffectiveness,
adverse effects, quality of intimate relationships and treatment costs all of which were shown to be the most
prevalent barriers to treatment use [363].

46 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Figure 5.5: Management algorithm for erectile dysfunction

Comprehensive medical and sexual history

(assessing a detailed aeological framework)

Before any therapeuc suggesons:

Idenfy paent needs and expectaons
Shared decision-making
Offer conjoint psycho-sexual and
medical/physical treatment

Idenfy and treat Lifestyle changes Provide educaon

“curable” causes of and risk factor and counselling to
erecle dysfuncon modificaons paent (and their
partner, where
appropriate)

Intracavernosal Vacuum Oral Topical/

injecon device therapy Intra-urethral
with alprostadil Vasculogenic
PDE5Is ED only

Paents with Assess therapeuc outcomes in terms of:

definive severe ED • Paent self-perceived treatment invasiveness LI-SWT
(Major non nerve- • Treatment-associated improvement of erecle (with/without
sparing pelvic funcon PDE5Is)
,
surgery neurogenic • Treatment-related side effects
or traumac causes) • Treatment-associated sasfacon

Inadequate treatment
outcome

• Assess adequate use of treatment opons

• Provide new instrucons and counselling
• Re-trial
• Treatment-associated sasfacon
• Consider treatment alternave or combined
therapies

Inadequate treatment outcome

Penile prostheses implant

Diagnosis Treatment Follow-up

ED = erectile dysfunction; PDE5Is = phosphodiesterase type 5 inhibitors; Li-SWT = low-intensity shockwave

therapy.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 47

5.6.1 Patient education
Educational intervention is often the first approach to sexual complaints and consists of informing patients
about the psychological and physiological processes involved in the individual’s sexual response, in ways the
patient can understand. This baseline approach has been shown to favour sexual satisfaction in men with ED
[364]. Accordingly, consultation with the patient should include a discussion of the expectations and needs of
the patient’s and his sexual partner. It should also review the patient’s and partner’s understanding of ED and the
results of diagnostic tests, and provide a rationale for treatment selection [362].

5.6.2 Modifiable risk factors

Erectile dysfunction may be associated with modifiable or reversible risk factors, including lifestyle or drug-
related factors [365]. These factors may be modified either before, or at the same time as, specific therapies are
used. Likewise, ED may be associated with concomitant and underlying conditions (e.g., endocrine disorders
and metabolic disorders such as diabetes, and some cardiovascular problems such as hypertension) which
should always be well-controlled as the first step of any ED treatment [366]. Overall, several studies have shown
that lifestyle modifications including physical activity especially aerobic exercise, weight loss including via
bariatric surgery and treatment for CVD risk factors may be of help in improving sexual function in men with
ED [263, 365, 367-371]. Regarding the use of statins, although previous meta-analyses had demonstrated an
improvement in ED [372, 373].

5.6.3 Phosphodiesterase type 5 inhibitors

Four potent selective PDE5Is have been approved by the EMA for treatment of ED [374]. The efficacy of all four
PD5EIs in almost every subgroup of patients with ED has been successfully established [374-377]. Efficacy is
defined as an erection, with rigidity, sufficient for satisfactory intercourse [366]. In addition, adverse events for
the four PDE5Is are generally mild and self-limiting [378-382]. The pharmacokinetic data for all four PDE5Is and
their associated adverse events are presented in Tables 5.3 and 5.4, respectively. Choice of PDE5I depends
on frequency of intercourse and the patient’s personal experience. Two meta-analyses demonstrated that ED
patients who prioritise high efficacy should use sildenafil 50 mg whereas those who optimise tolerability should
initially use tadalafil 10 mg [375, 383]. It is important to highlight that a meta-analysis investigating the placebo
responses in patients treated with PDE5Is showed a significant improvement of ED, especially among men with
ED-related post-traumatic stress disorder [384].

5.6.3.1 Sildenafil
Sildenafil is administered in doses of 25, 50 and 100 mg. The recommended starting dose is 50 mg and should
be adapted according to the patient’s response and adverse effects [385]. The window of effectiveness ranges
from 30-60 minutes after administration [385] up to 12 hours [386]. In a 24-week dose-response study, improved
erections were reported by 56%, 77% and 84% of general ED patients taking 25, 50 and 100 mg sildenafil,
respectively, compared to 25% of men taking placebo [387]. Sildenafil also significantly improved patient scores
for IIEF, sexual encounter profile question 2 (SEP2), SEP question 3 (SEP3), General Assessment Questionnaire
(GAQ) and treatment satisfaction [387]. Furthermore, an orally disintegrating tablet (ODT) of sildenafil citrate at
doses of 25, 50, 75 and 100 mg has been developed, mainly for patients who have difficulty swallowing solid
dosage forms [388]. Likewise, a sildenafil oral suspension treatment has been developed, with clinically relevant
results [2000, 2001].

5.6.3.2 Tadalafil
Tadalafil is administered in on-demand doses of 10 and 20 mg or a daily dose of 5 mg. The recommended
on-demand starting dose is 10 mg and should be adapted according to the patient’s response and adverse
effects [389, 390]. The window of effectiveness ranges from 30 minutes after administration (peak efficacy
after approximately 2 hours) up to 36 hours [389]. In a 12-week dose-response study improved erections were
reported by 67% and 81% of men with ED taking 10 and 20 mg tadalafil, respectively, compared to 35% of men
taking placebo [389]. Tadalafil has also been shown to have a net clinical benefit in the short-term on ejaculatory
and orgasmic functions in ED patients [391].
Data have also shown that 40% of men aged > 45 years were combined responders for ED and LUTS/
BPH when treated with tadalafil 5 mg once daily, with symptom improvement after 12 weeks [392]. Therefore, its
use may be considered in both patients with ED only and in patients also complaining of concomitant LUTS, and
wishing to benefit from a single therapy [393].

48 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

5.6.3.3 Vardenafil
Vardenafil is administered in on-demand doses of 5, 10 and 20 mg. The recommended starting dose is 10 mg
and should be adapted according to the patient’s response and adverse effects [380]. Vardenafil is effective
from 30 minutes after administration [394], with one of three patients achieving satisfactory erections within
15 minutes of ingestion [395]. In a 12-week dose-response study, improved erections were reported by 66%,
76% and 80% of men with ED taking 5, 10 and 20 mg vardenafil, respectively, compared with 30% of men taking
placebo [380, 396]. Vardenafil significantly improved patient scores for IIEF, SEP2, SEP3, and GAQ and treatment
satisfaction. An orodispersable tablet (ODT) formulation of vardenafil has also been released [396]. The
efficacy of vardenafil ODT has been demonstrated in several RCTs and did not seem to differ from the regular
formulation [397-399].

5.6.3.4 Avanafil
Avanafil is administered in on-demand doses of 50, 100 and 200 mg [381]. The recommended starting dose
is 100 mg taken as needed 15-30 minutes before sexual activity and the dose may be adapted according to
efficacy and tolerability [381, 382, 400]. In a general ED population the mean percentage of successful sexual
attempts resulting in intercourse were 47%, 58% and 59% for the 50, 100 and 200 mg groups, respectively, as
compared with 28% for the placebo group [381, 382]. A meta-analysis confirmed that avanafil had comparable
efficacy with sildenafil, vardenafil and tadalafil [401].

5.6.3.5 Continuous use of PDE5Is

According to the EMA, a once-daily regimen with tadalafil 2.5 or 5 mg may be considered suitable, based on
patients’ choice and physicians’ judgement. In these patients, the recommended dose is 5 mg, taken once daily
at approximately the same time each day. Tadalafil, 5 mg once daily, provides an alternative to on-demand
tadalafil for couples who prefer spontaneous rather than scheduled sexual activities or who anticipate frequent
sexual activity, with the advantage that dosing and sexual activity no longer need to be linked. regardless of the
type of ED population, there is no clinically significant difference between a tadalafil treatment administered
with continuous (once daily) vs. on-demand tadalafil [402]. Overall, treatment with tadalafil 5 mg once daily in
men complaining of ED of various severities is well-tolerated and effective [403] and may improve EF among
men who have a partial response to on-demand PDE5I therapy [404]. The appropriateness of the continuous use
of a daily regimen should be re-assessed periodically [403, 405].

Table 5.3: Pharmacokinetics data for PDE5Is EMA approved for the treatment of ED*

Parameter Sildenafil, 100 mg Tadalafil, 20 mg Vardenafil, 20 mg Avanafil, 200mg

Cmax 560 μg/L 378 μg/L 18.7 μg/L 5.2 μg/L
Tmax (median) 0.8-1 hours 2 hours 0.9 hours 0.5-0.75 hours
T1/2 2.6-3.7 hours 17.5 hours 3.9 hours 6-17 hours
AUC 1,685 μg.h/L 8,066 μg.h/L 56.8 μg.h/L 11.6 μg.h/L
Protein binding 96% 94% 94% 99%
Bioavailability 41% NA 15% 8-10%
* Fasted state, higher recommended dose. Data adapted from EMA statements on product characteristics.
Cmax = maximal concentration; Tmax = time-to-maximum plasma concentration; T1/2 = plasma elimination halftime;
AUC = area under curve or serum concentration-time curve.

Table 5.4: Common adverse events of the four PDE5Is currently EMA-approved to treat ED*

Adverse event Sildenafil Tadalafil Vardenafil Avanafil, 200mg

Headache 12.8% 14.5% 16% 9.3%
Flushing 10.4% 4.1% 12% 3.7%
Dyspepsia 4.6% 12.3% 4% uncommon
Nasal congestion 1.1% 4.3% 10% 1.9%
Dizziness 1.2% 2.3% 2% 0.6%
Abnormal vision 1.9% < 2% None
Back pain 6.5% < 2%
Myalgia 5.7% < 2%
* Adapted from EMA statements on product characteristics.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 49

5.6.3.6 Safety concerns for PDE5Is
5.6.3.6.1 Cardiovascular safety
No RCTs or open-label studies have demonstrated an increase in myocardial infarction (MI) rates in patients
receiving PDE5Is. In contrast, an observational study demonstrated that in men with stable CAD, treatment with
PDE5I is associated with lower risks of death, MI, heart failure, and revascularization compared with alprostadil
treatment [406]. None of the PDE5Is have an adverse effect on total exercise time or time-to-ischaemia during
exercise testing in men with stable angina [374, 407]. This EAU Guidelines panel agrees to maintain the
recommendations provided by the 3rd Princeton Consensus Panel in terms of prescription of all PDE5Is in
patients with CVD or in those with high CV risk [330-332].

5.6.3.6.2 Contraindications for the concomitant use of organic nitrates and nicorandil
An absolute contraindication to PDE5Is is the concomitant use of any form of organic nitrate or NO donors
including recreational use of amyl nitrite or nitrate (poppers). Concomitant use results in cGMP accumulation
and unpredictable falls in blood pressure and symptoms of hypotension [408-411]. Concurrent use of nicorandil
and PDE5Is is contraindicated due to the potential of the nitric oxide donating properties of nicorandil to
increase cGMP levels [412].

5.6.3.6.3 Antihypertensive drugs

Co-administration of PDE5Is with antihypertensive agents may result in small additive decreases in blood
pressure, which are usually minor [330]. In general, the adverse event profile of a PDE5I is not worsened by a
background of antihypertensive medication, even when the patient is taking several antihypertensive agents
[413-415].

5.6.3.6.4 Interactions with α-blockers

Tadalafil 5 mg is currently the only licensed drug for the treatment of both ED and LUTS demonstrating overall
good efficacy in relieving urinary symptoms and improving EF [393]. Therefore, treatment with tadalafil 5 mg
should be considered in patients suffering from mild to moderate LUTS associated with ED either alone or in
combination with α-blockers. Conversely, as both drugs are vasodilators a certain degree of caution has been
observed for combination therapy with PDE5Is and alpha-blockers due to the potential cumulative effects
on blood pressure described in some studies [386, 395, 416]. However, a meta-analysis concluded that a
concomitant treatment with α-blockers [both non-uroselective (e.g., terazosin and doxazosin) and uro-selective
(e.g., alfuzosin, tamsulosin and silodosin) and PDE5Is may produce changes in haemodynamic parameters, but
it does not increase the rate of adverse events due to hypotension [416]. Therefore, there is no current limitation
in the simultaneous use of α-blockers and PDE5I.

5.6.3.7 Management of non- or poor-responders to PDE5Is

The management of non-responders depends upon identifying the underlying cause [417]. Clinicians should
begin by ensuring that the medication has been properly prescribed, is being correctly used by the patient and
that the patient has been using a licensed medication. Absorption of sildenafil, vardenafil and avanafil can be
delayed by high-fat meals [418-420]. Timing is important and patients may be waiting either too short or too
long after the medication before attempting sexual intercourse. Studies suggest that patient education can
help salvage an apparent non-responder to a PDE5I [417, 421-424]. After emphasising the importance of dose,
timing, and sexual stimulation to the patient, EF can be effectively restored following re-administration of the
relevant PDE5I [417, 421, 422].

Studies have demonstrated that hypogonadal patients not responding to PDE5Is may improve their response
to PDE5Is after initiating testosterone therapy [87, 366, 425]. Therefore, if diagnostic criteria suggestive for
testosterone deficiency are present, testosterone therapy may be more appropriate even in ED patients [3, 87].
Limited data suggest that some patients might respond better to one PDE5I than to another [426], raising the
possibility that, despite an identical mode of action, switching to a different PDE5I may be beneficial. However,
no evidence for this has been reported in the available RCTs [427, 428].

In refractory, complex, or difficult-to-treat cases of ED a combination therapy should be considered as a first-

line approach. Although the available data are still limited, there are several strategies that can be considered
including: PDE5Is with antioxidant agents, LI-SWT or a vacuum erection device (VED) [429]; daily tadalafil with
an on-demand short-acting PDE5I (such as sildenafil) [430]; Li-SWT with VED [431]; and PDE5Is with topical
alprostadil [432].

50 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

5.6.3.8 Topical/Intraurethral alprostadil
The vasoactive agent alprostadil can be administered inside the urethra with two different formulations. The
first delivery method is topical, using a cream that includes a permeation enhancer to facilitate absorption
of alprostadil (200 and 300 μg) via the urethral meatus [433, 434]. Clinical data are still limited. Significant
improvement compared to placebo was recorded for IIEF-EF domain score, SEP2 and SEP3 in a broad range
of patients with mild-to-severe ED [435]. Adverse effects include penile erythema, penile burning, and pain that
usually resolve within two hours of application. Topical alprostadil (VITAROSTM) at a dose of 300 μg is available
in some European countries. Recently, a randomised cross-over clinical trial has shown that, compared to the
standard administration route, direct delivery within the urethral meatus can increase efficacy and confidence
among patients, without increasing adverse effects [436].
The second delivery method is by intra-urethral insertion of a specific formulation of alprostadil (125-
1000 μg) in a medicated pellet (MUSE™) [229]. Erections sufficient for intercourse are achieved in 30-65.9% of
patients. In clinical practice, it is recommended that intra-urethral alprostadil is initiated at a dose of 500 μg, as
it has a higher efficacy than the 250 μg dose, with minimal differences with regards to adverse events. In case
of unsatisfactory clinical response, the dose can be increased to 1000 μg [437-439]. Overall, the most common
adverse events are local pain (29-41%) and dizziness with possible hypotension (1.9-14%). Penile fibrosis and
priapism are rare (< 1%). Urethral bleeding (5%) and urinary tract infections (0.2%) are adverse events related to
the mode of administration.
Efficacy rates are significantly lower than for intracavernous pharmacotherapy [440], with 30%
adherence to long-term therapy. Intraurethral pharmacotherapy provides an alternative to intracavernous
injections in patients who prefer a less-invasive, although less-efficacious treatment.

5.6.4 Psychosocial intervention and therapy

Psychosocial interventions including different modalities (e.g., sexual skills training, marital therapy,
psychosexual education) [364], and Cognitive and Behavioural Therapy (CBT - group or couple format), even
if conducted online, are recommended [359, 441]. Cognitive and Behaviour Therapy is aimed at altering
dysfunctional cognitive and behavioural patterns influencing ED, and increasing adjustment during the course of
the disorder. The CBT approach combined with medical treatment for ED has received empirical support and is
considered an optimal procedure [442].

5.6.5 Hormonal treatment

When clinically indicated, testosterone therapy (intramuscular, transdermal, or oral) can be considered for men
with low or low-normal testosterone levels and concomitant problems with sexual desire, EF and dissatisfaction
derived from intercourse and overall sex life (see Section 3.4 for a comprehensive discussion of testosterone
therapy) [443, 444], even in patients with a history of CVD [445].

5.6.6 Vacuum erection devices

Published data report that efficacy, in terms of erections satisfactory for intercourse, is as high as 90%,
regardless of the cause of ED and satisfaction rates range between 27% and 94% [446, 447]. Long-term use
of VEDs decreases to 50-64% after two years [448]. The most common adverse events include pain, inability
to ejaculate, petechiae, bruising, and numbness [447]. Serious adverse events (skin necrosis) can be avoided
if patients remove the constriction ring within 30 minutes. Vacuum erection devices are contraindicated in
patients with bleeding disorders or on anticoagulant therapy [449, 450]. Vacuum erection devices may be the
treatment of choice in well-informed older patients with infrequent sexual intercourse and comorbidity requiring
non-invasive, drug-free management of ED [446, 447, 451].

5.6.7 Intracavernous injections therapy

Intracavernous administration of vasoactive drugs was the first medical treatment introduced for ED [424, 452].
Patients may be offered intracavernous injections at every stage of a tailored treatment work-up.

5.6.7.1 Alprostadil
Alprostadil (CaverjectTM, Edex/ViridalTM) was the first and only drug approved for intracavernous treatment
of ED [424, 453]. Intracavernous alprostadil is most efficacious as a monotherapy at a dose of 5-40 μg (40
μg may be offered off label in some European countries). The erection appears after 5-15 minutes and lasts
according to the dose injected, but with significant heterogeneity among patients. An office-training programme
is required for patients to learn the injection technique. Efficacy rates for intracavernous alprostadil of > 70%
have been found in the general ED population, as well as in patient subgroups (e.g., men with diabetes or CVD),
with reported satisfaction rates of 87-93.5% in patients and 86-90.3% in partners after the injections [424, 452].
Complications of intracavernous alprostadil include penile pain (50% of patients reported pain only after 11%
of total injections), excessively prolonged and undesired erections (5%), priapism (1%), and fibrosis (2%) [424,

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 51

452, 454]. Pain is usually self-limited after prolonged use and it can be alleviated with the addition of sodium
bicarbonate or local anaesthesia [424, 452, 455]. Cavernosal fibrosis usually clears within a few months after
temporary discontinuation of the injection programme. However, tunical fibrosis suggests early onset of
Peyronie’s disease and may indicate the need to discontinue intracavernous injections indefinitely. Systemic
adverse effects are uncommon. The most common is mild hypotension, especially when using higher doses.
In a large population study including 16,548 men with a history of ischemic CVD, those treated with alprostadil
had higher risk of a further cardiovascular event as compared to those receiving PDE5Is [406]. Contraindications
include men with a history of hypersensitivity to alprostadil, men at risk of priapism, and men with bleeding
disorders. Despite these favourable data, drop-out rates of 41-68% have been reported for intracavernous
pharmacotherapy [424, 452, 456, 457], with most discontinuations occurring within the first two to three months.
Careful counselling of patients during the office-training phase as well as close follow-up are important in
addressing patient withdrawal from an intracavernous injection programme [458-460].

5.6.7.2 Other vasoactive intracavernous treatments

Table 5.5 details the available intracavernous injection therapies (compounds and characteristics). Combination
therapy enables a patient to take advantage of the different modes of action of the drugs being used, as well as
alleviating adverse effects by using lower doses of each drug.
• Papaverine (20-80 mg) was the first oral drug used for intracavernous injections. It is most commonly
used in combination therapy because of its high incidence of adverse effects as monotherapy. Papaverine
is currently not licensed for treatment of ED.
• Phentolamine has been used in combination therapy to increase efficacy. As monotherapy, it produces a
poor erectile response. Phentolamine is currently not licensed for treatment of ED.
• Limited data support the use of other drugs, such as vasoactive intestinal peptide (VIP), NO donors
(linsidomine), forskolin, potassium channel openers, moxisylyte or calcitonin gene-related peptide, usually
combined with the main drugs [461, 462]. Most combinations are not standardised and some drugs have
limited availability worldwide.
• Bimix, (papaverine 7.5-45 mg plus phentolamine 0.25-1.5 mg) and Trimix (papaverine 8-16 mg plus
phentolamine 0.2-0.4 mg plus alprostadil 10-20 μg), have been widely used with improved efficacy rates,
although they have never been licensed for ED [463, 464]. Trimix has the highest efficacy rates, reaching
92%; this combination has similar adverse effects as alprostadil monotherapy, but a lower incidence of
penile pain due to lower doses of alprostadil. However, fibrosis is more common (5-10%) when papaverine
is used (depending on total dose).
• InvicorpTM: Vasoactive intestinal peptide (25 μg) plus phentolamine mesylate (1-2 mg Invicorp), is a
combination of two active components with complementary modes of action. Clinical studies have shown
that the combination is effective for intracavernous injections in > 80% of men with ED, including those
who have failed to respond to other therapies and, unlike existing intracavernous therapies, is associated
with a low incidence of penile pain and a virtually negligible risk of priapism [465].

Overall, despite high efficacy rates, 5-10% of patients do not respond to combination intracavernous injections.

Table 5.5: Intracavernous injection therapy - compounds and characteristics

Name Substance Dosage Efficacy Adverse Events Comment

Caverject™ or Alprostadil 5-40 µg/mL ~ 70% Penile pain, Easily available
Edex/Viridal™ priapism, fibrosis
Papaverine Papaverine 20 - 80 mg < 55% Elevation of liver Abandoned as
enzymes, priapism, monotherapy
fibrosis
Phentolamine Phentolamine 0.5 mg/mL Poor Systemic Abandoned as
efficacy as hypotension, reflex monotherapy
monotherapy tachycardia, nasal
congestion, and
gastrointestinal
upset

52 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Bimix Papaverine + 30 mg/mL + ~ 90% Similar to Not licensed for
Phentolamine 0.5 mg/mL Alprostadil (less the treatment
pain) of ED
Trimix Papaverine + 30 mg/mL + ~ 92% Similar to Not licensed for
Phentolamine + 1 mg/mL + Alprostadil (less the treatment
Alprostadil 10 µg/mL pain) of ED
Invicorp™ Vasoactive 25 µg + 1-2 mg ~ 80% Similar as Easily available
intestinal Alprostadil without
peptide (VIP) + pain
Phentolamine

5.6.8 Innovative treatment modalities

There are currently several potential novel treatment modalities for ED. Most of these therapeutic approaches
require further investigation in large-scale, blinded, placebo-controlled randomised studies to achieve adequate
evidence-based and clinically-reliable recommendation grades [466-471].

5.6.8.1 Regenerative medicine therapies

5.6.8.1.1 Shockwave therapy
The use of LI-SWT has been increasingly proposed as a treatment for vasculogenic ED over the last decade, and
it’s the only currently marketed treatment that might offer a cure, which is the most desired outcome for most
men suffering from ED [343, 472-479].
Overall, several single-arm trials have shown a beneficial effect of LI-SWT on patient-reported EF.
However, there are significant differences in reported outcome measures due to the heterogeneity among
shockwave generators, type of shockwaves delivered (focal vs. radical), set-up parameters and treatment
protocols [480, 481]. In a trial trying to assess the best treatment parameters, no significant differences were
observed between various energy flux density levels; although, a 0.10 mJ/mm2 seems to perform slightly
better than lower energies [482]. The majority of trials have been conducted with generators delivering focal
shockwaves [343, 480, 481]. On the other hand, a RCT using radial wave therapy showed no difference was
found in terms of IIEF-EF and EHS score between treatment and placebo groups [483].
Despite this most studies have suggested that LI-SWT can significantly increase IIEF and EHS
scores in patients with mild vasculogenic ED, although this improvement appears modest and the rates of
patients reporting a satisfactory improvement range between 40-80% [343, 480]. Few studies have shown an
improvement in penile haemodynamic parameters after LI-SWT, but the clinical meaning of this improvement
remains unclear [480, 484]. Likewise, data suggest that LI-SWT could ameliorate erection quality even in patients
with severe ED who are either PDE5Is non-responders [477, 485, 486] or inadequate responders [487], thus
reducing the immediate need for more invasive treatments. Treatment effect appears to be clinically evident
starting from one to three months after treatment completion, with a subsequent progressive decrease of the
achieved benefit in terms of EF over time, although some effects could be still detected up to five years after
treatment [480, 482, 488]. Data from RCTs suggests that even better results could be achieved by combining
LI-SWT with other treatments such as a VED in men with T2DM [431] or daily tadalafil [489, 490].
Findings from a recent meta-analysis showed that LI-ESWT has a positive effect on early recovery
of EF in the context of penile rehabilitation of ED after RP. However, the authors clearly outlined that the level of
evidence was low; therefore, careful interpretation of the results is required [491-493].

5.6.8.1.2 Platelet-Rich Plasma

Intracavernous injection of platelet-rich plasma (PRP) has been investigated in several prospective and
retrospective trials [494-500]. The regenerative effect of PRP is deemed to be exerted through the high
concentrations of platelets containing several growth factors including VEGF, EGF, IGF-1, PDGF and FGF [501].
These factors may be responsible for angiogenesis stimulation and stem cell recruitment [501].
In the first RCT investigated the effect of intracavernous injection of PRP for ED, 60 patients with mild
to moderate vasculogenic ED were randomised to receive two injections of 10 mL PRP (n = 30) or placebo (n =
30) [500]. At 1, 3 and 6-month follow-up, the rate of patients reporting minimal clinically important difference
(MCID) in the IIEF-EF score was significantly higher in the treatment group, with 69% achieving MCID 6 months
after PRP vs. 27% in the placebo group (p < 0.001). IIEF-EF scores improved by a mean of 2.7 points at 1-month
and 3.9 points at 6-month assessment after treatment. Regarding safety, no haemorrhagic events or other side
effects were reported [500].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 53

A prospective randomised, double-blind, placebo-controlled study was carried out on 109 patients, aged 45-65
years, with mild to moderate ED, following cessation of any ED treatment [502]. At 1, 3 and 6 months after
PRP injections, patients in PRP group had a significant improvement compared to placebo in terms of IIEF-
EF, SEP2 and SEP3. Moreover, at 6-month post-treatment follow-up, 70% patients achieved a MCID in the PRP
group compared to 16% in the placebo group [502]. Even more recently, a further prospective, randomized,
double-blind, placebo control study on a relatively small cohort of mild to moderate ED patients who have been
treated with two PRP injections separated by 1 month showed that the treatment is safe, but the authors did
not find any difference in efficacy between PRP and placebo [503]. Of clinical relevance, patients were allowed
to continue PDE5Is during the study [503]. A meta-analysis of the above mentioned RCTs reported a mean
improvement in IIEF-EF score with PRP vs. placebo of 3.21 [95%CI: 1.82; 4.60] 6 months after treatment [504].

As a whole, despite a number of promising results that have been obtained for the treatment of primary
organic ED in terms of both efficacy and safety of PRP, the available evidence is still insufficient to provide a
recommendation regarding the use of PRP for ED treatment in clinical practice [505]. In this context, there is
heterogeneity among studies in terms of timing and dosing regimens, with no consensus regarding the optimal
activation method and platelet concentration for each PRP injection, and the need to measure qualitative and
quantitative composition of growth factors and cytokines [505, 506]. Therefore, intracavernous injection of PRP
should be used only in a clinical trial setting, as larger trials are needed to confirm original findings and define
the efficacy and safety of PRP for ED.

5.6.8.1.3 Stem-cells
The use of stem cells as a regenerative treatment for ED is currently under investigation. A systematic review
summarising the results of 18 phase I and II clinical trials reported a large heterogeneity in terms of the type of
stem cells used, treatment protocols and patients’ characteristics [507]. The overall number of included patients
was 373 and the results confirmed the safety of intracavernous injection of stem cells. No definitive conclusions
can be drawn in terms of efficacy given that only four small trials were placebo-controlled and their findings
were conflicting. To date, data are still insufficient for providing a clinical recommendation.

5.6.8.2 Botulinum Neurotoxin

Botulinum Neurotoxin A (BoNT-A) has been investigated as a possible ED treatment [508]. Two RCTs have
investigated the effect of BoNT-A for the treatment of patients with ED who were non-responders to PDE5Is
or ICI pro-erectile drugs [509, 510]. One trial randomised 70 patients with ED refractory to PDE5Is to receive a
single ICI of 100 UI of BoNT-A or saline [509]. Patients in both groups were instructed to keep using on-demand
high-dose PDE5Is. The RCT showed an improvement in EHS and PSV at two weeks post-treatment. At six weeks
the treatment group showed a 5 points improvement in the SHIM score vs. no improvement in the placebo
group, with 53% of patients reporting an erection hard enough for vaginal penetration [509]. The second trial
randomised 176 patients, all non-responders to PDE5Is or ICI trimix, to three treatment groups: BoNT-A 100 UI;
BoNT-A 50 UI; or placebo [510]. A significant improvement in SHIM, EHS and SEP scores was reported in both
treatment groups with a maximum response rate being reacted three months after treatment. Overall, the RCT
showed that up to 40% of patients were able to resume satisfactory sexual activity after treatment [510]. Both
trials reported only mild local side-effects with no systemic complications.
Other single-arm, non-controlled studies have confirmed these findings [511, 512]; therefore, showing
a promising role for BoNT-A in the treatment of patients who are non-responders to well-established ED
therapies. However, at present no recommendation for its use in clinical practice can be provided as larger trials
are needed to confirm original findings and define the efficacy and safety of BoNT-A for ED.

5.6.9 Herbal medicine and natural supplements

In recent years there has been an exponential growth in the market of medicinal herbs and natural supplements
for the treatment of ED, but with very little available evidence of robust scientific data to support their efficacy
and safety. A Cochrane review showed that ginseng may only have trivial effects on erectile function or
satisfaction with intercourse compared to placebo when assessed using validated tools [513]. A meta-analysis
including 18 trials comparing the effect of antioxidants alone or in combination with PDE5Is vs. placebo or
PDE5Is alone showed a small but significant positive effect of L-arginine with a mean increase in IIEF-EF of 2.74
(95%CI 1.67,3.81) compared to placebo but no difference in terms of sexual satisfaction score [514]. Similar
results were reported for antioxidants alone including folic acid, myoinositol, vitamin-E, L-carnitine, nicotinic
acid, pine bark extract, transresveratrol, L-citrulline and ginseng. However, this small improvement may not be
perceived as significant by patients. In another meta-analysis the combination of PDE5Is plus antioxidants
(including: propionyl-L-carnitine, acetyl-L-carnitine; L-arginine, folic acid, and trans-resveratrol) was associated
with better EF improvement compared to PDE5Is alone [429]. Overall, these data suggest that antioxidant
supplements and herbal compounds alone or in combination with PDE5Is may have a small positive effect on
EF, although further studies are needed to assess the clinical significance of these findings.

54 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

5.6.10 Erectile dysfunction after radical prostatectomy
Overall, urologists should have enhanced awareness of how to approach patients directly about their ED and
sexual dysfunction following RP and actively offer them treatment options [515]. Use of pro-erectile drugs
following RP is important in achieving post-operative EF and to allow patients to resume sexual activity. Several
trials have shown improvements in EF after RP in patients receiving drugs (any therapeutic or prophylactic) for
ED. Early compared with delayed EF treatment affects the natural recovery time for EF [516], although there is
limited data to support any specific regimen, which is either optimal for penile rehabilitation or may result in
the achievement of spontaneous, non-pharmacologically assisted erections [296, 517, 518]. Data from a small
pilot RCT showed that perioperative rehabilitation with PDE5Is may lead to better EF recovery compared to
post-operative rehabilitation [519]. However, there is no evidence that penile rehabilitation itself increases the
chances of spontaneous recovery of EF in men following nerve-sparing RP (NSRP) [518]. The currently available
therapeutic armamentarium follows the treatment algorithm for ED, which is shown in Figure 5.2.

In this context, PDE5Is have been considered as the first-line therapy in patients who have undergone NS
surgery, regardless of the surgical technique used [296, 301]. Several clinical parameters have been identified as
potential predictors of PDE5Is outcomes in men undergoing RP, i.e., patient age, baseline EF, and quality of NS
technique are key factors in preserving post-RP EF [301, 304, 520].

A Cochrane review analysing data from eight RCTs showed that scheduled PDE5Is may have little or no effect
on short-term (up to 12 months) self-reported potency when compared to placebo or no treatment [521]. In this
study, a daily PDE5I made little to no difference in short- and long-term EF. The authors conclude that penile
rehabilitation strategies using PDE5I following RP do not increase self-reported EF compared to on-demand use.
Conversely, an updated meta-analysis including 22 trials comparing 16 different rehabilitation protocols, showed
that daily administration of sildenafil 100 mg was the most effective strategy to recover EF after RP [522].

Intracavernous injections and penile implants had been suggested as second- and third-line treatments,
respectively, when oral PDE5Is are not adequately effective or not suitable for post-operative patients [296, 523].
A meta-analysis showed that the early use of VED has an excellent therapeutic effect on post-RP patients and
no serious adverse effects, therefore it should be considered as a therapeutic alternative [524]. Findings from
two network meta-analyses showed that combination therapy with VED and PDE5is offers clear advantages
over monotherapy, even in post-RP patients; therefore, this combined approach should be considered in the
clinical management of ED after RP [525]. A novel penile traction device yielded positive results compared to no
treatment in preserving penile length after RP [526].

Findings from a systematic review had suggested that pelvic floor muscle training (PFMT) combined with
bio-feedback is a promising alternative to pharmacological treatments, although there is a need for future well-
powered, rigorously designed RCTs to draw strong conclusions [527].

5.6.11 Surgical management

5.6.11.1 Surgery for post-traumatic arteriogenic ED
In young patients with pelvic or perineal trauma, surgical penile revascularisation has a 60-70% long-term
success rate [450, 528]. The stenosis must be confirmed by penile pharmaco-arteriography. Corporeal veno-
occlusive dysfunction is a contraindication to revascularisation and must be excluded by dynamic infusion
cavernosometry or cavernosography.

5.6.11.2 Venous ligation surgery

Venous ligation surgery for veno-occlusive dysfunction is no longer recommended because of poor long-term
results [528].

5.6.11.2.1 Penile prostheses

The surgical implantation of a penile prosthesis may be considered in patients who i) are not suitable for
different pharmacotherapies or prefer a definitive therapy; and, ii) do not respond to other treatment modalities
[529].

The two currently available classes of penile implants include inflatable (two- and three-piece) and semi-rigid
devices (malleable, mechanical and soft flexible) [301, 530-533]. There are currently no head-to-head studies
comparing the different manufacturers’ implants, demonstrating superiority of one implant type over another
[534]. Patients may prefer the three-piece inflatable devices due to the more “natural” erections obtained,
although no prospective RCTs have compared satisfaction rates with both types of implants. The two-piece
inflatable prosthesis can be a viable option among patients who are deemed at high-risk of complications with

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 55

reservoir placements (e.g., previous abdominal surgery). Semi-rigid prostheses result in a firm penis, which may
be manually placed in an erect or flaccid state and offer the advantage of a simple implant technique, as well
as easy use for the patient [301, 530-532]. Conversely, they can have the disadvantage of unnatural persistent
erection and reduced concealability [532, 535]. They may also be an option in men with limited manual dexterity.

There are two main surgical approaches for penile prosthesis implantation: peno-scrotal and infrapubic [531,
532, 535, 536]. A systematic review comparing the satisfaction and complication rates of the different surgical
approaches has shown that there is no specific advantage between the two, but rather it is recommended that
surgeons have knowledge of both techniques and are capable of tailoring the incision strategy for complex
cases [537]. Regardless of the indication, prosthesis implantation has one of the highest satisfaction rates
(92-100% in patients and 91-95% in partners) among the treatment options for ED with appropriate counselling
[301, 530, 531, 538-546]. Focused psychosexual counselling may improve sexuality and sexual well-being in
both patients and their partners after penile implant surgery [547]. There is sufficient evidence to recommend
this approach in patients who do not respond to less-invasive treatments due to its high efficacy, safety and
satisfaction rate [548].

The two main complications of penile prosthesis implantation are mechanical failure and infection. Several
technical modifications of the most commonly used three-piece prostheses (e.g., AMS 700CX/CXR™ and
Titan Zero degree™) resulted in mechanical failure rates of < 5% after 5 years of follow-up [530, 549, 550]. A
meta-analysis showed implant durability or survival rates of 93.3% at 1 year, 91.0% at 3 years, 87.2% at 5 years,
76.8% at 10 years, 63.7% at 15 years, and 52.9% at 20 years [551]. Careful surgical techniques with appropriate
antibiotic prophylaxis against Gram-positive and negative bacteria reduced infection rates to 2-3% with primary
implantation in low-risk patients and in high-volume centres [552-555]. The infection rate may be further reduced
to 1-2% by implanting an antibiotic-impregnated prosthesis (AMS Inhibizone™) or hydrophilic-coated prosthesis
(Coloplast Titan™) [530, 552, 556-559]. Methods that appear to decrease infection rates include using coated
prostheses and strictly adhering to surgical techniques and protocols that avoid prolonged wound exposure
and minimise skin contact (i.e., no-touch technique). Techniques that might prevent penile prostheses infection
but lack definitive evidence include the use of prolonged post-operative antibiotics (> 24 hours), shaving with
clippers, and preparation with chlorhexidine-alcohol [560, 561]. Identification and pre-treatment of patients who
are colonised with nasal Staphylococcus aureus with mupirocin and chlorhexidine prior to surgery has been
shown to reduce the incidence of post-operative surgical site infection from 4.4% to 0.9% RCT [562].

A large database-study has shown that diabetes mellitus is a risk factor for penile prostheses infection,
highlighting the need for optimal patient selection [667]. Unfortunately, there are no RCTs determining the
ideal and/or correct threshold of glycated haemoglobin that is acceptable prior to implant surgery in diabetic
patients [563]. A large-cohort, multicentre, retrospective analysis in men with diabetes who received a Coloplast
Titan™ implant demonstrated that vancomycin plus gentamicin was the most efficacious combination of
antibiotics used for implants dipping in terms of preventing postoperative infection and subsequent explantation
and revision [564]. A retrospective analysis of a large insurance claim database in the US, showed that
hypogonadism was independently associated with infection of the implant [565]. Patients with spinal cord injury
had higher risk of complications with up to 16% of cases reporting prosthesis infection in published series [566].

Prosthetic infection requires removal of the prosthesis and antibiotic administration. Alternatively, removal
of the infected device with immediate salvage and replacement with a new prosthesis has been described
using a wash-out protocol with successful salvages achieved in > 80% of cases [553, 567-569]. An absolute
recommendation on how to proceed after explantation in this setting cannot be given and must be focused on
the pros and cons of salvage therapy after full consultation with the patient.

Besides infection and mechanical failure, impending implant erosion involving the distal corpora, urethra, or
glans can occur in 1-6% of cases after surgery [570]. Moreover, non-infectious reservoir complications including
injury to pelvic structures such as bladder, bowel, and blood vessels have been described [571]. Similarly, glans
ischaemia and necrosis have been reported in about 1.5% of patients [570, 572]. Risk factors for these serious
complications are higher in those patients with significant vascular impairment, such as patients with diabetes,
or who have undergone concomitant lengthening procedures.

For penile prostheses models available on the market please see Appendix 3 online supplementary evidence
(https://uroweb.org/guidelines/sexual-and-reproductive-health/publications-appendices).

56 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

5.6.12 Summary of evidence and recommendations for treatment of ED

Summary of evidence LE
Lifestyle changes can lead to ED improvement in specific populations. 1a
PDE5Is are associated with significant improvement of EF with a good overall safety profile. 1a
There is no demonstrated differences among different PDE5Is in terms of treatment efficacy. 1a
Topical/intraurethral alprostadil is effective in improving EF but data are still limited. 1b
Vacuum therapy is able to improve EF with a wide range of treatment satisfaction rate. 2b
Intracavernous injection with alprostadil is an effective treatment of ED; however, it has relatively high 1a
treatment drop-out rates.
Low-intensity shockwave therapy is able to induce a mild improvement in EF among patients with 1a
vasculogenic ED.
Intracavernous injections of PRP have led to a mild improvement of EF among patients with organic ED, 1b
but the available evidence is still insufficient to provide a recommendation regarding its use.
BoNT-A has been shown to improve response rate to medical treatment for ED in patients who were 1b
non-responsive to oral or injective therapies, but data are still limited.
Penile rehabilitation with PDE5Is after RP does not increase the chance of spontaneous EF recovery. 1a
There is no difference in terms of efficacy and safety among different penile implants available or 3
surgical approach used.

Recommendations Strength rating

Fully inform patients of the mechanism of action and the ways in which phosphodiesterase Strong
type 5 inhibitors (PDE5Is) should be taken, as incorrect use/inadequate information is the
main causes of a lack of response to PDE5Is.
Direct the patient to Cognitive Behaviour Therapy as a psychological approach (include the Strong
partner), when indicated, combined with medical treatment to maximise treatment outcomes.
Discuss with patients undergoing active treatment for prostate cancer the risk of sexual Strong
changes other than erectile dysfunction (ED), including sexual desire reduction, changes in
orgasm, anejaculation, Peyronie’s like disease and penile size changes.
Initiate lifestyle changes and risk factor modification prior to, or at the same time as, Strong
initiating ED treatments.
Use PDE5Is as first-line therapy for the treatment of ED. Strong
Use intracavernous injections as an alternative first-line therapy in well-informed patients or Strong
as second-line therapy.
Use topical/intra-urethral alprostadil as an alternative first-line therapy in well-informed Weak
patients who:
• do not wish to have or are not suitable for oral vasoactive therapy;
• do not wish to have intracavernous injections;
• in patients who prefer a less-invasive therapy.
Use low intensity shockwave treatment (LI-SWT) with/without PDE5Is in patients: Weak
• with mild vasculogenic ED;
• as an alternative therapy in well-informed patients who do not wish to have or are not
suitable for oral vasoactive therapy;
• who are vasculogenic ED patients that are poor responders to PDE5Is.
Use vacuum erection devices in well-informed patients requesting non-invasive, drug-free Weak
management of ED.
Use supplements with L-arginine or ginseng daily in men with mild ED who refuse Weak
pharmacological treatment after counselling them that the improvement of EF could be mild.
Implant a penile prosthesis if other treatments fail or depending upon patient preference. Strong
Patients should be fully informed of the benefits and harms associated with the procedure.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 57

Inform patients that available data are inadequate to support any specific regimen for penile Weak
rehabilitation
Start pro-erectile treatments at the earliest opportunity after radical prostatectomy/pelvic Weak
surgery and other curative treatments for prostate cancer.

5.7 Follow-up
Follow-up is important in order to assess efficacy and safety of the treatment provided. It is also essential to
assess patient satisfaction since successful treatment for ED goes beyond efficacy and safety. Physicians
must be aware that there is no single treatment that fits all patients or all situations as described in detail in the
previous section.

6. DISORDERS OF EJACULATION
6.1 Introduction
Ejaculation is a complex physiological process that comprises emission and expulsion processes and is
mediated by interwoven neurological and hormonal pathways [573]. Any interference with those pathways
may cause a wide range of ejaculatory disorders. The spectrum of ejaculation disorders includes premature
ejaculation (PE), retarded or delayed ejaculation, anejaculation, painful ejaculation, retrograde ejaculation,
anorgasmia and haemospermia.

6.2 Premature ejaculation

6.2.1 Epidemiology
Historically, the main problem in assessing the prevalence of PE has been the lack of a universally recognised
definition at the time that surveys were conducted [574]. See Section 4.2 for a comprehensive discussion of the
epidemiology of PE.

6.2.2 Pathophysiology and risk factors

The aetiology of PE is relatively unknown, with limited data to support suggested biological and psychological
hypotheses, including anxiety [575-578], penile hypersensitivity [579-586] and 5-hydroxytryptamine (HT)
receptor dysfunction [587-592]. The classification of PE into four subtypes [206] has contributed to a better
delineation of lifelong, acquired, variable and subjective PE [593-595]. It has been hypothesised that the
pathophysiology of lifelong PE is mediated by a complex interplay of central and peripheral serotonergic,
dopaminergic, oxytocinergic, endocrinological, genetic and epigenetic factors [596]. Acquired PE may occur due
to psychological problems - such as sexual performance anxiety, and psychological or relationship problems
and/or co-morbidity, including ED, prostatitis, hyperthyroidism and poor sleep quality [597-600]. Variable PE
is considered to be a normal variation of sexual function whereas subjective PE can stem from cultural or
abnormal psychological constructs [206].

A significant proportion of men with ED also experience PE [210, 601]. High levels of performance anxiety
related to ED may worsen PE, with a risk of misdiagnosing PE instead of the underlying ED. According to
the National Health and Social Life Survey (NHSLS), the prevalence of PE is not affected by age [202], unlike
ED, which increases with age. Premature ejaculation is not affected by marital or income status [202, 602].
However, PE is more common in Black men, Hispanic men, and men from regions where an Islamic background
is common [202, 603, 604] and the prevalence may be higher in men with a lower educational level [202, 210].
Other reported risk factors for PE include genetic predisposition [592, 605-608], poor overall health status
and obesity [202], prostate inflammation [609-613], hyperthyroidism [597], low prolactin levels [614], high
testosterone levels [615], vitamin D and B12 deficiency [616, 617], diabetes [618, 619], MetS [620, 621], lack
of physical activity [622], emotional problems and stress [202, 623, 624], depressive symptoms [624], and
traumatic sexual experiences [202, 210].

6.2.3 Impact of PE on quality of life

Men with PE are more likely to report low satisfaction with their sexual relationship, low satisfaction with sexual
intercourse, difficulty relaxing during intercourse, and less-frequent intercourse [625-627]. Premature ejaculation
can have a detrimental effect on self-confidence and the relationship with the partner, and may sometimes
cause mental distress, anxiety, embarrassment and depression [625, 628, 629]. Moreover, PE may also affect
the partner’s sexual functioning and their satisfaction with the sexual relationship decreases with increasing
severity of the patient’s condition [630-632]. Despite the possible serious psychological and QoL consequences
of PE, few men seek treatment [203, 210, 633-636].

58 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

6.2.4 Classification
There is still little consensus about the definition and classification of PE [637]. It is now universally accepted
that “premature ejaculation” is a broad term that includes several concepts belonging to the common category
of PE. The most recent definition comes from the International Classification of Diseases 11th Revision, where
PE was renamed as Early Ejaculation [638]: “Male early ejaculation is characterized by ejaculation that occurs
prior to or within a very short duration of the initiation of vaginal penetration or other relevant sexual stimulation,
with no or little perceived control over ejaculation. The pattern of early ejaculation has occurred episodically or
persistently over a period of at least several months and is associated with clinically significant distress.”

This definition includes four categories: male early ejaculation, lifelong generalised and situational, acquired
generalised and situational, and unspecified. The Diagnostic and Statistical Manual of Mental Disorders V
(DSM-V) [212] and the International Society for Sexual Medicine (ISSM) [639] published definitions for lifelong
and acquired PE. These definitions are overlapping, with 3 shared factors (1. Time to ejaculation assessed by
IELT; 2. Perceived control; and, 3. Distress, bother, frustration, interpersonal difficulty related to the ejaculatory
dysfunction), resulting in a multi-dimensional diagnosis [639].

Two more PE syndromes have been proposed [594]:

• ‘Variable PE’ is characterised by inconsistent and irregular early ejaculations, representing a normal
variation in sexual performance.
• ‘Subjective PE’ is characterised by subjective perception of consistent or inconsistent rapid ejaculation
during intercourse, while ejaculation latency time is in the normal range or can even last longer. It should
not be regarded as a symptom or manifestation of true medical pathology [640].

6.2.5 Diagnostic evaluation

Diagnosis of PE is based on the patient’s medical and sexual history [641-644]. History should classify PE as
lifelong or acquired and determine whether PE is situational (under specific circumstances or with a specific
partner) or consistent. Special attention should be given to the duration time of ejaculation, degree of sexual
stimulus, impact on sexual activity and QoL, and drug use or abuse. It is also important to distinguish PE from
ED. Many patients with ED develop secondary PE caused by the anxiety associated with difficulty in attaining
and maintaining an erection [601, 645]. Furthermore, some patients are unaware that loss of erection after
ejaculation is normal and may erroneously complain of ED, while the actual problem is PE [636].

6.2.5.1 Intravaginal ejaculatory latency time (IELT)

Although it has been suggested as an objective diagnostic criterion and treatment outcome measure [646,
647], the use of IELT alone is not sufficient to define PE, as there is significant overlap between men with and
without PE [648, 649]. Moreover, some men may experience PE in their non-coital sexual activities (e.g., during
masturbation, oral sex or anal intercourse); thus, measuring IELT will not be suitable for their assessment.
Although PE is apparently less prevalent and less bothersome among men who have sex with men (MSM) [650],
many of them may also suffer from PE and IELT cannot be applied to them [651, 652]. Although some studies
demonstrated that MSM report longer ejaculation latency time compared to straight men [650], some others
failed to demonstrate such a difference [653].

In everyday clinical practice, self-estimated IELT is sufficient [654]. Self-estimated and stopwatch-measured IELT
are interchangeable and correctly assign PE status with 80% sensitivity and 80% specificity [655].

Measurement of IELT with a calibrated stopwatch is mandatory in clinical trials. For any drug treatment study of
PE, Waldinger et al. suggested using geometric mean instead of arithmetic mean IELT because the distributed
IELT data are skewed. Otherwise, any treatment-related ejaculation delay may be overestimated if the arithmetic
mean IELT is used instead of the geometric mean IELT [656].

6.2.5.2 Premature ejaculation assessment questionnaires

The need to objectively assess PE has led to the development of several questionnaires based on using PROMs.
Only two questionnaires can discriminate between patients who have PE and those who do not:

• Premature Ejaculation Diagnostic Tool (PEDT): A five-item questionnaire based on focus groups and
interviews from the USA, Germany, and Spain assesses control, frequency, minimal stimulation, distress
and interpersonal difficulty [657]. A total score of > 11 suggests a diagnosis of PE, 9 or 10 suggests a
probable diagnosis, and < 8 indicates a low likelihood of PE.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 59

• Arabic Index of Premature Ejaculation (AIPE): A seven-item questionnaire developed in Saudi Arabia
assesses sexual desire, hard erections for sufficient intercourse, time to ejaculation, control, satisfaction
of the patient and partner, and anxiety or depression [658]. A cut-off score of 30 (range 7-35) discriminates
PE diagnosis best. Severity of PE is classified as severe (score: 7-13), moderate (score: 14-19), mild-to-
moderate (score: 20-25) and mild (score: 26-30).

Other questionnaires used to characterise PE and determine treatment effects include the Premature
Ejaculation Profile (PEP) [649], Index of Premature Ejaculation (IPE) [659] and Male Sexual Health Questionnaire
Ejaculatory Dysfunction (MSHQ-EjD) [660]. Currently, their role is optional in everyday clinical practice. The
Masturbatory Premature Ejaculation Diagnostic Tool (MPEDT) has also been recently proposed [661], due to fact
that PE patients report longer IELTs and lesser bother/distress during masturbation than partnered sex [662];
however, further validation studies are required before the routine use of this questionnaire in this population.

6.2.5.3 Physical examination and investigations

Physical examination may be part of the initial assessment of men with PE. It may include a focused
examination of the urological, endocrine and neurological systems to identify underlying medical conditions
associated with PE or other sexual dysfunctions, such as endocrinopathy, Peyronie’s disease, urethritis or
prostatitis. Laboratory or physiological testing should be directed by specific findings from history or physical
examination and is not routinely recommended [643].

6.2.5.4 Summary of evidence and recommendations for the diagnostic evaluation of PE

Summary of evidence LE
A comprehensive medical history and a thorough physical examination can serve as valuable tools for 3
clinicians in identifying the underlying medical factors contributing to PE.
PE can negatively impact self-confidence, strain partner relationships, and potentially lead to emotional 2a
distress, anxiety, shame, and depression.
Several questionnaires can be used for the diagnosis of PE (PEDT, AIPE) and for assessing the 2b
therapeutic outcomes of PE interventions (PEP).
Although relying on IELT is inadequate for characterizing PE, self-reported IELT proves satisfactory in 3
routine clinical contexts.

Recommendations Strength rating

Perform the diagnosis and classification of premature ejaculation (PE) based on medical Strong
and sexual history, which should include assessment of intravaginal ejaculatory latency time
(IELT) (self-estimated), perceived control, distress and interpersonal difficulty due to the
ejaculatory dysfunction.
Use patient-reported outcomes in daily clinical practice. Weak
Include physical examination in the initial assessment of PE to identify anatomical Strong
abnormalities that may be associated with PE or other sexual dysfunctions, particularly
erectile dysfunction.
Do not perform routine laboratory or physiological tests. They should only be directed by Strong
specific findings from history or physical examination.

6.2.6 Disease management

Before commencing any treatment, it is essential to define the subtype of PE and discuss patient’s expectations
thoroughly. Pharmacotherapy must be considered the first-line treatment for patients with lifelong PE, whereas
treating the underlying cause (e.g., ED, prostatitis, LUTS, anxiety and hyperthyroidism) must be the initial goal
for patients with acquired PE [643]. Various behavioural techniques may be beneficial in treating variable
and subjective PE [663]. Psychotherapy can also be considered for PE patients who are uncomfortable with
pharmacological therapy or in combination with pharmacological therapy [664, 665]. However, there is weak
and inconsistent evidence regarding the effectiveness of these psychosexual interventions and their long-term
outcomes in PE are unknown [666].

60 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Dapoxetine (30 and 60 mg) is the first on-demand oral pharmacological agent approved for lifelong and
acquired PE in many countries, except for the USA [667]. The metered-dose aerosol spray of lidocaine (150
mg/mL) and prilocaine (50 mg/mL) combination is the first topical formulation to be officially approved for
on-demand treatment of lifelong PE by the EMA in the European Union [668]. All other medications used in PE
are off-label indications [669]. In this context, daily or on-demand use of selective serotonin re-uptake inhibitors
(SSRIs) and clomipramine and on-demand topical anaesthetic agents have consistently shown efficacy in PE
[670-673]. The long-term outcomes of pharmacological treatments are unknown. An evidence-based analysis
of all current treatment modalities was performed. Levels of evidence and grades of recommendation are
provided, and a treatment algorithm is presented (Figure 6.1).

Figure 6.1: Management of premature ejaculation

Clinical diagnosis of premature ejacula on based

on pa ent +/- partner history
• Time to ejaculaon (IELT)
• Perceived degree of ejaculatory control
• Degree of bother/stress
• Onset and duraon of PE
• Psychosocial/relaonship issues
• Medical history
• Physical examinaon

Treatment of premature ejacula on

Paent counselling/educaon
Discussion of treatment opons
If PE is secondary to ED, treat ED first
or concomitantly

• Pharmacotherapy (recommended as first-line

treatment opon in lifelong PE)
- Approved on-demand treatment opons for PE:
Dapoxene and Lidocaine/prilocaine spray
- Off-label treatments include chronic daily use
of andepressants (SSRIs or clomipramine) or
tramadol on demand
• Combinaon treatment (pharmacotherapy
with behavioural therapy)

Diagnosis Treatment Follow-up

ED = erectile dysfunction; PE = premature ejaculation; IELT = intravaginal ejaculatory latency time;

SSRI = selective serotonin receptor inhibitor.

6.2.6.1 Psychological aspects and intervention

Psychosexual interventions, whether behavioural, cognitive, or focused on the couple, are aimed at teaching
techniques to control/delay ejaculation, gaining confidence in sexual performance, reducing anxiety, and
promoting communication and problem-solving within the couple [663]. Interventions with a focus on sexual
education or acceptance may be positive as well [674]. However, psychosexual interventions alone regarding PE
lack empirical support. Recent evidence suggests that start-stop exercises, combined with psycho-education
and mindfulness techniques improve PE symptoms, as well as PE-associated distress, anxiety and depression
[675]. The potential benefits of mindfulness have been reported [676]. Behavioural therapy may be most
effective when used to ‘add value’ to medical interventions. Smartphone-delivered psychological intervention,
aimed at improving behavioural skills for ejaculatory delay and sexual self-confidence, has positive effects,
supporting E-health in the context of PE [677].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 61

Figure 6.2: Key aspects for psychosexual evaluation

Check for specific triggers

in case of acquired PE
Evaluate psychosexual history and
(e.g., anxiety, guilt, fear of
development
being caught, rapid
masturbation)

Include partner whenever

Evaluate dysfunctional cognitive and
possible; consider the
attention styles; focus on control
impact of PE on the
issues and interpersonal anxiety
partner

Decide on referral to
(sexual)psychotherapy;
include partner actively

6.2.6.1.1  ummary of evidence and recommendations for the assessment and treatment
S
(psychosexual approach) of PE

Summary of evidence LE
The incorporation of psychosexual approach, alongside psycho-educational guidance and mindfulness 2b
techniques, ameliorate symptoms of PE and alleviate the associated distress, anxiety, and depression.
The combination of psychosexual approaches and pharmacological treatments yields superior 3
outcomes compared to pharmacological interventions alone.

Recommendations Strength rating

Assess sexual history and psychosexual development. Strong
Assess anxiety, and interpersonal anxiety; focus on control issues. Strong
Include the partner if available; check for the impact of PE on the partner. Strong
Recommendations for treatment (psychosexual approach)
Use behavioural, cognitive and/or couple therapy approaches in combination with Weak
pharmacotherapy. Discuss the use of mindfulness exercises.

6.2.6.2 Pharmacotherapy
6.2.6.2.1 Dapoxetine
Dapoxetine hydrochloride is a short-acting SSRI with a pharmacokinetic profile suitable for on-demand
treatment for PE [678]. It has a rapid Tmax (1.3 hours) and a short half-life (95% clearance rate after 24 hours)
[679, 680]. It is approved for on-demand treatment of PE in European countries and elsewhere, but not in
the USA. Both available doses of dapoxetine (30 mg and 60 mg) have shown 2.5- and 3.0-fold increases,
respectively, in IELT overall, rising to 3.4- and 4.3-fold in patients with a baseline average IELT < 30 seconds [681].

In RCTs, dapoxetine, 30 mg or 60 mg 1-2 hours before intercourse, was effective at improving IELT and
increasing ejaculatory control, decreasing distress, and increasing satisfaction [681]. Dapoxetine has shown a
similar efficacy profile in men with lifelong and acquired PE [681, 682]. Treatment-related adverse effects were
dose-dependent and included nausea, diarrhoea, thirst, headache and dizziness [682]. Treatment-emergent
adverse events (TEAEs) were responsible for study discontinuation in 4% (30 mg) and 10% (60 mg) of subjects
[654]. There was no indication of an increased risk of suicidal ideation or suicide attempts and little indication
of withdrawal symptoms with abrupt dapoxetine cessation [681, 682]. Dapoxetine is safer than formal anti-
depressant compounds used for treatment of PE [683].

62 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

A low rate (0.1%) of vasovagal syncope was reported in phase 3 studies [684]. According to the summary
of product characteristics, vital orthostatic signs (blood pressure and heart rate) must be measured prior to
starting dapoxetine, and dose titration must be considered [685]. The EMA assessment report for dapoxetine
concluded that the potentially increased risk for syncope had been proven manageable with adequate risk
minimisation measures [686]. No cases of syncope were observed in a post-marketing observational study,
which identified patients at risk for the orthostatic reaction using the patient’s medical history and orthostatic
testing [687].

Many patients and physicians may prefer using dapoxetine in combination with a PDE5I to extend the time
until ejaculation and minimise the risk of ED due to dapoxetine treatment. Phase 1 studies of dapoxetine have
confirmed that it has no pharmacokinetic interactions with PDE5Is (i.e., tadalafil 20 mg and sildenafil 100 mg)
[688]. When dapoxetine is co-administered with PDE5Is, it is well tolerated, with a safety profile consistent with
previous phase 3 studies of dapoxetine alone [689]. An RCT, including PE patients without ED, demonstrated that
a combination of dapoxetine with sildenafil could significantly improve IELT values and PROs compared with
dapoxetine alone or sildenafil alone, with tolerable adverse events [690]. The efficacy and safety of dapoxetine/
sildenafil combination tablets for the treatment of PE have also been reported [691].

The discontinuation rates of dapoxetine seem moderate to high [692]. The cumulative discontinuation rates
increase over time, reaching 90% at 2 years after initiation of therapy. The reasons for the high discontinuation
rate are cost (29.9%), disappointment that PE was not curable and the on-demand nature of the drug (25%),
adverse effects (11.6%), perceived poor efficacy (9.8%), a search for other treatment options (5.5%), and
unknown (18.3%) [693]. Similarly, it was confirmed that many patients on dapoxetine treatment spontaneously
discontinued treatment, while this rate was reported at 50% for other SSRIs and 28.8% for paroxetine,
respectively [694]. In a Chinese cohort study, 13.6% of the patients discontinued dapoxetine due to lack of
efficacy (62%), adverse effects (24%), and low frequency of sexual intercourse (14%) [695].

6.2.6.2.2 Off-label use of antidepressants

Selective serotonin re-uptake inhibitors are used to treat mood disorders but can delay ejaculation and therefore
have been widely used ‘off-label’ for PE since the 1990s [696-698]. Commonly used SSRIs include continuous
intake of citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, all of which have similar efficacy,
whereas paroxetine exerts the most substantial ejaculation delay [646, 699, 700]. A novel 5-HT1A receptor
antagonist, GSK958108, significantly delayed ejaculation in a double-blind, placebo-controlled trial [701].

Clomipramine, the most serotoninergic tricyclic antidepressant, was first reported in 1977 as an effective
PE treatment [702, 703]. In a recent RCT, on-demand use of clomipramine 15 mg, 2-6 hours before sexual
intercourse was found to be associated with IELT fold change and significant improvements in PRO measures in
the treatment group as compared with the placebo group (4.66 ± 5.64 vs. 2.80 ± 2.19, P < 0.05) [704, 705]. The
most commonly reported TEAEs were nausea in 15.7% and dizziness in 4.9% of men, respectively [704, 705].

Several meta-analyses suggest SSRIs may increase the geometric mean IELT by 2.6-13.2-fold [706]. Paroxetine
is superior to fluoxetine, clomipramine and sertraline [707, 708]. Sertraline is superior to fluoxetine, whereas
the efficacy of clomipramine is not significantly different from that of fluoxetine and sertraline. Paroxetine was
evaluated in doses of 20-40 mg, sertraline 25-200 mg, fluoxetine 10-60 mg and clomipramine 25-50 mg [706-
708].

Ejaculation delay may start a few days after drug intake, but it is more evident after one to two weeks as
receptor desensitisation requires time to occur. Although efficacy may be maintained for several years,
tachyphylaxis (decreasing response to a drug following chronic administration) may occur after six to twelve
months [702]. Common TEAEs of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry mouth,
diarrhoea and perspiration; TEAEs are usually mild and gradually improve after two to three weeks of treatment
[702, 709]. Decreased libido, anorgasmia, anejaculation and ED have also been reported.

Due to the risk of suicidal ideation or suicide attempts, caution is suggested in prescribing SSRIs to young
adolescents aged ≤ 18 years with PE, and to men with PE and a comorbid depressive disorder, particularly when
associated with suicidal ideation. Patients should be advised to avoid sudden cessation or rapid dose reduction
of daily-dosed SSRIs, which may be related to SSRI withdrawal syndrome [654]. Moreover, PE patients trying to
conceive should avoid using these medications because of their detrimental effects on sperm cells [710-714].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 63

6.2.6.2.3 Topical anaesthetic agents
The use of local anaesthetics to delay ejaculation is the oldest form of pharmacological therapy for PE [715].
Several trials [582, 716, 717] support the hypothesis that topical desensitising agents reduce the sensitivity of
the glans penis thereby delaying ejaculatory latency, but without adversely affecting the sensation of ejaculation.
Meta-analyses have confirmed the efficacy and safety of these agents for the treatment of PE [718]. In a
meta-analysis, the efficacy of local anaesthetics was best among the other treatment options including SSRIs,
dapoxetine 30 and 60 mg, PDE5Is and tramadol for < 8 weeks of therapy [718].

6.2.6.2.3.1 Lidocaine/prilocaine cream

Lidocaine/prilocaine creams can significantly increase the stopwatch-measured IELT from 1-2 minutes to 6-9
minutes [719, 720]. Although no significant TEAEs have been reported, topical anaesthetics are contraindicated
in patients or partners with an allergy to any ingredient in the product. These anaesthetic creams/gels may
be transferred to the partner, resulting in vaginal numbness. Therefore, patients are advised to use a condom
after applying the cream to their penis. Alternatively, the penis can be washed to clean off any residual active
compound prior to sexual intercourse. Since these chemicals may be associated with cytotoxic effects on
fresh human sperm cells, couples seeking parenthood should not use topical lidocaine/prilocaine-containing
substances [721].

6.2.6.2.3.2 Lidocaine/prilocaine spray

The eutectic lidocaine/prilocaine spray is a metered-dose aerosol spray containing purely base forms of
lidocaine (150 mg/mL) and prilocaine (50 mg/mL), which has been officially approved by the EMA for the
treatment of lifelong PE [722]. Compared to topical creams, the metered-dose spray delivery system has been
proved to deposit the drug in a dose-controlled, concentrated film covering the glans penis, maximising neural
blockage and minimising the onset of numbness [723], without absorption through the penile shaft skin [724].

Several studies have demonstrated the efficacy of lidocaine/prilocaine spray in improving both IELT and PROs
three sprays administered 5 min before sexual intercourse [725, 726]. Published data showed that lidocaine/
prilocaine spray increases IELT over time up to 6.3-fold over 3 months, with a month-by-month improvement
through the course of the treatment in long-term studies [727]. A low incidence of local TEAEs in both patients
and partners has been reported, including genital hypoaesthesia (4.5% and 1.0% in men and female partners,
respectively) and ED (4.4%), and vulvovaginal burning sensation (3.9%), but is unlikely to be associated with
systemic TEAEs [728, 729]. Lidocaine-only sprays are also available and found to be effective in the treatment of
PE [730, 731].

6.2.6.2.4 Tramadol
Tramadol is a centrally-acting analgesic agent that combines opioid receptor activation and serotonin and
noradrenaline re-uptake inhibition. Tramadol is a mild-opioid receptor agonist, but it also displays antagonistic
properties on transporters of noradrenaline and 5-HT [732]. This mechanism of action distinguishes tramadol
from other opioids, including morphine. Tramadol is readily absorbed after oral administration and has an
elimination half-life of 5-7 hours.

Several clinical trials evaluated the efficacy and safety of tramadol ODT (62 and 89 mg) and tramadol HCI in
the treatment of PE [733]. Up to 2.5-fold increases in the median IELT have been reported among patients who
received on demand tramadol treatment [734, 735].

Adverse effects were reported at doses used for analgesic purposes (≤ 400 mg daily) and included constipation,
sedation and dry mouth. In May 2009, the US FDA released a warning letter about tramadol’s potential to cause
addiction and difficulty in breathing [736]. The tolerability during the twelve-week study period in men with
PE was acceptable [737]. Several other studies have also reported that tramadol exhibits a significant dose-
related efficacy along with potential adverse effects during the treatment of PE [734, 735]. The Guidelines Panel
considers tramadol as a potential alternative treatment to established first-line therapeutic options in men with
PE; however, it should be clearly outlined that the use of tramadol has to be considered with caution since there
is a lack of data on the long-term safety of the compound in this setting.

6.2.6.2.5 Phosphodiesterase type 5 inhibitors

Although IELT was not significantly improved, sildenafil increased confidence, the perception of ejaculatory
control and overall sexual satisfaction, reduced anxiety and the refractory time to achieve a second erection
after ejaculation [738, 739]. Several open-label studies have shown that a combination of PDE5Is and SSRIs is
superior to SSRI monotherapy, which has also been recently confirmed by a Bayesian network meta-analysis
[718, 740]:

64 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

6.2.6.2.6 Other drugs
In addition to the aforementioned drugs, there is continuous research into other treatment options. Considering
the abundant α1a-adrenergic receptors in seminal vesicles and the prostate and the role of the sympathetic
system in ejaculation physiology, the efficacy of selective α-blockers in the treatment of PE has been assessed
[741-743]. A study demonstrated that wake-promoting agent modafinil may be effective in delaying ejaculation
and improving PROMs [744]. Decreasing penile sensitivity with glans penis augmentation using hyaluronic acid
for the treatment of PE was initially proposed by Korean researchers in 2004 [745]. Since then, it has gained
popularity mainly in Asian countries [746, 747]. Randomised controlled studies demonstrated that hyaluronic
acid glans injections were safe, with a modest but significant increase in IELT along with improvements in PRO
measures [746, 747]. No serious TEAEs were reported related to glans penis injections with hyaluronic acid.
However, this procedure may result in serious complications, and more safety studies must be conducted
before recommending this treatment to PE patients [748]. Selective dorsal neurectomy has also been suggested
for the treatment of PE, mainly by Asian researchers [749-755]. However, considering the irreversible nature of
these procedures, more safety data are warranted.

Considering the importance of central oxytocin receptors in the ejaculation reflex, several researchers have
assessed the efficacy and safety of oxytocin receptor antagonists in the treatment of PE [756]. Epelsiban [757]
and cligosiban [758-761] have been found to be safe and mildly effective in delaying ejaculation, but further
controlled trials are needed [760, 761]. Delayed ejaculation was associated with the use of pregabalin, a new
generation of gapapentinoid, as a side-effect. On-demand oral pregabalin 150 mg was found to increase the
IELTs of patients 2.45 ± 1.43-fold. Treatment-emergent side effects (blurred vision, dizziness, vomiting) were
minimal and did not lead to drug discontinuation [762].

The role of other proposed treatment modalities for the treatment of PE, such as penis-root masturbation
[763], vibrator-assisted start-stop exercises [675], transcutaneous functional electric stimulation [764, 765],
transcutaneous posterior tibial nerve stimulation [766], acupuncture [767-769] and practicing yoga [770] need
more evidence to be considered in the clinical setting.

6.2.7 Summary of evidence and recommendations for the treatment of PE

Summary of evidence LE
Pharmacotherapy includes either dapoxetine on-demand (an oral short-acting SSRI) and eutectic 1a
lidocaine/prilocaine spray (a topical desensitising agent), which are the only approved treatments for
PE, or other off-label antidepressants (daily/on-demand SSRIs and clomipramine).
Both on-demand dapoxetine treatment and daily SSRI treatment improve IELT values significantly. 1a
Both on-demand dapoxetine treatment and daily SSRI treatment have generally tolerable side effects 1a
when used for treatment of PE.
Daily/on-demand clomipramine treatments improve IELT values significantly and have generally 1a
tolerable side effects when used for treatment of PE.
Cream and spray forms of lidocaine/prilocaine improve IELT values significantly and have a safe profile. 1b
Tramadol is effective in the treatment of PE but the evidence is still inadequate for its long-term safety 1a
profile including addiction potential.
Combination of PDE5Is and SSRIs overtakes SSRI monotherapy in effectiveness. 1a
Hyaluronic acid injections are effective in decreasing penile sensitivity. 2b

Recommendations Strength rating

Treat erectile dysfunction (ED), other sexual dysfunction or genitourinary infection (e.g., Strong
prostatitis) first.
Use either dapoxetine or the lidocaine/prilocaine spray as first-line treatments for lifelong Strong
premature ejaculation (PE).
Use off-label oral treatment with daily selective serotonin re-uptake inhibitor (SSRIs) or daily/ Strong
on-demand clomipramine as a viable alternative for second-line treatments.
Use off-label tramadol with caution as a viable on-demand third-line treatment alternative to Strong
on-demand/daily antidepressants (SSRIs or clomipramine).
Use PDE5Is alone or in combination with other therapies in patients with PE (without ED). Strong

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 65

Use psychological/behavioural therapies in combination with pharmacological treatment in Weak
the management of acquired PE.
Use hyaluronic acid injection with caution as a treatment option for PE compared to other Weak
more established treatment modalities.
Do not perform dorsal neurectomy as more safety data are warranted. Weak

6.3 Delayed Ejaculation (DE)

6.3.1 Definition and classification
The American Psychiatric Association defines delayed ejaculation (DE) as requiring one of two symptoms:
marked delay, infrequency or absence of ejaculation on 75-100% of occasions that persists for at least 6 months
and causes personal distress [212]. However, in a recent study, while ejaculatory latency and control were
significant criteria to differentiate men with DE from those without ejaculatory disorders, bother/distress did not
emerge as a significant factor [771]. Similar to PE, there are distinctions among lifelong, acquired and situational
DE [212]. A recent study demonstrated that men with lifelong DE are younger, report greater DE symptomatology,
less likely have a medical issue or medication that can cause DE and more likely to masturbate for anxiety/
distress reduction than for pleasure as compared with men with acquired delayed ejaculation [772]. Although
the evidence is limited, the prevalence of lifelong and acquired DE is estimated at around 1% and 4%,
respectively [213].

6.3.2 Pathophysiology and risk factors

The aetiology of DE can be psychological, organic (e.g., incomplete spinal cord lesion or iatrogenic penile nerve
damage), or pharmacological (e.g., SSRIs, antihypertensive drugs, or antipsychotics) [773, 774] (Table 6.1). Other
factors that may play a role in the aetiology of DE include tactile sensitivity and tissue atrophy [674]. Although
low testosterone level has been considered a risk factor in the past [615, 775], more contemporary studies have
not confirmed any association between ejaculation times and serum testosterone levels [776, 777]. Idiosyncratic
masturbation and lack of desire for stimuli are also proposed risk factors for DE [778-780].

Table 6.1: Aetiological causes of delayed ejaculation and anejaculation [781-784]

Ageing Men Degeneration of penile afferent nerves inhibited ejaculation

Congenital Mullerian duct cyst
Wolfian duct abnormalities
Prune Belly Syndrome
Imperforate Anus
Genetic abnormalities
Anatomic causes Transurethral resection of prostate
Bladder neck incision
Circumcision
Ejaculatory duct obstruction (can be congenital or acquired)
Neurogenic causes Diabetic autonomic neuropathy
Multiple sclerosis
Spinal cord injury
Radical prostatectomy
Proctocolectomy
Bilateral sympathectomy
Abdominal aortic aneurysmectomy
Para-aortic lymphadenectomy
Infective/Inflammation Urethritis
Genitourinary tuberculosis
Schistosomiasis
Prostatitis
Orchitis
Endocrine Hypogonadism
Hypothyroidism
Prolactin disorders
Disorders of lipid metabolism

66 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Medication Antihypertensives; thiazide diuretics
Alpha-adrenergic blockers
Antipsychotics and antidepressants
Alcohol
Antiandrogens
Ganglion blockers
Psychological Anxiety
Psychoses
Acute psychological distress
Relationship distress
Psychosexual skill deficit
Disconnect between arousal and sexual situations
Masturbation style

6.3.3 Investigation and treatment

Patients should have a full medical and sexual history performed along with a detailed physical examination
when evaluating for DE. Understanding the details of the ejaculatory response, sensation, frequency, and sexual
activity/techniques; cultural context and history of the disorder; quality of the sexual response cycle (desire,
arousal, ejaculation, orgasm, and refractory period); partner’s assessment of the disorder and if the partner
suffers from any sexual dysfunction her/himself; and the overall satisfaction of the sexual relationship are all
important to garner during history-taking [644]. It is incumbent on the clinician to diagnose medical pathologies
that cause or contribute to DE, such as assessing the hormonal milieu, anatomy, and overall medical condition.

6.3.3.1 Psychological aspects and intervention

There is scarce literature on the psychological aspects relating to DE, as well as on empirical evidence regarding
psychological treatment efficacy. Studies on psychological aspects have revealed that men with DE show a
strong need to control their sexual experiences. Delayed ejaculation is associated with difficulties surrendering
to sexual pleasure during sex - i.e., the sense of letting go [785] - which denotes an underlying psychological
mechanism influencing the reaching of orgasm [786]. As for psychological treatments, these may include,
but are not limited to: increased genital-specific stimulation; sexual education; role-playing on his own and
in front of his partner; retraining masturbatory practices; anxiety reduction on ejaculation and performance;
and, re-calibrating the mismatch of sexual fantasies with arousal (such as with pornography use and fantasy
stimulation compared to reality). Masturbation techniques that are either solo or partnered can be considered
practice for the “real performance”, which can eventually result in greater psychosexual arousal and orgasm for
both parties [780]. Although masturbation with fantasy can be harmful when not associated with appropriate
sexual arousal and context, fantasy can be supportive if it allows blockage of critical thoughts that may
prevent orgasm and ejaculation. Techniques geared towards reducing of anxiety are important skills that can
help overcome performance anxiety, as this can often interrupt the natural erectile function through orgasmic
progression. Referral to a sexual therapist, psychologist or psychiatrist is appropriate and often warranted.

6.3.3.2 Pharmacotherapy
Several pharmacological agents, including cabergoline, bupropion, alpha-1-adrenergic agonists
(pseudoephedrine, midodrine, imipramine and ephedrine), buspirone, oxytocin, testosterone, bethanechol,
yohimbine, amantadine, cyproheptadine and apomorphine have been used to treat DE with varied success
[674]. Unfortunately, there is no FDA or EMA-approved medications to treat DE, as most of the cited research is
based on case-cohort studies that were not randomised, blinded, or placebo-controlled. Many drugs have been
used as primary treatments and/or antidotes to other medications that can cause DE. A survey of sexual health
providers demonstrated an overall treatment success of 40% with most providers commonly using cabergoline,
bupropion or oxytocin [787]. However, this survey measured the anecdotal results of practitioners. There was no
proven efficacy or superiority of any drug due to a lack of placebo-controlled, randomised, blinded, comparative
trials [781]. In addition to pharmacotherapy, penile vibratory stimulation (PVS) is also used as an adjunct
therapy for DE [788]. Another study that used combined therapy of midodrine and PVS to increase autonomic
stimulation in 158 men with spinal cord injury led to ejaculation in almost 65% of the patients [789].

Summary of evidence LE
Delayed ejaculation can be caused by several aetiologies including congenital, anatomic, neurogenic, 3
infective, hormonal, drug-related and psychological.
There is not enough evidence to support a definitive treatment for DE. 3

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6.4 Anejaculation
6.4.1 Definition and classification
Anejaculation involves the complete absence of antegrade or retrograde ejaculation. It is caused by the failure
of semen emission from the seminal vesicles, prostate, and ejaculatory ducts into the urethra [790]. True
anejaculation is usually associated with a normal orgasmic sensation and is always associated with central or
peripheral nervous system dysfunction or with drugs [791].

6.4.2 Pathophysiology and risk factors

Generally, anejaculation shares similar aetiological factors with DE and retrograde ejaculation (Table 6.1).

6.4.3 Investigation and treatment

Drug treatment for anejaculation caused by lymphadenectomy and neuropathy, or psychosexual therapy for
anorgasmia, is not effective. In all these cases, and in men who have a spinal cord injury, PVS (i.e., application
of a vibrator to the penis) is the first-line therapy. In anejaculation, PVS evokes the ejaculation reflex [792],
which requires an intact lumbosacral spinal cord segment. If the quality of semen is poor or ejaculation is
retrograde, the couple may enter an in vitro fertilisation program whenever fathering is desired. If PVS has failed,
electro-ejaculation can be the therapy of choice [793]. Other sperm-retrieval techniques may be used when
electro-ejaculation fails or cannot be carried out [794]. Anejaculation following either retroperitoneal surgery for
testicular cancer or total mesorectal excision can be prevented using unilateral lymphadenectomy or autonomic
nerve preservation [795], respectively.

6.5 Painful Ejaculation

6.5.1 Definition and classification
Painful ejaculation is a condition in which a patient feels mild discomfort to severe pain during or after
ejaculation. The pain can involve the penis, scrotum, and perineum [796].

6.5.2 Pathophysiology and risk factors

Many medical conditions can result in painful ejaculation, but it can also be an idiopathic problem. Initial reports
demonstrated possible associations of painful ejaculation with calculi in the seminal vesicles [797], sexual
neurasthenia [798], sexually transmitted diseases (STIs) [796, 799], inflammation of the prostate [233, 800], PCa
[801, 802], BPH [231], prostate surgery [803, 804], pelvic radiation [805], herniorrhaphy [806] and antidepressants
[807-809]. Further case reports have suggested that mercury toxicity or Ciguatera toxin fish poisoning may
also result in painful ejaculation [810, 811]. Psychological issues may also be the cause of painful ejaculation,
especially if the patient does not experience this problem during masturbation [812].

6.5.3 Investigation and treatment

Treating painful ejaculation must be tailored to the underlying cause if detected. Psychotherapy or relationship
counselling, withdrawal of suspected agents (drugs, toxins, or radiation) [807, 808, 813] or the prescription of
appropriate medical treatment (antibiotics, α-blockers or anti-inflammatory agents) may ameliorate painful
ejaculation. Behavioural therapy, muscle relaxants, antidepressant treatment, anticonvulsant drugs and/or
opioids, and pelvic floor exercises, may be implemented if no underlying cause can be identified [814, 815].

6.5.3.1 Surgical intervention

If medical treatments fail, surgical operations such as TURP, transurethral resection of the ejaculatory duct
(TURED) and neurolysis of the pudendal nerve have been suggested [816, 817]. However, there is no strong
supporting evidence that surgical therapy improves painful ejaculation: therefore, it must be used with caution.

6.6 Retrograde ejaculation

6.6.1 Definition and classification
Retrograde ejaculation is the total, or sometimes partial, absence of antegrade ejaculation, due to semen
passing backwards through the bladder neck into the bladder. Patients may experience a normal or decreased
orgasmic sensation. The causes of retrograde ejaculation can be divided into neurogenic, pharmacological,
urethral, or bladder neck incompetence [796].

6.6.2 Pathophysiology and risk factors

The process of ejaculation requires complex co-ordination and interplay between the epididymis, vas
deferens, prostate, seminal vesicles, bladder neck and bulbourethral glands [818]. Upon ejaculation, sperm
are rapidly conveyed along the vas deferens and into the urethra via the ejaculatory ducts. From there,
the semen progresses in an antegrade fashion, partly maintained by coaptation of the bladder neck and
rhythmic contractions of the periurethral muscles, co-ordinated by a centrally mediated reflex [818]. Closure

68 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

of the bladder neck and seminal emission is initiated via the sympathetic nervous system from the lumbar
sympathetic ganglia and subsequently hypogastric nerve. Prostatic and seminal vesicle secretion, as well
as contraction of the bulbo-cavernosal, ischio-cavernosal and pelvic floor muscles are initiated by the S2-4
parasympathetic nervous system via the pelvic nerve [818].

Any factor that disrupts this reflex and inhibits contraction of the bladder neck (internal vesical sphincter) may
lead to retrograde passage of semen into the bladder. These can be broadly categorised as pharmacological,
neurogenic, anatomic and endocrinal causes of retrograde ejaculation (Table 6.2).

Table 6.2: Aetiology of retrograde ejaculation [796]

Neurogenic Spinal cord injury

Cauda equina lesions
Multiple sclerosis
Autonomic neuropathy
Retroperitoneal lymphadenectomy
Sympathectomy or aortoiliac surgery
Prostate, colorectal and anal surgery
Parkinson´s disease
Diabetes mellitus
Psychological/behavioural
Urethral Ectopic ureterocele
Urethral stricture
Urethral valves or verumontaneum hyperplasia
Congenital dopamine β-hydroxylase deficiency
Pharmacological Antihypertensives, thiazide diuretics
α-1-Adrenoceptor antagonists
Antipsychotics and antidepressants
Endocrine Hypothyroidism
Hypogonadism
Hyperprolactinaemia
Bladder neck incompetence Congenital defects/dysfunction of hemitrigone
Bladder neck resection (transurethral resection of the
prostate)
Prostatectomy

6.6.3 Disease management

6.6.3.1 Pharmacological
Sympathomimetics stimulate the release of noradrenaline and activate α- and β-adrenergic receptors, resulting
in closure of the internal urethral sphincter, restoring the antegrade flow of semen. The most common
sympathomimetics are synephrine, pseudoephedrine hydrochloride, ephedrine, phenylpropanolamine and
midodrine [819]. Unfortunately, as time progresses, their effect diminishes [820]. Many studies published about
the efficacy of sympathomimetics in the treatment of retrograde ejaculation suffer from small sample size, with
some represented by case reports.

An RCT randomised patients to receive one of four α-adrenergic agents (dextroamphetamine, ephedrine,
phenylpropanolamine and pseudoephedrine) with or without histamine. The patients suffered from failure
of ejaculation following retroperitoneal lymphadenectomy. They found that four days of treatment prior to
ejaculation was the most effective and that all the adrenergic agonists restored antegrade ejaculation [819]. In a
systematic review, the efficacy of this group of medications was found to be 28% [216]. The adverse effects of
sympathomimetics include dryness of mucous membranes and hypertension.

The use of antimuscarinics has been described, including brompheniramine maleate and imipramine, as well
as in combination with sympathomimetics. The calculated efficacy of antimuscarinics alone or in combination
with sympathomimetics is 22% and 39%, respectively [216]. Combination therapy appears to be more effective,
although statistical analysis is not yet possible due to the small sample sizes.

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6.6.3.2 Management of infertility
Infertility has been the major concern of patients with retrograde ejaculation. Beyond standard sperm-retrieval
techniques, such as testicular sperm aspiration/extraction (TESA/TESE), three different methods of sperm
acquisition have been identified for managing infertility in patients with retrograde ejaculation. These include: i)
centrifugation and resuspension of post-ejaculatory urine specimens; ii) the Hotchkiss (or modified Hotchkiss)
technique; and, iii) ejaculation on a full bladder.

1. Centrifugation and resuspension. In order to improve the ambient conditions for the sperm, the patient is
asked to increase their fluid intake or take sodium bicarbonate to dilute or alkalise the urine, respectively.
Afterwards, a post-orgasmic urine sample is collected by introducing a catheter or spontaneous voiding.
This sample is then centrifuged and suspended in a medium. The types of suspension fluids are
heterogeneous and can include bovine serum albumin, human serum albumin, Earle’s/Hank’s balanced
salt solution and the patient’s urine. The resultant modified sperm mixture can then be used in assisted
reproductive techniques. A systematic review of studies in couples in which male partner had retrograde
ejaculation found a 15% pregnancy rate per cycle (0-100%) [216].
2. Hotchkiss method. The Hotchkiss method involves emptying the bladder prior to ejaculation, using a
catheter, and then washing out and instilling a small quantity of Lactated Ringers to improve the ambient
condition of the bladder. The patient then ejaculates, and semen is retrieved by catheterisation or voiding
[821]. Modified Hotchkiss methods involve variance in the instillation medium. Pregnancy rates were 24%
per cycle (0-100%) [216].
3. Ejaculation on a full bladder. The patient is encouraged to ejaculate on a full bladder and semen is
suspended in Baker’s Buffer. The pregnancy rate in the two studies, which included only five patients,
have described results using this technique [822, 823].

6.7 Anorgasmia
6.7.1 Definition and classification
Anorgasmia is the perceived absence of orgasm and can give rise to anejaculation. Regardless of the presence
of ejaculation, anorgasmia can be a lifelong (primary) or acquired (secondary) disorder [213].

6.7.2 Pathophysiology and risk factors

Primary anorgasmia starts from a man’s first sexual intercourse and lasts throughout his life, while secondary
anorgasmia patients should have a normal period before the problem starts [824]. Substance abuse, obesity and
some non-specific psychological aspects, such as anxiety and fear, are considered risk factors for anorgasmia.
Only a few studies have described anorgasmia alone and generally, it has been considered a symptom linked
to ejaculatory disorders, especially with DE, and therefore, they are believed to share the same risk factors.
However, psychological factors are considered to be responsible for 90% of anorgasmia problems [825]. The
causes of delayed orgasm and anorgasmia are shown in Table 6.3 [824].

Table 6.3: Causes of delayed orgasm and anorgasmia [824]

Endocrine: Testosterone deficiency; and Hypothyroidism

Medications: Antidepressants; Antipsychotics; and Opiods
Psychosexual causes
Hyperstimulation
Penile sensation loss

6.7.3 Disease management

The psychological/behavioural strategies for anorgasmia are similar to those for DE. The patient and his partner
should be examined physically and psychosexually in detail, including determining the onset of anorgasmia,
medication and disease history, penile sensitivity and psychological issues. Adjunctive laboratory tests can also
be used to rule out organic causes, such as testosterone, prolactin and TSH levels. Patients who have loss of
penile sensitivity require further investigations [824].

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6.7.3.1 Psychological/behavioural strategies
Lifestyle changes can be recommended to affected individuals, including changing masturbation style, taking
steps to improve intimacy, and decreasing alcohol consumption. Several psychotherapy techniques or their
combinations have been offered, including alterations in arousal methods, reduction of sexual anxiety, role-
playing an exaggerated orgasm and increased genital stimulation [786, 826]. However, it is difficult to determine
the success rates from the literature.

6.7.3.2 Pharmacotherapy
Several drugs have been reported to reverse anorgasmia, including cyproheptadine, yohimbine, buspirone,
amantadine and oxytocin [827-832]. However, these reports are generally from case-cohort studies and drugs
have limited efficacy and significant adverse effect profiles. Therefore, current evidence is not strong enough to
recommend drugs to treat anorgasmia.

6.7.3.3 Management of infertility

If patients fail the treatment methods mentioned above, penile vibratory stimulation, electro-ejaculation or TESE
are options for sperm retrieval in anorgasmia cases [824].

6.8 Haemospermia
6.8.1 Definition and classification
Haemospermia is defined as the appearance of blood in the ejaculate. Although it is often regarded as a
symptom of minor significance, blood in the ejaculate causes anxiety in many men and may indicate underlying
pathology [236].

6.8.2 Pathophysiology and risk factors

Several causes of haemospermia have been acknowledged and can be classified into the following sub-
categories; idiopathic, congenital malformations, inflammatory conditions, obstruction, malignancies, vascular
abnormalities, iatrogenic/trauma and systemic causes (Table 6.4) [833].

Table 6.4: Pathology associated with haemospermia [833-836]

Category Causes
Congenital Seminal vesicle (SV) or ejaculatory duct cysts
Inflammatory Urethritis, prostatitis, epididymitis, tuberculosis, CMV, HIV, Schistosomiasis,
hydatid, condyloma of urethra and meatus, urinary tract infections
Obstruction Prostatic, SV and ejaculatory duct calculi, post-inflammatory, seminal
vesicle diverticula/cyst, urethral stricture, utricle cyst, BPH
Tumours Prostate, bladder, SV, urethra, testis, epididymis, melanoma
Vascular Prostatic varices, prostatic telangiectasia, haemangioma, posterior
urethral veins, excessive sex or masturbation
Trauma/ iatrogenic Perineum, testis, instrumentation, post-haemorrhoid injection, prostate
biopsy, vaso-venous fistula
Systemic Hypertension, haemophilia, purpura, scurvy, bleeding disorders, chronic
liver disease, renovascular disease, leukaemia, lymphoma, cirrhosis,
amyloidosis
Idiopathic -

The risk of any malignancy in patients presenting with haemospermia is approximately 3.5% (0-13.1%) [835,
837]. In a study in which 342 patients with haemospermia were included, the most relevant aetiology for
haemospermia was inflammation/infection (49.4%) while genitourinary cancers (i.e., prostate and testis) only
accounted for 3.2% of the cases [838].

6.8.3 Investigations
As with other clinical conditions, a systematic clinical history and assessment is undertaken to help identify the
cause of haemospermia. Although the differential diagnosis is extensive, most cases are caused by infections
or other inflammatory processes [236].

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The basic examination of haemospermia should start with a thorough symptom-specific and systemic clinical
history. The first step is to understand if the patient has true haemospermia. Pseudo-haemospermia may occur
as a consequence of haematuria or even suction of a partner’s blood into the urethra during copulation [796,
839, 840]. A sexual history should be taken to identify those whose haemospermia may be a consequence of
a STI. Recent foreign travel to areas affected by schistosomiasis or tuberculosis should also be considered.
The possibility of co-existing systemic diseases such as hypertension, liver disease and coagulopathy should
be investigated along with systemic features of malignancy such as weight loss, loss of appetite or bone pain.
Examination of the patient should also include measurement of blood pressure, as there have been several case
reports suggesting an association between uncontrolled hypertension and haemospermia [841, 842].

Most authors who propose an investigative baseline agree on the initial diagnostic tests, but there is no
consensus in this regard [833, 834, 837, 839]. Urinalysis should be performed along with sending the urine
for culture and sensitivity testing, as well as microscopy. If tuberculosis or schistosomiasis is the suspected
cause, the semen or prostatic secretions should be sent for analysis. A full sexually-transmitted disease
screen, including first-void urine as well as serum and genitourinary samples, should be tested for Chlamydia,
Ureaplasma and Herpes Simplex virus. Using this strategy, it may be possible to find an infectious agent among
cases that would have been labelled as idiopathic haemospermia [843].

Serum PSA should be taken in men aged > 40 years who have been appropriately counselled [237]. Blood work,
including a full blood count, liver function tests, and a clotting screen should be taken to identify systemic
diseases. The question of whether further investigation is warranted depends on clinician judgment, patient age
and an assessment of risk factors [833]. Digital rectal examination should also be performed, and the meatus
re-examined after DRE for bloody discharge [844]. Detection of a palpable nodule in the prostate is important
because an association between haemospermia and PCa has been postulated, although not completely proven.

Magnetic resonance imaging (MRI) is being increasingly used as a definitive means to investigate
haemospermia. The multiplanar ability of MRI to accurately represent structural changes in the prostate,
seminal vesicles, ampulla of vas deferens, and ejaculatory ducts has enabled the technique to be particularly
useful in determining the origin of midline or paramedian prostatic cysts and in determining optimal surgical
management [845]. The addition of an endorectal coil can improve diagnostic accuracy for identifying the site
and possible causes of haemorrhage [846].

Cystoscopy has been included in most suggested investigative protocols in patients with high-risk features
(patients who are refractory to conservative treatment and who have persistent haemospermia). It can provide
valuable information as it allows direct visualisation of the main structures in the urinary tract that can be
attributed to causes of haemospermia, such as polyps, urethritis, prostatic cysts, foreign bodies, calcifications
and vascular abnormalities [847, 848].

With the advancement of optics, the ability to create ureteroscopes of diameters small enough to allow
insertion into the ejaculatory duct and seminal vesicles has been made possible [849]. In a prospective study,
106 patients with prolonged haemospermia underwent transrectal US and seminal vesiculoscopy. With both
methods combined, the diagnosis was made in 87.7% of patients. When compared head-to-head, the diagnostic
yield for TRUS vs. seminal vesiculoscopy was 45.3% and 74.5%, respectively (P < 0.001) [850].

Melanospermia is a consequence of malignant melanoma involving the genitourinary tract and is a rare
condition that has been described in two case reports [851, 852]. Chromatography of the semen sample can be
used to distinguish the two by identifying the presence of melanin if needed.

6.8.4 Disease management

Conservative management is generally the primary treatment option when the patients are aged < 40 years and
have a single episode of haemospermia. The primary goal of treatment is to exclude malignant conditions like
prostate and bladder cancer and treat any other underlying cause. If no pathology is found, then the patient can
be reassured [236, 833].

Middle-aged patients with recurrent haemospermia warrant more aggressive intervention. Appropriate antibiotic
therapy should be given to patients who have urogenital infections or STIs. Urethral or prostate varices or
angiodyplastic vessels can be fulgurated, whereas cysts, either of the seminal vesicles or prostatic urethra, can
be aspirated transrectally [236]. Ejaculatory duct obstruction is managed by transurethral incision at the duct
opening [853, 854]. Systemic conditions should be treated appropriately [837, 840, 855, 856].

72 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Defining a management algorithm for haemospermia is based on the patient age and degree of haemospermia.
Patients often find blood in the ejaculate alarming, and investigations should be aimed at excluding a serious,
despite infrequent, underlying cause (e.g., cancer), while at the same time preventing over-investigation and
alleviating patient anxiety. The literature describes a multitude of causes for haemospermia, although many
of these are not commonly found after investigation. However, men may be stratified into higher-risk groups
according to several factors including: age > 40 years, recurrent or persistent haemospermia, the actual risk
for PCa (e.g., positive family history), and concurrent haematuria. Based upon the literature, a management
algorithm is proposed (Figure 6.3) [837, 840, 855, 856].

Figure 6.3: Management of haemospermia [837, 840, 855, 856]

Presentaon of haemospermia

• History and detailed physical examinaon

• Blood pressure
• Urinalysis
• Urine culture
• Complete blood count
• Serum coagulaon assessment
• Serum chemistry panel
• Semen analysis
• STI screening
• Condom test

Low risk High risk

Men < 40 years old, isolated Men ≥ 40 years old or man of any
haemospermia, and no other age with persistent haemospermia,
symptoms or signs of disease or haemospermia associated with
symptoms or signs of disease

Cure the aeology that can be

Conservave treatment and idenfied with roune clinical
watchful waing evaluaon (anbiocs, an-
Reassure the paent inflammatory drugs, etc.)
TRUS, pelvic MRI
Recurrence Prostate cancer screening with PSA
and DRE (in men ≥ 40 years old)
Rule out tescular tumour by US
(in men < 40 years old)
Cystourethroscopy ± biopsy

Diagnosis Treatment Follow-up

STI = Sexually transmitted infections; PSA = Prostate specific antigen; DRE = Digital rectal examination;
US = Ultrasonography; TRUS = Transrectal ultrasonography; MRI = Magnetic resonance imaging.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 73

6.8.5 Summary of evidence and recommendations for the investigation and management of haemospermia

Summary of evidence LE
While haemospermia has traditionally been attributed to benign causes, it is a potential indicator 3
warranting thorough diagnostic evaluation and, if necessary, targeted treatment.
The principal objective of treatment is to rule out malignancies, while addressing any other underlying 3
causes as well.

Recommendations Strength rating

Perform a full medical and sexual history with detailed physical examination. Strong
Use risk-stratification system to manage the disease systematically. Weak

7. LOW SEXUAL DESIRE AND MALE

HYPOACTIVE SEXUAL DESIRE DISORDER
7.1 Definition, classification and epidemiology
It has always been a challenge to define sexual desire properly because it has a complicated nature and it
can be conceptualised in many different ways. According to the International Classification of Diseases 10th
edition (ICD-10), lack or loss of sexual desire should be the principal problem and not other sexual problems
accompanying it such as ED [857]. In the DSM-V, male hypoactive sexual desire disorder (HSDD) is defined
as “the persistent or recurrent deficiency (or absence) of sexual or erotic thoughts or fantasies and desire for
sexual activity”. The clinician makes the judgment of deficiency, taking into account factors that affect sexual
functioning, such as age and general and socio-cultural contexts of the individual’s life [212]. According to the
fourth International Consultation on Sexual Medicine (ICSM), the definition of male HSDD was proposed as a
“persistent or recurrent deficiency or absence of sexual or erotic thoughts or fantasies and desire for sexual
activity (clinical principle)” [858]. Although the exact prevalence of low sexual desire (LSD) is unknown, a
prevalence of 4.7% was reported in a survey of a population-based sample of middle-aged German men (n =
12,646) [859].

7.2 Pathophysiology and risk factors

Several aetiological factors are considered to contribute to the pathophysiology of LSD. Levine proposed three
components of sexual desire as drive (biological), motivation (psychological) and wish (cultural) [860]. However,
it is believed that both in the surveys and clinical practice those three components are usually found interwoven
[861].

7.2.1 Psychological aspects

The endorsement of negative thoughts during sexual intercourse (i.e., concerns about erection, lack of erotic
thoughts, and restrictive attitudes toward sexuality) predicts LSD in men [862, 863]. Furthermore, feeling
shame during sexual intercourse, because of negative sexual thoughts (e.g., concern about achieving an
erection), characterises men with LSD as opposed to women with the same condition [864]. Psychopathological
symptoms stemming from a crisis context negatively impacted male sexual desire [355], as well. In addition,
dyadic male sexual desire was best accounted for by sexual satisfaction [865]. It is worth noting that, despite
LSD being less common in men than in women [858], it is the most frequent complaint in couples’ therapy
[866]. Therefore, the role of relationship factors must be addressed. In addition, anxiety proneness has been
associated with LSD in men and is expected to shift men’s attention from erotic cues to worrying thoughts,
thereby decreasing sexual desire [867]. Finally, it is worth noting that current approaches focus on sexual desire
discrepancies between partners; the focus on discrepancies rather than on the partner who presents low desire
not only reduces stigma, but also provides new opportunities for managing desire in the relationship context
[868].

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7.2.2 Biological aspects
Testosterone seems to be essential for a man’s sexual desire; however, sexual desire does not directly relate to
the circulating level of testosterone, especially in older men [869]. The biological and psychological components
that take place in the pathophysiology of LSD are shown in Table 7.1 [861, 870]. In addition to these factors,
there is some speculation about the role of thyroid and oxytocin hormones [597, 871].

Table 7.1: Common causes of low sexual desire in men [861, 870]

Androgen deficiency Post-traumatic stress syndrome

Hyperprolactinaemia Renal failure
Anger and anxiety Coronary disease and heart failure
Depression Ageing
Relationship conflict HIV infection
Stroke Body-building and eating disorders
Antidepressant therapy Erectile dysfunction
Epilepsy Prostatitis/chronic pelvic pain syndrome

7.2.3 Risk factors

In an international survey aimed at estimating the prevalence and correlates of sexual problems in 13,882
women and 13,618 men from 29 countries (Global Study of Sexual Attitudes and Behaviours), risk factors for
male LSD were age 60-69 and 70-80 years, poor overall health, vascular diseases, being a current smoker, belief
that ageing reduces sex, divorce in the past 3 years, financial problems in the last 3 years, major depression,
being worried about the future of a relationship and less than one sexual relation in a week [210]. In a recent
study that determined the factors associated with LSD in a large sample of middle-aged German men, PE,
ED, and lower urinary tract symptoms were associated with LSD [859]. In contrast, men having more than two
children, higher frequency of solo masturbation, perceived importance of sexuality, and higher sexual self-
esteem were less likely to have LSD [859].

7.3 Diagnostic work-up

7.3.1 Assessment questionnaires
Sexual Desire Inventory (SDI) evaluates different components influencing the development and expression
of sexual desire [872]. This self-administered questionnaire consists of 14 questions that weigh the strength,
frequency, and significance of an individual’s desire for sexual activity with others and by themselves. The SDI
suggests that desire can be split into two categories: dyadic and solitary desire. While dyadic desire refers to
“interest in or a wish to engage in sexual activity with another person and desire for sharing and intimacy with
another”, solitary desire refers to “an interest in engaging in sexual behaviour by oneself and may involve a wish
to refrain from intimacy and sharing with others” [872].

7.3.2 Physical examination and investigations

Similar to other forms of sexual dysfunctions, a thorough medical and sexual history must be obtained from
men who complain of LSD. The depressive symptoms of the patients must be assessed [873] and relationship
problems (e.g., conflict with the sexual partner) must be questioned. In the presence of accompanying
symptoms suggestive of endocrinological problems, circulating total testosterone [874], prolactin [875] and
thyroid hormones [597] levels can be evaluated.

7.4 Disease management

Treatment of LSD should be tailored according to the underlying aetiology.

7.4.1 Psychological intervention

Data on efficacy of psychological interventions for LSD are scarce. Accordingly, recommendations must be
interpreted with caution. Psychological interventions with a focus on cognitive and behavioural strategies may
be beneficial for LSD in men [359, 876] (Figure 7.1). Mindfulness treatments may be a strong candidate, as well
[876]. Since both members of a couple may experience age-related changes concurrently and interdependently,
it could be helpful to address the sexual health needs of the ageing couple (including LSD) as a whole rather
than treating the individual patient [877]. Indeed, psychologists are putting more emphasis on the concept of
sexual desire discrepancy. Sexual desire discrepancy is often found in couples or partners, and mirror a natural
part of life and partners’ dynamics. Clinical approaches based on this lens are less stigmatising as they consider

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 75

the normal variations in sexual desire that occur throughout the lifespan. This intervention option targets
couples distressed by sexual desire discrepancies rather than a single individual targeted as the one presenting
low sexual desire [868].

Figure 7.1: Flow-diagram of psychological evaluation of patients with low sexual desire

Evaluate psychosexual history and

development

Evaluate dysfunctional thinking style and Consider role of partner

expectations regarding sexuality and man’s
Consider whether lack of
sexual performance
desire is dyadic (desire
to engage in sexual
behaviour with the partner)
or solitary (desire to
Collect evidence for specific anxiety triggers engage in sexual behaviour
with one’s self)

Decide on referral to (sexual)psychotherapy

or psychological intervention

7.4.2 Pharmacotherapy
Low sexual desire secondary to low testosterone levels can be treated with different formulations of
testosterone. The favourable effect of testosterone therapy on sexual motivation and the presence of sexual
thoughts was shown in a meta-analysis [874]. The aim of treatment should be to reach the physiological range
of testosterone (see section 3.3).

Hyperprolactinaemia can also cause LSD and one of the most relevant aetiological factors is prolactin-secreting
pituitary adenomas. These adenomas can be easily diagnosed with MRI of the pituitary gland and can be treated
with dopamine agonist agents [878]. The other accompanying endocrine disorders, such as hypothyroidism,
hyperthyroidism and diabetes, should be treated accordingly.

Pharmacotherapy can also be used to treat major depression; however, it should be remembered that
antidepressants may negatively affect sexual functioning; therefore, antidepressant compounds with less effect
on sexual function should be chosen. Psychotherapy can increase the efficacy of pharmacotherapy, especially
for patients whose LSD is due to depression [879].

7.5 Recommendations for the treatment of low sexual desire

Recommendations Strength rating

Perform the diagnosis and classification of low sexual desire (LSD) based on medical and Weak
sexual history, which could include validated questionnaires.
Include physical examination in the initial assessment of LSD to identify anatomical Weak
abnormalities that may be associated with LSD or other sexual dysfunctions, particularly
erectile dysfunction.
Perform laboratory tests to rule out endocrine disorders. Strong
Modulate chronic therapies which can negatively impact toward sexual desire. Weak
Provide testosterone therapy if LSD is associated with signs and symptoms of testosterone Strong
deficiency.

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8. PENILE CURVATURE
8.1 Congenital penile curvature
8.1.1 Epidemiology/aetiology/pathophysiology
Congenital penile curvature (CPC) is a rare condition, with a reported incidence of < 1% [880], although some
studies have reported higher prevalence rates of 4-10%, in the absence of hypospadias [881]. Congenital penile
curvature results from disproportionate development of the tunica albuginea of the corporal bodies and is not
associated with urethral malformation. In most cases, the curvature is ventral, but it can also be lateral or, more
rarely, dorsal [882].

8.1.2 Diagnostic evaluation

Taking a medical and sexual history is usually sufficient to establish a diagnosis of CPC. Patients usually
present after reaching puberty as the curvature becomes more apparent with erections and sexual activity. The
more severe curvatures can make intercourse difficult or impossible. Physical examination and photographic
documentation during erection (preferably after intracavernous injection [ICI] of vasoactive drugs) are both
mandatory to document the curvature and exclude other pathologies [882].

8.1.3 Disease management

Surgery is the definitive treatment for this disorder and can be deferred until after puberty. However, a survey
has suggested that men with untreated ventral penile curvature report more dissatisfaction with penile
appearance, increased difficulty with intercourse, and psychological problems; supporting surgical correction
of CPC in childhood, although this should be discouraged as penile growth will not have maximised [883].
Surgical treatments for CPC generally share the same principles as in Peyronie’s disease. Plication techniques
(Nesbit, 16-dot, Yachia, Essed-Schröeder, and others) with or without neurovascular bundle elevation (medial/
lateral) and complete penile degloving, have been described [884-893]. Other approaches are based on corporal
body de-rotation with different technical refinements that enable correction of a ventral curvature, with reported
minimal narrowing and shortening [894-897]. There are no direct comparative studies; therefore, no single
technique can be recommended for surgical correction.

8.1.4 Summary of evidence and recommendation for diagnosis and treatment of congenital penile
curvature

Summary of evidence LE
Medical and sexual history are usually sufficient to establish a diagnosis of CPC. Physical examination 3
and photographic documentation during erection (preferably after ICI of vasoactive drugs) are
mandatory to document the curvature.
Surgery is the only treatment option for CPC, which should be deferred until after puberty and 3
performed at any time in adult life in individuals with significant functional impairment during
intercourse.

Recommendation Strength rating

Use the Nesbit procedure or plication techniques with or without neurovascular bundle Strong
dissection (medial/lateral) for satisfactory curvature correction.

8.2 Peyronie’s Disease

A discussion on the Aetiology, Risk factors and Pathophysiology of Peyronie’s disease (PD) can be found
in Appendix 4, online supplementary evidence (https://uroweb.org/guidelines/sexual-and-reproductive-health/
publications-appendices).

8.2.1 Epidemiology
Epidemiological data on PD are limited. Prevalence rates of 0.4-20.3% have been reported, with a higher
prevalence in patients with ED and diabetes [898-906]. A recent survey has indicated that the prevalence of
definitive and probable cases of PD in the USA is 0.7% and 11%, respectively, suggesting that PD is an under-
diagnosed condition [907]. Peyronie’s disease often occurs in older men with a typical age of onset of 50-60
years. However, PD also occurs in younger men (< 40 years), with a reported prevalence of 1.5-16.9% [902, 908,
909].

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8.2.2 Diagnostic evaluation
The aim of the initial evaluation is to obtain information on the presenting symptoms and their duration (e.g.,
pain on erection, palpable nodules, deformity, length and girth and erectile function). It is important to obtain
information on the distress caused by the symptoms and the potential risk factors for ED and PD. A disease-
specific questionnaire (Peyronie’s disease questionnaire [PDQ]) has been developed for use in clinical practice
and trials. The Peyronie’s disease questionnaire measures three domains, including psychological and physical
symptoms, penile pain and symptom bother [910].

Clinicians should take a focused history to distinguish between active and stable disease, as this will influence
medical treatment and the timing of surgery. Patients who are still likely to have active disease are those with
a shorter symptom duration, pain on erection, or a recent change in penile deformity. Resolution of pain and
stability of the curvature for at least three months are accepted criteria of disease stabilisation as well as
patients’ referral for specific medical therapy [911, 912] or surgical intervention, if indicated [913].

The examination should start with a focused genital assessment that is extended to the hands and feet
for detecting possible Dupuytren’s contracture or Ledderhosen scarring of the plantar fascia [914]. Penile
examination is performed to assess the presence of a palpable nodule or plaque. There is no correlation
between plaque size and degree of curvature [915]. Measurement of the stretched or erect penile length is
important because it may have an impact on the subsequent treatment decisions and potential medico-legal
implications [916-918].

An objective assessment of penile curvature with an erection is mandatory. This can be obtained by several
approaches, including home (self) photography of a natural erection (preferably), using a vacuum-assisted
erection test or an ICI using vasoactive agents. However, it has been suggested that the ICI method is superior,
as it is able to induce an erection similar to or better than that which the patient would experience when sexually
aroused [919-921]. Computed tomography and MRI have a limited role in the diagnosis of the curvature and are
not recommended on a routine basis. Erectile function can be assessed using validated instruments such as
the IIEF although this has not been validated in PD patients [922]. Erectile dysfunction is common in patients
with PD (30-70.6%) [923, 924]. The presence of ED and psychological factors may also have a profound impact
on the chosen treatment strategy [925]. Ultrasound measurement of plaque size is not accurate but may be
helpful to assess the presence of the plaque and its calcification and location [926, 927]. Doppler US may be
used for the assessment of penile haemodynamics and ED aetiology [924]. In particular to assess penile arterial
inflow in the context of the interventional modality to be undertaken (eg plaque incision and grafting) to exclude
arteriogenic ED.

8.2.2.1 Summary of evidence and recommendations for diagnosis of Peyronie’s disease

Summary of evidence LE
Ultrasound measurement of plaque size is inaccurate and operator dependent. 3
Doppler US may be used to assess penile haemodynamic and vascular anatomy. 2a
Intracavernous injection method is superior to other methods to provide an objective assessment of 4
penile curvature with an erection.

Recommendations Strength rating

Take a medical and sexual history of patients with Peyronie’s disease (PD), include duration Strong
of the disease, pain on erection, penile deformity, difficulty in vaginal/anal intromission due
to the deformity and erectile dysfunction (ED).
Perform a physical examination, including assessment of palpable plaques, stretched or Strong
erect penile length, degree of curvature (self-photography, vacuum-assisted erection test
or pharmacological-induced erection) and any other related diseases (e.g., Dupuytren’s
contracture, Ledderhose disease) in patients with PD.
Use the intracavernous injection method in the diagnostic work-up of PD to provide an Weak
objective assessment of penile curvature with an erection.
Use the PD specific questionnaire especially in clinical trials, but routine use in daily clinical Weak
practice is not mandatory.
Do not use ultrasound (US), computed tomography or magnetic resonance imaging to Weak
assess plaque size and deformity in routine clinical practice.

78 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Use penile Doppler US in the case of diagnostic evaluation of ED, to evaluate penile Weak
haemodynamic and vascular anatomy, and to assess location and calcification of plaques,
especially prior to surgery.

8.2.3 Disease management

8.2.3.1 Conservative treatment
Conservative treatment of PD is primarily focused on patients in the early stage of the disease as an adjunct
treatment to relieve pain and prevent disease progression or if the patient declines other treatment options
during the active phase [913, 914]. Several options have been suggested, including oral pharmacotherapy,
intralesional injection therapy, shockwave therapy (SWT) and other topical treatments (Table 8.1).

The results of the studies on conservative treatment for PD are often contradictory, making it difficult to provide
recommendations in everyday, real-life settings [928]. The Guidelines does not recommend the use of oral
treatments for PD including pentoxifylline, vitamin E, tamoxifen, procarbazine, potassium para-aminobenzoate
(potaba), omega-3 fatty acids or combination of vitamin E and L-carnitine because of their lack of proven
efficacy [913, 929-931]. Studies of these treatments have numerous methodological problems including their
uncontrolled nature, the limited number of patients treated, the short-term follow-up and the different outcome
measures used [932, 933]. Even in the absence of adverse events, treatment with these agents may delay the
use of other more efficacious treatments.

Table 8.1: Conservative treatments for Peyronie’s disease

Oral treatments
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Phosphodiesterase type 5 inhibitors (PDE5Is)
Intralesional treatments
Verapamil
Nicardipine
Clostridium collagenase
Interferon a2B
Hyaluronic acid
Botulinum toxin
Topical treatments
H-100 gel
Other
Traction devices
Multimodal treatment
Extracorporeal shockwave treatment
Vacuum Erection Device

8.2.3.1.1 Oral treatment

Phosphodiesterase type 5 inhibitors
Phosphodiesterase type 5 inhibitors were first suggested as a treatment for PD in 2003 to reduce collagen
deposition and increase apoptosis through the inhibition of transforming growth factor (TGF)-b1 [934-936].
The results of a retrospective study of 65 men indicated that treatment with tadalafil was helpful in decreasing
curvature and remodelling septal scars when compared to controls [937]. Another study concluded that
sildenafil was able to improve erectile function and pain in PD patients. Thirty-nine patients with PD were
divided into two groups receiving vitamin E (400 IU) or sildenafil 50 mg for twelve weeks with significantly
better outcomes in pain and IIEF score were seen in the sildenafil group [938]. Findings from a observational
retrospective study including patients in the acute phase of PD and ED who had been treated with Tadalafil 5
mg once daily compared to patients with comparable baseline parameters who decided not to take the daily
compound (i.e., 108 intervention vs. 83 controls) showed that treated men had lower curvature progression
rates at 12 weeks (25.9% vs. 39.7%, p = 0.042) [939]. Similarly, mean SHIM score and PDQ-Overall and PDQ-
Penile Pain scores significantly improved in the intervention group (p < 0.001).

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Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) may be offered to patients in active-phase PD in order to
ameliorate penile pain. Pain levels should be periodically reassessed whilst monitoring treatment efficacy.

8.2.3.1.2 Intralesional treatment

Injection of pharmacologically active agents directly into penile plaques represents another treatment option. It
allows a localised delivery of a pharmacological agent that provides higher concentrations of the drug inside the
plaque. However, delivery of the compound to the target area is difficult to ensure, particularly when a dense or
calcified plaque is present.

Calcium channel antagonists: verapamil and nicardipine

The rationale for intralesional use of channel antagonists in patients with PD is based on in vitro research
[940, 941]. Due to the use of different dosing schedules and the contradictory results obtained in published
studies, the evidence is not strong enough to support the clinical use of injected channel blockers verapamil
and nicardipine and the results do not demonstrate a meaningful improvement in penile curvature compared
to placebo [942-947]. In fact, most of the studies did not perform direct statistical comparison between these
groups.

Collagenase of Clostridium histolyticum

Collagenase of Clostridium histolyticum (CCH) is a chromatographically purified bacterial enzyme that
selectively targets collagen, the primary component of the PD plaque [948-951]. Intralesional injection of CCH
has been used in the treatment of PD since 1985. In 2014 the EMA approved CCH for the non-surgical treatment
of the stable phase of PD in men with palpable dorsal plaques in whom abnormal curvature of 30-90o and non-
ventrally located plaques are present. It should be administered by a healthcare professional who is experienced
and properly trained in the administration of CCH treatment for PD [952, 953]. However, CCH has been officially
withdrawn from the European market by its manufacturer. Despite this the evidence and recommendations for
CCH has been maintained by the Guidelines for completeness.

The original treatment protocol in all studies consists of two injections of 0.58 mg of CCH 24-72 hours apart
every 6 weeks for up to four cycles. Data from IMPRESS (Investigation for Maximal Peyronie´s Reduction
Efficacy and Safety Studies) II and II studies [976], as well as post approval trials [954], which demonstrated
the efficacy and safety of this treatment, and are summarised in Table S8.2 online supplementary evidence
Appendix 4.

The average improvement in curvature was 34% compared to 18.2% in the placebo group. Three adverse events
of corporeal rupture were surgically repaired. The greatest chance of curvature improvement was for curvatures
between 30° and 60°, longer duration of disease, IIEF > 17, and no calcification [912]. An 18.2% improvement
from baseline in the placebo arm was also observed. These findings raise questions regarding the proposed role
of plaque injection and penile modelling, regardless of the medication, in improving outcomes in men with PD as
the placebo or modelling arm resulted in relatively high curvature reduction compared to the treatment arm.

The conclusion of the IMPRESS I and II studies is that that CCH improves PD both physically and psychologically
[955]. A post hoc meta-analysis of the IMPRESS studies demonstrated better results in patients with curvatures
< 60o, > 2 years of onset, no calcification in the plaque and good erectile function [954].

Thereafter, a modified short protocol consisting of administration of a single (0.9 mg, one vial) injection per
cycle distributed along three lines around the point of maximum curvature up to three cycles, separated by
4-weekly intervals, has been proposed and rapidly popularised replacing physician modelling with a multi-
modal approach through penile stretching, modelling and VED at home [956]. The results from this modified
protocol were comparable to the results of the IMPRESS trials and appeared to decrease the cost and duration
of treatment, although these studies were non-randomised. However, these results were further explored in a
prospective non-randomised multi-centre study [982]. In another large single-arm multi-centre clinical study
using the shortened protocol, longer PD duration, greater baseline PC and basal and dorsal plaque location were
identified as clinically significant predictors of treatment success [957]. Accordingly, a nomogram developed
to predict treatment success after CCH for PD showed that patients with longer PD duration, greater baseline
penile curvature and basal plaque location had a greater chance of treatment success [957]; however, these
findings need to be externally validated.

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Regarding safety concerns, most PD patients treated with CCH experienced at least one mild or moderate
adverse event localised to the penis (penile haematoma (50.2%), penile pain (33.5%), penile swelling (28.9%) and
injection site pain (24.1%)), which resolved spontaneously within 14 days of injection [958]. The adverse reaction
profile was similar after each injection, regardless of the number of injections administered. Serious treatment-
emergent adverse events (TEAEs) (0.9%) included penile haematoma and corporeal rupture that require surgical
treatment. According to IMPRESS data and the shortened protocol, to prevent serious TEAEs men should be
advised to avoid sexual intercourse in the four weeks following injection. Recent preliminary data suggest that
treatment in the acute phase of the disease is effective and safe [922, 959-963].

Regarding safety concerns, most PD patients treated with CCH experienced at least one mild or moderate
adverse event localised to the penis (penile haematoma (50.2%), penile pain (33.5%), penile swelling (28.9%) and
injection site pain (24.1%), which resolved spontaneously within 14 days of injection [916]. The adverse reaction
profile was similar after each injection, regardless of the number of injections administered. Serious treatment-
emergent adverse events (TEAEs) (0.9%) included penile haematoma and corporeal rupture that require surgical
treatment. According to IMPRESS data and the shortened protocol, to prevent serious TEAEs men should be
advised to avoid sexual intercourse in the four weeks following injection. Recent preliminary data suggest that
treatment in the acute phase of the disease is effective and safe [880, 917-921].

In conclusion, CCH is a safe and established treatment for stable-phase disease with more recent evidence
suggesting that CCH also has a role in affecting the progression of active-phase disease. It should also be noted
that there is a large effect of traction or modelling in controlled studies, whilst studies reporting on modified
protocols have small numbers of patients and are largely uncontrolled. Therefore, patients should be counselled
fully on the efficacy of collagenase and the high cost of treatment.

It has been suggested that those patients with severe curvature may also benefit from CCH injections because
of a potential downgrading of the penile curvature: a decrease in curvature may allow for a penile plication
procedure instead of a plaque incision and grafting procedure, therefore avoiding the more negative impact on
erectile function from plaque incision and grafting. However, further studies are required to validate these initial
findings [922, 963].

Interferon α-2b
Intralesional injections (5x10^6 units of IFN-α2b in 10 mL saline every 2 weeks over 12 weeks for a total of six
injections) significantly improved penile curvature, plaque size and density, and pain compared to placebo.
Additionally, penile blood flow parameters are benefited by IFN-α2b [953, 964, 965]. Regardless of plaque
location, IFN-α2b is an effective treatment option. Treatment with IFN-α2b provides a > 20% reduction in
curvature in most men with PD, independent of plaque location [966]. Given the mild adverse effects, which
include sinusitis and flu-like symptoms, which can be effectively treated with NSAIDs before IFN-α2b injection,
and the moderate strength of data available, IFN-α2b is currently recommended for treatment of stable-phase
PD.

Steroids, hyaluronic acid and botulinum toxin (botox)

In the only single-blind, placebo-controlled study with intralesional administration of betamethasone, no
statistically significant changes in penile deformity, penile plaque size, and penile pain during erection were
reported [967]. Adverse effects include tissue atrophy, thinning of the skin and immunosuppression [968]. The
effect of hyaluronic acid treatment in patients with PD was investigated in a non-randomised study; intralesional
injection of hyaluronic acid was compared to intralesional verapamil in acute phase PD and significant
improvement of pain, curvature and IIEF-15 was observed [969]. In an RCT, oral administration of hyaluronic
acid combined with intralesional injection was found to be superior to intralesional injection only and an
improvement of 7.8±3.9 degrees in curvature and reduction in plaque size of 3.0 mm was observed [970]. There
is only a single study evaluating intralesional botox injections in men with PD; therefore, there is insufficient
evidence to support this treatment in clinical practice [971].

Platelet Rich Plasma (PRP)

Few studies in humans have evaluated the effect of PRP on penile curvature, plaque size, PDQ and IIEF [972-
977]. The effect of PRP in patients with PD remains to be proven and should be considered experimental. An
ongoing phase 2b randomised placebo-controlled crossover trial have enrolled 25 patients with a planned target
of 80 men with PD: first ongoing data on nine patients in treatment group vs eight in placebo group showed no
difference in curvature at three months in comparison to baseline [978]. A summary of available studies can
be found in Table S8.3 online supplementary evidence Appendix 4 (https://uroweb.org/guidelines/sexual-and-
reproductive-health/publications-appendices).

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 81

8.2.3.1.3 Topical treatments
Topical verapamil and H-100 Gel
There is insufficient evidence that topical treatments (verapamil and H-100 Gel) applied to the penile shaft, with
or without the use of iontophoresis (now known as transdermal electromotive drug administration), result in
adequate levels of the active compound within the tunica albuginea [979-982].

8.2.3.1.4 Other treatments

Extracorporeal shockwave treatment
The mechanism of action involved in ESWT for PD is still unclear.

Four RCTs and one meta-analysis [983-987] assessed the efficacy of ESWT for PD. Three were sham-controlled
trials while one compared ESWT with the combination of ESWT and PDE5I (tadalafil) [988].

All trials showed positive findings in terms of pain relief, but no effect on penile curvature and plaque size.
Inclusion criteria varied widely among studies and further investigation is needed. Therefore, ESWT should
not be used a primary treatment for penile curvature in men with PD. The results are summarised in Table
S8.4 online supplementary evidence Appendix 4 (https://uroweb.org/guidelines/sexual-and-reproductive-health/
publications-appendices).

Penile traction therapy

In men with PD, potential mechanisms for disease modification with penile traction therapy (PTT) have been
proposed, including collagen remodelling via decreased myofibroblast activity and matrix metalloproteinase
up-regulation [989, 990].

The stated clinical goals of PTT are to non-surgically reduce curvature, enhance girth, and recover lost length,
which are attractive to patients with PD. However, clinical evidence is limited due to the small number of
patients included (267 in total), the heterogeneity in the study designs, and the non-standardised inclusion and
exclusion criteria which make it impossible to draw any definitive conclusions about this therapy [991-995].

Most of the included patients will need further treatment to ameliorate their curvature for satisfactory sexual
intercourse. Moreover, the effect of PTT in patients with calcified plaques, hourglass or hinge deformities which
are, theoretically, less likely to respond to PTT has not been systematically studied. In addition, the treatment
can result in discomfort and be inconvenient as the device needs to be used for an extended period (2-8 hours
daily), but has been shown to be tolerated by highly-motivated patients. There were no reported serious adverse
effects, including skin changes, ulcerations, hypo-aesthesia or diminished rigidity [993, 996]. A summary of
the clinical evidence for PTT can be found in in Table S8.5 online supplementary evidence Appendix 4 (https://
uroweb.org/guidelines/sexual-and-reproductive-health/publications-appendices).
In conclusion, PTT seems to be effective and safe for patients with PD [997], but there is still lack of
evidence to give any definitive recommendation in terms of its use as a monotherapy for PD.

Vacuum erection device

Vacuum erection device (VED) therapy results in dilation of cavernous sinuses, decreased retrograde venous
blood flow and increased arterial inflow [998]. Intracorporeal molecular markers are affected by VED application,
including decreases in hypoxia-inducible factor-1α, TGF-β1, collagenase, and apoptosis, and increases
endothelial nitric oxide synthase (eNOS) and α-smooth muscle actin, given their role in the pathogenesis of PD
[999]. Only two retrospective studies assessed the efficacy of VED therapy in mechanically straightening the
penile curvature of PD as monotherapy and further studies are needed [1000, 1001].

Multimodal treatment
There are some evidence suggesting that a combination of different oral agents can be used for treatment of
the acute phase of PD. However, there does not seem to be a consensus on which drugs to combine or the
optimum drug dosage; nor has there been a comparison of different drug combinations.
A long-term study assessing the role of multimodal medical therapy (injectable verapamil associated
with antioxidants and local diclofenac) demonstrated that treatment was efficacious to treat PD patients. It
concluded that combination therapy reduced pain more effectively than verapamil alone, making this specific
combination treatment more effective compared to monotherapy [999]. Furthermore, combination protocols
including injectable therapies, such as CCH, have been studied in controlled trials. The addition of adjunctive
PTT and VED has been described; however, limited data are available regarding their use [1002].

82 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Penile traction therapy has been evaluated as an adjunct therapy to intralesional injections with interferon,
verapamil, or CCH [943, 1003, 1004]. These studies have failed to demonstrate significant improvements in
penile length or curvature, with the exception of one subset analysis identifying a 0.4 cm length increase among
men using the devices for > 3 hours/day [1004]. A meta-analysis demonstrated that men who used PTT as an
adjunct to surgery or injection therapy for PD had, on average, an increase in stretched penile length (SPL) of 1
cm compared to men who did not use adjunctive PTT. There was no significant change in curvature between the
two groups [1005].
Data available on the combined treatment of CCH and the use of VED between injection intervals
have shown significant mean improvements in curvature (-17o) and penile length (+0.4 cm) after treatment.
However, it is not possible to determine the isolated effect of VED because of a lack of control groups [956,
1005].
Data have suggested that combination of PDE5I (sildenafil 25 mg twice daily) after CCH treatment
(shortened protocol combined with VED) is superior to CCH alone for improving penile curvature and erectile
function [1006]. Further studies are necessary to externally validate those findings.

8.2.3.1.5 Summary of evidence and recommendations for conservative treatment of Peyronie’s disease

Summary of evidence LE
Conservative treatment for PD is primarily aimed at treating patients in the early stage of the disease in 3c
order to relieve symptoms and prevent progression.
There is no convincing evidence supporting oral treatment with acetyl esters of carnitine, vitamin E, 3c
potassium para-aminobenzoate (potaba) and pentoxifylline.
Due to adverse effects, treatment with oral tamoxifen is no longer recommended. 3c
Nonsteroidal anti-inflammatory drugs can be used to treat pain in the acute phase. 4
Contradictory evidence is available for intralesional treatment with calcium channel antagonists: 4
verapamil and nicardipine.
Intralesional treatment with Collagenase Clostridium histolyticum showed significant decreases in 1b
penile curvature, plaque diameter and plaque length in men with stable disease.
Intralesional treatment with interferon may improve penile curvature, plaque size, density, and pain. 2b
Intralesional treatment with steroids have been shown to have adverse effects, including tissue atrophy, 3c
thinning of the skin and immunosuppression.
No high-level evidence is available to support treatment with intralesional hyaluronic acid or botulinum 3c
toxin.
Intralesional hyaluronic acid may be used to improve pain, penile curvature and IIEF scores. 2b
Combination of oral and intralesional hyaluronic acid treatment improves penile curvature and plaque 1b
size.
There is no evidence that topical treatments applied to the penile shaft result in adequate levels of the 3c
active compound within the tunica albuginea.
There is no efficacy data for the use of iontophoresis. 3c
Extracorporeal shockwave treatment may be offered to treat penile pain, but it does not improve penile 2b
curvature and plaque size.
Treatment with penile traction therapy alone or in combination with injectable therapy as part of a 3c
multimodal approach may reduce penile curvature and increase penile length, although the available
studies have considerable limitations.

Recommendation Strength rating

Offer conservative treatment to patients not fit for surgery or when surgery is not acceptable Strong
to the patient.
Fully counsel patients regarding all available treatment options and outcomes before Strong
starting any treatment.
Do not offer oral treatment with vitamin E, potassium para-aminobenzoate (potaba), Strong
tamoxifen, pentoxifylline, colchicine and acetyl esters of carnitine to treat Peyronie’s disease
(PD).

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 83

Use nonsteroidal anti-inflammatory drugs to treat penile pain in the acute phase of PD. Strong
Use extracorporeal shockwave treatment (ESWT) to treat penile pain in the acute phase of Weak
PD.
Use phosphodiesterase type 5 inhibitors to treat concomitant erectile dysfunction or if the Weak
deformity results in difficulty in penetrative intercourse in order to optimise penetration.
Offer intralesional therapy with interferon alpha-2b to patients with stable curvature dorsal or Weak
lateral > 30 degrees seeking a minimal invasive procedure.
Offer intralesional therapy with Collagenase Clostridium Histolyticum to patients with Strong
stable PD and dorsal or lateral curvature > 30 degrees, who request non-surgical treatment,
although the placebo effects are high.
Do not offer intralesional treatment with steroids to reduce penile curvature, plaque size or Strong
pain.
Do not use intralesional platelet-rich plasma or hyaluronic acid, either alone or in Strong
combination with oral treatment, to reduce penile curvature, plaque size or pain outside the
confines of a clinical trial.
Do not offer ESWT to improve penile curvature and reduce plaque size. Strong
Offer penile traction devices and vacuum devices to reduce penile deformity or as part of a Weak
multimodal therapy approach, although outcome data is limited.

8.2.3.2 Surgical treatment

Although conservative treatment for PD may resolve painful erections in most men, only a small percentage
experience significant straightening of the penis. The aim of surgery is to correct curvature and allow
penetrative intercourse. Surgery is indicated in patients with significant penile deformity and difficulty with
intercourse associated with sexual bother. Patients must have a stable disease for 3-6 months (or more than
9-12 months after onset of PD) [913, 1007, 1008]. In addition to this requirement, there are other situations that
may precipitate an indication for surgery, such as failed conservative or medical therapies, extensive penile
plaques, or patient preference, when the disease is stable [1009, 1010].

Before considering reconstructive surgery, it is recommended to document the size and location of penile
plaques, the degree of curvature, complex deformities (hinge or hourglass), the penile length and the presence
or absence of ED. The potential aims and risks of surgery should be fully discussed with the patient so that he
can make an informed decision [1008]. Specific issues that should be mentioned during this discussion are:
risk of penile shortening; ED, penile numbness; and delayed orgasm, the risk of recurrent curvature, potential
for palpation of knots and stitches underneath the skin, potential need for circumcision at the time of surgery,
residual curvature and the risk of further penile wasting with shortening procedures [913, 1011]. Selection
of the most appropriate surgical intervention is based on penile length assessment, curvature severity and
erectile function status, including response to pharmacotherapy in cases of ED [913]. Patient expectations from
surgery must also be included in the pre-operative assessment. The main objective of surgery is to achieve
a “functionally straight” penis, and this must be fully understood by the patient to achieve the best possible
satisfaction outcomes after surgery [1008, 1012].

Three major types of reconstruction may be considered for PD: (i) tunical shortening procedures; (ii) tunical
lengthening procedures; and, (iii) penile prosthesis implantation, with or without straightening techniques in the
presence of concomitant ED and residual curvature [1013, 1014].

Penile degloving with associated circumcision (as a means of preventing post-operative phimosis) should be
considered the standard approach for all types of procedures, although modifications have been described.
Only one study has suggested that circumcision is not always necessary (e.g., in cases where the foreskin is
normal pre-operatively) [1015]. Non-degloving techniques have been described that have been shown to prevent
ischaemia and lymphatic complications after subcoronal circumcision [1016, 1017].

There are no standardised questionnaires for the evaluation of surgical outcomes. Data from well-designed
prospective studies are scarce, with low levels of evidence. Data are mainly based on retrospective single-centre
studies, typically non-comparative and non-randomised, or on expert opinion [913, 1018]. Therefore, surgical
outcomes must be treated with caution.

8.2.3.2.1 Tunical shortening procedures

Tunical shortening procedures achieve straightening of the penis by shortening the longer, convex side of the

84 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

penis. For men with good erectile function, adequate penile length, without complex deformities, such as an
hourglass or hinge type narrowing abnormalities, and non-severe curvature, a tunical shortening procedure can
be considered an appropriate surgical approach. Numerous different techniques have been described, although
they can be classified as excisional, incisional and plication techniques. The Nesbit procedure operation is
based on an elliptical excision of tunica albuginea opposite to the point of maximum curvature [1019, 1020].

The Yachia technique is based on a completely different concept, as it utilises the Heinke-Mikowitz principle
for which a longitudinal tunical incision is closed transversely to shorten the convex side of the penis. This
technique, initially described by Lemberger in 1984, was popularised by Yachia in 1990, when he reported a
series of 10 cases [1021-1026].

Pure plication techniques are simpler to perform. They are based on single or multiple plications performed
without making excisions or incisions on the tunical albuginea, to limit the potential damage to the veno-
occlusive mechanism [916, 1027-1043]. Another modification described the ’16-dot’ technique that consists of
application of two pairs of parallel Essed-Schroeder plications tensioned more or less depending on the degree
of curvature [1044-1047]. Results and satisfaction rates are similar to both incision/excision techniques.

In general, using these tunical shortening techniques, complete penile straightening is achieved in > 85% of
patients. Recurrence of the curvature and penile hypo-aesthesia is uncommon (~10%) and the risk of post-
operative ED is low. Penile shortening is the most commonly reported adverse outcome of these procedures.
Shortening of 1-1.5 cm has been reported for 22-69% of patients, which is rarely the cause of post-operative
sexual dysfunction and patients may perceive the loss of length as greater than it actually is. It is therefore
strongly advisable to measure and document the penile length peri-operatively, both before and after the
straightening procedure, whichever the technique used (Table 8.2).

As mentioned above, there are multiple techniques with small modifications and all of them have been reported
in retrospective studies, most of them without appropriate comparison between techniques and therefore the
level of evidence is not sufficient to recommend one particular method over another.

Table 8.2: Results of tunical shortening procedures for PD (data from different, non-comparable studies)
[916, 1021-1044, 1048-1051]

Tunical shortening procedures

Nesbit Modified Yachia 16-dot / Simple
Nesbit mod16-dot plication
No. of patients/studies 652 / 4 387 / 5 150 / 6 285 / 5 1068 / 18
Significant penile 8.7% (5-39) 3.2% (0-13) 3.5% (0-10) 5.9% (0-6) 8.9% (0-55)
shortening (%)*†
Any penile shortening 21.8% (9-39) 58.% (23-74) 69% (47-97) 44.6% (40-52) 33.4% (0-90)
(%)*
Penile straightening (%)* 88.5% (86-100) 97.6% (92-100) 95.5% (93-100) 96.9% (95-100) 94.7% (85-100)
Post-operative de novo 6.9% (0-17) 3% (0-13) 9.6% (0-13) 3.8% (0-13) 8.1% (0-38)
ED (%)*
Penile hypoesthesia 11. 8% (2-60) 5.6% (0-31) 1% (0-3) 8.2% (6-13) 9% (0-47)
(%)*
Overall satisfaction (%)* 83.5% (76-88) 95.4% (87-100) 86.8% (78-100) 94% (86-100) 86.4% (52-100)
Follow-up (months)* (69-84) (19-42) (10-24) (18-71) (12-141)
*Data are expressed as weighted average. † Defined as > 30 degrees of curvature. Ranges are in parentheses.
ED = Erectile dysfunction.

8.2.3.2.2 Tunical lengthening procedures

Tunical lengthening procedures are performed on the concave side of the penis after making an incision or
partial excision of the plaque, with coverage of the defect with a graft. Although tunical lengthening procedures
rarely lead to long-term penile length gain, they aim to minimise penile shortening caused by plication of
the tunica albuginea, and correct complex deformities. In practice, tunical lengthening procedures are often
combined with penile plication or shortening procedures to correct residual curvature and therefore may also
result in penile shortening [1052]. Tunical lengthening surgery is preferable in patients with significant penile

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 85

shortening, severe curvature and/or complex deformities (hourglass or hinge) but without underlying ED. The
definition of severe curvature has been proposed to be > 60o, although no studies have validated this threshold.
On the concave side of the penis, at the point of maximum curvature, which usually coincides with the location
of the plaque, an incision is made, creating a defect in the albuginea that is covered with a graft. Complete
plaque removal or plaque excision may be associated with higher rates of post-operative ED due to venous leak,
but partial excision in cases of florid calcification may be permissible [1053, 1054]. Patients who do not have
pre-operative ED should be informed of the significant risk of post-operative ED of up to 50% [1011].

A large number of different grafts have been used. The ideal graft should be resistant to traction, easy to
suture and manipulate, flexible (although not too much, to avoid aneurysmal dilations), readily available, cost-
effective, and morbidity should be minimal, especially when using autografts. No graft material meets all of
these requirements. Moreover, the studies performed did not compare different types of grafts and biomaterials
and were often single-centre retrospective studies so there is not a single graft that can be recommended for
surgeons [1055]. The use of geometric principles introduced by Egydio may help to determine the exact site of
the incision, and the shape and size of the defect to be grafted [1056].

Grafts for PD surgery can be classified into four types [1057]:

• Autografts: taken from the individual himself, they include the dermis, vein, temporalis fascia, fascia lata,
tunica vaginalis, tunica albuginea and buccal mucosa.
• Allografts: also of human origin but from a deceased donor, including the pericardium, fascia lata and dura
mater.
• Xenografts: extracted from different animal species and tissues, including bovine pericardium, porcine
small intestinal submucosa, bovine and porcine dermis, and TachoSil® (matrix of equine collagen).
• Synthetic grafts: these include Dacron® and Gore-Tex®.

All the autologous grafts have the inconvenience of possible graft harvesting complications. Dermal grafts are
commonly associated with veno-occlusive ED (20%) due to lack of adaptability, so they have not been used in
contemporary series [1055, 1058-1069]. Vein grafts have the theoretical advantage of endothelial-to-endothelial
contact when grafted to underlying cavernosal tissue. The saphenous vein has been the most commonly used
vein graft [1070-1085]. For some extensive albuginea defects, more than one incision may be needed. Tunica
albuginea grafts have perfect histological properties but have some limitations: the size that can be harvested,
the risk of weakening penile support and making future procedures (penile prosthesis implantation) more
complicated [1086-1088]. Tunica vaginalis is easy to harvest and has little tendency to contract due to its low
metabolic requirements, although better results can be obtained if a vascular flap is used [1089-1093]. Under the
pretext that by placing the submucosal layer on the corpus cavernosum the graft feeds on it and adheres more
quickly, the buccal mucosal graft has recently been used with good short-term results [1094-1100].

Cadaveric dura mater is no longer used due to concerns about the possibility of infection [1101, 1102].
Cadaveric pericardium (Tutoplast©) offers good results by coupling excellent tensile strength and
multidirectional elasticity/expansion by 30% [992, 1054, 1065, 1103, 1104]. Cadaveric or autologous fascia lata
or temporalis fascia offers biological stability and mechanical resistance [1105-1107].

Xenografts have become more popular in recent years. Small intestinal submucosa (SIS), a type I collagen-
based xenogenic graft derived from the submucosal layer of the porcine small intestine, has been shown to
promote tissue-specific regeneration and angiogenesis, and supports host cell migration, differentiation and
growth of endothelial cells, resulting in tissue structurally and functionally similar to the original [1108-1117].
As mentioned above, pericardium (bovine, in this case) has good traction resistance and adaptability, and good
host tolerance [1085, 1118-1121]. Grafting by collagen fleece (TachoSil©) in PD has some major advantages
such as decreased operating times, easy application and an additional haemostatic effect [1122-1127].

It is generally recommended that synthetic grafts, including polyester (Dacron®) and polytetrafluoroethylene
(Gore-Tex®) are avoided, due to increased risks of infection, secondary graft inflammation causing tissue
fibrosis, graft contractures, and possibility of allergic reactions [1024, 1128-1131].

Post-operative penile rehabilitation to improve surgical outcomes has been suggested with a number of
studies describing the use of VED and PTT to prevent penile length loss of up to 1.5 cm [1132]. Daily nocturnal
administration of PDE5I enhances nocturnal erections, encourages perfusion of the graft, and may minimise
post-operative ED rates [1133]. Massages and stretching of the penis have also been recommended once
wound healing is complete.

86 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Table 8.3: Results of tunical lengthening procedures for PD (data from different, non-comparable studies)
[992, 1024, 1054, 1058-1127, 1134, 1135]

Year of No. of Success (%)* Penile De novo ED Follow-

publication patients / shortening (%)* up (mo)*
studies (%)*
Autologous grafts
Dermis 1974-2019 718 / 12 81.2% (60-100) 59.9% (40-75) 20.5% (7-67) (6-180)
Vein grafts 1995-2019 690 / 17 85.6% (67-100) 32.7% (0-100) 14.8% (0-37) (12-120)
Tunica albuginea 2000-2012 56 / 3 85.2% (75-90) 16.3% (13-18) 17.8% (0-24) (6-41)
Tunica vaginalis 1980-2016 76 / 5 86.2% (66-100) 32.2% (0-83) 9.6% (0-41) (12-60)
Temporalis fascia / 1991-2004 24 / 2 100% 0% 0% (3-10)
Fascia lata
Buccal mucosa 2005-2016 137 / 7 94.1% (88-100) 15.2% (0-80) 5.3% (0-10) (12-45)
Allografts (cadaveric)
Pericardium 2001-2011 190 / 5 93.1% (56-100) 23.1% (0-33) 37.8% (30-63) (6-58)
Fascia lata 2006 14 / 1 78.6% 28.6% 7.1% 31
Dura matter 1988-2002 57 / 2 87.5% 30% 17.4% (15-23) (42-66)
Xenografts
Porcine SIS 2007-2018 429 / 10 83.9% (54-91) 19.6% (0-66) 21.9% (7-54) (9-75)
Bovine pericardium 2002-2020 318 / 6 87.4% (76.5-100) 20.1% (0-79.4) 26.5% (0-50) (14-67)
Bovine dermis 2016 28 / 1 93% 0% 25% 32
Porcine dermis 2020 19 / 1 73.7% 78.9% 63% 85
TachoSil® 2002-2020 529 / 7 92.6% (83.3-97.5) 13.4% (0-93) 13% (0-21) (0-63)
*Data are expressed as weighted average. Ranges are in parentheses.
ED = Erectile dysfunction; SIS = small intestinal submucosa.

It must be emphasised that there have been no RCTs comparing surgical outcomes in PD. The risk of ED
seems to be greater for penile lengthening procedures [913]. Recurrent curvature is likely to be the result
of failure to wait until the disease has stabilised before surgery is undertaken, re-activation of the condition
following the development of stable disease, or the use of early re-absorbable sutures (e.g., Vicryl) that lose
their tensile strength before ensuing fibrosis has resulted in acceptable strength of the repair. Accordingly, it is
recommended that only non-absorbable sutures or slowly re-absorbed absorbable sutures (e.g., polydioxanone)
should be used. With non-absorbable sutures, the knot should be buried to avoid troublesome irritation of the
penile skin, but this issue may be alleviated by the use of slowly re-absorbable sutures (e.g., polydioxanone)
[1136]. Penile numbness is a potential risk of any surgical procedure, involving mobilisation of the dorsal
neurovascular bundle. This is usually a temporary neuropraxia, due to bruising of the dorsal sensory nerves.
Given that the usual deformity is a dorsal deformity, the procedure most likely to induce this complication is a
lengthening (grafting) procedure, or the association with (albeit rare) ventral curvature [1013].

8.2.3.2.3 Penile prosthesis

Penile prosthesis (PP) implantation is typically reserved for the treatment of PD in patients with concomitant
ED not responding to conventional medical therapy (PDE5I or intracavernous injections of vasoactive agents)
[913]. Although inflatable prostheses (IPPs) have been considered more effective in the general population with
ED, some studies support the use of malleable prostheses in these patients with similar satisfaction rates [913,
1137, 1138]. The evidence suggests that there is no real difference between the available IPPs [1139]. Surgeons
can and should advise on which type of prosthesis best suits their patient but it is the patient who should
ultimately choose the prosthesis to be implanted [1140].

Most patients with mild-to-moderate curvature can expect an excellent outcome simply by cylinder insertion
[1083, 1141]. If the intra-operative curvature after placement of the prosthesis is < 30° no further action is
indicated, since the prosthesis itself will act as an internal tissue expander to correct the curvature during the
subsequent 6-9 months. If, the curvature is > 30°, the first-line treatment should be modelling with the prosthesis
maximally inflated (manually bent on the opposite side of the curvature for 90 seconds, often accompanied by
an audible crack) [1142, 1143]. If, after performing this manoeuvre, a deviation > 30° persists, subsequent steps

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 87

to be considered include incision with or without collagen fleece coverage (if the defect is small, it can be left
uncovered) or plaque incision and grafting is performed [1144-1149]. However, the defect may be covered if it is
larger, and this can be accomplished using grafts commonly used in grafting surgery (described above) which
prevent herniation and recurrent deformity and buckling due to the scarring of the defect [1150, 1151]. The risk
of complications (infection, malformation, etc.) is not increased compared to that in the general population.
However, a small risk of urethral perforation (3%) has been reported in patients with ‘modelling’ over the inflated
prosthesis [1142].

In selected cases of end-stage PD with ED and significant penile shortening, a lengthening procedure, which
involves simultaneous PP implantation and penile length restoration, such as the “sliding” technique has been
proposed [1152]. However, the “sliding” technique is not recommended due to reported cases of glans necrosis
because of the concomitant release of the neurovascular bundle and urethra, new approaches for these patients
have been recently described, such as the MoST (Modified Sliding Technique), MUST (Multiple-Slit Technique)
or MIT (Multiple-Incision Technique) techniques, but these should only be used by experienced high-volume
surgeons and after full patient counselling [1153-1156].

While patient satisfaction after IPP placement in the general population is high, satisfaction rates have been
found to be significantly lower in those with PD. Despite this, depression rates decreased after surgery in PD
patients (from 19.3%-10.9%) [1157]. The main cause of dissatisfaction after PPI in the general population is
shortening; therefore, patients with PD undergoing PP surgery must be counselled that the prostheses are not
designed to restore the previous penile length [1157, 1158].

8.2.3.2.4 Summary of evidence and recommendations for surgical treatment of Peyronie’s disease

Summary of evidence LE
Surgery for PD should only be offered in patients with stable disease and with functional impairment. 2b
In patients with concomitant PD and ED without response to medical treatment, penile prosthesis 2a
implantation with or without additional straightening manoeuvres is the technique of choice.
In other cases, factors such as penile length, rigidity of erection, degree of curvature, presence 3
of complex deformities and patient choice must be taken into account when deciding whether to
undertake tunical shortening or lengthening procedures.

Recommendation Strength rating

Perform surgery only when Peyronie’s disease (PD) has been stable for at least three months Strong
(without pain or deformity deterioration), which is usually the case after twelve months from
the onset of symptoms, and intercourse is compromised due to the deformity.
Assess penile length, curvature severity, erectile function (including response to Strong
pharmacotherapy in case of erectile dysfunction [ED]) and patient expectations prior to
surgery.
Use tunical shortening procedures as the first treatment option for congenital penile Weak
curvature and for PD with adequate penile length and rigidity, less severe curvatures and
absence of complex deformities (hourglass or hinge). The type of procedure used is
dependent on surgeon and patient preference, as no procedure has proven superior to its
counterparts.
Use tunical lengthening procedures for patients with PD and normal erectile function, without Weak
adequate penile length, severe curvature or presence of complex deformities (hourglass or
hinge). The type of graft used is dependent on the surgeon and patient preference, as no
graft has proven superior to its counterparts.
Do not use the sliding technique as there is a significant risk of life changing complications Strong
(e.g., glans necrosis).
Do not use synthetic grafts in PD reconstructive surgery. Strong
Use penile prosthesis implantation, with or without any additional straightening procedures Strong
(modelling, plication, incision or excision with or without grafting), in PD patients with ED not
responding to pharmacotherapy.

88 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Figure 8.1: Treatment algorithm for Peyronie’s disease

Treatment of Peyronie’s disease

Discuss natural history of the disease

Reassure pa ent that Peyronie’s doesn’t lead to
any form of malignancy
Discuss current treatment modali es
Shared decision-making

Active disease Stable disease

(pain, deformity deteriora on, (no pain, no deformity
progressive curvature) deteriora on, stable penile
curvature)

Pain control (consider NSAIDs,

tadalafil or LI-ESWT) Pa ent desires ac ve
Op onal: Trac on therapy, treatment
intralesional CCH or IFN-α2b

No ED ED

Response
Yes to ED
treatment

Palpable dorsal plaques Adequate penile Short penis

Non-calcified plaques length Severe curvature
Dorsal Curvature 30°-90° Absence of severe Complex deformies
No
Contraindicaons for curvature (hourglass, hinge)
surgery/paent does not Absence of complex
want surgery deformies

Intralesional Tunical shortening Tunical lengthening Penile

injecon treatment: procedures procedures prosthesis
CCH or interferon

Residual
> 30°
curvature

Manual
modeling

Residual
> 30° < 30°
curvature

Tunical plicaon/ No addional

Plaque incision + straightening
graŽing procedures

Diagnosis Treatment Follow-up

ED = erectile dysfunction; LI-ESWT= low-intensity extracorporeal shockwave treatment; NSAIDs =non-steroidal

anti-inflammatory drugs; CCH = Collagenase Clostridium histolyticum; IFN-α2b = Interferon-α2b.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 89

9. PENILE SIZE ABNORMALITIES AND
DYSMORPHOPHOBIA
9.1 Definition, epidemiology and classification
9.1.1 History
Throughout history, the size of the penis has symbolised a marker of masculinity [1159] and has created
intense debate in societies with different social and cultural implications [1160]. Indeed, along with the capacity
for vaginal penetration, the penis is linked to an ancestral sense of men’s fertility and sexual performance,
making the size of the penis a source of distinguishing male identity [1161, 1162]. Evidence of male supremacy
and dominance as represented by phallometric designs can be found across cultures and history and is still
currently supported by contemporary media, including the pornographic industry [1163, 1164].

Overall, cosmetic surgery has the potential to restore self-esteem, reduce anxiety, social phobia and depressive
mood states regarding body concerns, increasing individuals’ well-being and quality of life (QoL) [1165, 1166].
Yet, some candidates for cosmetic surgery may have psychopathological conditions and surgery may result in
negative outcomes [1166, 1167].

In the real-life setting, it is interesting to note that 84% women report being satisfied with their male partners’
penile size whereas 55% of the male partners were satisfied with their penile size and 45% of them report
that they would like to have a larger penis [1168]. In this context, men with a high level of social-desirability
were more likely than others to self-report having a larger penis [1169]. A recent study also demonstrated that
reducing the depth of penetration led to a statistically significant 18% reduction of overall sexual pleasure with
an average 15% reduction in length of the penis [1170].

Additionally, the subjective impression of penile size may have a negative effect on sexual functioning and QoL,
impacting sexual life in about 10% of men [1171-1173]. This prevalence sharply rises in patients seeking penile
augmentation procedures [1174, 1175].

Furthermore, the fact that a subgroup of men does not achieve reasonable levels of satisfaction and emotional
adjustment after penile augmentation procedures, underlines that with certain psychopathological conditions
men will not benefit from such invasive procedures [1176]. These men may represent a psychologically
vulnerable group of individuals in whom penile augmentation procedures will have negative effects and, as
such, require clinical and psychological support. Clinicians should be adept to anticipate and address such
vulnerability through a tailored psychological evaluation and further consider cultural standards enabling an
understanding of patient expectations [1177].

With the increased use of penile augmentation procedures worldwide, either medical or surgical, it becomes
crucial to create evidence-based recommendations to guide clinicians in this challenging and controversial area.

9.1.2 Definition
To date short penis condition represents both a diagnostic and treatment challenge [1178, 1179]. An accurate
measurement of the penile shaft is a mandatory step in the assessment of patients complaining of a short
penis and defining the norm [1180]. Indeed, a standard tool to address penile measurements and to counsel
patients seeking penile augmentation procedures is needed. To date, the standard penile size has yet to be
clearly defined. Even though several investigators have attempted to provide objective measurements to define
a normal penile size, there is still no consensus on this (Table S9.1 online supplementary evidence Appendix 5).
The other factor that strongly affects penile measurements is the interobserver variability and the
underestimation of the stretched penile length (SPL) when compared to the erect state [1181].
Despite the aforementioned limitations, SPL, defined as the distance between the pubic symphysis
and the apex of the glans, represents the most overlapping measurement of the erect penis. Accordingly, a
SPL of less than 2.5 standard deviations (SD) below the mean for the male’s age and race is considered as
micropenis [1182, 1183].

90 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Summary of evidence LE
There is a difference between true micropenis (anatomical-endocrinological)/short penis (complaint)/ 4
buried penis (complaint short penis + obesity) (panel consensus). Small penis anxiety/syndrome refers
to a man’s excessive anxiety regarding his normal-sized penis.
A true micropenis is a congenital condition where the stretched penile length is 2.5 SD cm less than the 3
average length in the population group and is the result of an underlying genetic or endocrine condition.
A buried penis is a normal sized penis where there is functional and visible loss of penile length due to 3
an underlying pathological condition such as obesity or traumatic loss of length. The penis is covered
by prepubic, scrotal or penile subcutaneous tissue or skin.
Penile Dysmorphic Disorder is a shorthand concept applied to Body Dysmorphic Disorder cases 3
characterised by a strong focus on a perceived deficiency or flaw in a normal size or shape penis,
resulting in mental health impairment and significant damage in important areas of the individual’s life.

9.1.3 Epidemiology and Classification

The overall incidence of micropenis in the male population is not clearly documented. Epidemiological studies
demonstrate that between 0.015% - 0.66% of male newborns have a micropenis [1184, 1185]. There are
concerns that the prevalence of this congenital abnormality is increasing due to in utero exposure to endocrine-
disrupting chemicals before and during pregnancy [1185]. Despite the limited prevalence of micropenis, there is
a major demand for penile augmentation procedures worldwide. This phenomenon can be partially explained by
the increased interest in pornography in recent years and the altered perception of a normal penile size [1160,
1186, 1187].
Due to the heterogeneity of clinical situations related to short penis conditions, a classification based
on the underlying aetiology is provided below (Table 9.1).

Table 9.1: Classification of the clinical conditions underlying a short penis condition or dysmorphophobia in
adults

Group name Aetiology Definition Pathogenesis Prevalence,

%
False penile Acquired Reduced exposure of Adult acquired buried penis NA
shortness the penile shaft in the
presence of normal
penile size
Intrinsic penile Congenital Small penis due to an • Hypogonadotropic hypogonadism 0.9 - 2.1
shortness incomplete genital • Genetic syndromes
development secondary • Bladder exstrophy–epispadias
to a congenital condition complex
Intrinsic penile Acquired Shortening/shrinking of • Peyronie’s Disease NA
shortness the corpora cavernosa • Radical prostatectomy
due to an acquired • Radical cystectomy
pathological process • Radiation therapy
• Low flow priapism
• Multiple penile operations (e.g.,
urethral surgery or PP infection)
• Penile traumatic event (traumatic
or surgical amputation for penile
cancer)
Body Acquired Perceived defect or • Penile Dysmorphic Disorder 1.8 – 9.5
dysmorphic flaw in the individual’s
disorder physical appearance
followed by significant
distress or impairment
in important areas of the
individual’s life

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 91

9.1.3.1 False penile shortness - congenital or acquired
Among causes underlying a false penile shortness, the buried penis is the only well-known condition.
Historically, buried penis has been considered a congenital disease affecting children: the so-called “concealed
penis” or “webbed penis” [1188, 1189]. Indeed, an abnormal development of the dartos fascia may lead to the
entrapment of the penile shaft to the peri-genital tissue leading to this clinical manifestation. On the other hand,
buried penis in the adult is widely recognised as an acquired condition, termed as the adult acquired buried
penis (AABP) [1190].

The aetiology underlying the development of AABP is deemed to be related to a chronic inflammatory state of
the penile dartos which leads to a progressive retraction and scarring of the peri-genital teguments [1191, 1192].
The progressive entrapment of the phallus causes a moist environment which facilitates bacterial and fungal
growth causing chronic inflammation [1193]. The ensuing fibrosis results in further entrapment of the penile
shaft in the peri-genital tissue [1192, 1193].

Although the exact prevalence of AABP is unknown, its incidence seems to be increasing along with the
growing prevalence of obesity, which represents the main risk factor [1194]. Other factors contributing to AABP
include aggressive circumcision, following surgical treatment in the obese or penile cancer (PC), or chronic
dermatological conditions such as lichen sclerosis (LS) [1195].

The AABP is commonly associated with erectile and voiding dysfunctions, difficulties in maintaining
adequate genital hygiene and a poor QoL [1195-1197]. A summary of risk factors for AABP and
underlying issues requiring surgery is detailed in Table S9.2 online supplementary evidence Appendix 5
(https://uroweb.org/guidelines/sexual-and-reproductive-health/publications-appendices).

The aim of AABP treatment is to restore the functional genital anatomy and to improve QoL [1195, 1196]. So far,
different authors have proposed a number of classifications for AABP based upon both clinical presentation and
the surgical procedure required [1190, 1198].

9.1.3.2 Intrinsic penile shortness – congenital

This category encompasses the so-called “true micropenis” [1199-1201]. Despite male genital malformations
being recognised as the most common birth defects, they represent a rare clinical entity with a prevalence
between 0.9% and 2.1% [1202, 1203]. Normal genital development is under the influence of hormonal
stimulation during the fetal and pubertal periods [1204]. Several genetic syndromes may cause disturbance of
the physiological hormonal axis needed for a normal genital development [1199, 1205]. Micropenis may also
exist as an isolated finding without a definitive etiological cause in up to 25% of the cases. The classification of
the clinical conditions associated with intrinsic penile shortness in the adult is presented in Table 9.2.

Table 9.2: Classification of the clinical conditions underlying intrinsic penile shortness in adults

Aetiology Underlying causes

Hypogonadotropic hypogonadism • Genetic diseases
• Iatrogenic or traumatic injury to pituitary gland or hypothalamus
Hypergonadotropic Hypogonadism • Chromosomal alterations (e.g., Klinefelter Syndrome)
• Androgen Synthesis Defects
• Dysgenetic gonads
Syndromic or Multiple Congenital • Bladder exstrophy–epispadias complex
Anomalies • Hypospadias
Unknown -

Amongst the pre-existing clinical entities associated with micropenis, the bladder exstrophy–epispadias
complex (BEEC) is the most studied [1195, 1196, 1201]. It represents a spectrum of genitourinary malformations
ranging in severity from epispadias to bladder exstrophy or exstrophy of the cloaca. It is considered as a rare
disease, with a prevalence at birth of 1/10,000 [1199, 1201, 1203, 1206]. Even though surgical reconstruction
aims to improve body image, this clinical entity is frequently burdened by psychosocial and psychosexual
dysfunctions in the long term [1207-1213]. Additionally, male infertility is frequently associated due to poor
sperm quantity or quality and hormonal impairment [1214].

92 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

9.1.3.3 Intrinsic penile shortness – acquired
This category includes a series of pathological entities that lead to the shortening of the corpora cavernosa.
The different aetiologies are classified in Table 9.2. The mechanism underlying intrinsic penile shortening
can be acute, as in the case of penile trauma or surgical amputation due to penile cancer or chronic due to a
progressive fibrotic process involving the corpora cavernosa [1215-1217].

Traumatic genital injuries may commonly result from traffic accidents and gunshot wounds [1217]. Rarely, a
penile amputation can be the result of circumcision and genital surgical procedures such as hypospadias repair,
penile prosthesis implantation or urethroplasty, and may result in a decrease in penile length [1218-1222].

Among chronic causes of penile shortening, PD, treatments for prostate cancer, particularly radical
prostatectomy (RP) and radical cystectomy represent the most common [1174, 1215, 1216, 1223-1231].

9.1.3.4 Body dysmorphic disorder

Body dysmorphic disorder (BDD) is a clinical diagnosis defined by the American Psychiatric Association
(APA; DSM-5) as the strong distress generated by perceived defect(s) or flaw(s) in the individual’s physical
appearance. This flaw is not observable to others, or, in case it exists, it appears only slightly [1232]. This
condition is followed by significant impairment in important areas of the individual’s social or occupational
life. Body dysmorphic disorder has been allocated to the Obsessive Compulsive and Related Disorders section
[1232]. Muscle dysmorphia is a typology within BDD characterising individuals – usually men – with a strong
pre-occupation with their perceived small muscles and body shape. Sometimes, men with BDD/muscle
dysmorphia also present with an exaggerated focus on the size or shape of their penis. In those cases, Penile
Dysmorphic Disorder (PDD) can be used as a shorthand concept – not listed in APA’s DSM-5 coding system.
Both BDD and PDD are conceptually different from small penis anxiety (SPA) or small penis syndrome, which
refers to a man’s excessive anxiety regarding his normal-sized penis. Small penis anxiety is not included under
APA’s nomenclature but men with SPA may be at risk for BDD [1233]. All these definitions exclude men with true
micropenis [1232, 1234, 1235]. Prevalence data shows that 2.2% of men in the USA and 1.8% in Germany suffer
from BDD [1232]. Between 3%-16% of patients undergoing cosmetic surgery are expected to present BDD, a
higher rate in men (15.3%) than in women (10.9%) [1236].

These psychopathological entities must be differentiated from Gender Dysphoria, i.e., the clinical distress
associated with the incongruence between gender identity and the gender assigned at birth; and from Koro, i.e.,
sudden anxiety about the penis falling back into the abdomen [1232].

9.1.4 Summary of evidence and recommendations for classification

Summary of evidence LE
Male genital malformations represent a rare clinical entity with an overall prevalence between 0.9% and 3
2.1%.
Obesity, lichen sclerosis and penile cancer treatment are risk factors for AABP. 4
Adult acquired buried penis is commonly associated with erectile and voiding dysfunctions, difficulties 3
in maintaining adequate genital hygiene and a poor quality of life.
Adult acquired buried penis condition can be staged upon both clinical presentation and the surgical 3
procedure required according to available classification systems.
Bladder exstrophy–epispadias complex (BEEC) is a rare clinical condition frequently associated with 2b
male genital malformations, particularly micropenis.
Penile traumatic or surgical amputation due to penile cancer are the most common acute causes of 3
intrinsic penile shortening.
The most frequent aetiologies leading to a chronic intrinsic penile shortening are PD, treatments for 2b
prostate cancer (RP, radiation therapy and androgen-deprivation therapy) and radical cystectomy.
Body dysmorphic disorder (BDD) is a clinical entity associated with a significant distress or impairment 2b
in important areas of the individual’s life.
Penile Dysmorphic Disorder (PDD) can be used as a shorthand concept to describe BDD patients 4
mainly focused on penile size/shape.
Body dysmorphic disorder/PDD can be revealed in patients requiring cosmetic surgery. 3

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 93

Recommendations Strength rating
Perform a detailed genital examination in all men and particularly in men with BMI > 30, Strong
lichen sclerosis or penile cancer history and complaints of urinary/sexual difficulties or poor
cosmesis to exclude the presence of an adult acquired buried penis (AABP) condition.
Use classification systems to classify AABP clinical presentation and surgical management. Weak
Inquire on the presence of body dysmorphic disorder/penile dysmorphic disorder in patients Strong
with normal-sized penis complaining of short penile size.

9.2 Diagnosis
9.2.1 Medical history, physical examination and psychological assessment
9.2.1.1 Medical History
The first step in the evaluation of short penis is a detailed medical history [1237]. Common causes of penile
shortness should be screened and observed (e.g., history of phimosis, priapism, hypospadias/epispadias, penile
trauma, penile cancer, prostate cancer, penile pain with or without acquired penile curvature suggestive of PD). A
past or present diagnosis of BDD should also be noted.

9.2.1.2 Sexual history

Besides a comprehensive clinical interview with open questions regarding sexual education, development, or
previous sexual experiences and fantasies, psychometric tools can be used. These include measurements of
sexual functioning (e.g., The International Index of Erectile Function [IIEF]), sexual distress (e.g., The Sexual
Distress Scale for men), and sexual satisfaction (e.g., Global Measure of Sexual Satisfaction) [315, 1238, 1239].
The propensities for sexual excitation and sexual inhibition may be further considered, (e.g., Sexual Inhibition/
Sexual Excitation Scales), as well as measurements of relationship satisfaction (e.g., Global Measure of
Relationship Satisfaction) [1239, 1240]. Special focus should be put on the assessment of sexual performance
expectations (e.g., The Dysfunctional Sexual Beliefs Questionnaire) [1241]. As a complementary assessment,
body image perception can be further considered (e.g., The Body-Image Questionnaire).

9.2.1.3 Physical examination and penile size measurements

An accurate physical examination focused on the genital area is essential to the patient's initial assessment.
The assessment of penile size and shape is mandatory to plan any subsequent medical or surgical treatment
but methods for penile measurements seem to vary amongst surgeons [1180, 1242]. The EAU Guidelines Panel
on Sexual and Reproductive Health considers a stretch penile length measurement as the bare minimum. If
possible, the Panel also advocates additional measurements in both flaccid and erect state after intracavernosal
injection of erectogenic agents, compulsory before any surgical indication. Stretched penile length can be
measured both dorsally and/or ventrally from the penopubic skin junction-to-glans tip (STT) or dorsally from the
pubic bone-to-glans tip (BTT) using either a measuring tape or a Vernier calliper. Overall, the measurement of
penile size has not been standardised and to date there is no consensus definition due to high heterogeneity in
terms of data assessment and reporting methodologies amongst different studies [1242].

Moreover, penile girth should be noted in every patient. As for girth, both distal (coronal) and mid-shaft
measurements should be recorded. Furthermore, both measures of circumference can be compared to the
head-to-base ratio. The former can help classify penile shape which can be documented through photography
[1243]. Although used as a surrogate, STT clearly underestimates erect penile length by about 20% [918,
1244]. Nonetheless, it is important to note that BTT seems to have a better correlation with erect penile length,
especially in overweight and obese men [918].

94 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Table 9.3: Penile size measurement

Length
State
Erect, stretched or flaccid
Anatomic Landmarks
Dorsal and/or ventrally from the penopubic skin junction-to-glans tip (STT)
Dorsally from the pubic bone-to-glans tip (BTT)
Girth
State
Erect or flaccid
Anatomic Landmarks
Proximal (penopubic skin junction)
Middle shaft
Distal (Coronal or subcoronal)
Shape
Head-to-base ratio
Standardised photography

9.2.1.4 Psychological assessment

A sub-group of men requesting penile augmentation procedures, usually surgery, present with strong
psychological vulnerability, including BDD [1233]. This subgroup of men may be at risk for increasing
psychopathology and suicide attempts and will be unlikely to achieve their surgery expectations [1245].
Currently, there is a set of freely available self-reported tools that may be used to screen patients at risk for
psychopathology or poor surgical outcomes, including the Body Dysmorphic Disorder Questionnaire and The
Cosmetic Procedure Screening Scale for Penile Dysmorphic Disorder, screening for psychopathological cases
regarding body and penile dysmorphic disorder [1233, 1246]. Likewise, The Male Genital Self-Image Scale,
and the Index of Male Genital Image, measuring men’s perceptions and satisfaction regarding their genitals
[1247, 1248]. In addition, the Beliefs About Penile Size Scale captures beliefs about the size of the penis as
well as internal psychological processes [1249]. However, evidence on BDD/PDD, further psychopathological
comorbidities, and the differential diagnosis regarding personality disorders, and disorders from the obsessive-
compulsive, psychotic, or emotional spectrum, should be performed by an accredited mental health expert. In
addition, the subjective penile size perception should be evaluated [1176].

9.2.1.5 Counselling and outcomes assessment - Validated questionnaires

The Augmentation Phalloplasty Patient Selection and Satisfaction Inventory (APPSSI) questionnaire is a 5-item
questionnaire proposed for the assessment and counselling about penile augmentation surgical treatment
[1250]. The Beliefs about Penis Size (BAPS) is a 10-item questionnaire created for audit and outcome research
to assess men’s beliefs about penile size [1249]. Both questionnaires have failed to correlate with penile size
and lack of objective validation has restricted their use.

Other well-known self-reported psychosexual questionnaires may be considered: the IIEF-15 and the Male
Sexual Health Questionnaire (MSHQ) should be administered to record baseline sexual function status and can
also be used to assess its changes after treatment; the Erectile Dysfunction Inventory of Treatment Satisfaction
(EDITS) can also be helpful to assess patient and partner's treatment satisfaction [315, 1251, 1252].

9.2.2 Imaging
There is a lack of evidence regarding the use of imaging techniques in the assessment of patients complaining
about penile shortness. Although a penile Doppler ultrasound or a penile magnetic resonance imaging may
provide additional data regarding the penile anatomy and the extent of penile burying, there is no evidence that
this additional information could contribute to the physical examination to justify its routine use in this clinical
scenario [1180, 1253-1256].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 95

Summary of evidence LE
Medical/sexual history taking and physical examination are essential parts of the evaluation of men 4
with a short penis complaint.
Among stretched penile measurements STT may underestimate erect penile length. 2b
Among stretched penile measurements BTT has a better correlation with erect penile length, especially 2b
in overweight and obese men.
Flaccid and erect state measurements to assess penile length may add useful information on penile 4
size.
Penile girth assessment may add useful information on penile size and shape. 4
The Body Dysmorphic Disorder Questionnaire, The Cosmetic Procedure Screening Scale for Penile 2b
Dysmorphic Disorder, The Male Genital Self-Image Scale and the Index of Male Genital Image are self-
reported tools useful to screen patients at risk for psychopathology.
Mental health counselling is helpful in detecting men requesting penile augmentation procedures 2b
present with strong psychological vulnerability, including BDD/PDD.
Validated questionnaire (e.g., APPSSI, BAPS, IIEF-15, MSHQ, EDITS) are helpful in assessing baseline 4
sexual function and beliefs about penile size.

Recommendations Strength rating

Take a comprehensive medical and sexual history in every patient complaining of short Strong
penile size.
Use stretched penile measurements (skin junction-to-glans tip or dorsally from the pubic Weak
bone-to-glans tip) to define penile length.
Measure flaccid and erect measurements to assess penile length in detail. Weak
Measure penile girth in every patient presenting complaining of a short penile size. Weak
Use validated questionnaires to screen for body dysmorphic disorder (BDD) in cases of a Weak
normal-sized penis.
Use validated questionnaires (e.g., IIEF-15, BAPS) to assess baseline sexual function and Weak
beliefs concerning penile size.
Refer patients with suspected BDD for mental health counselling. Strong

9.3 Management
9.3.1 Non-surgical Treatments
9.3.1.1 Psychotherapy
Penile augmentation is often motivated by the desire to improve self-perception and self-esteem [1257].
Cosmetic treatments may help increase individuals’ well-being and QoL, improving self-esteem and emotional
states [1165, 1166, 1180]. Still, psychotherapy is recommended when psychopathological comorbidities are
detected, or when aversive relationship dynamics may underly the request for penile augmentation. Addressing
patients’ and partners’ motivations and expectations regarding penile augmentation seems to be a key
psychotherapeutic target while no other empirical evidence is described. Similarly, men with BDD and SPA
present a significant discrepancy between the perceived and ideal size of the penis, internalising the belief
they should have a larger penis [1258]. Cognitive behaviour therapy for BDD could be applied to cases of
anxiety regarding penis size, although no clinical trials have been reported [1259]. In all, it is worth noting
that psychotherapy should normalise the great variability of genital shape and size [1175]. Managing patient
expectations could be a means to improve results and well-being associated with the surgery process.

9.3.1.2 Penile traction therapy

Despite the various surgical techniques, there are also non-invasive methods that are used to enhance penile
length, including penile traction therapy (PTT) [1260]. In a pilot phase-II prospective study that evaluated the
efficacy and tolerability of a penile-extender device in the treatment of short penis, Gontero et al., used the same
traction device for at least 4 hours/day for 6 months and achieved a significant gain in length, of +2.3 and +1.7
cm for the flaccid and stretched penis, respectively (both p < 0.001) [1261]. However, the change in the penile
girth was not significant. In a further prospective study, these results were confirmed by Nikoobakht et al., who
found a significant improvement in the mean length both for the flaccid (8.8 ± 1.2 cm to 10.5 ± 1.2 cm, P < 0.05)
and the stretched state (11.5 ± 1.0 cm to 13.2 ± 1.4 cm, p < 0.05) following 3 months of use of a penile traction
device [1262]. At 6-month follow-up, compared to baseline, a mean gain of +1.7 ± 0.8, +1.3 ± 0.4, and +1.2 ± 0.4

96 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

cm was reported for the flaccid, stretched, and erect penile lengths, respectively (p < 0.001, for all). The broad
spectrum of available PTT studies is summarised in Table 9.4.

Overall, PTT seems effective in lengthening the penis both in the flaccid and stretched state with minimal side
effects. Yet it is not effective for penile girth enhancement. However, the quality of evidence is poor due to the
lack of RCTs, and the availability of only heterogenous and small cohorts PTT has also been proven effective in
the restoration of length or correction of deformities due to several diseases, including PD, or post-RP conditions
[526, 997, 1263, 1264].

Table 9.4: Penile traction therapy (PPT)

Author (year) n Study Device Treatment protocol Mean age Mean gain in penile
design ± SD dimensions cm (SD)
Nowroozi 54 Prospective AndroPenis 4-6 hours per day for 6 30.1 ± 4.8 Flaccid length: 1.7 ± 0.8
et al. [1265] months Stretched length: 1.3 ± 0.4
Erected length: 1.2 ± 0.4
Nikoobakht et 23 Prospective Golden Erect 4–6 hours per day during 26.5 ± 8.1 Flaccid length: 1.7
al. [1262] the first 2 weeks and then 9 Stretched length: 1.71
hours per day until the end of Circumference: -0.22
the third month Glans penis
circumference: -0.35
Gontero et al. 21 Prospective Golden Erect at least 4 h/day for 6 months 45.7 ± 11.1 Flaccid length: 2.3
[1261] Stretched length: 1.7
Circumference: NR
NR = not reported.

9.3.1.3 Vacuum erection device

Vacuum erection devises (VED) are generally considered for patients who fail oral ED therapies [447, 1237]. In
contrast, data regarding the use of VEDs on penile elongation is scarce. In a study with 27 men whose SPL was
< 10 cm, the use of a VED three times a week for 20 minutes on each occasion, for 6 months, did not result in a
significant increase in flaccid or SPL [1266]. On the other hand, the benefits of using a VED following PPI and RP
have been demonstrated in the literature [1266-1271].

9.3.1.4 Endocrinological therapies

Testosterone administration has been used for a long time to increase the length of the penis in infant or pre-
pubertal boys with micropenis. Topical administration of T or DHT has also been proposed by other authors with
reported better outcomes with DHT, especially in poor responders to T or in those with type 2 alpha reductase
deficiency [1272, 1273]. Finally, the possible use of the combination of hCG and FSH treatment has also been
proposed with positive outcomes [1274, 1275]. Despite the treatment suggested it should be recognised that no
face-to-face comparisons are available so far.

9.3.1.5 Summary of evidence and recommendations for the non-surgical management of short penile size

Summary of evidence LE
Psychotherapy should not be undertaken in the realm of preventing individuals’ legitimate choice 3
to improve their lives. Conversely, psychotherapy is recommended when psychopathological
comorbidities are detected, or when aversive relationship dynamics may underlie the request for penile
augmentation.
Cognitive behaviour therapy for BDD could be applied to cases of anxiety regarding penis size. 3
Penile traction therapy proved to be an effective treatment to achieve penile lengthening. 3
Vacuum erection devices proved to be an ineffective treatment in achieving penile lengthening. 3
Testosterone therapy, transdermal dihydrotestosterone and recombinant gonadotropins can restore 2b
penile size in boys with micropenis or disorders of sex development.
Testosterone therapy does not increase penile size in adult men and in men with late-onset 3
hypogonadism.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 97

Recommendations Strength rating
Consider psychotherapy when psychopathological comorbidities are detected, or when Strong
aversive relationship dynamics may underlie the request for penile augmentation.
Consider the use of penile traction therapy as a conservative treatment to increase penile Weak
length.
Consider the use of vacuum erection devises to increase penile length. Weak
Use endocrinological therapies to restore penile size in boys with micropenis or disorders of Strong
sex development.
Do not use testosterone therapy or other hormonal therapies to increase penile size in men Strong
after puberty.

9.3.2 Surgical Treatments

9.3.2.1 Surgical treatment of adult acquired buried penis
9.3.2.1.1 Adult acquired buried penis surgical procedures classification
According to the classification proposed by Pariser et al. different procedures may range from low complexity
(including un-burying of penile shaft, reconstruction of penile shaft with the use of skin flaps or grafts, plastic
surgical techniques to reconstruct the scrotum) to high complexity (including surgical removal of the suprapubic
fat pad (escutcheonectomy) and operations to skin and subcutaneous fat layers of the abdominal wall
(apronectomy) [1198].

The purpose of any surgical approach is to unbury the penile shaft, reconstruct genital teguments and eventually
remove peri-genital or excess abdominal tissue in order to reduce the risk of recurrence. The goal is to balance
an effective surgical procedure aiming to improve patient QoL, while minimising the incidence of postoperative
complications. Lifestyle changes and risk factors modification, particularly weight loss, are widely considered
as a proactive approach to minimise AABP surgical complications and should be encouraged before surgical
intervention is undertaken. The broad spectrum of surgical interventions described to manage AABP is
summarised in Table S9.3 in online supplementary evidence Appendix 5.

The current evidence highlights the efficacy of AABP surgical treatment which has a low incidence of recurrence
and satisfactory functional outcomes, as shown in Table S9.4 in online supplementary evidence Appendix 5,
yet there is a significant incidence of post-operative complications (up to 3.5% of grade V according to Clavien-
Dindo Classification) [1276].

The current evidence highlights the efficacy of AABP surgical treatment which has a low incidence of recurrence
and satisfactory functional outcomes, as shown in Table 26, yet there is a significant incidence of post-operative
complications (up to 3.5% of grade V according to Clavien-Dindo Classification) [1277].

Summary of evidence LE
Various surgical procedures may be considered to restore genital anatomy in AABP patients. 3
Adult acquired buried penis surgery is burdened by a significant incidence of postoperative 3
complications.
Lifestyle changes and risk factors modification, particularly weight loss, are widely considered as a 4
proactive approach to minimise AABP surgical complications.
Adult acquired buried penis surgery may provide satisfactory functional outcomes with a low incidence 3
of recurrence.

Recommendations Strength rating

Extensively counsel patients on the benefits and complications of adult acquired buried Strong
penis (AABP) surgery.
Initiate lifestyle changes and modification of risk factors, particularly weight loss, to Strong
minimise AABP surgical complications and to optimise surgical outcomes.
Consider surgical treatment to address AABP. Weak

98 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

9.3.2.2 Surgical treatment of congenital intrinsic penile shortness
Current literature reports a wide spectrum of possible surgical interventions aimed to address penile
shortness. Nonetheless, the proposed spectrum of surgical interventions starts from less invasive procedures
- such as suspensory ligament release (SLR) - to more complex genital reconstruction - such as total phallic
reconstruction (TPR) [1277, 1278].

9.3.2.2.1 Suspensory ligament release

This technique involves a surgical incision and SLR of the penis which attaches the penis to the pubic bone. The
surgical access is via an infrapubic incision and may be combined with an elongating V-Y skin plasty [1278].
Several authors reported outcomes of SLR in the context of a congenital intrinsic penile shortness (Table S9.5
online supplementary evidence Appendix 5).

Littara et al., conducted penile elongation in 21 patients, enlargement in 33 and combined elongation and
enlargement in 301, respectively [1279]. The technique was based on penile lipofilling combined with V-Y
infrapubic skin plasty and SLR. At 12 months following the surgical procedure, length at rest significantly
increased from 8.8 cm to 11.4 cm, SPL significantly increased from 12.4 cm to 13.5 cm and circumference at
rest significantly increased from 8.3 cm to 11.06 cm. The IIEF-5 also increased from 21.5 to 23. The outcomes
of SLR are summarized in Table S9.5 online supplementary evidence Appendix 5.

9.3.2.2.2 Ventral phalloplasty/scrotoplasty

This intervention is based on a ventral shaft skin plasty to move the peno-scrotal angle proximally and increase
the exposure of the penile shaft. A longitudinal incision or Z-plasty at the penoscrotal junction, securing of the
tunica albuginea to the proximal tunica dartos was performed by Xu et al., in 41 patients [1280]. Correction was
successful in all patients with an improved median length of +2.1 cm in the flaccid state.

9.3.2.2.3 Suprapubic lipoplasty/liposuction/lipectomy

This intervention aims to reduce the thickness of the suprapubic fat pad either with a minimally invasive
approach (liposuction) or surgically (lipectomy). The flattening of suprapubic fat pad aims to increase penile
shaft exposure.

Ghanem et al., performed liposuction in ten patients using a 50-cc syringe with a 3- and 6-mm liposuction
needle [1281]. The amount of fat removed ranged from 325 to 850 mL with a mean of 495.50 ± 155.39 mL.
Three (30%) of the patients were very satisfied with the post-operative result, five (50%) patients were satisfied,
one patient (10%) was neither satisfied nor dissatisfied, and one (10%) patient was dissatisfied. No patients
were very dissatisfied. Shaeer’s monsplasty technique was investigated in 20 patients [1282]. At 3 months
post-operatively, the flaccid visible length was 7.1 ± 2.1cm, with a 57.9% improvement in length, and erect
visible length was 11.8 ± 2.1cm, with a 32% improvement in length. At final follow-up (18 months) a 73.1%
improvement in satisfaction rate was detected.

9.3.2.2.4 Total phallic reconstruction

This represents the most complex genital reconstruction possible, aiming to create a new phallus with a
neo-urethra. The operation is reserved for the severe penile insufficiency cases (e.g., congenital micropenis,
exstrophy-epispadias complex) as benefit should be balanced over possible complications [1277].

Lumen et al., treated seven male patients (aged 15 to 42 years) with phalloplasty (6 with radial forearm
free flap and 1 with anterolateral thigh flap) and implant surgery was offered approximately 1 year after the
phallic reconstruction [1283]. There were no complications after surgical formation of the neophallus. Two
complications were reported in the early post-operative period. Two patients developed urinary complications
(stricture and/or fistula). Patient satisfaction after surgery was high in six cases and moderate in one case. Four
patients underwent penile implant surgery and 50% were subsequently removed.

Perovic et al., conducted TPR using musculocutaneous latissimus dorsi (MLD) in 12 patients [1284]. The mean
(range) follow-up was 31 (6–74) months, and the penile size was 16 (14–18) cm long and 13 (11–15) cm in
circumference. There was no flap loss or partial skin necrosis.

Garaffa et al., reported a series of TPR using the radial artery forearm free flap in 16 patients with bladder/
cloacal exstrophy and micropenis-epispadias complex [1285]. In one patient the distal third of the phallus
was lost due to acute thrombosis of the arterial anastomosis immediately post-operatively. Almost all (93%)
were fully satisfied in terms of cosmesis and size. Urethral stricture and fistula were the most common
complications, which developed only at the native neourethral anastomosis. They were successfully managed
by revision surgery. Sexual intercourse was achieved in 11 of the 12 patients who underwent PPI.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 99

9.3.2.2.5  ummary of evidence and recommendations for surgical treatment of congenital intrinsic penile
S
shortness

Summary of evidence LE
Considering the wide spectrum and the complexity of surgical interventions aimed to address penile 4
shortness, this surgery should be reserved to high volume centres.
Suspensory ligament release, ventral phalloplasty and suprapubic lipoplasty/liposuction/lipectomy 3
provide an objective increase in penile length.
Suspensory ligament release, ventral phalloplasty and suprapubic lipoplasty/liposuction/lipectomy are 3
associated with a significant incidence of complications.
Total phallic reconstruction provides satisfactory surgical and functional outcomes in men with 3
micropenis.

Recommendations Strength rating

Perform surgery for adult acquired buried penis (AABP) in high volume centres. Strong
Use suspensory ligament release, ventral phalloplasty and suprapubic lipoplasty/liposuction/ Weak
lipectomy to address penile lengthening.
Extensively discuss possible complications related to suspensory ligament release, ventral Strong
phalloplasty and suprapubic lipoplasty/liposuction/lipectomy.
Use total phallic reconstruction to restore genital anatomy in patients affected by congenital Weak
micropenis.

9.3.2.3 Surgical treatment of acquired penile shortness

9.3.2.3.1 Penile prosthesis implantation (PPI)
The literature fails to show a direct relationship between PPI and penile length in men with ED and no
concomitant PD. In a study by Deveci et al., SPL was evaluated in men undergoing primary implant surgery
due to diabetes or RP [1286]. Either three-piece (Alpha-1, Mentor, USA) and two-piece implants (Ambicor, AMS,
Boston Scientific, USA) were used and most patients (72%) reported a subjective decrease in penile length,
although no statistically significant difference was demonstrated in measured SPL [1286]. In another study, 45
patients with PD with no deformity or penile curvature < 30° or severe penile fibrosis/scarring were implanted
with an AMS 700 LGX [1287]. The mean stretched penile length improved from 13.1 ± 1.2 cm to 13.7 ± 1.1 cm
and 14.2 ± 1.2 cm at 6 and 12 months, respectively. A significant difference was also observed in the length of
the stretched flaccid penis between 6 and 12 months [1287].

Some authors have evaluated the erect penile length following PPI. In a prospective study where patients
with PD were excluded, erect penile length was compared from baseline achieved by intracavernosal injection
and after PPI inflation. The authors demonstrated that there were 0.83 ± 0.25, 0.75 ± 0.20 and 0.74 ± 0.15 cm
decreases in erect penile length 6 weeks, 6 months, and one year post-operatively, respectively [1288]. A study
where patients with PD were excluded confirmed these results as the median pre-operative pharmacologically
induced length (14.25 ± 2 cm) was decreased to median post-prosthesis penile length (13.5 ± 2.13 cm) [1289].

9.3.2.3.2 Penile disassembly

Penile disassembly has been described as a technique for penile lengthening [1290]. It basically consists of the
separation of the penis into its anatomical components and inserting autologous cartilage to the space created
between the glans cap and the tip of corpora cavernosa. Perovic et al., in a study with 19 patients submitted
to penile disassembly and implantation of autologous rib cartilage followed by VED therapy, reported an
increase of 3 cm and 3.1 cm in SPL and erect length, respectively [1290]. The results of this surgery are poorly
documented and significant complications such as glans necrosis can ensue.

9.3.2.3.3 Lengthening corporal manoeuvres

Penile length restoration with the use of the sliding technique (ST) and concomitant PPI was first described
in a small series of three patients in 2012, and further supported by a larger series of 28-patient in a multi-
centre study in 2015 [1152, 1156]. Although this technique is only used in cases of end-stage PD with severe
shortening of the shaft, 95% of men were satisfied with their increase in length with an average penile
lengthening of 3.2 cm (range, 2.5-4 cm). The modified sliding technique (MoST) and multiple slit technique
(MuST) are further modifications of the original ST [1153, 1154]. In a series by Egydio et al., 143 patients with

100 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

penile shortening and narrowing due to PD amongst other aetiologies underwent MoST or MuST procedures.
The mean (range) penile length gain was 3.1 (2-7) cm at a median (range) follow-up of 9.7 (6-18) months [1153].

9.3.2.3.4 Total phallic reconstruction (TPR)

Radial forearm free flap is the most used reconstructive approach for TPR. In a single-centre study, Falcone et
al., reported their experience of 10 patients who underwent TPR using RAFFF after traumatic penile loss [1291].
In 6 individuals, the urethral stump was sufficient for primary anastomosis and neourethra formation. The
remaining patients had total penile avulsion and were voiding via a perineal urethrostomy. Consequently, a two-
stage urethroplasty was necessary. Two patients developed an acute arterial thrombosis of the microsurgical
anastomosis, which was successfully treated with emergency exploration. One patient had a neourethral
stricture and fistula that required revision. All patients who underwent complete urethral repair were able to void
and ejaculate through the phallus. After a median follow-up of 51 months, all patients were satisfied with the
acquired size, cosmesis, and sensation. Six patients received a PPI and were able to also engage in penetrative
intercourses. However, three patients had revision surgery (2 due to infection and 1 due to mechanical failure)
[1291].

9.3.2.3.5 Summary of evidence and recommendations for surgical treatment of acquired penile shortness

Summary of evidence LE
Penile prosthesis implantation is not effective in increasing penile length. 3
The evidence for the use of penile disassembly manoeuvres and the sliding technique are limited. 3
Total phallic reconstruction yields to satisfactory outcomes despite the high incidence of post- 3
operative complications.

Recommendations Strength rating

Do not recommend penile prosthesis implantation, penile disassembly or sliding technique Strong
to patients seeking penile lengthening options.
Use total phallic reconstruction to restore genital anatomy in genetic males with penile Weak
inadequacy due to traumatic loss.

9.3.2.4 Penile girth enhancement

9.3.2.4.1 Penile Girth enhancement history
Mean flaccid penis circumference is 9.31 cm (± 0.90 cm), and the erect penile circumference is 11.66 ± 1.10
cm [1178]. Unlike penile lengthening, there are no precise definitions or indications for penile girth enlargement
in the literature or existing international guidelines [1292]. In recent years, men have increasingly approached
urologists for penile girth enhancement to increase their self-confidence, to be cosmetically satisfied or to
satisfy their partners [1293]. Current reports on penile girth enhancement techniques are from recent years
[1293, 1294]. Although these surgical techniques are more and more frequently requested, the level of evidence
for their use in clinical practice is low, notwithstanding the ethical considerations of surgery in this vulnerable
group of patients.

9.3.2.4.2 Injection therapy

Injectable filling materials can be classified according to their different properties. They can be autologous,
biological or synthetic in nature. The fat injection material is obtained from the patient’s own tissue
(autologous), usually by liposuction (see the following surgical therapy section). Biological fillers can be
of human and animal (collagen) or bacterial (Hyaluronic acid) origin. Poly-l-lactic acid (PLA), hydroxyethyl
methacrylate, polyalkylimide hydrogel (PAAG), polymethylmethacrylate (PMMA), calcium hydroxyapatite (CHA),
silicon and paraffin constitute filler materials of synthetic origin (Table 9.5) [1295].

Table 9.5: Origin of injectable filling materials

Autologous Autologous fat tissue

Biological Hyaluronic acid
Synthetic Poly-l-lactic acid, hydroxyethyl methacrylate, polyalkylamide hydrogel,
polymethylmethacrylate, calcium hydroxyapatite, silicon, paraffin

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 101

9.3.2.4.2.1 Soft tissue fillers (Hyaluronic acid and PMMA)
Hyaluronic acid
Injection of hyaluronic acid (HA) gel is one of the most commonly used injectable fillers in the field of plastic
surgery [1237, 1296]. The application of HA for penile girth enhancement has recently gained increasing
popularity due to its biocompatibility and infrequent mild temporary side effects. The newly invented cross-
linked HA has a more lasting effect over time [1297]. Hyaluronic acid has been used for patients for penile
girth enhancement. Studies have reported that an increase of 1.4 to 3.78 cm in penile girth is achieved with HA
injection (Table S9.6 online supplementary evidence Appendix 5). Patient satisfaction is high (78-100%) and no
severe side effects have been reported [746, 1298-1301].

Polymethylmethacrylate (PMMA)
Polymethylmethacrylate (PMMA) microspheres have been injected as a wrinkle filler. An average increase in
penile circumference of 3.5 cm was reported in two studies using PMMA for penile girth enhancement [1302,
1303]. The authors reported that post-operative swelling and inflammatory reaction resolved within a few days
and no pattern of PMMA microspheres migration to neighbouring regions was seen.

Poly-l-lactic acid
Poly-l-lactic acid (PLA) is another widely used soft tissue filler. Poly-l-lactic acid has enhanced effects by
stimulating fibroblast proliferation and increasing collagen deposition in tissue. An average increase of 1.2 to
2.4 cm has been reported in the penile girth with PLA injection. No complications other than temporary local
pain and swelling were reported in the treated patients [1298, 1304].

9.3.2.4.2.2 Other Fillers (silicone, paraffin)

Foreign body injections are still frequently practiced in many countries (especially in east Asia and east
Europe), either by the patient himself or by healthcare workers, using various substances such as paraffin,
silicone or petroleum jelly (Vaseline), to increase the circumference of the penis [1305]. This results in a chronic
granulomatous inflammatory foreign body reaction [1305, 1306]. The result of this practice is a pathological
condition called sclerosing lipogranuloma of the penis also referred as paraffinoma or siliconoma according to
the substance used [1305]. The resultant inflammatory process ranges from oedema and infection to Fournier’s
gangrene. Penile reconstructive surgeries may be required when siliconoma and paraffinoma require excision
[1305-1311].

9.3.2.4.3 Surgical therapy

9.3.2.4.3.1 Autologous fat injection
This is a surgical technique based upon thinning the lower abdomen with liposuction and injecting the harvested
fat tissue into the penile shaft [1312-1315]. In retrospective studies, an average increase of 2 to 3.5 cm in penile
circumference was reported in patients who underwent autologous fat injection. No statistically significant
decrease was observed in IIEF scores and no serious adverse events, such as penile abscess or deformity
requiring reoperation occurred. Post-operative satisfaction survey showed that more than 75% of patients were
satisfied (Table S9.7 online supplementary evidence) [1279, 1312, 1313, 1316].

9.3.2.4.3.2 Grafting procedures (albugineal and peri-cavernosal)

Until more rigorous multi-institutional studies reporting on complications and validated outcomes are known,
penile girth enhancement procedures using grafts should be considered experimental (Table S9.8 online
supplementary evidence Appendix 5).

In a study of 69 patients using the porcine dermal acellular matrix graft (InteXen; American Medical Systems,
Minnetonka, MN, USA) a 3.2 cm increase in flaccid state and 2.4 cm in erect state was reported at one year
following surgery. The procedure was performed with an infrapubic incision, and 68 of 69 patients reported
significant satisfaction using the Augmentation Phalloplasty Patient Selection and Satisfaction Inventory. Graft
fibrosis has been observed in up to 13% of patients, and a mean reduction in penile length of 0.5 cm has been
reported in patients with fibrosis [1317].

Techniques using venous grafts for penile girth enhancement have also been described [1318]. Initial results are
encouraging, but better designed RCTs are needed.

Dermal fat grafts are free only grafts composed of deepithelialized dermis and subcutaneous fat. An area of
approximately 10 x 5 cm is required for graft harvesting. An increase in penile girth of 1.67 to 2.3 cm has been
reported in studies with the dermal fat graft technique. Penile oedema up to 27%, painful erection up to 27%,
and curvature due to graft fibrosis up to 9% have been reported. Side effects such as penile hypoesthesia, skin
necrosis, and infection were not reported [1250, 1319, 1320].

102 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

9.3.2.4.3.3 Biodegradable scaffolds
This is a technique based on using fibroblasts (harvested from patients’ own scrotum skin and dartos tissue)
in tissue cultures and seeding them in microporous biodegradable poly-lacti-co-glycolic acid (PLGA) scaffolds
and implanting these scaffolds between Dartos and Buck’s fascia. A limited number of studies have reported
girth gain of up to 4.02 cm with implantation of biodegradable scaffolds [1321-1323] (Table S9.9 online
supplementary evidence Appendix 5).

9.3.2.4.3.4 Subcutaneous penile implant (Penuma®)

Recently, a silicone penile implant called “Penuma®” (International Medical Devices [Beverly Hills, CA, USA])
has been approved and has shown promising results for penile girth enhancement. Penuma® is a soft silicone
subcutaneous implant placed on 3/4 of the penile shaft and fixed to the glans with a polyester mesh [1324].
Studies have reported an average increase in penile circumference of 2 to 5 cm with Penuma® insertion.
According to published data complication rates (usually mild and transient, occur in <5%) and the removal rate
(1%) of the implant has been reported to be relatively low [1324, 1325].

9.3.2.4.4 Summary of evidence and recommendations for penile girth enhancement

Summary of evidence LE
Various surgical approaches with specific outcomes and complications have been considered to 3
address penile girth enhancement, with limited benefit.
Hyaluronic acid (HA), Poly-l-lactic acid (PLA), hydroxyethyl methacrylate, polyalkylamide hydrogel 3
(PAAG), polymethylmethacrylate (PMMA), calcium hydroxyapatite are used as injectable materials for
penile girth enhancement.
Patient satisfaction with soft tissue fillers (especially HA, PMMA and PLA) is high (> 78%). 3
No complications other than temporary local pain and swelling were reported in patients treated with 3
soft tissue fillers.
Using silicone, paraffin and petroleum jelly (Vaseline) in penile girth enhancement causes a range of 3
complications ranging from oedema up to infection to Fournier’s gangrene.
Not enough long-term data are available on autologous fat injection for penile girth enhancement. 4
Not enough long-term data are available on grafting procedures (dermal acellular matrix graft, venous 4
grafts or dermal fat grafts).
Grafting procedures are associated with high complication rate and low rate of patient’s satisfaction. 3
Not enough long term data are available on biodegradable scaffolds and subcutaneous penile implant 4
(Penuma®) .

Recommendations Strength rating

Counsel patients extensively regarding the risks and benefits of penile girth enhancement Strong
techniques.
Do not use silicone, paraffin and petroleum jelly (Vaseline) to address penile girth Strong
enhancement.
Use hyaluronic acid, soft tissue fillers and autologous fat injection to address penile girth Weak
enhancement.
Do not use hyaluronic acid, soft tissue fillers and autologous fat injection to address penile Strong
girth enhancement in men with penile dysmorphic disorder.
Do not use grafts in penile girth enhancement as they are considered experimental. Strong
Do not use biodegradable scaffolds and subcutaneous penile implant (Penuma®) to address Strong
penile girth enhancement as they are considered experimental.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 103

Figure 9.1: Management of short penile size

Short penile size complaint

Medical and psychosexual history (use ofvalidated instruments, eg. BAPS)

Idenfy common causes Idenfy other sexual Assess for body

of penile shortness problems (ED, PE) dysmorphia

Focused physical examinaon (document penile size and shape*)

Intrinsic congenital Intrinsic acquired “False”penile shortness

Normal penile size
penile shortness# penile shortness# (AABP)#

Suspensory ligament Penile tracon therapy Follow AABP Psychosexual assessment

release (Weak) (Weak) management (Strong) (Strong)

Ventral phalloplasty/ Total phallic

scrotoplasty (Weak) reconstrucon (Strong)

Sustrabupic lipoplasty Not recommended: Body Dysmorphic

(Weak) • Penile lengthening Disorder (BDD) suspected No BDD suspicion#
with/without penile
prothesis
implantaon (Weak)
• Penile disassembly Psychotherapy (Strong) Psychotherapy (Weak)
(Weak)
Penile tracon therapy (Weak)

Suspensory ligament release

(Weak)

Penile girth enhancement

• SoŒ ssue fillers** (Weak)
• Biodegradable scaffolds
and subcutaneous penile
implant (Experimental,
Diagnosis Treatment Follow-up
Weak)

* Penile length should be measured stretched both from the penopubic skin junction-to-glans tip (STT) and from
the pubic bone-to-glans tip (BTT).
* Penile length should be measured stretched both from penopubic skin junction-to-glans tip (STT) and from the
pubic bone-to-glans tip (BTT).
# There is lack of evidence to recommend one treatment over another.
** Hyaluronic acid (HA), poly-l-lactic acid (PLA), hydroxyethyl methacrylate, polymethylmethacrylate (PMMA),
polyalkylamide hydrogel (PAAG) and calcium hydroxyapatite are considered as injectable materials for penile
girth enhancement. Although the level of evidence is low, there is more evidence for HA, PLA and PMMA. Do not
use silicone, paraffin or Vaseline (Strong evidence against).
Strength of recommendations is depicted between brackets where appropriate.

9.3.2.5 Functional outcomes: sexual function, sensitivity, impact on quality of life and emotional adjustment
Cosmetic treatments, including surgery, help to restore self-esteem, reduce anxiety, social phobia, and
depressive mood states regarding body concerns, increasing individuals’ well-being and QoL [1165, 1166].
Therefore, we can expect men with genuine short penis to use available resources to adjust the length or girth
of their penis as a mean to improve their sense of identity and fit cultural standards regarding penile size and
function. Currently, the results of penile augmentation techniques seem mixed. The use of fillers resulted in
improved genital self-image and self-esteem, lower PDD symptoms, but no effects were found regarding self-
confidence or sexual relationship satisfaction [1257]. Likewise, penile lengthening or girth enhancement surgery
seem to result in poor satisfaction, poor erectile function and sensitivity in men with normal penis size [1176].
Despite those negative outcomes, cases of increased satisfaction have been registered [1326]. Male genital
self-image has been related to IIEF domains: sexual desire, orgasmic and erectile function, intercourse and
overall satisfaction [1247]. Similarly, perceived penis size seems to predict erectile function more than objective
size [1172]. In addition, reduced penetrative and receptive oral sex are associated with men’s dissatisfaction
regarding their penis [1327]. For these reasons, more efforts should be made in order to clarify the impact of
penile augmentation treatments on men’s and partners’ well-being and QoL. As for men with BDD, they have
shown reduced erectile and orgasmic function, as well as less intercourse satisfaction as compared with

104 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

controls, while men with SPA revealed reduced satisfaction. Sexual desire seemed untouched in BDD and SPA
cases [1257, 1328].

9.3.2.6 Final remarks

The complaint of “short penis” is variable in presentation and aetiology. Some patients demonstrate anatomical
and pathological conditions while others do not. A vast array of treatments for different aetiologies of “short
penis,” both surgical and non-surgical, have been reviewed. If psychopathological symptoms are detected, the
patient must be referred for further medical diagnosis. Treatment for short-penis syndrome requires a multi-
disciplinary approach, including medical and ethical considerations, and the majority of reported outcomes are
based on a paucity of evidence.

10. PRIAPISM
Priapism is a persistent or prolonged erection in the absence of sexual stimulation that fails to subside. It can
be divided into ischaemic, non-ischaemic and stuttering priapism. The guidelines are based on three systematic
reviews addressing the medical and surgical management of ischaemic and non-ischaemic priapism and the
overall management of priapism related to sickle cell disease [1329-1331].

10.1 Ischaemic (Low-Flow or Veno-Occlusive) Priapism

10.1.1 Epidemiology, aetiology, pathophysiology and Diagnosis
Ischaemic priapism is a persistent erection marked by rigidity of the corpora cavernosa and by little or no
cavernous arterial inflow [1332]. Ischaemic priapism is the most common subtype of priapism, accounting for
> 95% of all episodes [1332, 1333]. In ischaemic priapism, there are time-dependent metabolic alterations within
the corpus cavernosum progressively leading to hypoxia, hypercapnia, glucopenia and acidosis [1334, 1335].

Ischaemic priapism that lasts beyond 4 hours is similar to a compartment syndrome and characterised by the
development of ischaemia within the closed space of the corpora cavernosa, which severely compromises
the cavernosal circulation. Emergency medical intervention is required to minimise irreversible consequences,
such as smooth muscle necrosis, corporal fibrosis and the development of permanent erectile dysfunction
(ED) [1336, 1337]. The duration of ischaemic priapism represents the most significant predictor for irreversible
consequences, thus including ED. In this context, interventions beyond 48-72 hours of onset may help to relieve
the erection and pain, but have little clinical benefit in preventing long-term ED [1338].

No specific pathophysiological causes of ischaemic priapism can be identified in most cases [1332, 1339],
although the common aetiological factors include sickle cell disease (SCD), haematological dyscrasias,
neoplastic syndromes, and several pharmacological agents (e.g., intracavernosal PGE1 therapy) (Table 10.1).
Ischaemic priapism may occur (0.4-35%) after intracavernosal injection of erectogenic agents [1332, 1336,
1340-1342]. The risk is higher with papaverine-based combinations [1343], while the risk of priapism is < 1%
following prostaglandin E1 injection [1344].

Second-generation antipsychotics (33.8%), other medications (11.3%), and alpha-adrenergic antagonists (8.8%)
accounted for the greatest percentage of published drug-induced priapism cases [1345]. Isolated cases of
priapism have been described in men who have taken PDE5Is [1332]. Data from the FDA Adverse Reporting
System Public Dashboard showed that PDE5Is-induced priapism accounted for only 2.9% of drug-induced
priapism. However, most of these men also had other risk factors for priapism, and it is unclear whether PDE5Is
per se can cause ischaemic priapism [1332, 1346]. Since most men who experience priapism following PDE5I
treatment have additional risk factors for ischaemic priapism, PDE5Is use is usually not regarded as a risk factor
in itself. In terms of haemoglobinopathies, SCD is the most common cause of priapism in childhood, accounting
for 63% of cases. It is the primary aetiology in 23% of adult cases [1344].

Mechanisms of SCD-associated priapism may involve derangements of several signalling pathways in the penis
[1347]. Contrary to traditional belief, maintenance of physiological testosterone levels does not cause priapism,
but rather preserves penile homeostasis and promotes normal erectile function [1348, 1349]. Testosterone
deficiency is considered a controversial risk factor: it is prevalent in patients with SCD, but recent evidence
indicates that it may not be a risk factor for priapism [1350].

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Priapism resulting from metastatic or regional infiltration by tumour is rare and usually reflects an infiltrative
process, more often involving the bladder and prostate as the primary cancer sites [1351]. In a large
retrospective study including 412 men with ischaemic priapism, eleven (3.5%) had malignant priapism, of
which seven cases were a consequence of local invasion while the others were secondary to haematological
malignancy [1352]. The conventional therapeutic recommendations for pharmacological treatment are unlikely
to be effective and all of these men should have MRI of the penis and be offered supportive care and medical
intervention for their primary cancer. In selected cases where palliative treatment options fail to control penile
pain, a palliative penectomy can be considered.

Partial priapism, or idiopathic partial segmental thrombosis of the corpus cavemosum, is a rare condition. It
is often classified as a subtype of priapism limited to a single crura without ischaemia, but rather a thrombus
is present within the corpus cavernosum. Its aetiology is unknown, but bicycle riding, trauma, drug use, sexual
intercourse, haematological diseases and α-blocker intake have all been associated with partial segmental
thrombosis [1353]. The presence of a congenital web within the corpora is also a risk factor [1354].

Table 10.1: Aetiological factors for the development of priapism

Idiopathic
-
Haematological dyscrasias, vascular and other disorders
• SCD
• thalassemia
• leukaemia
• multiple myeloma
• haemoglobin Olmsted variant
• fat emboli during hyperalimentation
• haemodialysis
• glucose-6-phosphate dehydrogenase deficiency
• factor V Leiden mutation
• vessel vasculitis
• (e.g., Henoch-Schönlein purpura; Behçet's disease; anti-phospholipid antibodies syndrome)
Infections (toxin-mediated)
• scorpion sting
• spider bite
• rabies
Metabolic disorders
• amyloidosis
• Fabry’s disease
• gout
Neurogenic disorders
• syphilis
• spinal cord injury
• cauda equina
• syndrome
• autonomic neuropathy
• lumbar disc herniation
• spinal stenosis
• cerebrovascular accident
• brain tumour
• spinal anaesthesia
Neoplasms (metastatic or regional infiltration)
• prostate
• urethra
• testis
• bladder
• rectal
• lung, kidney

106 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Medications
• Vasoactive erectile agents (i.e., papaverine, phentolamine, prostaglandin E1/alprostadil, combination of
intracavernous therapies)
• α-adrenergic receptor antagonists (i.e., prazosin, terazosin, doxazosin and tamsulosin)
• Anti-anxiety agents (hydroxyzine)
• Anticoagulants (heparin and warfarin)
• Antidepressants and antipsychotics (i.e., trazodone, bupropion, fluoxetine, sertraline, lithium, clozapine,
risperidone, olanzapine, chlorpromazine, thiorizadine, phenothiazines and methylphenidate)
• Antihypertensives (i.e., hydralazine, guanethidine and propranolol)
• Hormones (i.e., gonadotropin-releasing hormone and testosterone)
• Recreational drugs (i.e., alcohol, marijuana, cocaine [intranasal and topical], and crack, cocaine)

10.1.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of ischaemic priapism

Summary of evidence LE
Ischaemic priapism is the most common type, accounting for more than 95% of all cases. 1b
Ischaemic priapism is identified as idiopathic in most patients, while sickle cell disease is the most 1b
common cause in childhood.
Ischaemic priapism occurs relatively often (about 5%) after intracavernous injections of papaverine- 2a
based combinations, while it is rare (< 1%) after prostaglandin E1 monotherapy.
Priapism is rare in men who have taken PDE5Is, with only sporadic cases reported. 4

10.1.2 Diagnostic evaluation

10.1.2.1 History
Taking a comprehensive history is critical in priapism diagnosis and treatment [1332, 1355]. The medical history
must specifically enquire about SCD or any other haematological abnormality [1356, 1357] and a history of
pelvic, genital or perineal trauma. The sexual history must include the duration of the erection; the presence and
degree of pain; prior drug treatment and recreational drug use; history of priapism and methods of treatment;
and erectile function prior to the last priapism episode [1332]. The history can help to determine the underlying
priapism subtype (Table 10.2). Ischaemic priapism is classically associated with progressive penile pain and
the erection is rigid. Conversely, non-ischaemic priapism is often painless and the erections often fluctuate in
rigidity.

Table 10.2: Key findings in priapism (adapted from Broderick et al. [1332])

Ischaemic priapism Non-ischaemic priapism

Corpora cavernosa fully rigid Typically Seldom
Penile pain Typically Seldom
Abnormal penile blood gas Typically Seldom
Haematological abnormalities Sometimes Seldom
Recent intracavernosal injection Sometimes Sometimes
Perineal trauma Seldom Typically

10.1.2.2 Physical examination

In ischaemic priapism, the corpora are fully rigid and tender, but the glans penis is soft. The patient usually
complains of severe pain. Pelvic examination may reveal an underlying pelvic or genitourinary malignancy
[1352].

10.1.2.3 Laboratory testing

Laboratory testing should include a complete blood count, white blood cell count with blood cell differential,
platelet count and coagulation profile to assess anaemia and detect haematological abnormalities [1332, 1355].

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Aspiration of blood from the corpora cavernosa is compulsory as an entry level investigation. It usually reveals
dark ischaemic blood. Blood gas analysis is essential to differentiate between ischaemic and non-ischaemic
priapism (Table 10.3). Further laboratory testing should be directed by the history, clinical examination and
laboratory findings. These may include specific tests (e.g., haemoglobin electrophoresis) for diagnosis of SCD
or other haemoglobinopathies.

10.1.2.4 Penile imaging

Colour Doppler US of the penis and perineum is recommended after clinical diagnosis and can differentiate
ischaemic from non-ischaemic priapism as an alternative or adjunct to blood gas analysis (Figure 10.1) [1358-
1361]. Colour Doppler US can identify the presence of the fistula as a blush with 100% sensitivity and 73%
specificity [1360].

Ultrasound of the penis should be performed before corporal blood aspiration in ischaemic priapism to prevent
aberrant blood flow which can mimic a non-ischaemic or reperfusion picture after intervention for low-flow
priapism [1362].

Penile MRI can be used in the diagnostic evaluation of priapism and may be helpful in selected cases of
ischaemic priapism to assess the viability of the corpora cavernosa and the presence of penile fibrosis. In cases
of refractory priapism or delayed presentation (> 48 hours), smooth muscle viability can be indirectly assessed.
In a prospective study of 38 patients with ischaemic priapism, the sensitivity of MRI in predicting non-viable
smooth muscle was 100%, when correlated with corpus cavernosum biopsies [1362]. All patients with viable
smooth muscle on MRI maintained erectile function on clinical follow-up with the non-viable group being offered
early prosthesis.

Table 10.3: Typical blood gas values (adapted from Broderick et al. [1332])

Source pO2 (mmHg) pCO2 (mmHg) pH

Normal arterial blood (room air) > 90 < 40 7.40
(similar values are found in arterial priapism)
Normal mixed venous blood (room air) 40 50 7.35
Ischaemic priapism (first corporal aspirate) < 30 > 60 < 7.25
pCO2 partial pressure of carbon dioxide; pO2 partial pressure of oxygen.

108 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Figure 10.1: Differential diagnosis of priapism

Prolonged erecon
For > 4 hours

Ischaemic Non-ischaemic
priapism priapism

Penile Penile
Penile Penile
History blood gas History blood gas
Doppler US Doppler US
analysis analysis

Normal arterial
Perineal or
Dark blood; Bright red flow and
Sluggish or penile trauma;
Painful, rigid hypoxia, blood; may show
non-existent painless,
erecon hypercapnia arterial blood turbulent flow
blood flow fluctuang
andacidosis gas values at the site of
erecon
a fistula

Diagnosis Treatment Follow-up

10.1.2.5 Summary of evidence and recommendations for the diagnosis of ischaemic priapism

Summary of evidence LE
Medical history including the assessment of known haematological abnormalities (e.g., SCD), history of 3
pelvic/perineal/genital trauma, prior drug treatment or recreational drug use is essential to identify the
possible etiology and the type of priapism.
Blood gas analysis performed before blood aspiration from the corpora is able to differentiate between 3
ischaemic and non-ischaemic priapism. Full blood count and haemoglobinopathy screen could reveal
haematological alterations.
Penile Colour Doppler US can differentiate from ischaemic and non-ischaemic priapism when 3
performed before corporal blood aspiration.
Penile MRI is able to predict non-viable smooth muscle in patients with ischaemic priapism. 3

Recommendations Strength rating

Take a comprehensive history to establish the diagnosis which can help to determine the Strong
priapism subtype.
Include a physical examination of the genitalia, perineum and abdomen in the diagnostic Strong
evaluation.
Include a full blood count, white blood cell count with blood cell differential, platelet count Strong
and coagulation profile for laboratory testing. Perform directed further laboratory testing
depending upon history and clinical and laboratory findings. Perform a complete evaluation
of all possible causes of priapism in children.
Perform a haemoglobinopathy screen in patients with low flow priapism who are at high risk Strong
of sickle cell disease or thalassemia.
Analyse the blood gas parameters from blood aspirated from the penis to differentiate Strong
between ischaemic and non-ischaemic priapism.
Perform colour duplex ultrasound of the penis and perineum before aspiration to Strong
differentiate between ischaemic and non-ischaemic priapism.

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Use magnetic resonance imaging of the penis in cases of prolonged ischaemic priapism or Weak
refractory priapism, and as an adjunct to predict smooth muscle viability.

10.1.3 Disease management

Acute ischaemic priapism is a medical emergency. Urgent intervention is mandatory and should follow a
stepwise approach. The aim of any treatment is to restore penile detumescence, without pain, in order to prevent
corporal smooth muscle fibrosis and subsequent ED.

10.1.3.1 Medical Management – first-line treatment

First-line medical treatments for ischaemic priapism of more than 4 hours duration are strongly recommended
before any surgical treatment. Conversely, first-line treatments initiated beyond 48 hours, while relieving
priapism, have little documented benefit in terms of long-term erectile function preservation. This is likely
to be the consequence of irreversible smooth muscle hypoxia and damage that begins to be established by
approximately 48 hours of onset of ischaemia [1336-1338]. It has been shown in a series of 50 patients with
low-flow priapism who were successfully treated and followed-up for a mean of 66 months, that those with
priapism lasting for more than 48 hours had a significant risk of ED [1336].

Historically, several first-line treatments have been described including exercise, ejaculation, ice packs, cold
baths, and cold water enemas [1332]. However, there is limited evidence for the benefit of these measures and
they may even exacerbate the condition in SCD patients. Success rates for these conservative measures alone
have rarely been reported. In a small series, cold water enemas have been reported to induce detumescence in
six out of ten cases [1363]. In another study 24.5% of 122 patients achieved detumescence following priapic
episodes lasting for more than 6 hours by cooling of the penis and perineum, and walking upstairs [1364].

10.1.3.1.1 Penile anaesthesia/analgesia

Blood aspiration and intracavernous injection of a sympathomimetic agent can be performed without any
anaesthesia; however, anaesthesia may be necessary when there is severe penile pain. Whilst anaesthesia may
not alleviate the ischaemic pain, cutaneous anaesthesia facilitates subsequent therapies. The treatment options
for penile anaesthesia/systemic analgesia include:
• dorsal nerve block;
• circumferential penile block;
• subcutaneous local penile shaft block;
• oral conscious sedation (for paediatric patients).

10.1.3.1.2 Aspiration ± irrigation with 0.9% w/v saline solution

The first intervention for an episode of priapism lasting more than 4 hours consists of corporal blood aspiration
to drain the stagnant blood from the corporal bodies, making it possible to relieve the compartment-syndrome-
like condition within the corpus cavernosum. Blood aspiration may be performed with intracorporeal access
either through the glans or via percutaneous needle access to the lateral aspect of the proximal penile shaft,
using a 16 or 18 G angio-catheter or butterfly needle. The needle must penetrate the skin, the subcutaneous
tissue and the tunica albuginea to drain blood from the corpus cavernosum .

Some clinicians advocate using two angiocatheters or butterfly needles at the same time to accelerate drainage,
as well as aspirating and irrigating simultaneously with a saline solution [1364]. Aspiration should be continued
until bright red, oxygenated blood is aspirated.

Several case series have reported outcomes for first-line treatments; however, although in most cases,
aspiration and irrigation were combined with intracavernosal injection of sympathomimetic agents [1330], thus
making it difficult to draw conclusions about the success rate of aspiration + irrigation
alone [1330]. Overall, case series and retrospective studies reported a success rate ranging from 0 to 100%
of cases [1330]. In a RCT, 70 patients with ischaemic priapism lasting more than 6 hours secondary to
intracavernosal injection and were treated with aspiration plus saline irrigation at different temperatures [1364].
The study reported an 85% success rate with the optimum results achieved using a 10°C saline infusion after
blood aspiration.

There are insufficient data to determine whether aspiration followed by saline intracorporeal irrigation is more
effective than aspiration alone.

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10.1.3.1.3 A
 spiration ± irrigation with 0.9% w/v saline solution in combination with intracavernous injection of
pharmacological agents.
This combination is currently considered the standard of care for treatment of ischaemic priapism [1332, 1365,
1366]. Pharmacological agents include sympathomimetic drugs or α-adrenergic agonists. Intracavernous
sympathomimetic agents include phenylephrine, etilephrine, ephedrine, epinephrine, norepinephrine
and metaraminol with a resolution rate of up to 80% [1332, 1365, 1367-1374]. The use of intracavernous
adrenaline injection alone has also been sporadically reported [1375]. It has been reported that the use of a
sympathomimetic agent combined with prior intracavernosal aspiration or irrigation had a resolution ranging
from 80 to 100% of cases as compared with 58% in those who had a sympathomimetic injection alone [1330,
1366].

The potential treatment-related adverse effects of intracavernous phenylephrine (and other sympathomimetic
agents) include headache, dizziness, hypertension, reflex bradycardia, tachycardia and palpitations and
sporadic subarachnoid haemorrhage [368]. Monitoring of blood pressure and pulse should be performed during
intracavernous administration of sympathomimetic agents. As intracavernous sympathomimetic agents can
cause hypertension, the Guidelines Panel is of the opinion that these agents are contraindicated in patients
with malignant or poorly controlled hypertension, as there are case reports of significant cardiovascular and
neurological complications following the use of these pharmacological agents for priapism [1368, 1376, 1377].
Similarly, there are data suggesting that sympathomimetic agents cause a hypertensive crisis when given with
monoamine oxidase inhibitors, hence these medications should not be used together [1378].

10.1.3.1.4 Intracavernosal and oral pharmacological agents

Pharmacological agents for the treatment of priapism are discussed in more detail in the following section.
Table 10.4 summarises dosing and administration of these agents.

• Phenylephrine
Phenylephrine is a selective α-1-adrenergic receptor agonist that has been observed in small case series to be
effective at producing detumescence in priapism, when given as an intracavernosal injection, with few adverse
effects [1373, 1379]. Phenylephrine is the recommended adrenergic agonist drug of choice due to its high
selectivity for the α-1-adrenergic receptor, without concomitant β-mediated inotropic and chronotropic cardiac
effects [1367, 1371, 1372].

Phenylephrine has potential cardiovascular adverse effects [1332, 1365, 1367, 1368, 1371, 1372] and it is
recommended that blood pressure and pulse are monitored every fifteen minutes for 1 hour after injection. This
is particularly important in older men with pre-existing cardiovascular diseases. After injection, the puncture site
should be compressed and the corpus cavernosum massaged to facilitate drug distribution.

• Etilephrine
Etilephrine is also an adrenergic agonist that directly stimulates both  and  adrenergic receptors [1366]. Most
of the literature describing the use of etilephrine for treatment of priapism is related to men with SCD but there
are small retrospective case series that have reported its benefits for priapism secondary to iatrogenic causes
[1380, 1381]. Etilephrine is the second most widely used sympathomimetic agent [1368].

• Methylene blue
Methylene blue is a guanylate cyclase inhibitor, that may be a potential inhibitor of endothelial-mediated
cavernous smooth muscle relaxation. Small retrospective case series have reported its successful use for
treating short-term pharmacologically-induced priapism [1382, 1383]. Treatment-related adverse effects include
a transient burning sensation and blue discolouration of the penis.

• Adrenaline
Adrenaline produces both -adrenergic receptor agonist and -adrenergic receptor activity. Intracavernosal
adrenaline has been used in patients with ischaemic priapism due to an intracavernous injection of vasoactive
agents. The limited literature [1375, 1384] suggests that adrenaline can achieve detumescence in short-term
priapism, with one small case series reporting a success rate of over 50% after a single injection, with an overall
success rate of 95% with repeated injections [1375, 1384].

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• β-2-agonists
Oral terbutaline is a β-2-agonist with minor β-1 effects and some α-agonist activity; although its mechanism
of action is not yet fully understood [1385-1387]. The main use of terbutaline is for prevention of recurrent
episodes of prolonged erection. Oral treatment with terbutaline was tested in three placebo-controlled RCTs
[1386-1388] showing a success rate of 30 to 60% in patients with ischemic priapism associated with
intracavernous injection of erectogenic agents. Terbutaline should be given cautiously in patients with coronary
artery disease, increased intravascular fluid volume, oedema or hypokalaemia [1387]. In a single multi-centre
prospective study, another β-2-agonist, salbutamol, has been reported to induce detumescence in 34% of cases
of prolonged erection (more than 3 hours) after intracavernous injection of erectogenic agents [1389]. However,
more robust data are needed to recommend oral salbutamol for the treatment of ischaemic priapism.

Table 10.4: Medical treatment of ischaemic priapism

Drug Dose/Instructions for use

Phenylephrine • Intracavernous injection of 200 μg every 3-5 minutes.
• Maximum dosage is 1 mg within 1 hour.
• Lower doses are recommended in children and patients with severe
cardiovascular diseases.
Etilephrine • Intracavernosal injection at a concentration of 2.5 mg in 1-2 mL normal
saline.
Methylene blue • Intracavernous injection of 50-100 mg, left for 5 minutes. It is then aspirated
and the penis compressed for an additional 5 minutes.
Adrenaline • Intracavernous injection of 2 mL of 1/100,000 adrenaline solution up to five
times over a 20-minute period.
Terbutaline • Oral administration of 5 mg for priapism lasting more than 2.5 hours, after
intracavernous injection of vasoactive agents.

10.1.3.1.5 Management of priapism related to sickle cell disease

The results of a systematic review on the overall management of priapism related to SCD found that few studies
were conducted exclusively on patients with SCD and studies on mixed populations usually did not report
separate data on SCD patients [1331]. Clear and systematic reporting of patient characteristics, interventions
and outcomes was lacking, and the length of follow-up, if reported, varied significantly among the studies.
Overall, the quality of studies was deemed poor to allow high-quality, evidence-based recommendations to be
made.

Urgent intervention is essential and the general approach is similar to that described for other cases of
ischaemic priapism and should be co-ordinated with a haematologist [1390-1392].

However, as with other haematological disorders, other therapeutic interventions may also need to be
implemented [1390, 1392, 1393]. Specific measures for SCD-related priapism include intravenous hydration and
narcotic analgesia while preparing the patient for aspiration and irrigation. Additionally, supplemental oxygen
administration and alkalinisation with bicarbonate can be helpful [1347, 1391].

Haemoglobin S (HbS) percentage should be measured in all SCD patients with acute priapism. Exchange
blood transfusion has also been proposed, with the aim of increasing tissue delivery of oxygen [1394]. The
transfused blood should be sickle cell haemoglobin negative and Rh and Kell antigen matched [1395]; however,
the evidence is inconclusive as to whether exchange transfusion itself helps to resolve priapism. A systematic
review reported that the mean time to detumescence was eleven days with exchange transfusions compared to
eight days with conventional treatment. Moreover, there were 9 cases of ASPEN syndrome (association of SCD,
priapism, exchange transfusion and neurological events) as a consequence of blood transfusion [1396].

A series of 10 patients with SCD-related priapism showed that it was safe to perform exchange transfusion
[1394]; however, several reports suggest that exchange transfusion may result in serious neurological sequelae
[1396]. Therefore, routine use of exchange transfusion is not recommended as a primary treatment intervention
in this group unless there is a risk of SCD-related symptoms. However, in patients who failed medical
management, transfusion may be required to enable general anaesthesia to be safely administered prior to
definitive surgery [1397].

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10.1.3.2 Surgical management- second-line treatments
Second-line intervention typically refers to surgical intervention in the form of penile shunt surgery and penile
implant insertion for refractory or delayed ischaemic priapism, and should only be considered when other
medical management options have failed. There is no evidence detailing the time frames before moving
on to surgery after first-line treatment, although a period of at least 1 hour of first-line treatment without
detumescence can be considered prior to moving to surgical intervention.

A number of clinical indicators suggest failure of first-line treatment including continuing corporal rigidity,
cavernosal acidosis, anoxia, severe glucopenia, absence of cavernosal artery inflow by penile colour duplex US,
and elevated intracorporal pressure [1398].

10.1.3.2.1 Penile shunt surgery

Penile shunt surgery aims to produce an outflow for ischaemic blood from the corpus cavernosum into
the corpus spongiosal tissues, thereby allowing restoration of normal circulation within these structures.
Accordingly, a shunt creates an opening in the tunica albuginea, with either the glans, corpus spongiosum, or a
vein for blood drainage [1332, 1365, 1399].

The type of shunt procedure is chosen according to the surgeon’s preference and familiarity with the procedure.
It is conventional practice for distal shunt procedures to be tried before considering proximal shunting.

It is important to assess the success of surgery by direct observation of penile rigidity or by repeated testing
(e.g., cavernous blood gas testing) [1332, 1365, 1400, 1401]. The use of penile colour US may not give
appropriate information because of the hyperaemic (reperfusion) period that follows decompression after the
ischaemic state [1402].

The recovery rates of erectile function in men undergoing shunt surgery following prolonged episodes of
priapism are low and are directly related to the duration of priapism, pre-operative erectile status and age
[1400, 1401, 1403]. If ischaemic priapism resolves within 24 hours of onset, it has been reported that 78-100%
of patients regain spontaneous functional erections (with or without PDE5Is use). In contrast, other studies
have shown that priapism for more than 36-48 hours appears to result in both structural and functional effects
on corporal smooth muscle, with poorer outcomes (ED > 90%) [1400, 1404]. In general, shunt procedures
undertaken after this time period (36-48 hours) may only serve to limit pain without any beneficial effects on
erectile function and early penile prosthesis insertion can be considered [1338, 1405].

Procedures for shunting require incision through the tunica albuginea and expose collagen to coagulation
factors in the penile blood and thus activate the blood-clotting cascade. Peri-operative anti-coagulation is
advocated to facilitate resolution of the priapism. There was an 84% decrease in priapism recurrence in the
shunt group that received peri-procedural anti-thrombotic treatment (325 mg acetylsalicylic acid pre-operatively,
and 5000 IU intraoperative heparin, 81 mg acetylsalicylic acid and 75 mg clopidogrel post-operatively for 5 days)
compared with the group that did not receive peri-procedural anti-thrombotic treatment after failed aspiration
[1406].

Four categories of shunt procedures have been reported [1332, 1366, 1399, 1405]. The limited data available
does not allow one procedure to be recommended over another. However, distal shunts are less invasive
and associated with lower rates of post-operative ED and therefore are recommended as the first surgical
intervention of choice (Appendix 6 online supplementary evidence Table S10.1).

• Percutaneous distal (corpora-glanular) shunts

Winter’s procedure uses a Trucut biopsy needle to create a fistula between the glans penis and each corpus
cavernosum [1332, 1344, 1366, 1402, 1407]. Post-operative sequelae are uncommon [1408]. Winter’s shunt is
easy to perform, but has been reported as the least successful operation to create a distal shunt [1401]. This
is because the diameter of the Trucut needle is only 1.6 mm (14-18 g) and therefore cannot accommodate the
increased blood flow from post-ischaemic hyperaemia, resulting in poor drainage, increased intracavernous
pressure and consequent premature closure of the shunt [1402].

Ebbehoj’s technique involves making multiple tunical incision windows between the glans and each tip of the
corpus cavernosum by means of a size 11 blade scalpel passed several times percutaneously [1332, 1366,
1402, 1409, 1410].

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T-Shunt involves performing a bilateral procedure using a scalpel with a size 10 blade inserted through the glans
just lateral to the urethral meatus until it enters the tip of the corpus cavernosum. The blade is then rotated 90°
away (to the lateral side) from the urethral meatus and withdrawn [1332, 1366, 1402, 1411]. If unsuccessful, the
procedure is repeated on the opposite side. The T-shunt can be followed by a tunnelling procedure using a size
8/10 Hegar dilator inserted through the glans and into the corpus cavernosum, which can also be performed
using US guidance, mainly to avoid urethral injury [1411]. The entry sites in the glans are sutured following
detumescence. Tunnelling with a 7 mm metal sound or 7/8 Hegar dilator is necessary in patients with priapism
duration > 48 hours. Tunnelling is a potentially attractive procedure as it combines the features of distal and
proximal shunts with proximal drainage of the corpus cavernosum and may ameliorate the profibrotic effect of
sludged blood retained in the corpus cavernosum [1403, 1405, 1411].

• Open distal (corpora-glanular) shunts

Al-Ghorab’s procedure consists of an open bilateral excision of circular cone segments of the distal tunica
albuginea via the glans penis, along with subsequent glans closure by running suture with absorbable material.
A transverse incision on the glans may compromise arterial blood flow because distal deep dorsal arteries run
longitudinally in the glans [1332, 1366, 1402, 1412-1414].

Burnett’s technique (Snake manoeuvre) is a modification of the Al-Ghorab corpora-glanular shunt. It involves
retrograde insertion of a 7/8 Hegar dilator into the distal end of each corpus cavernosum through the original
Al-Ghorab glandular excision. After removal of the dilator from the corpus cavernosum, blood evacuation
is facilitated by manual compression of the penis sequentially from a proximal to distal direction. After
detumescence, the glans penis is closed as in the Al-Ghorab procedure [1332, 1366, 1402, 1415, 1416]. Reported
complications include wound infection, penile skin necrosis and urethrocutaneous fistulae [1416].

• Open proximal (corpora-spongiosal) shunts

Quackles’s technique uses a trans-scrotal or perineal approach; a proximal open shunt technique creates a
communication between the corpus cavernosum and the corpus spongiosum. The most frequent complications
include an unwanted urethro-cavernous fistula and urethral stricture or cavernositis [1332, 1366, 1399, 1417].
The risk of urethral injury is less with a perineal approach to the bulb of the corpus spongiosum. Proximal shunts
are more invasive and ED rates are documented to be higher [1398].

• Peno-scrotal decompression
More recently a proximal decompression technique with the aim to spare the glans with high success rates
has been described. The technique is based upon opening of the proximal corpus cavernosum combined with
proximal and distal tunnelling using a suction tip [1418]. In a cohort of 25 patients, 12 had undergone previous
corpora-glanular shunt surgery. Recurrence was observed in two of 25 patients with unilateral peno-scrotal
decompression. In the 15 patients who had follow-up data, 40% had ED. Whilst, representing a promising
technique, PSD in cases of refractory priapism may further delay penile prosthesis insertion with potential
detrimental effects on surgical outcomes including penile shortening and prosthetic infection.

• Vein anastomoses/shunts
Grayhack’s procedure mobilises the saphenous vein below the junction of the femoral vein and anastomoses the
vein end-to-side onto the corpus cavernosum. Venous shunts may be complicated by saphenofemoral thrombus
formation and by pulmonary embolism [1332, 1366, 1419-1421].

10.1.3.2.2 Immediate penile prosthesis implantation

The studies pertaining to penile implantation surgery are principally retrospective non-randomised case series
(Table S10.3 Appendix 6 online supplementary evidence). All of the studies described priapism resolution rate,
sexual function and surgical adverse events although the follow-up period was variable [1329].

Refractory, therapy-resistant, acute ischaemic priapism or episodes lasting more than 48 hours usually result
in complete ED, and possibly significant penile deformity in the long-term. In these cases, immediate penile
prosthesis implantation surgery is advocated [1422-1425].

Gadolinium-enhanced penile MRI [1362] and cavernosal smooth muscle biopsy have been used to diagnose
smooth muscle necrosis (which, if present, would suggest that shunting is likely to fail) and may help in
decision-making and patient counselling in cases of refractory or delayed presentation (> 48 hours) that may be
considered for immediate penile prosthesis insertion.

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Early implantation of a penile prosthesis is associated with lower infection rates (6-7% vs. 19-30%), penile
shortening (3% vs. 40%) and revision rates (9% vs. 27%) compared to late insertion. General satisfaction
rate for early implantation is higher (96%) than for late implantation (60%) [1338] (Table S10.4 Appendix 6
online supplementary evidence). Potential complications that could compromise immediate penile prosthesis
implantation include distal erosion and infection [1422, 1424], along with a small rate of revision surgery [1422].
Early surgery also offers the opportunity to maintain penile length and girth and prevent penile curvature due
to cavernosal fibrosis. The prosthesis can be exchanged for an inflatable prosthesis at a later date, which may
allow upsizing of the implant cylinders [1426].

The decision on which type of implant to insert is dependent on patient suitability, surgeons’ experience,
and availability and cost of the equipment. The immediate insertion of a malleable penile prosthesis is
recommended to avoid the difficulty and complications of delayed prosthetic surgery in the presence of corporal
fibrosis.

There are no randomised trials comparing the efficacy and complication rates of malleable and inflatable penile
prostheses. Despite the higher infection rate in priapism patients compared to those with virgin prosthesis, in
patients who are well-motivated and counselled prior to the procedure, immediate inflatable penile prosthesis
implantation may be undertaken, although in most cases a semi-rigid implant is more suitable as it is easier to
implant and reduces operative time and hence the risk of prosthetic infection. A further issue with immediate
insertion of an inflatable penile prosthesis is that the patient must begin cycling the device immediately to
avoid a fibrous capsule forming and contracting. Early cycling of an inflatable penile prosthesis prevents penile
curvature and shortening [1338].

Currently, there are no clear indications for immediately implanting a penile prosthesis in men with acute
ischaemic priapism, although this can be considered in men with delayed or refractory priapism [1365].

Relative indications include [1332]:

• Ischaemia that has been present for more than 48 hours.
• Failure of aspiration and sympathomimetic intracavernous injections in delayed priapism (> 48 hours).
• Magnetic resonance imaging or corporal biopsy evidence of corporal smooth muscle necrosis [1332, 1422].
• Failure of a shunting procedure; although, in delayed cases (> 48 hours), implantation might be considered
ahead of shunt surgery.
• Refractory priapism in patients who have undergone shunting procedures.

The optimal time for implantation is within the first three weeks from the priapism episode [1338, 1398, 1427].
If shunt surgery has been performed, penile prosthesis implantation can be further delayed in order to allow
reduction of oedema, wound healing and risk of prosthetic infection. A vacuum device to avoid fibrosis and
penile shortening may be used during this waiting period [1428].

10.1.3.2.3 Surgery for non-acute sequelae after ischaemic priapism

Structural changes may occur after ischaemic priapism including cavernosal tissue necrosis and fibrosis with
consequent penile scarring, megalophallic deformities, penile shortening, and occasional penile loss [1399,
1422, 1429, 1430]. Erectile dysfunction is also often observed [1332, 1431]. Unfortunately, these outcomes can
still occur despite apparently successful first or second-line treatment in detumescence of the penis.

Penile prosthesis implantation is occasionally indicated in SCD patients with severe ED because other
therapeutic options, such as PDE5Is and intracavernous injections are avoided as they may provoke a further
priapism event [1332, 1365]. In severe corporal fibrosis, narrow-based prosthetic devices are preferable because
they are easier to insert and need less dilatation [1422]. After severe priapism that has resulted in penile
destruction with complicated deformities or even loss of penile tissue, it may be necessary to make changes
to the surgical technique. Multiple corporotomies, corporal excavation, optical corporotomy-Shaeer technique,
dilatation with Carrion-Rosello cavernotome, Uramix or Mooreville cavernotome, excision of scar tissue, and use
of small-diameter prosthesis, or penile reconstruction using grafts can be utilised, if concomitant prosthesis
implantation is considered [1404, 1432].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 115

Figure 10.2: Management work-up of ischaemic priapism

Inial conservave measures

• Local anaesthesia of the penis
• Insert wide bore bu erfly (16-18 G) through the glans into the corpora cavernosa or directly laterally
in the corpora cavernosa (both sides)
• Aspirate cavernosal blood unl bright red arterial blood is obtained

Cavernosal irrigaon
• Irrigate with 0.90% w/v saline soluon

Intracavernosal therapy
• Inject intracavernosal adrenoceptor agonist
• Current first-line therapy is phenylephrine* with aliquots of 200 µg being injected every 3-5 minutes
unl detumescence is achieved (maximum dose of phenylephrine is 1mg within 1 hour) *

Surgical therapy
• Surgical shunng
• Consider primary penile implantaon if priapism has been present for more than 48 hours

Diagnosis Treatment Follow-up

(*) Dose of phenylephrine should be reduced in children. It can result in significant hypertension and should be
used with caution in men with cardiovascular disease. Monitoring of pulse and blood pressure is advisable in all
patients during administration and for one hour afterwards. Its use is contraindicated in men with a history of
cerebro-vascular disease and significant hypertension.

116 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Figure 10.3: Surgical management of priapism

Aspiraon and
injecon failed IP

< 24h 24-48h > 48h

T-shunt ± No Penile Necrosis PPI

tunnelling necrosis MRI

failure Peno-scrotal
decompression

Diagnosis Treatment Follow-up

MRI = Magnetic resonance imaging; PPI = penile prosthesis implantation; IP = ischaemic priapism.

10.1.4 Summary of evidence and recommendations for treatment of ischaemic priapism

Summary of evidence LE
Ischaemic priapism is a medical emergency and immediate intervention is mandatory. 2b
Erectile function preservation is directly related to the duration of ischaemic priapism, age and pre- 2b
operative erectile status.
Medical treatment is variably effective in case of priapism lasting less than 48 hours 2b
Aspiration ± irrigation with 0.9% results in over 80% success rate when combined with intracavernous 2b
injection of sympathomimetic drugs
Phenylephrine is the recommended drug due to its favourable safety profile in the cardiovascular 2b
system compared to other drugs. Phenylephrine is usually diluted in normal saline with a concentration
of 100-500 μg/mL and given in 200 μg doses every three to five minutes directly into the corpus
cavernosum. Maximum dosage is 1 mg within one hour. Patient monitoring is highly recommended.
Oral terbutaline has a success rate in up to 60% of cases when priapism is associated with 1b
intracavernous injection of erectogenic agents.
Exchange transfusion in patients with priapism associated with SCD may result in serious neurological 2b
sequelae.
Shunt procedures are effective to resolve priapism and provide pain relief. No clear recommendation 2b
of the superiority of one type of shunt over another can be given. Distal shunts are less invasive and
associated with lower rate of erectile dysfunction.
Peri- and post-operative anticoagulant prophylaxis (325 mg acetylsalicylic acid pre-operatively, 5,000 3
IU heparin intra-operatively and 81 mg acetylsalicylic acid and 75 mg clopidogrel five days post-
operatively) may prevent priapism recurrence.
Erectile dysfunction is almost inevitable in prolonged cases or ischaemic priapism. Early implantation 2b
of penile prosthesis is associated with lower infection rates and complications compared to late
implantation.

Recommendations Strength rating

Start management of ischaemic priapism as early as possible (within four to six hours) and Strong
follow a stepwise approach.
Decompress the corpus cavernosum by penile aspiration and washout until fresh red blood Strong
is obtained as first treatment step.

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Replace blood aspiration with intracavernous injection of a sympathomimetic drug as the Strong
first step in priapism secondary to intracavernous injections of vasoactive agents.
Perform intracavernous injection of a sympathomimetic drug in priapism that persists Strong
despite aspiration.
Repeat aspiration and intracavernous injection of a sympathomimetic drug in cases that Strong
persist despite prior aspiration and intracavernous injection of a sympathomimetic drug,
before considering surgical intervention.
Treat ischaemic priapism associated with sickle cell disease in the same fashion as Strong
idiopathic ischaemic priapism. Do not use exchange transfusion as a primary treatment.
Provide other supportive measures (intravenous hydration, oxygen administration with
alkalisation with bicarbonate, blood exchange transfusions), but do not delay initial
treatment to the penis.
Proceed to surgical treatment only when blood aspiration and intracavernous injection of Strong
sympathomimetic drugs have failed.
Perform distal shunt surgical procedures first and combine them with tunnelling if necessary. Weak
Use proximal procedures in cases of distal shunt failure (< 48 hours) or in patients who do Weak
not wish to proceed with immediate penile implant insertion.
Discuss implantation of a penile prosthesis in cases of delayed presentation (> 48 hours) Weak
and in cases refractory to injection therapy and distal shunting.
Delay implantation of a penile prosthesis if a shunt has been performed, to minimise the risk Strong
of infection and erosion of the implant.
Decide on which type of implant to insert based on: Strong
• patient suitability;
• surgeons’ experience; and
• availability and cost of equipment.
If a malleable penile prosthesis is implanted it can be exchanged for an inflatable penile
implant.

10.2 Priapism in Special Situations

10.2.1 Stuttering (recurrent or intermittent) priapism
Stuttering priapism, also termed intermittent or recurrent priapism, is a distinct condition that is characterised
by repetitive and painful episodes of prolonged erections. Erections are self-limiting with intervening periods
of detumescence [1391, 1433]. These are analogous to repeated episodes of ischaemic priapism. In stuttering
priapism the duration of the erections is generally shorter than in ischaemic priapism [1366]. The frequency
and/or duration of these episodes are variable and a single episode can sometimes progress into prolonged
ischaemic priapism.

Robust epidemiological studies of stuttering priapism are lacking [1434, 1435]. However, recurrent priapism
episodes are common in men with SCD (42-64%) [1436, 1437] while in adolescents and young men the
incidence of priapism is 35%, of whom 72% have a history of stuttering priapism [1434].

The aetiology of stuttering priapism is similar to that of ischaemic priapism. Whilst SCD is the most common
cause, idiopathic cases and cases due to a neurological disorder have been reported. Men who have acute
ischaemic priapism, especially which has been prolonged (for more than 4 hours) are at risk of developing
stuttering priapism [1431].

Several studies have proposed alternative mechanisms for stuttering priapism including inflammation, cellular
adhesion, NO metabolism, vascular reactivity and coagulation [1332, 1348, 1391, 1433, 1438-1441]. Although
debated, androgens have also been observed to have an association with priapism [1442]. Therefore, one of
the options for the treatment of stuttering priapism is to reduce serum testosterone levels to hypogonadal
levels, which then suppresses androgen-associated mechanisms believed to be involved in triggering recurrent
priapism.

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10.2.1.1 Diagnostic evaluation
History, physical examination, laboratory testing and penile imaging follow the same principals as ischaemic
priapism. In stuttering priapism there is a history of recurrent episodes of prolonged erections. These episodes
can occur from several daily to isolated incidents every few months, continuously or followed by incident-free
periods, of unknown duration, even months and years [1443]. The onset of the priapic episodes usually occurs
during sleep and detumescence does not occur upon waking. These episodes can be painful and may be the
reason that the patient first seeks medical attention. Erections are painful and the penis is rigid as in ischaemic
priapism, but the duration of events is usually shorter. Between erections the penis is usually normal, but in
some cases signs of fibrosis can be found. Rarely, the penis may become enlarged, a condition known as
megalo-phallus.

Recommendations for the diagnosis of stuttering priapism are the same as those described in section 10.1.2.5

10.2.1.2 Disease management

The primary goal in the management of patients with stuttering priapism is the prevention of further episodes
and limiting the chances of developing a prolonged ischaemic priapism that is refractory to conventional
treatment options. In most cases, stuttering priapism can be managed by pharmacological treatment.
The management of each acute episode is similar to that for ischaemic priapism; aspiration/irrigation in
combination with intracavernous injections of α-adrenergic agonists.

10.2.1.2.1 α-Adrenergic agonists

Studies of oral α-adrenergic agonists have suggested some prophylactic benefit for daily treatment with these
agents [1444]. Adverse effects include tachycardia and palpitations. Pseudoephedrine is widely used as an
oral decongestant and can be a first-line treatment option for stuttering priapism [1386]. However, its effect on
corporal smooth muscle is not fully understood. Etilephrine has been used successfully to prevent stuttering
priapism caused by SCD. It is usually taken orally at doses of 5-10 mg daily, with response rates of up to 72%
[1445-1447]. In one RCT, placebo-controlled clinical study comparing medical prophylaxis with etilephrine and
ephedrine, there was no difference in efficacy between the two drugs.

10.2.1.2.2 Hormonal manipulations of circulating testosterone

The aim of hormonal manipulation is to down-regulate circulating testosterone levels to suppress the action
of androgens on penile erection [1347, 1391, 1448]. This can be achieved by GnRH agonists or antagonists,
antiandrogens or oestrogens [1449, 1450]. Potential adverse effects may include hot flushes, gynaecomastia,
ED, loss of libido, and asthenia. All approaches have a similar efficacy profile while the potential cardiovascular
toxicity of oestrogens limits their clinical use. Alternative endocrine approaches that have been used with some
success include 5-α-reductase inhibitors [1451, 1452] and ketoconazole; an anti-fungal agent that reduces
adrenal and testicular androgen production [1448, 1453].

The duration of hormonal treatment for effective suppression of recurrent priapism is problematic. It is not
possible to draw any conclusions on the dose, duration of treatment and the efficacy. Caution is strongly
advised when prescribing hormonal treatments to pre-pubertal boys and adolescents, and specialist advice
from paediatric endocrinologists should be sought. Likewise, hormonal agents have a contraceptive effect
and interfere with normal sexual maturation and spermatogenesis and affect fertility. Therefore, men who are
trying with their partner to conceive should be comprehensively counselled before using hormonal treatment.
Moreover, sperm cryopreservation may be considered to mitigate any potential effects of anti-androgen therapy
on fertility.

10.2.1.2.3 Digoxin
Digoxin is a cardiac glycoside and positive inotrope that is used to treat congestive heart failure. Digoxin
regulates smooth muscle tone through several different pathways leading to penile detumescence [1347, 1391,
1454]. The use of maintenance digoxin doses (0.25-0.5 mg/daily) in idiopathic stuttering priapism reduces the
number of hospital visits and improves QoL [1391]. In a small, clinical, double-blind, placebo-controlled study,
digoxin decreased sexual desire and excitement with a concomitant reduction in penile rigidity, regardless of
any significant change in plasma levels of testosterone, oestrogens and LH [1454]. Adverse effects include
decreased libido, anorexia, nausea, vomiting, confusion, blurred vision, headache, gynaecomastia, rash and
arrhythmia.

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10.2.1.2.4 Terbutaline
Terbutaline has been used to prevent stuttering priapism with detumescence rates of 36% in patients with
alprostadil-induced priapism [1386]. The only RCT (n = 68) in patients with pharmacologically-induced priapism,
demonstrated detumescence in 42% of the terbutaline-treated group compared to only 15% in the placebo-
treated group [1387]. Adverse effects include nervousness, shakiness, drowsiness, palpitations, headache,
dizziness, hot flushes, nausea and weakness.

10.2.1.2.5 Gabapentin
Gabapentin has anticonvulsant, antinociceptive and anxiolytic properties and is widely used as an analgesic
and anti-epileptic agent. Its proposed mechanism of action is to inhibit voltage-gated calcium channels, which
attenuates synaptic transmission [1448], and reduces testosterone and FSH levels [1455]. It is given at a dose
of 400 mg, four times daily, up to 2,400 mg daily, until complete penile detumescence occurs, with subsequent
maintenance administration of 300 mg/daily [1456]. Adverse effects include anorgasmia and impaired erectile
function.

10.2.1.2.6 Baclofen
Baclofen is a gamma-aminobutyric acid (GABA) derivative that acts as a muscle relaxant and anti-muscle
spasm agent. It can inhibit penile erection and ejaculation through GABA activity and prevents recurrent
reflexogenic erections or prolonged erections from neurological diseases [1347]. Oral baclofen has little efficacy
and it is not usually used in stuttering priapism but intrathecal administration is more effective [1391, 1457-
1459]. Adverse effects include drowsiness, confusion, dizziness, weakness, fatigue, headache, hypotension and
nausea.

10.2.1.2.7 Hydroxyurea
Hydroxyurea blocks the synthesis of deoxyribonucleic acid (DNA) by inhibiting ribonucleotide reductase,
which has the effect of arresting cells in the S-phase [1448, 1460]. Hydroxyurea is an established treatment
for ameliorating SCD and improving life expectancy [1390, 1461]. For patients with recurrent priapism, there is
limited evidence to suggest a prophylactic role of hydroxyurea, [1448, 1460, 1462]. Adverse effects include oligo-
zoospermia and leg ulcers.

10.2.1.2.8 Phosphodiesterase type 5 inhibitors

Low doses of PDE5Is have a paradoxical effect in alleviating and preventing stuttering priapism; mainly
in patients with idiopathic and SCD-associated priapism [1347, 1391, 1439, 1463-1467]. It is important to
remember that therapy should be started when the penis is in its flaccid state and not during an acute episode.
There is a delay of one week before treatment is effective. There are no reported impairments in male sexual
function.

10.2.1.2.9 Intracavernosal injections

Some patients with stuttering priapism, who have started on systemic treatment to prevent recurrence of
unwanted erections, may not see therapeutic benefits immediately and temporarily require intracavernous
self-injections at home with sympathomimetic agents [1347, 1391]. The most commonly used drugs are
phenylephrine and etilephrine [1332, 1366, 1435, 1446].

Tissue plasminogen activator (TPA) is a secreted serine protease that converts the pro-enzyme plasminogen to
plasmin, which acts as a fibrinolytic enzyme. Limited clinical data have suggested that a single intracavernous
injection of TPA can successfully treat patients with recalcitrant priapism [1448, 1468]. Mild bleeding is the most
commonly observed adverse effect.

10.2.1.2.10 Penile prosthesis

Patients with medically refractory stuttering priapism require frequent visits to the emergency department and
are always at risk of a major ischaemic episode, which can be mitigated with insertion of a penile prosthesis
[1404, 1425, 1469]. Nevertheless, penile prosthesis for preventing stuttering priapism should not be offered
before medical treatment and a penile prosthesis should be performed only in carefully selected patients as a
last resort [1404]. In patients with permanent ED due to stuttering priapism, medical treatments for ED should be
used cautiously because of the risk of inducing an ischaemic episode and a penile prosthesis can be considered
[1404, 1470].

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10.2.1.3 Summary of evidence and recommendations for treatment of stuttering priapism

Summary of evidence LE
The primary goal in the management of patients with stuttering priapism is prevention of future 2b
episodes, which can generally be achieved pharmacologically.
Hormonal therapy with GnRH agonists or antagonists or anti-androgens is able to reduce the risk of 3
recurrent priapism episodes although it is associated with adverse events (hot flushes, gynaecomastia,
ED, loss of libido, asthenia and infertility).
Phosphodiesterase type 5 inhibitors have a paradoxical effect in alleviating and preventing stuttering 3
priapism, mainly in patients with idiopathic and sickle cell disease-associated priapism.
The evidence for other systemic drugs (digoxin, α-adrenergic agonists, baclofen, gabapentin and 3
terbutaline, hydroxyurea) is limited.

Recommendations Strength rating

Manage each acute episode according to the treatment recommendations for ischaemic Strong
priapism (section 10.1.4).
Use hormonal therapies (mainly gonadotropin-receptor hormone agonists or antagonists) Weak
and/or anti-androgens for the prevention of future episodes in patients with frequent
relapses. Do not use them before sexual maturation is reached.
Initiate treatment with phosphodiesterase type 5 inhibitors only when the penis is in its Weak
flaccid state.
Use digoxin, α-adrenergic agonists, baclofen, gabapentin or terbutaline only in patients with Weak
frequent and uncontrolled relapses.
Use intracavernous self-injections of sympathomimetic drugs at home for treatment of acute Weak
episodes on an interim basis until ischaemic priapism has been alleviated.

10.2.1.4 Follow-up
Follow-up for stuttering priapism includes history and clinical examination to assess the efficacy of treatment in
preventing or alleviating erectile events as well as assessing erectile function and penile fibrosis.

10.2.2 Priapism in children

The classification of priapism in children is similar to that in adults. In addition to ischaemic, stuttering and non-
ischaemic priapism, a fourth type, neonatal priapism is also described [1332]. Priapism in children is considered
rare as no data on its prevalence exist. Sickle cell disease is the major cause of priapism in children, followed
by leukaemia (10%), trauma (10%), idiopathic causes (19%) and drugs (5%) [1471]. One study showed that 25%
of children experienced SCD-related priapism in a pre-pubertal period [1472]. Another study revealed that 90%
of men with SCD had their first priapism episode before age 20 years [1437]. Priapism in children should be
evaluated and treated in a timely manner, as untreated ischaemic priapism may lead to ED and psychosexual
disorders in adulthood [1473]. A multi-disciplinary team approach should be utilised with specialist input from
haematologists and paediatric endocrinologists.

10.3 Non-ischaemic (high-flow or arterial) priapism

Non-ischaemic priapism is a persistent erection caused by unregulated cavernous arterial inflow [1332].
According to aetiology, non-ischaemic priapism can be categorised into four types: traumatic, neurogenic,
iatrogenic and idiopathic in origin.

10.3.1 Epidemiology/aetiology/pathophysiology
Epidemiological data on non-ischaemic priapism are almost exclusively derived from small case series [1332,
1360, 1474-1476]. Non-ischaemic priapism is significantly less common than the ischaemic type, comprising
only 5% of all priapism cases [1332]. The most frequent cause of non-ischaemic priapism is blunt perineal or
penile trauma [1477]. The injury results in a laceration in the cavernosal artery or branches, leading to a fistula
between the artery and the lacunar spaces of the sinusoidal space [1476]. The resultant increased blood flow
results in a persistent and prolonged erection [1478].

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There is often a delay between the trauma and the development of the priapism that may be up to two to three
weeks [1479]. This is suggested to reflect either spasm or ischaemic necrosis of the injured artery, with the
fistula only developing as the spasm resolves or when the ischaemic segment “blows up”. The priapism typically
occurs after a nocturnal erection or an erection related to sexual activity, resulting in the sudden increase of
blood flow and pressure in the cavernous arteries [1480]. The patient typically reports an erection that is not
fully rigid and is not associated with pain because the venous drainage is not compromised and the penile
tissue does not become ischaemic [1481].

Non-ischaemic priapism can occur after acute spinal cord injury, presumably due to loss of sympathetic input,
leading to predominant parasympathetic input and increased arterial flow [1482]. It has also been reported to
occur following internal urethrotomy [1483], Nesbit procedure [1484], circumcision [1485], transrectal prostate
biopsy [1486], and brachytherapy for prostate cancer [1487]. Some cases have also been described following
shunting procedures performed for ischaemic priapism due to a lacerated cavernosal artery (conversion of
low-flow to high-flow priapism) [1488-1490]. Although SCD is usually associated with ischaemic priapism,
occasional cases of high-flow priapism have been reported; however, the pathophysiological mechanism
remains unclear [1491]. Finally, metastatic malignancy to the penis can also rarely cause non-ischaemic
priapism [1492, 1493].

10.3.2 Diagnostic evaluation

10.3.2.1 History
A comprehensive history is mandatory in non-ischaemic priapism diagnosis and follows the same principles as
described in section 10.1.2.1. Arterial priapism should be suspected when the patient reports a history of pelvic,
perineal, or genital trauma; no penile pain (discomfort is possible); and a persistent, not fully rigid erection.
The corpus cavernosum can become fully rigid with sexual stimulation, so sexual intercourse is usually not
compromised. The onset of post-traumatic non-ischaemic priapism can be delayed by several hours to weeks
following the initial injury [1332].

10.3.2.2 Physical examination

In non-ischaemic priapism, the corpora are tumescent but not fully rigid. Abdominal, penile and perineal
examination may reveal evidence of trauma [1332]. Neurological examination is indicated if a neurogenic
aetiology is suspected.

10.3.2.3 Laboratory testing

Laboratory testing should include a blood count with white blood cell differential and a coagulation profile to
assess for anaemia and other haematological abnormalities. Blood aspiration from the corpus cavernosum
shows bright red arterial blood in arterial priapism, while blood is dark in ischaemic priapism. Blood gas analysis
is essential to differentiate between non-ischaemic and ischaemic priapism. Blood gas values in high-flow
priapism show normal arterial blood [1332] (Table 10.3).

10.3.2.4 Penile imaging

Colour duplex US of the penis and perineum is recommended and can differentiate non-ischaemic from
ischaemic priapism [1358-1360]. Ultrasound must be performed without intracavernosal vasoactive drug
injection [1494]. In non-ischaemic priapism, US helps to localise the fistula site and appears as a characteristic
colour blush and turbulent high-velocity flow on Doppler analysis [1495]. Patients with non-ischaemic priapism
have normal to high blood velocities in the cavernous arteries [1361, 1496].

Selective pudendal arteriography can reveal a characteristic blush at the site of injury in arterial priapism [1497,
1498]. However, due to its invasiveness, it should be reserved for the management of non-ischaemic priapism
when embolisation is being considered [1332, 1355].

The role of MRI in the diagnostic evaluation of priapism is controversial. Its role in non-ischaemic priapism is
limited because the small penile vessels and fistulae cannot be easily demonstrated [1499].

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10.3.2.5 Summary of evidence and recommendations for the diagnosis of non-ischaemic priapism

Summary of evidence LE
Non-ischemic priapism is less common than ischemic and is usually associated with blunt perineal or 2b
penile trauma leading to the development of intracavernosal fistula.
Medical history and blood gas analysis are able to differentiate between ischemic and non-ischemic 2b
priapism.
Blood aspiration from the corpora in case of non-ischemic priapism reveal bright red arterial blood with 2b
normal arterial gas values.
Penile duplex US is able to identify intracavernosal fistula responsible for non-ischemic priapism. 2b

Recommendations Strength rating

Take a comprehensive history to establish the diagnosis, which can help to determine the Strong
priapism subtype.
Include a physical examination of the genitalia, perineum and abdomen in the diagnostic Strong
evaluation.
Include a neurological examination if neurogenic non-ischaemic priapism is suspected. Strong
Include complete blood count, with white blood cell differential, and coagulation profile for Strong
laboratory testing.
Analyse the blood gas parameters from blood aspirated from the penis to differentiate Strong
between ischaemic and non-ischaemic priapism.
Perform colour duplex ultrasound of the penis and perineum to differentiate between Strong
ischaemic and non-ischaemic priapism.
Perform selected pudendal arteriography when embolisation is planned for non-ischaemic Strong
priapism.

10.3.3 Disease management

Although the conventional belief is that the management of non-ischaemic priapism is not an emergency
because the corpus cavernosum does not contain ischaemic blood; however, recent data indicate that the
duration of non-ischaemic priapism can also impact EF. In a case series consisting of six patients with high-
flow priapism after median follow-up of 4.5 (2-12) weeks, all patients reported development of ED or distal
penile flaccidity [1426]. The goal of treatment is closure of the fistula. Non-ischaemic priapism can be managed
conservatively or by direct perineal compression. Failure of conservative treatment requires selective arterial
embolisation [1500]. The optimal time interval between conservative treatment and arterial embolisation is
under debate. Definitive management can be performed at the discretion of the treating physician and should be
discussed with the patient so that they can understand the risks of treatment [1332, 1355].

10.3.3.1 Conservative management

Conservative management may include applying ice to the perineum or perineal compression, which is typically
US-guided. The fistula occasionally closes spontaneously. Even in cases where the fistula remains patent,
intercourse is still possible [1360, 1475, 1501, 1502]. Androgen deprivation therapy (e.g., leuprolide injections,
bicalutamide and ketoconazole) has been reported in case series to enable closure of the fistula reducing
spontaneous and sleep-related erections [1503]. However, sexual dysfunction due to these treatments must be
considered. Patients may develop ED or distal penile flaccidity while undergoing conservative treatment [1426].

Blood aspiration is not helpful for the treatment of arterial priapism and the use of α-adrenergic antagonists
is not recommended because of potential severe adverse effects (e.g., transfer of the drug into the systemic
circulation).

10.3.3.2 Selective arterial embolisation

Selective arterial embolisation can be performed using temporary substances, such as autologous blood
clot [1504-1506] and gel foam [1505, 1507], or permanent substances such as microcoils [1505, 1507-1509],
ethylene-vinyl alcohol copolymer (PVA), and N-butyl-cyanoacrylate (NBCA) [1510]. It is assumed that temporary
embolisation provides a decreased risk of ED, with the disadvantage of higher failure/recurrence rates, as
a consequence of artery embolisation using temporary materials. However, there is insufficient evidence to

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support this hypothesis. Success rates ranging between 61.7 and 83.3%, and ED rates from 0-33.3% after the
first arterial embolization have been reported, suggesting that failure/recurrence may not be significantly higher
with temporary embolisation materials, and preservation of erectile function may not be that different between
the two modalities either [1480]. Other potential complications of arterial embolisation include penile gangrene,
gluteal ischaemia, cavernositis, and perineal abscess [1332, 1511]. Repeated embolisation is a reasonable
option for treating non-ischaemic priapism, both in terms of efficacy and safety [1480].

10.3.3.3 Surgical management

Surgical ligation of the fistula is possible through a transcorporeal or inguinoscrotal approach, using intra-
operative Doppler US. Surgery is technically challenging and associated with significant risks, particularly of ED
[1512]. Surgery is rarely performed and should only be considered when there are contraindications for selective
embolisation, if embolisation is unavailable, or repeated embolisations have failed. If the patient desires more
definitive treatment and is not sexually active or has pre-existing ED, surgical intervention can be an appropriate
option [1480]. Erectile dysfunction rates ranging from 0-50% have been reported following treatment for non-
ischaemic priapism, with surgical ligation having the highest reported rates [1480]. Patients can require penile
prosthesis implantation for ED in the long-term [1404].

10.3.3.4 Summary of evidence and recommendations for the treatment of non-ischaemic priapism

Summary of evidence LE
Non-ischaemic priapism can cause erectile dysfunction over time and early definitive management 3
should be undertaken.
Conservative management applying ice to the perineum or site-specific perineal compression is an 3
option in all cases. The use of androgen deprivation therapy may enable closure of the fistula reducing
spontaneous and sleep-related erections.
Selective artery embolisation, using temporary or permanent substances, has high success rates. No 3
definitive statement can be made on the best substance for embolisation in terms of sexual function
preservation and success rate.
Repeated embolisation is a reasonable option for the treatment of non-ischaemic priapism. 2b
Selective surgical ligation of the fistula is associated with high risk of erectile dysfunction. 3

Recommendations Strength rating

Perform definitive management for non-ischaemic priapism at the discretion of the treating Weak
physician as it is not a medical emergency.
Manage non-ischaemic priapism conservatively with the use of site-specific perineal Weak
compression as the first step. Consider androgen deprivation therapy only in adults.
Perform selective arterial embolisation when conservative management has failed. Strong
Perform the first selective arterial embolisation using temporary material. Weak
Repeat selective arterial embolisation with temporary or permanent material for recurrent Weak
non-ischaemic priapism following selective arterial embolisation.
Reserve selective surgical ligation of a fistula as a final treatment option when repeated Weak
arterial embolisation has failed.

10.3.3.5 High-flow priapism in children

Non-ischaemic priapism is a rare condition, especially in children. The embarrassment that children may have in
speaking about it to their parents can lead to misdiagnosis and underestimating the prevalence of this condition
[1513]. The aetiology, clinical presentation, diagnostic and therapeutic principles are comparable with those of
arterial priapism in adults. However, some differentiating features should be noted.

Idiopathic non-ischaemic priapism can be found in a significant percentage of children [1514]. Perineal
compression with the thumb may be a useful manoeuvre to distinguish ischaemic and non-ischaemic priapism,
particularly in children, where it may result in immediate detumescence, followed by the return of the erection
with the removal of compression [1480]. Conservative management using ice applied to the perineum or site-
specific perineal compression may be successful, particularly in children [1515, 1516]. Although reportedly
successful, embolisation in children is technically challenging and requires treatment within a specialist
paediatric vascular radiology department [1370, 1517].

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10.3.3.6 Follow-up
During conservative management of non-ischaemic priapism, physical examination and colour duplex US can
be useful tools to assess treatment efficacy. Close follow-up using colour duplex US and MRI can help detect
distal penile fibrosis and be beneficial in clinical decision-making to intervene with embolisation earlier [1426].
Follow-up after selective arterial embolisation should include clinical examination, colour duplex US, and erectile
function assessment. If in doubt, repeat arteriography is required. The goals are to determine if the treatment
was successful, identify signs of recurrence, and verify any anatomical and functional sequelae [1494].

11. MALE INFERTILITY

11.1 Definition and classification
Infertility is defined by the inability of a sexually active, non-contraceptive couple to achieve spontaneous
pregnancy within 12 months [1518]. Primary infertility refers to couples that have never had a child and cannot
achieve pregnancy after at least 12 consecutive months having sex without using birth control methods.
Secondary infertility refers to infertile couples who have been able to achieve pregnancy at least once before
(with the same or different sexual partner).

In 30-40% of cases, no male-associated factor is found to explain the underlying impairment of sperm
parameters and historically was referred to as idiopathic male infertility. These men present with no previous
history of diseases affecting fertility and have normal findings on physical examination and endocrine, genetic
and biochemical laboratory testing, although semen analysis may reveal pathological findings (see Section
10.3.2). It is now believed that idiopathic male infertility may be associated with several previously unidentified
pathological factors, which include but are not limited to endocrine disruption as a result of environmental
pollution, generation of reactive oxygen species (ROS)/sperm DNA damage, or genetic and epigenetic
abnormalities [1519]. Unexplained male infertility is defined as infertility of unknown origin with normal sperm
parameters and partner evaluation. Between 20 and 30% of couples will have unexplained infertility.

11.2 Epidemiology/aetiology/pathophysiology/risk factors

11.2.1 Introduction
About 15% of couples do not achieve pregnancy within 12 consecutive months and seek medical treatment for
infertility [1520]. One in eight couples encounter problems when attempting to conceive a first child and one in
six when attempting to conceive a subsequent child [1521]. In 50% of involuntarily childless couples, a male-
infertility-associated factor is found, usually together with abnormal semen parameters [1518]. For this reason,
in all infertile couples the male should undergo medical evaluation by a urologist trained in male reproduction.

Male fertility can be impaired as a result of many different conditions, thus including [1518]:
• congenital or acquired urogenital abnormalities;
• genetic abnormalities;
• malignancies;
• urogenital tract infections;
• varicocele;
• increased scrotal temperature (e.g., as a consequence of varicocele);
• endocrine disturbances;
• immunological factors.
• iatrogenic factors (e.g., previous scrotal surgery);
• gonadotoxic exposure (e.g., radiotherapy or chemotherapy).

Advanced paternal age (APA) has emerged as one of the additional risk factors associated with the progressive
increase in the prevalence of male factor infertility [1522-1529].

Likewise, advanced maternal age must be considered in the management of every infertile couple, and in the
subsequent decisions in the diagnostic and therapeutic strategy of the male partner [1530, 1531]. This should
include the age and ovarian reserve of the female partner, since these parameters might determine decision-
making in terms of timing and therapeutic strategies (e.g., assisted reproductive technology [ART] vs. surgical
intervention) [1522-1525]. Earlier evaluation is still a matter of debate in couples in with female partners
older than 35 years who have not conceived for 6 months as ovarian reserve may fall [1532-1534]. Table 11.1
summarises the main male-infertility-associated factors.

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Table 11.1: M
 ale infertility causes and associated factors and percentage of distribution in 10,469 patients
[1535]

Diagnosis Unselected patients Azoospermic patients

(n = 12,945) (n = 1,446)
All 100% 11.2%
Infertility of known (possible) cause 42.6% 42.6%
Maldescended testes 8.4 17.2
Varicocele 14.8 10.9
Sperm auto-antibodies 3.9 -
Testicular tumour 1.2 2.8
Others 5.0 1.2
Idiopathic infertility 30.0 13.3
Hypogonadism 10.1 16.4
Klinefelter syndrome (47, XXY) 2.6 13.7
XX male 0.1 0.6
Primary hypogonadism of unknown cause 2.3 0.8
Secondary (hypogonadotropic) hypogonadism 1.6 1.9
Kallmann syndrome 0.3 0.5
Idiopathic hypogonadotropic hypogonadism 0.4 0.4
Residual after pituitary surgery < 0.1 0.3
Late-onset hypogonadism 2.2 -
Constitutional delay of puberty 1.4 -
Others 0.8 0.8
General/systemic disease 2.2 0.5
Cryopreservation due to malignant disease 7.8 12.5
Testicular tumour 5.0 4.3
Lymphoma 1.5 4.6
Leukaemia 0.7 2.2
Sarcoma 0.6 0.9
Disturbance of erection/ejaculation 2.4 -
Obstruction 2.2 10.3
Vasectomy 0.9 5.3
C
 ystic fibrosis (congenital bilateral absence of 0.5 3.0
vas deferens)
Others 0.8 1.9

11.2.2 Summary of evidence and recommendations on epidemiology and aetiology of male infertility

Summary of evidence LE
Infertility affects 15% of couples of reproductive age. 3
A male factor infertility can be identified in about 50% of infertile couples. 2a
A pure male factor infertility can be identified in about 20% of infertile couples. 2a
Several risk factors such as genetic factors, urogenital abnormalities, endocrine disorders, malignant 2a
diseases and gonadotoxic treatments can cause male infertility.

126 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Recommendations Strength rating
Perform infertility evaluation in couples who have not conceived after twelve consecutive Strong
months of regular, unprotected intercourse.
Investigate both partners simultaneously to categorise the cause of infertility. Strong
Investigate all men belonging to couples seeking medical help for fertility problems. Strong

11.3 Diagnostic work-up

Important treatment decisions are based on the results of semen analysis and most studies indicate semen
parameters are a surrogate outcome for male fertility. However, a semen analysis per se cannot distinguish
fertile from infertile men [1536].
The Guidelines panel concludes that a comprehensive andrological examination is always indicated
in infertile couples, both if semen analysis shows abnormalities and in men with normal sperm parameters
as compared with reference values [1537-1539]. Infertile men should be properly counselled and followed up
considering their higher risk of developing malignant and non-malignant comorbid conditions later in life [1540,
1541].
Focused evaluation of male patients should include: a medical and reproductive history; physical
examination; semen analysis – with strict adherence to World Health Organization (WHO) reference values for
human semen characteristics [1542, 1543], and hormonal evaluation [1544]. Other investigations (e.g., genetic
analysis and imaging) may be required depending on the clinical features and semen parameters.

11.3.1 Medical/reproductive history and physical examination

11.3.1.1 Medical and reproductive history
Medical history should evaluate any risk factors and behavioural patterns that could affect the male partner’s
fertility, such as lifestyle, family history (including, testicular cancer), comorbidities (including systemic
diseases; e.g., hypertension, diabetes mellitus, obesity, MetS, testicular cancer, etc.), genito-urinary infections
(including sexually transmitted infections), history of testicular surgery and exclude any potential known
gonadotoxic medication or recreational drugs [1544].

Typical findings from the history of a patient with infertility include:

• cryptorchidism (uni- or bilateral);
• testicular torsion and trauma;
• genitourinary infections;
• exposure to environmental toxins;
• gonadotoxic medications (anabolic drugs, chemotherapeutic agents, etc.);
• exposure to radiation or cytotoxic agents.

11.3.1.2 Physical examination

A focused physical examination is compulsory in the evaluation of every infertile male, including presence of
secondary sexual characteristics. The size, texture and consistency of the testes must be evaluated. In clinical
practice, testicular volume is assessed by Prader’s orchidometer [1545]; orchidometry may over-estimate
testicular volume compared to US assessment [1546]. There are no uniform reference values in terms of
Prader’s orchidometer-derived testicular volume, due to differences in the populations studied (e.g., geographic
area, nourishment, ethnicity and environmental factors) [1545-1547]. The mean Prader’s orchidometer-derived
testis volume reported in the European general population is 20.0 ± 5.0 mL [1545], whereas in infertile patients
it is 18.0 ± 5.0 mL [1545, 1548-1550]. The presence of the vas deferens, fullness of epididymis and presence
of a varicocele should be always determined. Likewise, palpable abnormalities of the testis, epididymis,
and vas deferens should be evaluated. Other physical alterations, such as abnormalities of the penis (e.g.,
phimosis, short frenulum, fibrotic nodules, epispadias, hypospadias, etc.), abnormal body hair distribution and
gynecomastia, should also be evaluated.

Typical findings from the physical examination of a patient with characteristics suggestive for testicular
deficiency include:
• abnormal secondary sexual characteristics;
• abnormal testicular volume and/or consistency;
• testicular masses (potentially suggestive of cancer);
• absence of testes (uni-bilaterally);
• gynaecomastia;
• varicocele.

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11.3.2 Semen analysis
The 6th edition the WHO Manual for the Examination and Processing of Human Semen [1543] has been
published on July 2021 and comprises of three sections: i) semen examination; ii) sperm preparation and
cryopreservation; and, iii) quality assessment and quality control.

Procedures for semen examination are divided:

• Basic examinations, that should be performed by every laboratory, based on standardised
procedures and evidence-based techniques.
• Extended analyses, which are performed by choice of the laboratory or by special request
from the clinicians.
• Advanced examinations.

Basic examination summary [1542]:

• Assessment of sperm numbers: the laboratory should not stop assessing the number of
sperm at low concentrations (2 million/mL), as suggested in the 5th edition, but report
lower concentrations, noting that the errors associated with counting a small number of
spermatozoa may be high. It is recognised that the total sperm numbers per ejaculate (sperm
output) have more diagnostic value than sperm concentration; therefore, semen volume must
be measured accurately.
• Assessment of sperm motility: the categorisation of sperm motility has reverted back to fast
progressively motile, slow progressively motile, non-progressively motile and immotile (grade
a, b, c or d) because presence (or absence) of rapid progressive spermatozoa is recognised
to be clinically important.
• Assessment of sperm morphology: the 6th edition has recommended the Tygerberg strict
criteria by sperm adapted Papanicolaou staining.
• Assessment of vitality should not be performed in all samples, only if more than 60% of
spermatozoa are immotile.

Extended examinations
This chapter contains procedures to detect leukocytes and markers of genital tract inflammation, sperm
antibodies, indices of multiple sperm defects, sequence of ejaculation, methods to detect sperm aneuploidy,
semen biochemistry and sperm DNA fragmentation (SDF).

Reference ranges and reference limits

The lower fifth percentile of the distribution of semen analysis values from approximately 3,500 men in 12
countries who have contributed to a natural conception within 12 months of trying does not represent a limit
between fertile and infertile men. For a general prediction of live birth in vivo as well as in vitro, a multiparametric
interpretation of the entire men’s and partner’s reproductive potential are needed. Reference values for semen
parameters are represented in Table 11.2 [1537].

Moreover, more complex testing than classic semen analysis may be required in everyday clinical practice,
particularly in men belonging to couples with recurrent pregnancy loss from natural conception or ART and in
men with unexplained male infertility. Although definitive conclusions cannot be drawn, given the heterogeneity
of the studies, increased sperm DNA damage is associated with pregnancy failure [1519, 1551, 1552].

Table 11.2: Lower reference limits (5th centiles and their 95% CIs) for semen characteristics

Parameter 2021 Lower reference limit

(95% CI)
Semen volume (mL) 1.4 (1.3-1.5)
Total sperm number (106/ejaculate) 39 (35-40)
Sperm concentration (106/mL) 16 (15-18)
Total motility (PR + NP, %) 42 (40-43)
Progressive motility (PR, %) 30 (29-31)
Vitality (live spermatozoa, %) 54 (50-56)
Sperm morphology (normal forms, %) 4 (3.9-4.0)

128 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Other consensus threshold values
pH > 7.2
Peroxidase-positive leukocytes (106/mL) < 1.0
Tests for antibodies on spermatozoa
MAR test (motile spermatozoa with bound particles, %) No evidence-based reference values. Each
laboratory should define its normal reference
ranges by testing a sufficiently large number
of fertile men.
Immunobead test (motile spermatozoa with bound beads, %) No evidence-based reference limits.
Accessory gland function
Seminal zinc (μmol/ejaculate) > 2.4
Seminal fructose (μmol/ejaculate) > 13
Seminal neutral α-glucosidase (mU/ejaculate) > 20
CIs = confidence intervals; MAR = mixed antiglobulin reaction; NP = non-progressive; PR = progressive
(a+b motility).
*D istribution of data from the population is presented with one-sided intervals (extremes of the reference
population data). The lower 5th percentile represents the level under which only results from 5% of the men in the
reference population were found.

If semen analysis is normal according to WHO criteria, a single test is sufficient. If the results are abnormal on at
least two tests, further andrological investigation is indicated.

None of the individual sperm parameters (e.g., concentration, morphology and motility), are diagnostic per se of
infertility. According to WHO 5th edition reference criteria it is important to differentiate between the following
[1553]:
• oligozoospermia: < 16 million sperm/mL;
• asthenozoospermia: < 32% progressive motile sperm;
• teratozoospermia: < 4% normal forms.

According to the WHO 6th edition reference criteria this subdivision is not reported, although the EAU Guidelines
panel considers this further segregation still clinically relevant in the everyday clinical practice.

Often, all three anomalies occur simultaneously, which is defined as oligo-astheno-terato-zoospermia (OAT)
syndrome. As in azoospermia (namely, the complete absence of spermatozoa in semen), in severe cases of
oligozoospermia (spermatozoa < 5 million/mL) [1554], there is an increased incidence of obstruction of the
male genital tract and genetic abnormalities. In case of azoospermia, full andrological investigation should be
warranted to classify obstructive azoospermia versus non-obstructive azoospermia. A recommended method to
diagnose absolute azoospermia versus cryptozoospermia is semen centrifugation at 3,000 g for 15 minutes and
a thorough microscopic examination by phase contrast optics at ×200 magnification of the pellet. All samples
can be stained and re-examined microscopically [1555]. This is to ensure that small quantities of sperm are
detected, which may be potentially used for intra-cytoplasmic sperm injection (ICSI); therefore removing the
need for surgical intervention.

Advanced examinations
Obsolete tests such as the human oocyte and human zona pellucida binding and the hamster oocyte
penetration tests have been completely removed. Research tests include assessment of ROS and oxidative
stress, membrane ion channels, acrosome reaction and sperm chromatin structure and stability, computer-
assisted sperm analysis (CASA).

Measurement of Oxidative Stress

Oxidative stress is considered to be central in male infertility by affecting sperm quality, function, as well as the
integrity of sperm [1556]. Oxidative stress may lead to sperm DNA damage and poorer DNA integrity, which are
associated with poor embryo development, miscarriage and infertility [1557, 1558]. Spermatozoa are vulnerable
to oxidative stress and have limited capacity to repair damaged DNA. Oxidative stress is generally associated
with poor lifestyle (e.g., smoking) and environmental exposure, and therefore antioxidant regimens and lifestyle
interventions may reduce the risk of DNA fragmentation and improve sperm quality [1559]. However, these data
have not been supported by RCTs. Although ROS can be measured by various assays (e.g., chemiluminescence),

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no standardised testing methods for ROS are available and routine measurement of ROS testing should remain
experimental until these tests are validated in RCTs [1560].

11.3.3 Measurement of sperm DNA Fragmentation Index (SDF)

Sperm DNA fragmentation, or the accumulation of single- and double-strand DNA breaks occur in sperm, and
an increase in the level of SDT has been shown to reduce the chances of natural conception [1561]. Although
no studies have unequivocally and directly tested the impact of SDF on the clinical management of infertile
couples, SDF is more common in infertile men and has been identified as a major contributor to male infertility,
as well as poorer outcomes following ART [1562, 1563], including impaired embryo development [1562],
miscarriage, recurrent pregnancy loss [1551, 1552, 1564], and birth defects [1562]. Sperm DNA fragmentation
can be increased by several factors including hormonal anomalies, varicocele, chronic infection and lifestyle
factors (e.g., smoking) [1563, 1565]. Repeated ejaculation separated by a 3-hour time interval has been reported
to significantly decrease SDF [1566]. In a cohort study of 10,000 semen samples, SDF was also increased in
men in older age groups [1567].

Several assays have been described to measure SDF. It has been suggested that current methods for assessing
sperm DNA integrity still do not reliably predict treatment outcomes from ART and there is controversy whether
to recommend them routinely for clinical use [1563, 1568, 1569]. Terminal deoxynucleotidyl transferase
mediated deoxyuridine triphosphate nick end labelling (TUNEL) and the alkaline comet test (COMET) directly
measure DNA damage. Conversely, sperm chromatin structure assay (SCSA) and sperm chromatic dispersion
test (SCD) are indirect tools for SDF assessment. The SCSA is still the most widely studied and one of the
most commonly used techniques to detect SDF [1570, 1571]. In SCSA, the number of cells with DNA damage
is indicated by the DNA fragmentation index (DFI) [1572], whereas the proportion of immature sperm with
defects in the histone-to-protamine transition is indicated by high DNA stainability [1573]. It is suggested
that a threshold DFI of 25% as measured with SCSA, is associated with reduced pregnancy rates via natural
conception or intra-uterine insemination (IUI) [1571]. Furthermore, DFI values > 50% on SCSA are associated
with poorer outcomes from in vitro fertilisation (IVF). More recently, the mean COMET score and scores for
proportions of sperm with high or low DNA damage have been shown to be of value in diagnosing male infertility
and providing additional discriminatory information for the prediction of both IVF and ICSI live births [1563].

• Raised SDF in pregnancy loss or spontaneous abortion

Recurrent pregnancy loss or repeated spontaneous abortion is not defined uniformly in the literature. In a meta-
analysis SDF assessed by seven SCSA studies, nine SCD studies and eight TUNEL studies was associated with
recurrent pregnancy loss. Although the meta-analysis was limited by the small numbers of participants in each
trial and heterogeneity in definition and inclusion criteria, clinicians should be aware of this association and
opportunity to assess a possible correctable biomarker for paternal contribution to pregnancy loss [1551].

• Testicular sperm in men with raised SDF in ejaculated sperm

Testicular sperm is reported to have lower levels of SDF compared to ejaculated sperm [1574]. The use of
testicular sperm for ICSI is associated with potentially improved outcomes as compared with ejaculated
sperm in men with high SDF [1574, 1575]. Men with unexplained infertility with raised DNA fragmentation
may be considered for TESE after failure of ART, although they should be counselled that live-birth rates are
under reported in the literature and patients must weigh up the risks of performing an invasive procedure in a
potentially normozoospermic or unexplained condition. The advantages of the use of testicular sperm in men
with cryptozoospermia or oligozoospermia have not yet been confirmed in large scale randomised studies
[1576, 1577]. A meta-analysis has suggested that TESE-ICSI may improve the outcomes from ART but there is
significant heterogeneity of data and the authors suggest that RCTs are needed to validate the use of TESE in
men with raised SDF [1578].

In terms of a practical approach, urologists may offer the use of testicular sperm in patients with high SDF on
a case-by-case basis and after a full discussion including reproductive specialists. However, patients should be
counselled regarding the low levels of evidence for this. Furthermore, testicular sperm should only be used in
this setting once the common associations of SDF have been excluded, including varicoceles, modifications of
dietary/lifestyle factors, treatment of accessory gland infections and reduction of abstinence time. Additionally,
any confounding female factors must also be taken into consideration before using TESE in this setting.

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11.3.4 Hormonal determinations
In men with testicular deficiency, hypergonadotropic hypogonadism (also called primary hypogonadism)
is usually present, with high levels of FSH and LH and, with or without low levels of testosterone. Generally,
the levels of FSH negatively correlate with the number of spermatogonia [1579]. When spermatogonia are
absent or markedly diminished, FSH level is usually elevated; when the number of spermatogonia is normal,
but maturation arrest exists at the spermatocyte or spermatid level, FSH level is usually within the normal
range [1579]. However, for patients undergoing TESE, FSH levels do not accurately predict the presence of
spermatogenesis, as men with maturation arrest on histology can have both normal FSH and testicular volume
[1580, 1581]. Furthermore, men with non-obstructive azoospermia (NOA) and high levels of FSH may still
harbour focal areas of spermatogenesis at the time of TESE or microdissection TESE (mTESE) [1581, 1582].
Despite current findings need to be confirmed, growing data suggest that lower preoperative serum anti-
Müllerian hormone (AMH) levels are associated with higher likelihood of positive sperm retrieval outcomes in
men undergoing mTESE [1583, 1584].

11.3.5 Genetic testing

All urologists working in andrology must have an understanding of the genetic abnormalities most commonly
associated with infertility, so that they can provide correct advice to couples seeking fertility treatment.
Current routine clinical practice in genetic testing is based on the screening of genomic DNA from peripheral
blood samples. However, screening of chromosomal anomalies in spermatozoa (sperm aneuploidy) and
preimplantation genetic testing (PGT) are also feasible and indicated in selected cases (e.g., recurrent
miscarriage) [1585-1591].

11.3.5.1 Chromosomal abnormalities

Chromosomal abnormalities can be numerical (e.g., trisomy) or structural (e.g., inversions or translocations).
In a survey of pooled data from 11 publications, including 9,766 infertile men, the incidence of chromosomal
abnormalities was 5.8% [1592]. Of these, sex chromosome abnormalities accounted for 4.2% and autosomal
abnormalities for 1.5%. In comparison, the incidence of abnormalities was 0.38% in pooled data from three
series, with a total of 94,465 new-born male infants, of whom 131 (0.14%) had sex chromosomal abnormalities
and 232 (0.25%) autosomal abnormalities [1592]. The frequency of chromosomal abnormalities increases as
testicular deficiency becomes more severe. Patients with sperm count < 5 million/mL already show a 10-fold
higher incidence (4%) of mainly autosomal structural abnormalities compared to the general population [1593,
1594]. Men with NOA are at highest risk, especially for sex chromosomal anomalies (e.g., Klinefelter syndrome)
[1595, 1596].

Based on the frequencies of chromosomal aberrations in patients with different sperm concentration, karyotype
analysis is currently indicated in men with azoospermia or oligozoospermia (spermatozoa < 10 million/mL)
[1594]. Notwithstanding, the clinical value of spermatozoa < 10 million/mL remains a valid threshold until further
studies, evaluating the cost-effectiveness, in which costs of adverse events due to chromosomal abnormalities
(e.g., miscarriages and children with congenital anomalies) are performed [1597].

11.3.5.1.1 S ex chromosome abnormalities (Klinefelter syndrome and variants [47,XXY; 46,XY/47, XX

mosaicism])
Klinefelter syndrome is the most common sex chromosomal abnormality [1598]. Adult men with Klinefelter
syndrome usually have small firm testes along with features of primary hypogonadism. The phenotype is the
final result of a combination between genetic, hormonal and age-related factors [12]. The phenotype varies
from that of a normally virilised male to one with the stigmata of androgen deficiency. In most cases infertility
and reduced testicular volume are the only clinical features that can be detected, although neuro-psychological
features, learning or language processing disabilities are often present. Leydig cell function is also commonly
impaired in men with Klinefelter syndrome and thus testosterone deficiency is more frequently observed than
in the general population [1599], although rarely observed during the peri-pubertal period, which usually occurs
in a normal manner [12, 1600]. Rarely, more pronounced signs and symptoms of hypogonadism can be present,
along with congenital abnormalities including heart and renal problems [1601].

The presence of germ cells and sperm production are variable in men with Klinefelter syndrome and are more
frequently observed in mosaicism, 46,XY/47,XXY. In patients with azoospermia, TESE or mTESE are therapeutic
options as spermatozoa can be recovered in up to 50% of cases [1602, 1603]. Although the data are not unique
[1603], there is some evidence that TESE or mTESE yields higher sperm recovery rates when performed at a
younger age, although an age threshold cannot be provided [1595, 1604].

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Since Klinefelter syndrome is associated with several general health problems, appropriate medical follow-up
is therefore advised [13, 1605, 1606]. Testosterone therapy may be considered if testosterone levels are in the
hypogonadal range when fertility issues have been addressed [15]. Moreover, men with Klinefelter syndrome
are at higher risk of metabolic and cardiovascular diseases (CVD), including venous thromboembolism (VTE)
and diabetes, particularly when starting testosterone therapy [1607]. In addition, a higher risk of haematological
malignancies has been reported in men with Klinefelter syndrome [13].

Testicular sperm extraction in peri-pubertal or pre-pubertal boys with Klinefelter syndrome aiming at
cryopreservation of testicular spermatogonial stem cells is still considered experimental and should only be
performed within a research setting [1608]. The same applies to sperm retrieval in older boys who have not
considered their fertility potential [1609]. Although the data are not unique [1603], there is growing evidence that
TESE or mTESE yields higher sperm recovery rates when performed at a younger age [1595, 1604].

11.3.5.1.2 Autosomal abnormalities

Genetic counselling should be offered to all couples seeking fertility treatment (including IVF/ICSI) when the
male partner has an autosomal karyotype abnormality. The most common autosomal karyotype abnormalities
are Robertsonian translocations, reciprocal translocations, paracentric inversions, and marker chromosomes. It
is important to look for these structural chromosomal anomalies because there is an increased associated risk
of aneuploidy or unbalanced chromosomal complements in the foetus. When IVF/ICSI is carried out for men
with translocations, PGT or amniocentesis should be performed [1610, 1611].

11.3.5.2 Cystic fibrosis gene mutations

Cystic fibrosis (CF) is an autosomal-recessive disorder [1612]. It is the most common genetic disease of
Caucasians; 4% are carriers of gene mutations involving the CF transmembrane conductance regulator
(CFTR) gene located on chromosome 7p. It encodes a membrane protein that functions as an ion channel
and influences the formation of the ejaculatory duct, seminal vesicle, vas deferens and distal two-thirds of the
epididymis. Approximately 2,000 CFTR mutations have been identified and any CFTR alteration may lead to
congenital bilateral absence of the vas deferens (CBAVD). However, only those with homozygous mutations
exhibit CF disease [1613]. Congenital bilateral absence of the vas deferens is a rare reason of male factor
infertility, which is found 1% of infertile men and in up to 6% of men with obstructive azoospermia [1614].
Clinical diagnosis of absent vasa is easy to miss and all men with azoospermia should be carefully examined
to exclude CBAVD, particularly those semen volume < 1.0 mL and acidic pH < 7.0 [1615-1617]. In patients with
CBAVD-only or CF, epididymal sperm aspiration (micro or percutaneous; MESA and PESA respectively), TESA, or
TESE in combination with ICSI, can be used to achieve pregnancy. However, higher sperm quality, easier sperm
retrieval and better ICSI outcomes are associated with CBAVD-only patients as compared with CF patients
[1613].

The most frequently found mutations are F508, R117H and W1282X (according to their traditional definitions),
but their frequency and the presence of other mutations largely depend on the ethnicity of the patient [1618,
1619]. Given the functional relevance of a DNA variant (the 5T allele) in a non-coding region of CFTR [1620], it
is now considered a mild CFTR mutation rather than a polymorphism and it should be analysed in each CBAVD
patient. Men with CBAVD often have mild clinical stigmata of CF (e.g., history of chest infections). When a man
has CBAVD, it is important to test his partner for CF mutations. If the female partner is found to be a carrier of
CFTR mutations, the couple must consider carefully whether to proceed with ICSI, as the risk of having a child
with CF or CBAVD will be 50%, depending on the type of mutations carried by the parents. If the female partner is
negative for known mutations, the risk of being a carrier of unknown mutations is ~0.4% [1621].

11.3.5.2.1 Unilateral or bilateral absence/abnormality of the vas and renal anomalies

Congenital unilateral absence of the vas deferens (CUAVD) is usually associated with ipsilateral absence of
the kidney and probably has a different genetic causation [1622]. Cystic fibrosis transmembrane conductance
regulator gene mutation screening is indicated in men with unilateral absence of the vas deferens with normal
kidneys. The prevalence of renal anomalies is rare for patients who have CBAVD and CFTR mutations [1623].
Abdominal US should be undertaken both in unilateral and bilateral absence of vas deferens without CFTR
mutations. Findings may range from CUAVD with ipsilateral absence of the kidney, to bilateral vessel and renal
abnormalities, such as pelvic kidney [1624].

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11.3.5.3 Y microdeletions – partial and complete
Microdeletions on the Y-chromosome are termed AZFa, AZFb and AZFc deletions [1625]. Clinically relevant
deletions remove partially, or in most cases completely, one or more of the AZF regions, and are the most
frequent molecular genetic cause of severe oligozoospermia and azoospermia [1626]. In each AZF region, there
are several spermatogenesis candidate genes [1627].

11.3.5.3.1 Clinical implications of Y microdeletions

The clinical significance of Yq microdeletions can be summarised as follows:
• They are not found in normozoospermic men, proving there is a clear cut cause-and-effect
relationship between Y-deletions and spermatogenic failure [1628].
• The highest frequency of Y-deletions is found in azoospermic men (8-12%), followed by
oligozoospermic (3-7%) men [1629, 1630].
• Deletions are extremely rare with a sperm concentration > 5 million/mL (~0.7%) [1631].
• AZFc deletions are most common (65-70%), followed by Y-deletions of the AZFb and AZFb+c
or AZFa+b+c regions (25-30%). AZFa region deletions are rare (5%) [1632].
• Complete deletion of the AZFa region is associated with severe testicular phenotype (Sertoli
cell only syndrome [SCOS]), while complete deletions of the AZFb region is associated with
spermatogenic arrest. Complete deletions that include the AZFa and AZFb regions are of
poor prognostic significance for retrieving sperm with TESE. Therefore, TESE should not be
attempted in these patients [1633, 1634].
• Deletions of the AZFc region causes a variable phenotype ranging from azoospermia to
oligozoospermia.
• Testicular sperm can be found in 50-75% of men with AZFc microdeletions [1633-1635].
• Men with AZFc microdeletions who are oligo-azoospermic or in whom sperm is found at the
time of TESE must be counselled that any male offspring will inherit the deletion.
• Classical (complete) AZF deletions do not confer a risk for cryptorchidism or testicular
cancer [1631, 1636].
• A meta-analysis indicated that the fertilisation rate but not live birth rate or male birth rate
after ICSI in men with Y chromosome microdeletions was significantly decreased, compared
to ICSI controls [1637]. The quality of the included studies were limited by sample size, but
counselling of patients may be refined.

The specificity and genotype/phenotype correlation reported above means that Y-deletion analysis has both a
diagnostic and prognostic value for testicular sperm retrieval [1636].

11.3.5.3.1.1 Testing for Y microdeletion

Historically, indications for AZF deletion screening are based on sperm count and include azoospermia and
severe oligozoospermia (spermatozoa count < 5 million/mL). A meta-analysis assessing the prevalence of
microdeletions on the Y chromosome in oligo-zoospermic men in 37 European and North American studies
(n = 12,492 oligo-zoospermic men) showed that the majority of microdeletions occurred in men with sperm
concentrations ≤ 1 million sperm/mL, with < 1% identified in men with > 1 million sperm/mL [1631]. In this
context, while an absolute threshold for clinical testing cannot be universally given, patients may be offered
testing if sperm counts are < 5 million sperm/mL, but must be tested if ≤1 million sperm/mL.

With the contribution of the European Academy of Andrology (EAA) guidelines and the European Molecular
Genetics Quality Network external quality control programme (http://www.emqn.org/emqn/), Yq testing has
become more reliable in different routine genetic laboratories. The EAA guidelines provide a set of primers
capable of detecting > 95% of clinically relevant deletions [1638].

11.3.5.4 Exome sequencing

The diagnostic yield of exome sequencing in males with NOA is increasing rapidly revealing monogenic causes
of male factor infertility, genetic variants that may impact the function of genes with potential involvement in
male factor infertility, and candidate genes [1639, 1640]. As such, the diagnostic yield in patients with presumed
idiopathic spermatogenic failure may also increase significantly in time [1641]. Case control series of exome
sequencing in men with asthenoteratozoospermia add significant genetic variants that may add to panels for
ciliopathy/sperm flagellum phenotype. Catalogues of human genes associated with specific sperm morphology
and dysfunction characteristics underline the increase in knowledge and the importance of genotyping for
specific severe male factor infertility conditions [1642, 1643]. These findings suggest that the introduction of
exome sequencing in NOA will improve diagnosis and possible management of patients, although validation in
cohorts with different geographical and ethnic backgrounds are needed before recommendations can be made
for standard clinical.

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In addition, single nucleotide polymorphisms (SNPs) in the genetic makeup of the methylenetetrahyudrofolate
reductase gene (MTHFR) have been identified as a potential genetic vulnerability factor to male factor infertility
in predominantly Asian population cohorts [1644]. A possible protective role of SNPs associated with oxidative
stress pathway genes, and associated with seminal plasma antioxidant capacity are under investigation [1645].
A recent meta-analysis reported on the possible role of XRCC1 gene polymorphism as a risk factor for male
factor infertility, although gene-environment interaction could not be evaluated [1646].

11.3.6 Imaging in infertile men

In addition to physical examination, a scrotal US may be helpful in: (i) measuring testicular volume; (ii) assessing
testicular anatomy and structure in terms of US patterns, thus detecting signs of testicular dysgenesis often
related to impaired spermatogenesis (e.g., non-homogeneous testicular architecture and microcalcifications)
and testicular tumours; and, (iii) finding indirect signs of obstruction (e.g., dilatation of rete testis, enlarged
epididymis with cystic lesions, or absent vas deferens) [1546]. In clinical practice, Prader’s orchidometer-derived
testicular volume is considered a reliable surrogate of US-measured testicular volume, easier to perform and
cost-effective [1545]. Nevertheless, scrotal US has a relevant role in testicular volume assessment when
Prader’s orchidometer is unreliable (e.g., large hydrocele, inguinal testis, epididymal enlargement/fibrosis,
thickened scrotal skin; small testis, where the epididymis is large in comparison to the total testicular volume
[1545, 1546]). Ultrasound patterns of testicular inhomogeneity [1647, 1648] is usually associated with ageing,
although it has also been reported in association with testicular atrophy and fibrosis [1546]. A diagnostic
testicular biopsy is not recommended when testicular inhomogeneity is detected [1647, 1648].

11.3.6.1 Scrotal US
Scrotal US is widely used in everyday clinical practice in patients with oligo-zoospermia or azoospermia, as
infertility has been found to be an additional risk factor for testicular cancer [1649, 1650]. It can be used in
the diagnosis of several diseases causing infertility including obstructive azoospermia (see section 11.4),
testicular neoplasms and providing specific radiological metrics e.g. venous diameter, reflux for the diagnosis of
varicoceles.

11.3.6.1.1 Testicular neoplasms

Men with infertility had an increased risk of testicular cancer compared to fertile controls (pooled OR =
1.91, 95% CI: 1.52-2.42) [1651]. When infertility was refined according to individual semen parameters,
oligozoospermic men had an increased risk of cancer compared with fertile control subjects (HR 11.9) [1652].
In a recent systematic review infertile men with testicular microcalcification (TM) were found to have a ~18-
fold higher prevalence of testicular cancer [1653]. The utility of US as a routine screening tool in men with
infertility to detect testicular cancer remains a matter of debate [1649, 1650]. Indeed, these testicular lesions are
difficult to characterise as being benign or malignant based only upon US criteria, including size, vascularity and
echogenicity.

A dichotomous cut-off of certainty in terms of lesion size that may definitely distinguish benign from malignant
testicular masses is currently not available. A systematic review and meta-analysis was carried out by the
Testicular Cancer and the Sexual and reproductive health EAU Guidelines panels to to define which scrotal US
or magnetic resonance imaging (MRI) characteristics can predict benign or malignant disease in pre- or post-
pubertal males with indeterminate testicular masses [1654]. Benign and malignant masses were classified
using the reported reference test: i.e., histopathology, or 12 months progression-free radiological surveillance.
A total of 32 studies were identified, including 1692 masses of which 28 studies and 1550 masses reported
scrotal US features, 4 studies and 142 masses reported MRI features. Meta-analysis of different scrotal US
(B-mode) values in post-pubertal men demonstrated that a size of ≤0.5 cm had a significantly lower OR of
malignancy compared to masses of > 0.5 cm (p < 0.001). Comparison of masses of 0.6-1.0 cm and masses of
> 1.5 cm also demonstrated a significantly lower OR of malignancy (p = 0.04). There was no significant
difference between masses of 0.6-1.0 and 1.1-1.5 cm. Scrotal US in post-pubertal men also had a
significantly lower OR of malignancy for heterogenous masses compared to homogenous masses (p = 0.04),
hyperechogenic vs. hypoechogenic masses (p < 0.01), normal vs. increased enhancement (p < 0.01), and
peripheral vs. central vascularity (p < 0.01), respectively. There were limited data on pre-pubertal SUS, pre-
pubertal MRI and post-pubertal MRI [1654].

Small hypoechoic/hyperechoic areas may be diagnosed as intra-testicular cysts, focal Leydig cell hyperplasia,
fibrosis and focal testicular inhomogeneity after previous pathological conditions. Hence, they require careful
periodic US assessment and follow-up, especially if additional risk factors for malignancy are present (i.e.,
infertility, bilateral TM, history of cryptorchidism, testicular atrophy, inhomogeneous parenchyma, history of
testicular tumour, history of/contralateral tumour) [1546].

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In the case of interval growth of a lesion and/or the presence of additional risk factors for malignancy, testicular
biopsy/surgery may be considered, although the evidence for adopting such a management policy is limited.
In 145 men referred for azoospermia who underwent US before testicular biopsy, 49 (34%) had a focal US
abnormality; a hypoechoic lesion was found in 20 patients (14%), hyperechoic lesions were seen in 10 patients
(7%); and, a heterogeneous appearance of the testicular parenchyma was seen in 19 patients (13%). Of 18
evaluable patients, 11 had lesions < 5 mm; all of which were confirmed to be benign. All other patients with
hyperechoic or heterogeneous areas on US with subsequent tissue diagnoses were found to have benign
lesions. The authors concluded that men with severe infertility who have incidental testicular lesions, negative
tumour markers and lesions < 5 mm may be observed with serial scrotal US examinations and enlarging lesions
or those of greater dimension can be considered for histological biopsy [1655].

Other studies have suggested that if a testicular lesion is hyperechoic and non-vascular on colour Doppler US
and associated with negative tumour markers, the likelihood of malignancy is low and consideration can be
given to regular testicular surveillance, as an alternative to radical surgery. In contrast, hypoechoic and vascular
lesions are more likely to be malignant [1656-1660]. However, most lesions cannot be characterised by US
(indeterminate), and histology remains the only certain diagnostic tool. A multidisciplinary team discussion
(MDT), including invasive diagnostic modalities, should therefore be considered in these patients.

The role of US-guided intra-operative frozen section analysis in the diagnosis of testicular cancer in
indeterminate lesions can be considered, and several authors have proposed its value in the intra-operative
diagnosis of indeterminate testicular lesions [1661]. Although the default treatment after patient counselling and
MDT discussion may be radical orchidectomy, an US-guided biopsy with intra-operative frozen section analysis
may be offered as an alternative to radical orchidectomy and potentially obviate the need for removal of the
testis in a patient seeking fertility treatment. In men with azoospermia a concurrent TESE with sperm banking
can also be performed at the time of surgical intervention.

11.3.6.1.2 Varicocele
At present, the clinical management of varicocele is still mainly based on physical examination; nevertheless,
scrotal colour Doppler US is useful in assessing venous reflux and diameter, when palpation is unreliable and/or
in detecting recurrence/persistence after surgery [1546]. Definitive evidence of reflux and venous diameter may
be utilised in the decision to treat (see Section 11.4.3.1 and 11.4.3.2).

11.3.6.1.3 Other
Scrotal US is able to detect changes in the proximal part of the seminal tract due to obstruction. Especially
for CBAVD patients, scrotal US is a favourable option to detect the abnormal appearance of the epididymis.
Given that, three types of epididymal findings are described in CBAVD patients: tubular ectasia (honeycomb
appearance), meshwork pattern, and complete or partial absence of the epididymis [1662, 1663].

11.3.6.2 Transrectal US
For patients with a low seminal volume, acidic pH and severe oligozoospermia or azoospermia, in whom
obstruction is suspected, scrotal and transrectal US are of clinical value in detecting CBAVD and presence or
absence of the epididymis and/or seminal vesicles (SV) (e.g., abnormalities/agenesis). Likewise, transrectal
US (TRUS) has an important role in assessing obstructive azoospermia (OA) secondary to CBAVD or anomalies
related to the obstruction of the ejaculatory ducts, such as ejaculatory duct cysts, seminal vesicle dilatation or
hypoplasia/atrophy, although retrograde ejaculation should be excluded as a differential diagnosis [1546, 1664].

11.3.7 Summary of evidence and recommendations for the diagnostic work-up of male infertility

Summary of evidence LE
Semen analysis alone cannot distinguish fertile from infertile men. 2a
Diagnosis of male infertility is associated with an increased risk of malignant and non-malignant 2a
comorbidities.
Male infertility evaluation should include a medical, reproductive and family history, assessment of 2a
lifestyle and behavioural risk factors, physical examination, semen analysis and hormonal evaluation.
Genetic analysis and imaging may be required depending on the clinical features and semen 2a
parameters.
Testicular volume can be measured with a Prader’s orchidometer or using testicular ultrasound. 2a

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Semen analyses is described in the latest edition of the WHO Manual for the Examination and Processing 3
of Human Semen. Abnormal semen characteristics are expressed as below the 5th percentiles of a
reference population of 3,500 men who contributed to a natural conception within 12 consecutive
months.
Oxidative stress has a detrimental impact on sperm quality but there is a lack of validated assays to 2b
measure reactive oxygen species (ROS) and oxidative stress.
High sperm DNA fragmentation index (SDF) is associated with reduced pregnancy rates via natural 2a
conception or intra-uterine insemination, poor assisted reproductive techniques (ART) outcomes,
recurrent pregnancy loss and unexplained infertility.
A possible advantage of the use of testicular sperm for ICSI in patients with high SDF in ejaculated 3
sperm has not been confirmed in large scale RCTs.
Gonadotropins and total testosterone measurement are useful to diagnose testicular deficiency and to 2a
classify the type of hypogonadism.
Follicle-stimulating hormone values have been negatively associated with sperm count. 2a
Chromosomal abnormalities are frequently found in men with severe oligozoospermia (spermatozoa 2a
<5 million/mL) or azoospermia.
Klinefelter syndrome is associated with non-obstructive azoospermia, hypogonadism and general 2a
health problems, including metabolic, cardiovascular and oncologic diseases.
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations may be associated 2a
with congenital bilateral absence of the vas deferens congenital bilateral absence of the vas deferens
(CBAVD) and obstructive azoospermia.
The prevalence of renal anomalies is rare for patients with unilateral and bilateral absence of the vas 2a
deferens and CFTR mutations.
The highest frequency of Y-microdeletions is found in azoospermic men followed by oligospermic men 2a
but is extremely rare with a sperm concentration > 5 million/mL.
Complete deletions that include the AZFa and AZFb regions are of poor prognostic significance for 2a
retrieving sperm with surgery.
Testicular sperm can be found in 50-75% of men with AZFc microdeletions. 2a
Male offspring of men with AZF microdeletions will inherit the deletion. 2a
Genetic abnormalities found during the diagnostic work-up might impact on the psychological and 2a
overall health of the couple and the offspring.
The diagnostic yield of exome sequencing in men with NOA, specific sperm morphology, sperm 2a
flagellum or sperm function defects is increasing.
Scrotal ultrasound is used to measure testicular volume, assess testicular anatomy including detecting 2a
signs of obstruction and testicular dysgenesis.
Infertile men have a higher risk of testicular cancer compared to fertile controls. 2a
An essential approach for infertile men with US-detected indeterminate testicular lesion is a 2a
multidisciplinary discussion with focus on the size of the lesion, echogenicity, vascularity and previous
patient’s history (e.g., cryptorchidism, previous history of germ cell tumour [GCT]).
Scrotal ultrasound is useful in assessing venous reflux and diameter of the spermatic vein, mostly 2a
when palpation is unreliable or in detecting recurrence/persistence after surgery.
In patients with a low seminal volume, acidic pH and either severe oligozoospermia or azoospermia in 2b
the absence of CBAVD, transrectal ultrasound should be used to detect complete or partial ejaculatory
duct obstruction.

Recommendations Strength rating

Include a parallel assessment of the fertility status, including ovarian reserve, of the female Strong
partner during the diagnosis and management of the infertile male, since this might
determine decision making in terms of timing and therapeutic strategies (e.g., assisted
reproductive technology (ART) versus surgical intervention).
Examine all men seeking medical help for fertility problems, including men with abnormal Strong
semen parameters.
Take a complete medical, reproductive and family history, assessment of lifestyle and Strong
behaviour risk factors, physical examination and semen analysis.

136 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Counsel infertile men or men with abnormal semen parameters on the associated health risks. Weak
Assess testicular volume with a Prader’s orchidometer or testicular ultrasound (US). Weak
Perform semen analyses according to the latest edition of the WHO Manual for the Strong
Examination and Processing of Human Semen.
Perform at least two consecutive semen analyses if the baseline analysis was abnormal. Strong
Do not routinely use reactive oxygen species (ROS) testing in the diagnosis and management Weak
of the male partner of an infertile couple.
Perform sperm DNA fragmentation (SDF) testing in the assessment of couples with Strong
recurrent pregnancy loss from natural conception and failure of ART or men with unexplained
infertility.
Consider the use of testicular sperm for intra-cytoplasmic sperm injection (ICSI) in patients Weak
with high SDF in ejaculated sperm as experimental.
Perform a hormonal evaluation including serum total testosterone and Follicle Stimulating Strong
Hormone/Luteinising Hormone at least in all cases of oligozoospermia and azoospermia.
Offer standard karyotype analysis and genetic counselling to all men with azoospermia and Strong
oligozoospermia (spermatozoa < 5 million/mL) for diagnostic purposes.
Provide long-term endocrine follow-up and appropriate medical treatment to men with Strong
Klinefelter syndrome.
Perform Y-chromosome microdeletion testing in men with sperm concentrations of ≤ 1 Strong
million sperm/mL. Consider it in men with sperm concentrations of < 5 million sperm/mL.
Inform men with Yq microdeletion and their partners who wish to proceed with ICSI that Strong
microdeletions will be passed to sons.
Do not perform testicular sperm extraction in patients with complete deletions that include Strong
the AZFa and AZFb regions.
Test men with structural abnormalities of the vas deferens (unilateral or bilateral absence Strong
with no renal anomalies) and their partners for cystic fibrosis transmembrane conductance
regulator gene mutations.
Provide genetic counselling in all couples with a genetic abnormality found on clinical or Strong
genetic investigation and in patients who carry a (potential) inheritable disease.
Perform scrotal US in patients with infertility, as there is a higher risk of testis cancer. Weak
Discuss invasive diagnostic modalities (e.g., US-guided testicular biopsy with frozen Weak
section versus radical orchidectomy versus surveillance) in infertile men with US-detected
indeterminate testicular lesions, especially if additional risk factors for malignancy are
present in a multidisciplinary team setting.
Perform transrectal US if a partial or complete distal obstruction is suspected. Strong

11.4 Special Conditions and Relevant Clinical Entities

11.4.1 Cryptorchidism
Cryptorchidism is the most common congenital abnormality of the male genitalia; at 1 year of age nearly 1%
of all full-term male infants have cryptorchidism [1665]. Approximately 30% of undescended testes are non-
palpable and may be located within the abdominal cavity. These guidelines will only deal with management of
cryptorchidism in adults.

11.4.1.1 Classification
The classification of cryptorchidism is based on the duration of the condition and the anatomical position of
the testes. If the undescended testis has been identified from birth then it is termed congenital while diagnosis
of acquired cryptorchidism refers to men in whom testes were situated within the scrotum. Cryptorchidism is
categorised as bilateral or unilateral and the location of the testes (inguinal, intra-abdominal or ectopic).

Studies have shown that treatment of congenital and acquired cryptorchidism results in similar hormonal
profiles, semen analysis and testicular volumes [1666, 1667]. However, testicular volume and hormonal function
are reduced in adults treated for congenital bilateral cryptorchidism compared to unilateral cryptorchidism
[1668].

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11.4.1.1.1 Aetiology and pathophysiology
It has been postulated that cryptorchidism may be a part of the so-called testicular dysgenesis syndrome
(TDS), which is a developmental disorder of the gonads caused by environmental and/or genetic influences
early in pregnancy, including exposure to endocrine disrupting chemicals. Besides cryptorchidism, TDS
includes hypospadias, reduced fertility, increased risk of malignancy, and Leydig/Sertoli cell dysfunction [1669].
Cryptorchidism has also been linked with maternal gestational smoking [1670] and premature birth [1671].

11.4.1.1.2 Pathophysiological effects in maldescended testes

11.4.1.1.2.1 Degeneration of germ cells
The degeneration of germ cells in maldescended testes is apparent even after the first year of life and varies,
depending on the position of the testes [1672]. During the second year, the number of germ cells declines
further. Treatment between the age of six to 18 months is therefore recommended to conserve spermatogonial
stem cells, safe guard future spermatogenesis and hormone production, as well as to decrease the risk for
tumours [1673]. Surgical treatment is the most effective. Meta-analyses on the use of medical treatment with
GnRH and hCG have demonstrated poor success rates [1674, 1675]. It has been reported that hCG treatment
may be harmful to future spermatogenesis [1676]. The EAU Guidelines on Paediatric Urology do not recommend
endocrine treatment to achieve testicular descent on a routine basis, but endocrine treatment with GnRH
analogues in boys with bilateral undescended testis is recommended [1677].

There is increasing evidence to suggest that in unilateral undescended testis, the contralateral normal
descended testis may also have structural abnormalities, including smaller volume, softer consistency and
reduced markers of future fertility potential (spermatogonia/tubule ratio and dark spermatogonia) [1666, 1678].
This implies that unilateral cryptorchidism may affect the contralateral testis and patients and parents should be
counselled appropriately.

11.4.1.1.2.2 Relationship with fertility

Semen parameters are often impaired in men with a history of cryptorchidism [1679]. Early surgical treatment
may have a positive effect on subsequent fertility [1680]. In men with a history of unilateral cryptorchidism,
paternity is almost equal (89.7%) to that in men without cryptorchidism (93.7%). Outcome studies for untreated
bilateral undescended testes revealed that 100% are oligospermic and 75% azoospermic. Among those
successfully treated for bilateral undescended testes, 75% still remain oligospermic and 42% azoospermic
[1681]. It is also important to screen for hypogonadism, as this is a potential long-term sequelae of
cryptorchidism and could contribute to impaired fertility and potential problems such as testosterone deficiency
and MetS [1682].

11.4.1.1.2.3 Germ cell tumours

As a component of TDS, cryptorchidism is a risk factor for testicular cancer and is associated with testicular
microcalcifications and intratubular germ cell neoplasia in situ (GCNIS), formerly known as carcinoma in
situ (CIS) of the testes. In 5-10% of testicular cancers, there is a history of cryptorchidism [1683]. The risk of
a germ cell tumour is 3.6-7.4 times higher than in the general population and 2-6% of men with a history of
cryptorchidism will develop a testicular tumour [1665]. Orchidopexy performed before the onset of puberty
has been reported to decrease the risk of testicular cancer [1684]. However, there is evidence to suggest that
even men who undergo early orchidopexy still harbour a higher risk of testicular cancer than men without
cryptorchidism [1685]. Therefore, all men with a history of cryptorchidism should be warned that they are at
increased risk of developing testicular cancer and should perform regular testicular self-examination [1686].

11.4.1.2 Disease management

11.4.1.2.1 Hormonal treatment
Human chorionic gonadotropin or GnRH is not recommended for the treatment of cryptorchidism in adulthood.

11.4.1.2.2 Surgical treatment

In adolescence, removal of an intra-abdominal testis (with a normal contralateral testis) can be recommended,
because of the risk of malignancy [1687]. In adults, with a palpable undescended testis and a normal functioning
contralateral testis (i.e., biochemically eugonadal), an orchidectomy may be offered as there is evidence that
the undescended testis confers a higher risk of GCNIS and future development of a GCT [1688] and regular
testicular self-examination is not an option in these patients. In patients with unilateral undescended testis and
impaired testicular function on the contralateral testis as demonstrated by biochemical hypogonadism and/
or impaired sperm production (infertility), an orchidopexy may be offered to preserve androgen production
and fertility. However, based on Panel consensus multiple biopsies of the unilateral undescended testis are
recommended at the time of orchidopexy to exclude intra-testicular GCNIS as a prognostic indicator of future

138 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

development of GCT. As indicated above, the correction of bilateral cryptorchidism, even in adulthood, can
lead to sperm production in previously azoospermic men and therefore may be considered in these patients
or in patients who place a high value on fertility preservation [1689]. Vascular damage is the most severe
complication of orchidopexy and can cause testicular atrophy in 1-2% of cases. In men with non-palpable testes,
the post-operative atrophy rate was 12% in cases with long vascular pedicles that enabled scrotal positioning.
Post-operative atrophy in staged orchidopexy has been reported in up to 40% of patients [1690]. At the time of
orchidectomy in the treatment of GCT, biopsy of the contralateral testis should be offered to patients at high risk
for GCNIS (i.e., history of cryptorchidism, < 12 mL testicular volume, poor spermatogenesis [1691]).

11.4.1.3 Summary of evidence recommendations for cryptorchidism

Summary of evidence LE
Cryptorchidism is multifactorial in origin and can be caused by genetic factors and endocrine disruption 2a
early in pregnancy.
Cryptorchidism is often associated with testicular dysgenesis and is a risk factor for infertility and 2b
GCTs and patients should be counselled appropriately.
Paternity in men with corrected unilateral cryptorchidism is almost equal to men without 1b
cryptorchidism.
Bilateral cryptorchidism significantly reduces the likelihood of paternity and patients should be 1b
counselled appropriately.

Recommendations Strength rating

Do not use hormonal treatment for cryptorchidism in post-pubertal men. Strong
Perform simultaneous testicular biopsy, for the detection of intratubular germ cell neoplasia Strong
in situ (formerly carcinoma in situ), if undescended testes are corrected in adulthood.
Offer adult men with unilateral undescended testis and normal hormonal function/ Strong
spermatogenesis orchidectomy.
Offer adult men with unilateral or bilateral undescended testis with biochemical Weak
hypogonadism and or spermatogenic failure (i.e., infertility) unilateral or bilateral
orchidopexy, if technically feasible.

11.4.2 Germ cell malignancy and male infertility

Testicular germ cell tumour (TGCT) is the most common malignancy in Caucasian men aged 15-40 years, and
affects approximately 1% of sub-fertile men [1692]. The lifetime risk of TGCT varies among ethnic groups and
countries. The highest annual incidence of TGCT occurs in Caucasians, and varies from 10/100,000 (e.g., in
Denmark and Norway) to 2/100,000 (e.g., in Finland and the Baltic countries). Generally, seminomas and non-
seminomas are preceded by GCNIS, and untreated GCNIS eventually progresses to invasive cancer [1693-1695].
There has been a general decline in male reproductive health and an increase in testicular cancer in western
countries [1696, 1697]. In almost all countries with reliable cancer registries, the incidence of testicular cancer
has increased [1636, 1698]. This has been postulated to be related to TDS, which is a developmental disorder
of the testes caused by environmental and/or genetic influences in pregnancy. Endocrine disrupting chemicals
have also been associated with sexual dysfunction [1699] and abnormal semen parameters [1700]. These
cancers arise from premalignant gonocytes or GCNIS [1701]. Testicular microcalcification, seen on US, can be
associated with TGCT and GCNIS of the testes [1653, 1702, 1703].

11.4.2.1 Testicular germ cell cancer and reproductive function

All men with cancer must be offered sperm cryopreservation prior to the therapeutic use of gonadotoxic
agents or ablative surgery that may impair spermatogenesis or ejaculation (i.e., chemotherapy, radiotherapy or
retroperitoneal surgery) [1704, 1705].

Men with TGCT have decreased semen quality, even before cancer treatment. Azoospermia has been observed
in 24% of men with TGCT [1706] and oligospermia in 50% [1707]. Given that the average 10-year survival rate for
testicular cancer is 98% and it is the most common cancer in men of reproductive potential, it is mandatory to
include counselling regarding fertility preservation prior to any gonadotoxic treatment [1707, 1708]. All patients
should be offered ejaculated semen preservation as the most cost-effective strategy for fertility preservation,
or sperm extracted surgically (e.g., c/mTESE). Indeed, treatment for TGCT, including orchidectomy because of

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 139

the risk of a non-functioning remaining testicle, may have a negative impact on reproductive function [1706].
If shown to be azoospermic or severely oligozoospermic, it is recommended that men should undergo sperm
cryopreservation prior to orchidectomy to allow an opportunity to perform a concomitant TESE and prior to
further potential gonadotoxic/ablative surgery [1707]. The surgical principles in onco-TESE do not differ from the
technique of TESE for men with infertility (e.g., NOA) [1709, 1710]. In this context, it is recommended to organise
cryopreservation care delivery networks that enables referral to a urologist adept in TESE.

Rates of under-utilisation of semen analysis and sperm cryopreservation have been reported to be high;
resulting in the failure to identify azoospermic or severely oligozoospermic patients at diagnosis who may
benefit from advanced fertility-preserving procedures such as oncoTESE. The argument that performing
cryopreservation prior to orchidectomy may delay subsequent treatment is not supported by contemporary
clinical practice, indeed adverse impact on survival has not been investigated. In this context, orchidectomy
should not be unduly delayed if there are no facilities for cryopreservation or there is a potential delay in
treatment.

Since chemotherapy and RT are teratogenic, contraception must be used during treatment and for at least
six months after completion [1711]. Both chemotherapy and radiation treatment (RT) can impair fertility.
Long-term infertility is rare after RT and dose-cumulative-dependent with chemotherapy. Treatment of TGCT
can result in additional impairment of semen quality [1712] and increased sperm aneuploidy up to two years
following gonadotoxic therapy [1713]. Spermatogenesis usually recovers one to four years after chemotherapy
[75]. Chemotherapy is also associated with DNA damage and an increased SDF rate [1714]. However, sperm
aneuploidy levels often decline to pre-treatment levels 18-24 months after treatment [1713]. Several studies
reviewing the offspring of cancer survivors have not shown a significant increased risk of genetic abnormalities
in the context of previous chemotherapy and radiotherapy [1715].

In addition to spermatogenic failure, patients with TGCT have Leydig cell dysfunction, even in the contralateral
testis [1716]. The measurement of pre-treatment levels of testosterone, SHBG, LH and oestradiol may help
to stratify those patients at increased risk of hypogonadism and provide a baseline for post-treatment
hypogonadism. The risk of hypogonadism may be increased in men treated for TGCT. Likewise, the risk of
hypogonadism is increased in the survivors of testicular cancer and serum testosterone levels should be
evaluated during the management of these patients [1717]. However, this risk is greatest at 6-12 months
post-treatment and suggests that there may be some improvement in Leydig cell function after treatment.
Therefore, it is reasonable to delay initiation of testosterone therapy, until the patient shows continuous signs
or symptoms of testosterone deficiency [1693]. The risk of low libido and erectile dysfunction is also increased
in TGCT patients [1718]. Patients treated for TGCT are also at increased risk of CVD [1714]. Therefore, patients
may require a multi-disciplinary therapy approach and, in this context, survivorship programmes incorporating
a holistic view of patients considering psychological, medical and social needs could be beneficial. In patients
who place a high value on fertility potential, the use of testosterone therapy in men with symptoms suggestive
for TDS needs to be balanced with worsening spermatogenesis. In these patients consideration can be given to
the use of selective oestrogen receptor modulators (SERMs; e.g., clomiphene) or gonadotrophin analogues (e.g.,
hCG), although these are off-label treatments in this particular clinical setting.

11.4.2.2 Testicular microcalcification (TM)

Microcalcification inside the testicular parenchyma can be found in 0.6-9% of men referred for testicular US
[1719, 1720]. Although the true incidence of TM in the general population is unknown, it is most probably
rare. Ultrasound findings of TM have been seen in men with TGCT, cryptorchidism, infertility, testicular torsion
and atrophy, Klinefelter syndrome, hypogonadism, Disorders of Sex Development and varicocele [1670]. The
incidence reported seems to be higher with high-frequency US machines [1721]. The relationship between TM
and infertility is unclear, but may relate to testicular dysgenesis, with degenerate cells being sloughed inside
an obstructed seminiferous tubule and failure of the Sertoli cells to phagocytose the debris. Subsequently,
calcification with hydroxyapatite occurs. Testicular microcalcification is found in testes at risk of malignant
development, with a reported incidence of TM in men with TGCT of 6-46% [1722-1724]. A systematic review and
meta-analysis of case-control studies indicated that the presence of TM is associated with a ~18-fold higher
odds ratio for testicular cancer in infertile men (pooled OR: 18.11, 95% CI: 8.09, 40.55; p < 0.0001) [1653].

Testicular microcalcification should therefore be considered pre-malignant in this setting and patients
counselled accordingly. Testicular biopsies from men with TM have found a higher prevalence of GCNIS,
especially in those with bilateral microcalcifications [1725]. However, TM can also occur in benign testicular
conditions and the microcalcification itself is not malignant. Therefore, the association of TM and TGCT is
controversial and the challenge is to identify those men at risk of harbouring GCNIS and future risk of TGCT.

140 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

Further investigation of the association between TM and GCNIS requires testicular biopsies in large series of
men without signs of TGCT with or without risk factors for TGCT. However, clinicians and patients should be
reassured that testicular cancer does not develop in most men with asymptomatic TM [1703]. Men potentially
at high-risk of harbouring or developing GCNIS include those with infertility, atrophic testes, undescended
testes, history of TGCT, and contralateral TM and it has been suggested that men with these risk factors could
be offered testicular biopsy [1697, 1702]. Patients with a history of TGCT and TM in the contralateral testis
and sub-fertile patients have been demonstrated to have an increased risk of GCNIS [1703], while there are
only a few studies showing a further increase in GCNIS with TM in the context of cryptorchidism [1697, 1720,
1726]. A useful algorithm has been proposed [1697] to stratifying those patients at increased risk of GCNIS
who may benefit from testicular biopsy. However, when undertaking a biopsy in this setting, the full risks and
complications of adopting this strategy must be explained to the patient.

Decastro et al. [1727] suggested that testicular cancer would not develop in most men with TM (98.4%) during a
5-year follow-up. As such, an extensive screening programme would only benefit men at significant risk. In this
context it would be prudent to advise patients with TM and risk factors for testicular cancer to at least undergo
regular testicular examination. It has been suggested that these patients could also be offered annual physical
examination by a urologist and US follow-up, although follow-up protocols may be difficult to implement in this
invariably young cohort of patients [1670]. As testicular atrophy and infertility have an association with testicular
cancer, some authors recommend biopsy or follow-up US if TM is seen [1697]. However, most patients who
are azoospermic will be undergoing therapeutic biopsy (i.e., with the specific purpose of sperm retrieval) and
therefore a definitive diagnosis can be made and there is a lack of evidence demonstrating a higher prevalence
of testicular cancer in patients with both TM and testicular atrophy. In patients with incidental TM, the risk of
GCNIS is low and a logical approach is to instruct patients to perform regular testicular self-examination.

11.4.2.3 Summary of evidence and recommendations for germ cell malignancy and testicular microcalcification

Summary of evidence LE
Testicular germ cell tumour (TGCT) affects approximately 1% of sub-fertile men. 2b
Men with TGCT frequently have impaired sperm parameters at diagnosis. 2a
Semen analysis and sperm cryopreservation before orchidectomy allows the identification of TGCT 2b
patients with azoospermia, who may benefit from concomitant surgical sperm retrieval (i.e., onco-
TESE).
Treatment of TGCT can result in decreased sperm quality, sperm aneuploidy, increased SDF, 2a
hypogonadism, sexual dysfunction and cardiovascular diseases.
Testicular microcalcifications can be found in men with benign conditions (e.g., cryptorchidism, 2a
infertility, testicular torsion and atrophy, Klinefelter syndrome, hypogonadism, DSD, varicocele) and
(pre)malignant (GCNIS) or malignant conditions (TGCT).
Testicular microcalcifications are associated with a higher risk of testicular cancer in infertile men. 1a
Men potentially at risk for harbouring or developing GCNIS include those with bilateral TM, infertility, 2a
atrophic testes, undescended testes, history of TGCT, and contralateral TM.
Since TGCT will not develop in most men with TM, an extensive screening programme or invasive 2b
testicular biopsy is not indicated without additional risk factors.

Recommendations Strength rating

Advise men with testicular microcalcification (TM) to perform self-examination even without Weak
additional risk factors, as this may result in early detection of a testicular germ cell tumour
(TGCT).
Do not perform testicular biopsy, follow-up scrotal ultrasound (US), measure biochemical Strong
tumour markers, or abdominal or pelvic computed tomography, in men with isolated TM
without associated risk factors (e.g., infertility, cryptorchidism, testicular cancer, and atrophic
testis).
Offer testicular biopsy to infertile men with TM, who belong to one of the following higher Weak
risk groups: spermatogenic failure (infertility), bilateral TM, atrophic testes (< 12 mL), history
of undescended testes and TGCT.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 141

Perform inguinal surgical exploration with testicular biopsy or offer orchidectomy after multi- Strong
disciplinary team meeting and discussion with the patient, if there are suspicious findings on
physical examination or US in patients with TM with associated lesions.
Manage men treated for TGCT in a multi-disciplinary team setting with a dedicated late- Strong
effects clinic and survivorship program, since they are at increased risk of developing
hypogonadism, sexual dysfunction and cardiovascular risk.
Perform sperm cryopreservation prior to planned orchidectomy or before additional Strong
neoadjuvant or adjuvant oncological therapies.
Offer onco-testicular sperm extraction (onco-TESE) at the time of radical orchidectomy Strong
in men with testicular cancer and azoospermia or severe abnormalities in their semen
parameters.

11.4.3 Varicocele
Varicocele is a common congenital abnormality, that may be associated with the following andrological
conditions:
• failure of ipsilateral testicular growth and development;
• male sub-fertility;
• symptoms of pain and discomfort;
• hypogonadism.

11.4.3.1 Classification
The following classification of varicocele [1518] is useful in clinical practice:
• Subclinical: not palpable or visible at rest or during Valsalva manoeuvre, but can be shown by
special tests (Doppler US).
• Grade 1: palpable during Valsalva manoeuvre.
• Grade 2: palpable at rest.
• Grade 3: visible and palpable at rest.

11.4.3.2 Diagnostic evaluation

The diagnosis of varicocele is made by physical examination and Scrotal Doppler US is indicated if physical
examination is inconclusive or semen analysis remains unsatisfactory after varicocele repair to identify
persistent and recurrent varicocele [1518, 1728]. A maximum venous diameter of > 3 mm in the upright position
and during the Valsalva manoeuvre and venous reflux with a duration > 2 seconds correlate with the presence
of a clinically significant varicocele [1729, 1730]. To calculate testicular volume Lambert’s formula (V=L x W x H
x 0.71) should be used, as it correlates well with testicular function in patients with infertility and/or varicocele
[1731]. Patients with isolated, clinical right varicocele should be examined further for abdominal, retroperitoneal
and congenital pathology and anomalies.

11.4.3.3 Basic considerations

11.4.3.3.1 Varicocele and fertility
Varicocele is present in almost 15% of the normal male population, in 25% of men with abnormal semen
analysis and in 35-40% of men presenting with infertility [1518, 1732-1734]. The incidence of varicocele among
men with primary infertility is estimated at 35–44%, whereas the incidence in men with secondary infertility is
45–81% [1518, 1733, 1734]. Worsening semen parameters are associated with a higher grade of varicocele and
age [1733, 1735].

The exact association between reduced male fertility and varicocele is unknown. Increased scrotal temperature,
hypoxia and reflux of toxic metabolites can cause testicular dysfunction and infertility due to increased overall
survival and DNA damage [1732, 1734].

11.4.3.3.2 Varicocelectomy
Varicocele repair has been a subject of debate for several decades. A meta-analysis of RCTs and observational
studies in men with only clinical varicoceles has shown that surgical varicocelectomy significantly
improves semen parameters in men with abnormal semen parameters, including men with NOA with hypo-
spermatogenesis or late maturation (spermatid) arrest on testicular pathology [1732, 1736-1739]. A meta-
analysis showed that improvements in semen parameters are usually observed after surgical correction in
men with abnormal semen parameters [1740-1742]. Varicocelectomy can also reverse sperm DNA damage
and improve OS levels [1732, 1734]. Pain resolution after varicocelectomy occurs in 48-90% of patients [1743].
A systematic review has shown greater improvement in higher-grade varicoceles and this should be taken into
account during patient counselling [1744].

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In RCTs, varicocele repair in men with a subclinical varicocele was ineffective at increasing the chances of
spontaneous pregnancy [1745]. Also, in randomised studies that included mainly men with normal semen
parameters no benefit was found to favour treatment over observation. This was also reported in a systematic
review and meta-analysis including prospective randomised and non-randomised studies [1746]. In studies
including patients with abnormal semen parameters pregnancy rates (OR 1.29, 95% CI 1.00–1.65, p = 0.04)
and total sperm count (mean difference: 12.34 million/ml, 95% CI 3.49–21.18, p = 0.006) were significantly
improved by varicocele treatment compared with observation. A benefit for varicocele treatment was not found
for sperm progressive motility and normal sperm morphology [1746]. When pre- versus post-treatment values
were considered in the varicocele treatment arm only a benefit in terms of sperm count, progressive motility,
and normal morphology was found [1746]. Another systematic review and meta-analysis evaluated the change
in conventional semen parameters after varicocele repair (n=1,426) compared to untreated controls (n=996)
[1747]. Significantly improved post-operative semen parameters where reported in treated patients compared to
controls with regards to sperm concentration (SMD 1.73; 95% CI 1.12 to 2.34; p<0.001), total sperm count (SMD
1.89; 95% CI 0.56 to 3.22; p < 0.05), progressive sperm motility (SMD 3.30; 95% CI 2.16 to 4.43; p < 0.01), total
sperm motility (SMD 0.88; 95% CI 0.03 to 1.73; p=0.04) and normal sperm morphology (SMD 1.67; 95% CI 0.87
to 2.47; p < 0.05) [1747].

A Cochrane review from 2012 concluded that there is evidence to suggest that treatment of a varicocele in men
from couples with otherwise unexplained subfertility may improve a couple’s chance of spontaneous pregnancy
[1748]. Similarly, a Cochrane review from 2021 including 5,384 participants showed that varicocele treatment
may improve pregnancy rates compared to delayed or no treatment (RR 1.55, 95% CI 1.06 to 2.26) [1749]. Two
meta-analyses of RCTs comparing treatment to observation in men with a clinical varicocele, oligozoospermia
and otherwise unexplained infertility, favoured treatment, with a combined OR of 2.39-4.15 (95% CI: 1.56-3.66)
and (95% CI: 2.31-7.45), respectively [1739, 1748]. Average time to improvement in semen parameters is up
to two spermatogenic cycles [1750, 1751] with spontaneous pregnancy occurring between 6 and 12 months
after varicocelectomy [1752, 1753]. A further meta-analysis has reported that varicocelectomy may improve
outcomes following ART in oligozoospermic men with an OR of 1.69 (95% CI: 0.95-3.02) [1754].

11.4.3.3.3 Prophylactic varicocelectomy

In adolescents with a varicocele, there is a significant risk of over-treatment because most adolescents with
a varicocele have no problem achieving pregnancy later in life [1755]. Prophylactic treatment is only advised
in case of documented testicular growth deterioration confirmed by serial clinical or Doppler US examinations
and/or abnormal semen analysis [1756, 1757].

Varicocelectomy and NOA

Several non-randomised studies have suggested that varicocelectomy may lead to sperm appearing in the
ejaculate in men with azoospermia. In one such study, microsurgical varicocelectomy in men with NOA led
to sperm in the ejaculate post-operatively with an increase in ensuing natural or assisted pregnancies [1758].
Meta-analyses have further corroborated these findings; 468 patients diagnosed with NOA and varicocele
underwent surgical varicocele repair or percutaneous embolisation. In patients who underwent varicocelectomy,
SRRs increased compared to those without varicocele repair (OR: 2.65; 95% CI: 1.69-4.14; p < 0.001). In 43.9%
of the patients (range: 20.8%-55.0%), sperm were found in post-operative ejaculate. These findings indicate
that varicocelectomy in patients with NOA and clinical varicocele is associated with improved SRR, that sperm
retrieval may be avoided when sperm reappear in the ejaculate following varicocelectomy. However, the quality
of evidence available is low and the risks and benefits of varicocele repair must be discussed fully with the
patient with NOA and a clinically significant varicocele prior to embarking upon treatment intervention [1737,
1759]. The current understanding of the underlying genetic defects of NOA must be taken into account when
interpreting contemporary literature.

Varicocelectomy and hypogonadism

Evidence also suggests that men with clinical varicoceles who are hypogonadal may benefit from varicocele
intervention. One meta-analysis studied the efficacy of varicocele intervention by comparing the pre-operative
and post-operative serum testosterone of 712 men. The combined analysis of seven studies demonstrated that
the mean post-operative serum testosterone improved by 34.3 ng/dL (95% CI: 22.57-46.04, p < 0.00001, I² = 0%)
compared with their pre-operative levels. An analysis of surgery vs. untreated control results showed that mean
testosterone among hypogonad patients increased by 105.65 ng/dL (95% CI: 77.99-133.32 ng/dL), favouring
varicocelectomy [1760]. However, results must be treated with caution and adequate cost-benefit analysis must
be undertaken to determine the risks and benefits of surgical intervention over testosterone therapy in this
setting. Although, varicocelectomy may be offered to hypogonadal men with clinically significant varicoceles,
patients must be advised that the full benefits of treatment in this setting must be further evaluated with
prospective RCTs.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 143

11.4.3.3.4 Varicocelectomy for assisted reproductive technology and raised SDF
Varicocelectomy can improve sperm DNA integrity [1755, 1761-1763]. A systematic review and meta-analysis
analysed data from 1,070 infertile men with clinical varicocele and showed that varicocelectomy was associated
with reduced post-operative SDF rates (weighted mean difference 7.23%; 95% CI: 8.86 to 5.59) [1764].
Improvement of DNA integrity was independent from the assay used (SCSA vs. TUNEL vs. SCD) and the surgical
technique performed. The estimated weighted mean difference was greater in studies with pre-operative mean
fragmentation index ≥ 20% than that in studies with SDF < 20%, suggesting that varicocelectomy might be more
beneficial in men with elevated baseline SDF values [1764]. The magnitude of the effect size increased as a
function of preoperative SDF levels (coefficient: 0.23; 95%CI: 0.07 to 0.39).

There is now increasing evidence that varicocele treatment may improve DNA fragmentation and outcomes
from ART [1754, 1755]. As a consequence, more recently it has been suggested that the indications for
varicocele intervention should be expanded to include men with raised DNA fragmentation. If a patient has failed
ART (e.g., failure of implantation, embryogenesis or recurrent pregnancy loss) there is an argument that if DNA
damage is raised, consideration could be given to varicocele intervention after extensive counselling [1765], and
exclusion of other causes of raised SDF [1755, 1766].The dilemma remains as to whether varicocele treatment
is indicated in men with raised SDF and normal semen parameters. This decision would need a full and open
discussion with the infertile couple, taking into consideration the female partners ovarian reserve and the
surgical risks and potential delays in ART associated with varicocele intervention.

In a meta-analysis of non-azoospermic infertile men with clinical varicocele by Estevez et al., four retrospective
studies were included of men undergoing ICSI, and included 870 cycles (438 subjected to ICSI with prior
varicocelectomy, and 432 without prior varicocelectomy). There was a significant increase in the clinical
pregnancy rates (OR 1.59, 95% CI: 1.19-2.12, I2 = 25%) and live birth rates (OR 2.17, 95% CI: 1.55-3.06, I2 =
0%) in the varicocelectomy group compared to the group subjected to ICSI without previous varicocelectomy.
A further study evaluated the effects of varicocele repair and its impact on pregnancy and live birth rates in
infertile couples undergoing ART in male partners with oligo-azoospermia or azoospermia and a varicocele
[1754]. In 1,241 patients, a meta-analysis demonstrated that varicocelectomy improved live birth rates for the
oligospermic (OR = 1.699) men and combined oligo-azoospermic/azoospermic groups (OR = 1.761). Pregnancy
rates were higher in the azoospermic group (OR = 2.336) and combined oligo-azoospermic/azoospermic groups
(OR 1.760). Live birth rates were higher for patients undergoing IUI after intervention (OR 8.360).

11.4.3.4 Disease management

Several treatments are available for varicocele (Table 11.3).

Impact on pregnancy rate and semen parameters

Current evidence indicates that microsurgical varicocelectomy is the most effective among the different
varicocelectomy techniques [1755, 1767]. A Cochrane review reported that microsurgical subinguinal
varicocelectomy probably improves pregnancy rates slightly more compared to other surgical treatments (RR
1.18, 95% CI 1.02 to 1.36) [1749]. A subgroup analysis from a systematic review of prospective randomised and
non-randomised studies reported that surgical approach (including all possible surgical techniques) significantly
improved pregnancy rates and sperm concentration as compared with controls, while the same was not
demonstrated for radiological treatment [1746]. However, the most recent Cochrane review showed inconclusive
results about the effect of surgical vs. radiological treatment on pregnancy rates and varicocele recurrence
[1749]. There are no large prospective RCTs comparing the efficacy of the various interventions for varicocele.

Complications
Microsurgical repair results in fewer complications and lower recurrence rates compared to the other
techniques [1749, 1768, 1769]; however, this procedure, requires microsurgical training. The various other
techniques are still considered viable options, although recurrences and hydrocele formation appear to be
higher [1769].
Radiological techniques (sclerotherapy and embolisation) are minimally invasive approaches
for varicocele treatment. Although higher recurrence rates have been reported compared to microscopic
varicocelectomy [1754], a meta-analysis showed that the incidence of varicocele recurrence was similar
after surgical ligation and sclero-embolisation [1770]. In terms of complications, a meta-analysis of twelve
studies comparing 738 cases of surgical ligation vs. 647 cases of sclero-embolisation, showed that overall
complications rate did not differ significantly between the groups (OR 1.48; 95% CI 0.86–2.57, p = 0.16) [1770].
The incidence of post-operative hydrocele is significantly higher after surgical ligation than sclero-embolisation,
but radiological techniques are associated with higher incidence of post-operative orchiepidydimitys [1770].

144 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

 Robot-assisted varicocelectomy has a similar success rate compared to the microscopic
varicocelectomy technique, although larger prospective randomised studies are needed to establish the most
effective method [1771-1773].

Table 11.3: Recurrence and complication rates associated with treatments for varicocele

Treatment Recurrence/ Overall complications Specific Complications

Persistence
Antegrade 5-9% Hydrocele (5.5%), Technical failure 1-9%,
sclerotherapy haematoma, infection, scrotal left-flank erythema
[1773, 1774] pain, testicular atrophy,
epididymitis
Retrograde 6-9.8% Hydrocele (3.3%), wound Technical failure 6-7.5%, adverse
sclerotherapy infection, scrotal pain reaction to contrast medium, flank pain,
[1775, 1776] persistent thrombophlebitis, venous
perforation
Retrograde 3-11% Hydrocele (10%), haematoma, Technical failure 7-27%, pain due
embolization wound infection to thrombophlebitis, radiological
[1775, 1777] complications (e.g., reaction to contrast
media), misplacement or migration of
coils (to femoral vein or right atrium),
retroperitoneal haemorrhage, fibrosis,
ureteric obstruction, venous perforation
Open operation
Scrotal operation - Testicular atrophy, arterial
damage with risk of
devascularisation and
testicular gangrene, scrotal
haematoma, post-operative
hydrocele
Inguinal approach 2.6-13% Hydrocele (7.3%), testicular Post-operative pain due to incision of
[1778, 1779] atrophy, epididymo-orchitis, external oblique fascia, genitofemoral
wound complications nerve damage
Open 15-29% Hydrocele (5-10%),testicular External spermatic vein ligation failure
retroperitoneal atrophy, scrotal oedema
high ligation
[1767, 1780]
Microsurgical 0.4% Hydrocele (0.44%), scrotal
inguinal or haematoma
Subinguinal
[1768, 1778, 1781,
1782]
Laparoscopy 3-6% Hydrocele (7-43%), External spermatic vein ligation failure,
[1735, 1767, 1768, epididymitis, wound infection, intestinal, vascular and nerve damage;
1783, 1784] testicular atrophy due to injury pulmonary embolism; pneumo-scrotum;
of testicular artery, bleeding peritonitis; post-operative pain in
right shoulder (due to diaphragmatic
stretching during pneumo-peritoneum)

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11.4.3.5 Summary of evidence and recommendations for varicocele

Summary of evidence LE
The presence of varicocele in some men is associated with progressive testicular damage from 2a
adolescence onwards and a consequent potential reduction in fertility.
Although the treatment of varicocele in adolescents may be effective, there is a significant risk of over- 3
treatment as the majority of boys with a varicocele will have no fertility problems later in life.
Varicocele repair may be effective in men with abnormal semen parameters, a clinical varicocele and 1a
otherwise unexplained male factor infertility.
Varicocele repair may improve pregnancy rates and sperm concentration in adult infertile men with 1a
abnormal semen analyses, while benefits in sperm motility and normal morphology are less clear.
Although there are no prospective randomised studies evaluating this, meta-analyses have suggested 2
that varicocele repair is associated with sperm appearing in the ejaculate of men with non-obstructive
azoospermia.
Microscopic approach (inguinal/subinguinal) may have lower recurrence and complications rates than 2a
non-microscopic approaches (retroperitoneal and laparoscopic), although no RCTs are available yet.
Varicocele is associated with raised sperm DNA fragmentation (SDF) and intervention has been shown 2a
to reduce SDF and may improve the outcomes from ART.

Recommendations Strength rating

In adolescents offer surgery for varicocele associated with a persistent small testis (size Strong
difference of > 2 mL or 20%), which should be confirmed on two subsequent visits performed
six months apart.
Do not treat varicocele in infertile men who have normal semen analysis and in men with a Strong
sub-clinical varicocele.
Treat infertile men with a clinical varicocele, abnormal semen parameters and otherwise Strong
unexplained infertility in a couple where the female partner has good ovarian reserve to
improve fertility rates.
Varicocelectomy may be considered in men with raised sperm DNA fragmentation with Weak
otherwise unexplained infertility or who have suffered from failure of assisted reproductive
techniques, including recurrent pregnancy loss, failure of embryogenesis and implantation.

11.4.4 Male accessory gland infections and infertility

11.4.4.1 Introduction
Infection of the male urogenital tract is a potentially curable cause of male infertility [1785-1787]. The WHO
considers urethritis, prostatitis, orchitis and epididymitis to be male accessory gland infections (MAGIs) [1785].
The effect of symptomatic or asymptomatic infections on sperm quality is contradictory [1788]. A systematic
review of the relationship between sexually transmitted infections, such as those caused by Chlamydia
trachomatis, genital mycoplasmas, Neisseria gonorrhoeae, Trichomonas vaginalis and viruses, and infertility
was unable to draw a strong association between sexually transmitted infections and male infertility due to the
limited quality of reported data [1789].

11.4.4.2 Diagnostic evaluation

11.4.4.2.1 Semen analysis
Semen analysis (see Section 11.3.2) clarifies whether the prostate is involved as part of a generalised MAGI and
provides information regarding sperm quality.

11.4.4.2.2 Microbiological findings

After exclusion of UTI (including urethritis), > 106 peroxidase-positive white blood-cells (WBCs) per millilitre
of ejaculate indicate an inflammatory process. Semen culture or polymerase chain reaction (PCR) analysis
should be performed for common urinary tract pathogens in all suspected cases of genitourinary tract
infections. A concentration of > 103 CFU/mL urinary tract pathogens in the ejaculate is indicative of significant
bacteriospermia [1790]. The sampling should be delivered the same day to the laboratory because the sampling
time can influence the rate of positive micro-organisms in semen and the frequency of isolation of different
strains [1791]. The ideal diagnostic test for isolating C. trachomatis in semen has not yet been established
[1792], but the most accurate method is PCR [1793-1795].

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Historical data show that Ureaplasma urealyticum is pathogenic only in high concentrations (> 103 CFU/mL
ejaculate). Fewer than 10% of samples analysed for Ureaplasma exceeded this concentration [1796]. Normal
colonisation of the urethra hampers the significance of mycoplasma-associated urogenital infections, using
samples such as the ejaculate [1797].

A meta-analysis indicated that Ureaplasma parvum and Mycoplasma genitalium were not associated with
male infertility, but a significant relationship existed between U. urealyticum (OR: 3.03 95% CI: 1.02–8.99)
and Mycoplasma hominis (OR: 2.8; 95% CI: 0.93– 3.64) [1798]. For these reasons, the treatment is not always
recommended.

Human papilloma virus (HPV) is commonly found in semen samples, with a reported prevalence of 20% in
infertile populations and 8% in men from the general population [1799]. Systematic reviews have reported
an association between male infertility, poorer pregnancy outcomes and semen HPV positivity [1799-1802].
However, data still needs to be prospectively validated to clearly define the clinical impact of HPV infection in
semen. Additionally, seminal presence of Herpes Simplex virus (HSV)-2 in infertile men may be associated with
lower sperm quality compared to that in HSV-negative infertile men [1788]. However, it is unclear if anti-viral
therapy improves fertility rates in these men.

11.4.4.2.3 White blood cells

The clinical significance of an increased concentration of leukocytes in the ejaculate is controversial [1803].
Although leukocytospermia is a sign of inflammation, it is not necessarily associated with bacterial or viral
infections, and therefore cannot be considered a reliable indicator [1804]. According to the WHO classification,
leukocytospermia is defined as > 106 WBCs/mL. Only two studies have analysed alterations of WBCs in the
ejaculate of patients with proven prostatitis [1805, 1806]. Both studies found more leukocytes in men with
prostatitis compared to those without inflammation (CPPS, type NIH 3b). Furthermore, leukocytospermia
should be further confirmed by performing a peroxidase test on the semen. A meta-analysis of case-control
studies showed that leukocytospermia in men seeking consultation for couple subfertility was not associated
with reduced fertility after ART and altered semen quality in men without symptoms of genital tract infections
[1807]. There is currently no evidence that treatment of leukocytospermia alone without evidence of infective
organisms improves conception rates [1808].

11.4.4.2.4 Sperm quality

The deleterious effects of chronic prostatitis (CP/CPPS) on sperm density, motility and morphology have been
demonstrated in a recent systematic review based on case-controlled studies [1809]. Both C. trachomatis and
Ureoplasma spp. can cause decreased sperm density, motility, altered morphology and increased DNA damage.
Data from a retrospective cross-sectional study showed that U. urealyticum was the most frequent single
pathogen in semen of asymptomatic infertile men; a positive semen culture was both univariably (p < 0.001) and
multi-variably (p = 0.04) associated with lower sperm concentration [1810]. Human papilloma virus is associated
with changes in semen density, sperm motility and sperm DNA damage [1811, 1812]. Mycoplasma spp. can
cause decreased motility and development of anti-sperm antibodies [1788].

11.4.4.2.5 Seminal plasma alterations

Seminal plasma elastase is a biochemical indicator of polymorphonuclear lymphocyte activity in the ejaculate
[1787, 1813, 1814]. Various cytokines are involved in inflammation and can influence sperm function. Several
studies have investigated the association between interleukin (IL) concentration, leukocytes, and sperm function
through different pathways, but no correlations have been found [1815-1817]. The prostate is the main site
of origin of IL-6 and IL-8 in the seminal plasma. Cytokines, especially IL-6, play an important role in the male
accessory gland inflammatory process [1818]. However, elevated cytokine levels do not depend on the number
of leukocytes in expressed prostatic secretion [1819].

11.4.4.2.6 Glandular secretory dysfunction

The secretory function of the prostate gland can be evaluated by measuring seminal plasma pH, citric acid,
or γ-glutamine transpeptidase levels, although these parameters are not evaluated anymore in numerous
laboratories; the seminal plasma concentrations of these factors are usually altered during infection and
inflammation. However, they are not recommended as diagnostic markers for MAGIs [1820].

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11.4.4.2.7 Reactive oxygen species (ROS)
Reactive oxygen species may be increased in infertile patients with asymptomatic C. trachomatis and M.
hominis infection, with subsequent decrease in ROS upon antibiotic treatment. However, ROS levels in infertile
patients with asymptomatic C. trachomatis and M. hominis in the semen are low, making it difficult to draw any
firm conclusions [1821]. Chronic urogenital infections are also associated with increased leukocyte numbers
[1822]. However, their biological significance in prostatitis remains unclear [1787].

11.4.4.2.8 Disease management

Only antibiotic therapy of chronic bacterial prostatitis (NIH II according to the classification) has provided
symptomatic relief, eradication of micro-organisms, and a decrease in cellular and humoral inflammatory
parameters in urogenital secretions. Although antibiotics might improve sperm quality [1823], there is no
evidence that treatment of CP/CPPS increases the probability of natural conception [1787, 1824].

Asymptomatic presence of C. trachomatis and M. hominis in the semen can be correlated with impaired sperm
quality, which recovers after antibiotic treatment. However further research is required to confirm these findings
[1821].

11.4.4.3 Epididymitis
Inflammation of the epididymis causes unilateral pain and swelling, usually with acute onset. Among sexually
active men aged < 35 years, epididymitis is most often caused by C. trachomatis or N. gonorrhoea [1825, 1826].
Sexually transmitted epididymitis is usually accompanied by urethritis. Non-sexually transmitted epididymitis is
associated with UTIs and occurs more often in men aged > 35 years [1827].

11.4.4.3.1 Diagnostic evaluation

11.4.4.3.1.1 Ejaculate analysis
Ejaculate analysis according to WHO Laboratory Manual for the Examination and Processing of Human Semen
(6th edn) criteria, may indicate persistent inflammatory activity. Transient reductions in sperm counts and
progressive sperm motility can be observed [1825, 1828, 1829]. Semen culture might help to identify pathogenic
micro-organisms. Development of stenosis of the epididymal ducts, reduction of sperm count, and azoospermia
are more important potential sequelae to consider in the follow-up of bilateral epididymitis (see Section 11.3.2).

11.4.4.3.1.2 Disease management

Treatment of epididymitis results in:
• microbiological cure of infection;
• improvement of clinical signs and symptoms;
• prevention of potential testicular damage;
• prevention of transmission;
• decrease of potential complications (e.g., infertility or chronic pain).

Patients with epididymitis known or suspected to be caused by N. gonorrhoeae or C. trachomatis must be told to
also refer their sexual partners for evaluation and treatment [1830].

11.4.4.4 Summary of evidence and recommendation for male accessory gland infections

Summary of evidence LE
Male accessory gland infections are not clearly associated with impaired natural conception. 3
Antibiotic treatment often only eradicates micro-organisms; it has no positive effect on inflammatory 2a
alterations and cannot reverse functional deficits and anatomical abnormalities.
Although antibiotic treatment for MAGIs may result in improvement in sperm quality, it does not 2a
enhance the probability of conception.
Data are insufficient to conclude whether antibiotics and antioxidants for the treatment of infertile men 3
with leukocytospermia improve fertility outcomes.

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Recommendations Strength rating
Treat male accessory gland infections as it may improve sperm quality, although it does not Weak
necessarily improve the probability of conception.
Refer sexual partners of patients with accessory sex gland infections that are known or Strong
suspected to be caused by sexually transmitted diseases for evaluation and treatment.

11.5 Non-Invasive Male Infertility Management

11.5.1 Empirical treatments
11.5.1.1 Life-style
Environmental and lifestyle factors may contribute to male infertility acting additively on a susceptible genetic
background [83, 1650]. Hence, lifestyle improvement can have a positive effect on sperm parameters.
This includes:
• Weight loss: non-controlled studies have suggested that weight loss can result in improved sperm
parameters [83, 1831, 1832]. However, data derived from RCTs are more conflicting. A meta-analysis of 28
cohort studies and 1,022 patients, documented that bariatric surgery did not improve sperm quality and
function in morbidly obese men [1833]. Data on ART outcomes are lacking. Furthermore, weight loss can
improve obesity-related secondary hypogonadism, which may result in better outcomes in couples seeking
medical care for infertility [1831, 1833].
• Physical activity: a meta-analysis has documented that moderate-intensity (20–40 metabolic equivalents
[METs]/week) or even high-intensity (40–80 METs-h/week) recreational physical activity can result in
better semen parameters [1834]. Moreover, physical activity might improve hormonal profile [1831].
• Smoking: data derived from a large meta-analysis of 20 studies with 5,865 participants showed a negative
association between smoking and sperm parameters [1835].
• Alcohol consumption: Data derived from a recent meta-analysis including 15 cross-sectional studies and
16,395 men suggested that moderate alcohol does not adversely affect semen parameters, whereas high
alcohol intake can have a detrimental effect on male fertility [1836] heavy chronic alcohol consumption
(defined as > 2 drinks/day [1837]) can reduce testosterone levels [1837].

11.5.1.2 Antioxidant treatment

Oxidative stress is considered to be of the most important contributing factors in the pathogenesis of idiopathic
infertility. Reactive oxygen species, the final products of OS, can impair sperm function acting at several levels,
including plasma membrane lipid peroxidation, which can affect sperm motility, the acrosome reaction and
chromatin maturation leading to increased SDF [1838]. Accordingly, seminal levels of ROS have been negatively
associated with ART outcomes [1839]. Despite this, evidence for the role of antioxidant therapy in male infertility
is still conflicting. A Cochrane systematic review and meta-analysis including 34 RCTs and 2,876 couples using
various antioxidant compounds, it was concluded that antioxidant therapy had a positive impact on live-birth
and pregnancy rates in sub-fertile couples undergoing ART cycles [1840]. Similar results were also reported
in a meta-analysis including 61 studies with 6,264 infertile men, aged 18-65 years [1841]. However, the quality
of the reported studies is poor. The Males, Antioxidants, and Infertility (MOXI) trial found that antioxidants did
not improve semen parameters or DNA integrity compared to placebo among infertile men with male factor
infertility. Moreover, cumulative live-birth rate did not differ at 6 months between the antioxidant and placebo
groups (15% vs. 24%) [1842]. No clear conclusions were possible regarding the specific antioxidants to use or
and/or therapeutic regimes for improving sperm parameters and pregnancy rate [1841].

11.5.1.3 Probiotic treatment

Prebiotic/probiotic supplementation may influence hormone secretion, facilitating the scavenging of free
radicals, and improving the microenvironment of the prostate and indirectly enhance sperm function. A RCT
including 56 men with idiopathic infertility treated with a prebiotic/probiotic compound vs. placebo showed a
significant increase in sperm parameters in the treated group (i.e., sperm concentration, motility and normal
morphology) as well as an increase in DNA integrity [1843]. An RCT of 78 infertile men who underwent
varicocelectomy with or without postoperative probiotic supplementation found a significant early (3 months)
increase of sperm parameters (sperm concentration and normal morphology) in favour of the probiotic group
vs. placebo [1844]. Further high-powered RCTs are warranted to further investigate the use of prebiotic/probiotic
supplementation in the context of male infertility.

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11.5.1.4 Selective oestrogen receptor modulators
Selective oestrogen receptor modulators (SERMs) block oestrogen receptors at the level of the hypothalamus,
which results in stimulation of GnRH secretion, leading to an increase in pituitary gonadotropin release and
stimulation of spermatogenesis [1845]. Meta-analysed data derived from eleven RCTs showed that SERMs
significantly increased pregnancy rate, sperm and hormonal parameters [1846]. Similar results were confirmed
in the latest updated meta-analysis of sixteen studies [1845]. However, previous SR failed to find any association
between SERMs and pregnancy rate [1847]. It should be recognised that the quality of the papers considered
was low and only a few studies were placebo-controlled. In conclusion, although some positive results relating
to the use of SERMs in men with idiopathic infertility have been reported, no conclusive recommendations can
be drawn due to poor quality of the available evidence. Furthermore, complications from the use of SERMs were
under-reported.

11.5.1.5 Aromatase inhibitors

Aromatase, a cytochrome p450 enzyme, is present in the testes, prostate, brain, bone, and adipose tissue
of men; it converts testosterone and androstenedione to oestradiol and oestrone, respectively. Oestradiol
negatively feeds back on the hypothalamus and pituitary to reduce gonadotropic secretions, ultimately affecting
spermatogenesis. In this context, aromatase inhibitors (AIs) may decrease oestrogen production by reversibly
inhibiting cytochrome p450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex inhibiting the
negative feedback of oestrogen on the hypothalamus resulting in stronger GnRH pulses that stimulate the
pituitary to increase production of FSH [1848-1851]. Aromatase activity has been associated with male
infertility characterised by testicular dysfunction with low serum testosterone and/or testosterone to oestradiol
ratio. In this context, AIs have been reported to increase endogenous testosterone production and improve
spermatogenesis in the setting of infertility as an off-label option for treatment [1852]. Either steroidal
(testolactone) and non-steroidal (anastrozole and letrozole) AIs significantly improve hormonal and semen
parameters in infertile men, with a safe tolerability profile, although prospective RCTs are necessary to better
define the efficacy of these medications in this clinical setting [1850, 1852].

11.5.2 Summary of evidence and recommendation for Non-Invasive Male Infertility Management

Summary of evidence LE
In infertile men life style factors including obesity, low physical activity, smoking and high alcohol 2a
intake are associated with decreased sperm quality.
In men with idiopathic oligo-astheno-teratozoospermia, life-style changes including weight loss and 2a
increased physical activity, smoking cessation and alcohol intake reduction may improve sperm quality
and the chances of conception.
No conclusive data are available regarding the beneficial treatment with antioxidants in men with 1b
idiopathic infertility, although they may improve semen parameters.
No conclusive data is available regarding the beneficial treatment with prebiotic/probiotic in men with 1b
idiopathic infertility; although, they may improve semen parameters.
No conclusive data are available regarding the use of selective oestrogen receptor modulators (SERMs) 1b
in men with idiopathic infertility.
No conclusive data are available regarding the use of steroidal (testolactone) or nonsteroidal 1b
(anastrozole and letrozole) aromatase inhibitors in men with idiopathic infertility.

Recommendations Strength rating

Inform infertile men about the detrimental effects of obesity, low physical activity, smoking Strong
and high alcohol intake on sperm quality and testosterone levels. Therefore, advise infertile
men to improve life style factors to improve their chances of conception.
Do not routinely treat patients with idiopathic infertility with antioxidants, prebiotic/probiotic, Weak
selective oestrogen receptor modulators (SERMs) or aromatase inhibitors (AIs).

11.5.3 Hormonal therapy

11.5.3.1 Secondary hypogonadism
A brief discussion on Pre-Pubertal-Onset can be found in Appendix 7, online supplementary evidence.

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Post-Pubertal Onset: Human Chorionic Gonadotrophin (hCG) alone is usually required first to stimulate
spermatogenesis. A starting dose of 250 IU hCG twice weekly is suggested, and if normal testosterone
levels are reached, hCG doses may be increased up to 2,000 IU twice weekly. Again, semen analysis should
be performed every 3 months to assess response, unless conception has taken place. If there is a failure of
stimulation of spermatogenesis, then FSH can be added (75 IU three times per week, increasing to 150 IU three
times per week if indicated). Similarly, combination therapy with FSH and hCG can be administered from the
beginning of treatment, promoting better outcomes in men with HH [126]. No difference in outcomes were
observed when urinary-derived, highly purified FSH was compared to recombinant FSH [126].

Greater baseline testicular volume is a good prognostic indicator for response to gonadotrophin treatment
while previous testosterone therapy can have a negative impact on gonadotropin treatment outcomes in men
with hypogonadotropic hypogonadism [1853]. However, this observation has been subsequently refuted by a
meta-analysis that did not confirm a real negative role of testosterone therapy in terms of future fertility in this
specific setting [126].

11.5.3.1.1 Secondary hypogonadism due to hyperprolactinemia

In the presence of hyperprolactinaemia, causing suppression of gonadotrophins resulting in sub-fertility the
treatment independent of aetiology (including a pituitary adenoma) is dopamine agonist therapy or withdrawal
of the drug that causes the condition. Dopamine agonists used include bromocriptine, cabergoline and
quinagolide.

11.5.3.2 Primary Hypogonadism

There is no substantial evidence that gonadotrophin therapy has any beneficial effect in the presence of
classical testicular failure. Likewise, there are no data to support the use of other hormonal treatments
(including SERMs or AIs) in the case of primary hypogonadism to improve spermatogenesis [84, 1854].

11.5.3.3 Idiopathic Male Factor Infertility

There is some evidence that FSH treatment increases sperm parameters in idiopathic oligozoospermic men
with FSH levels within the normal range (generally 1.5 – 8 mIU/mL) [1855]. In a meta-analysis including 12 trials
with 924 patients, FSH treatment resulted in an improvement of both semen parameter and SDF [1856]. It has
also been reported that FSH along with improvement of SDF rates may ameliorate AMH and inhibin levels [1857-
1860]. High-dose FSH therapy is more effective in achieving a testicular response than lower doses are [1861].
A Cochrane review including six RCTs with 456 participants, different treatment protocols and follow-up periods
concluded that FSH treatment resulted in higher live-birth and pregnancy rates compared with placebo or no
treatment. However, no significant difference among groups was observed when ICSI or IUI were considered
[1862]. In a meta-analysis including 15 trials with > 1,200 patients, similar findings after FSH treatment were
observed in terms of both spontaneous pregnancies and pregnancies after ART [1863]. A further study
showed that in azoospermic men undergoing TESE-ICSI there were improved SRRs and higher pregnancy and
fertilisation rates in men treated with FSH compared to untreated men [1864]. In men with NOA, combination
hCG/FSH therapy was shown to increase SRR in only one study [1865]. Human chorionic gonadotrophin alone
prior to TESE in NOA has not been found to have any benefit on SRRs [1866]. Overall, the evidence for the use of
hormone therapy prior to SSR is limited and treatment should be confined to clinical trials and not used routinely
in clinical practice.

11.5.3.4 Anabolic Steroid Abuse

Oligospermia or azoospermia as a result of anabolic abuse should be treated initially by withdrawal of the
anabolic steroid. There is no common indication for treating this disorder; the management is based on case
reports and clinical experience. Usually, adequate sperm numbers and quality will improve over a six to twelve-
month period from cessation. If after this interval the condition persists, then hCG without or in combination
with FSH as an alternative to clomiphene can be used to stimulate spermatogenesis [1867].

11.5.3.5 Summary of evidence and recommendations for treatment of male infertility with hormonal therapy

Summary of evidence LE
Follicle stimulating hormone (FSH) promotes spermatogenesis and testicular growth during puberty. 2b
Human chorionic gonadotropin (hCG) acts like luteinizing hormone (LH) and is used to stimulate
intratesticular testosterone production and spermatogenesis in men with hypopituitarism after puberty.
Prepubertal secondary hypogonadism requires the association of FSH and hCG or pulsatile GnRH, even 1b
if its use is limited by the difficult administration.

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Secondary hypogonadism in adults can be effectively treated with subcutaneous hCG and FSH. 2b
The use of GnRH therapy is more expensive and does not offer any advantages compared to 3
gonadotropins for the treatment of hypogonadotropic hypogonadism.
In postpubertal forms of secondary hypogonadism, sequential use of hCG and FSH or their 1b
combination from the beginning are options.
Testicular volume is one of the main predictors of response to gonadotropin therapy in men with 2a
hypogonadotropic hypogonadism.
Dopamine agonists are used to treat hyperprolactinaemia. 2a
FSH therapy (any formulation) has been associated with improvement in sperm quality and increased 2a
spontaneous and assisted pregnancy rates in idiopathic infertile males.
No conclusive recommendations can be given on the use of high-dose FSH in men with idiopathic 2a
infertility and prior (m)TESE and therefore cannot be routinely advocated.
Testosterone therapy is contraindicated in infertile men. 1a

Recommendations Strength rating

Induce spermatogenesis in men with congenital or acquired hypogonadotropic Strong
hypogonadism who wish to conceive by effective drug therapy (hCG; human menopausal
gonadotropins; recombinant FSH; highly purified FSH).
Use FSH treatment in men with idiopathic oligozoospermia and FSH values within the normal Weak
range, to increase spermatogenesis.
Do not treat idiopathic infertility with high dose FSH. Weak
Do not start hormonal stimulation prior to TESE in men with non-obstructive azoospermia Weak
(NOA) outside clinical trials.
Do not use testosterone therapy for the treatment of male infertility. Strong
Provide testosterone therapy for symptomatic patients with primary and secondary Strong
hypogonadism who are not considering parenthood.
Offer dopamine agonist therapy in men with proven hyperprolactinemia to improve sperm Weak
quality.
Withdraw anabolic steroids in infertile men for six to twelve months before considering Weak
treatment with selective oestrogen receptor modulators or gonadotrophin therapy to induce
spermatogenesis.

11.6 Invasive Male Infertility Management

11.6.1 Obstructive azoospermia
Obstructive azoospermia (OA) is the absence of spermatozoa in the sediment of a centrifuged sample of
ejaculate due to obstruction [1785]. Obstructive azoospermia occurs in 20-40% of men with azoospermia [1868,
1869] and it is characterised by normal FSH values, testes of normal size and epididymal enlargement [1870].
The most common causes of OA are reported in Table 11.4.

Table 11.4: Causes of obstruction of the genitourinary system

Intratesticular (15%)
Epididymis (30-67%)
Infection (acute/chronic epididymitis)
Trauma
Post-surgical iatrogenic obstruction (i.e., MESA, hydrocelectomy or other scrotal surgery)
Congenital epididymal obstruction (usually manifests as congenital bilateral absence of the vas deferens
[CBAVD])
Other congenital forms of epididymal obstruction (Young’s syndrome)

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Vas deferens
Vasectomy
Vasotomy/vasography (with improper technique)
Post-surgical iatrogenic obstruction (i.e., scrotal surgery or herniorraphy)
Congenital unilateral (CUAVD) or bilateral absence of the vas deferens (CBAVD)
Ejaculatory ducts
Cysts (Mullerian utricular, prostatic or seminal vesicular)
Infection (acute/chronic epididymitis)
Traumatic
Postsurgical iatrogenic obstruction
Functional obstruction
Idiopathic/acquired local neurogenic dysfunction

11.6.1.1 Diagnostic evaluation

Clinical history-taking should follow the investigation and diagnostic evaluation of infertile men (See Section
11.3). Risk factors for obstruction include prior surgery, iatrogenic injury during inguinal herniorrhaphy,
orchidopexy or hydrocelectomy.

11.6.1.1.1 Clinical examination

Clinical examination should follow the guidelines for the diagnostic evaluation of infertile men. Obstructive
azoospermia is indicated by at least one testis with a volume > 15 mL, although a smaller volume may be found
in some patients with obstructive azoospermia and concomitant partial testicular failure. Other finding might
include:
• enlarged and dilated epididymis;
• nodules in the epididymis or vas deferens;
• absence or partial atresia of the vas deferens.

When semen volume is low, or absent a search must be made for spermatozoa in urine after ejaculation.
Absence of spermatozoa and immature germ cells in the semen pellet suggest complete seminal duct
obstruction.

11.6.1.1.2 Hormone levels

Hormones including FSH and inhibin-B should be normal, but do not exclude other causes of testicular
azoospermia (e.g., NOA). Although inhibin‐B concentration is a good index of Sertoli cell integrity reflecting
closely the state of spermatogenesis, its diagnostic value is no better than that of FSH and its use in clinical
practice has not been widely advocated [1871].

11.6.1.1.3 Genetic testing

Cystic fibrose transmembrane conductance regulator gene testing should be performed in any patient with
unilateral or bilateral absence of the vas deferens or seminal vesicle agenesis [1872].

11.6.1.1.4 Testicular biopsy

Testis biopsies (including fine needle aspiration [FNA]) without performing simultaneously a therapeutic sperm
retrieval are not recommended, as this will require a subsequent invasive procedure. Furthermore, even patients
with extremes of spermatogenic failure (e.g., Sertoli Cell Only syndrome [SCOS]) may harbour focal areas of
spermatogenesis [1873, 1874].

11.6.1.2 Disease management

11.6.1.2.1 Sperm retrieval
Intratesticular obstruction
Only testicular sperm retrieval can extract sperm in these patients and is therefore recommended.

Epididymal obstruction
Microsurgical epididymal sperm aspiration (MESA) or percutaneous epididymal sperm aspiration (PESA) [1875]
is indicated in men with CBAVD. Testicular sperm extraction and percutaneous testicular sperm aspiration
(TESA), are also options [1876]. The source of sperm used for ICSI in cases of OA and the aetiology of the
obstruction do not affect the outcome in terms of pregnancy or miscarriage rates [1877, 1878]. Usually, one

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MESA procedure provides sufficient material for a number of ICSI cycles [1879] and it produces high pregnancy
and fertilisation rates [1880]. Overall, pregnancy outcomes from ICSI in men with OA are comparable between
epididymal and testicular sperm and also between fresh and frozen–thawed epididymal sperm [1881]. However,
these results are from studies of low evidence.
In patients with OA due to acquired epididymal obstruction and with a female partner with good
ovarian reserve, microsurgical epididymovasostomy (EV) is recommended [1882]. Epididymovasostomy can be
performed with different techniques such as end-to-site and intussusception [1883]. Anatomical recanalisation
following surgery may require 3-18 months. A systematic review indicated that the time to patency in EV varies
between 2.8 to 6.6 months. Reports of late failure are heterogeneous and vary between 1 and 50% [1884].
At the time of microsurgery, and in all cases in which reconstruction is impossible, sperm retrieval should be
performed intra-operatively by MESA/TESE and cryopreserved to be used for subsequent ICSI procedures
[1885].
Patency rates range between 63% and 85% and cumulative natural pregnancy rates between 21% and
45% [1886-1888]. Better patency rates might be achieved by performing bilateral EV and by targeting the caudal
or corpus part of the epididymis when possible [1888, 1889]. Recanalisation success rates may be adversely
affected by pre-operative and intra-operative findings. Robot-assisted EV has similar success rates but larger
studies are needed [1890].

Vas deferens obstruction after vasectomy

Vas deferens obstruction after vasectomy requires microsurgical vasectomy reversal. The mean post-procedural
patency and pregnancy rates weighted by sample size were 90-97% and 52-73%, respectively [1886, 1887].
The average time to patency is 1.7-4.3 months and late failures are uncommon (0-12%) [1884]. Robot-assisted
vasovasostomy has similar success rates, and larger studies, including cost-benefit analysis, are needed to
establish its benefits over standard microsurgical procedures [1890].
The absence of spermatozoa in the intra-operative vas deferens fluid suggests the presence of
a secondary epididymal obstruction, especially if the seminal fluid of the proximal vas deferens has a thick
“toothpaste” appearance; in this case microsurgical EV may be indicated [1891-1893]. Simultaneous sperm
retrieval may be performed for future cryopreservation and use for ICSI; likewise, patients should be counselled
appropriately.

Vas deferens obstruction at the inguinal level

It is usually impossible to correct large bilateral vas deferens defects, resulting from involuntary excision of the
vasa deferentia during hernia surgery in early childhood or previous orchidopexy. In these cases, TESE/MESA/
PESA or proximal vas deferens sperm aspiration [1894] can be used for cryopreservation for future ICSI.

Ejaculatory duct obstruction

The treatment of ejaculatory duct obstruction (EDO) depends on its aetiology. Transurethral resection of the
ejaculatory ducts (TURED) can be used in post-inflammatory obstruction and cystic obstruction [1885, 1895].
Resection may remove part of the verumontanum. In cases of obstruction due to a midline intraprostatic cyst,
incision, unroofing or aspiration of the cyst is required [1885, 1895].
Pregnancy rates after TURED are 20-25% [1707, 1895, 1896]. Complications following TURED include
epididymitis, UTI, gross haematuria, haematospermia, azoospermia (in cases with partial distal ejaculatory duct
obstruction) and urine reflux into the ejaculatory ducts and seminal vesicles [1895].
Alternative therapies for EDO include, seminal vesiculoscopy to remove debris or calculi and balloon
dilation and laser incision for calcification on TRUS [1897]. The alternatives to TURED are MESA, PESA, TESA,
TESE, proximal vas deferens sperm aspiration and seminal vesicle-ultrasonically guided aspiration.

11.6.1.3 Summary of evidence and recommendations for obstructive azoospermia

Summary of evidence LE
Obstructive lesions of the seminal tract are frequent in azoospermic or severely oligozoospermic 3
patients, usually with normal-sized testes and normal reproductive hormones.

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Recommendations Strength rating
Perform microsurgical vasovasostomy or epididymovasostomy for azoospermia caused by Strong
vasal or epididymal obstruction in men with female partners with good ovarian reserve.
Use sperm retrieval techniques, such as microsurgical epididymal sperm aspiration (MESA), Strong
testicular sperm extraction (TESE) and percutaneous techniques (PESA and TESA) either as
an adjunct to reconstructive surgery, or if the condition is not amenable to surgical repair, or
when the ovarian reserve of the partner is limited or patient preference is not to undertake
surgical reconstruction and the couple prefer to proceed to ICSI treatment directly.

11.6.2 Non-obstructive azoospermia

Non-obstructive azoospermia (NOA) is defined as the absence of sperm in the ejaculate after centrifugation.
Ejaculate volume is usually normal. Azoospermia should be confirmed by at least two consecutives semen
analyses [1555]. The severe deficit in spermatogenesis observed in NOA patients is often a consequence of
primary testicular dysfunction or may be related to a dysfunction of the hypothalamus-pituitary-gonadal (HPG)
axis.

11.6.2.1 Investigation of non-obstructive azoospermia

Clinical history-taking and clinical examination should follow the investigation and diagnostic evaluation
of infertile men (See Section 11.3). Non-obstructive azoospermia can be the first sign of pituitary or germ
cell tumours of the testis [1898-1900]. Patients with NOA have been shown to be at increased risk of long-
term chronic non-communicable diseases (e.g., cardio-metabolic diseases, cancer) and mortality [1901-1906].
Therefore, investigation of infertile men provides an opportunity for long-term risk stratification for other
comorbid conditions [1907]. A complete hormonal investigation and scrotal US are important in the diagnostic
work-up of NOA men [1908, 1909].

Concomitant hypogonadism, has been found in about 30% of patients with NOA [295, 1908, 1909]. Biochemical
evaluation should be performed to differentiate the types of hypogonadism (i.e., hypogonadotropic
hypogonadism vs. hypergonadotropic vs. compensated hypogonadism) as this will determine different
therapeutic strategies to treat the hypogonadal male [1910].

Scrotal US may show signs of testicular dysgenesis (e.g., non-homogeneous testicular architecture and/or
microcalcifications) and rare testicular tumours can be identified. Testicular volume may be a predictor of
spermatogenic function [1546] and is usually, but not invariably, low in patients with NOA. Some authors have
advocated that testicular perfusion detected at US Doppler assessment can predict surgical sperm retrieval at
TESE and guide testicular biopsies [1911]; however, to date, data are inconsistent to support a routine role of
testicular Doppler evaluation before TESE in order to predict sperm retrieval outcome.

As discussed (see Section 11.3), patients should undergo karyotype analysis [1805, 1806], along with a
screening of Y-chromosome micro-deletions [1631, 1912]. In patients with clinical suspicion of CBAVD
assessement of mutations in the gene coding for CFTR is also to be recommended [1618, 1619]. Genetic
counselling for eventual transmissible and health-relevant genetic conditions should be provided to couples.

11.6.2.2 Surgery for non-obstructive azoospermia

Surgical treatment for NOA is aimed at retrieval of vital sperm directly from the testes (either uni- or bilaterally).
This treatment is normally part of ART protocols, including IVF cycles via ICSI. Testicular biopsy before TESE is
not recommended.

11.6.2.3 Indications and techniques of sperm retrieval

Spermatogenesis within the testes may be focal, which means that spermatozoa can usually be found in small
and isolated foci. With a wide variability among cohorts and techniques, positive SRRs have been reported in up
to 50% of patients with NOA [1913, 1914]. Numerous predictive factors for positive SSR have been investigated
(see below), although no definitive factors have been demonstrated to predict SSR [1914].
• Histology: The presence of hypospermatogenesis at testicular biopsy showed good accuracy in predicting
positive sperm retrieval after TESE compared with maturation arrest pattern or SCOS [1915-1917].
• Hormonal levels: FSH, LH, inhibin B and AMH have been variably correlated with sperm retrieval outcomes,
but data from retrospective series are controversial [1583, 1864, 1918-1922].
• Testicular volume has been inconsistently found to be a predictor of positive SSR [1864, 1915, 1921].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 155

In case of complete AZFa and AZFb microdeletions, the likelihood of sperm retrieval is almost zero and
therefore TESE procedures are contraindicated [1636]. Conversely, patients with Klinefelter syndrome [1603]
and a history of undescended testes have been shown to have higher chance of finding sperm at surgery [1603,
1921, 1923, 1924]. Studies investigating the use of machine learning algorithms to predict sperm retrieval in
men with NOA are emerging and might prove a useful tool in the future [1582, 1925].

Fine needle aspiration mapping

Fine needle aspiration (FNA) mapping technique has been proposed as a prognostic procedure aimed to
select patients with NOA for TESE and ICSI [1926]. The retrieved tissue is sent for cytological and histological
evaluation to provide information on the presence of mature sperm and on testicular histological pattern. FNA
mapping may provide information on the sites with the higher probability of retrieving sperm, thus serving as a
guide for further sperm retrieval surgery in the context of ART procedures (e.g., ICSI). A positive FNA requires a
secondary therapeutic invasive surgical approach, which may increase the risk of testicular damage, and without
appropriate cost-benefit analysis, is not justifiable. No studies have evaluated the salvage rate of mTESE in men
who have undergone FNA mapping. Therefore, FNA mapping is not recommended as a primary therapeutic
procedure in men with NOA until further RCTs are undertaken.

Testicular sperm aspiration

Testicular sperm aspiration (TESA) is a minimally invasive, office-based, procedure in which testicular tissue is
retrieved with a biopsy needle under local anaesthesia. Reported SRRs with TESA range from 11 to 60% according
to patient profile and surgical techniques [1927-1930]. Complications after TESA are uncommon and mainly
include minor bleeding with scrotal haematoma and post-operative pain [1930]. A meta-analysis including data
from case-control studies, reported that TESE was two times (95% CI: 1.8-2.2) more likely to result in successful
SSR as compared with TESA [1914]. Given the low success rates compared with TESE, TESA is no longer
recommended in men with NOA.

Conventional and mTESE

Conventional TESE requires a scrotal incision and open biopsy of the testes [1931]. Reported SRRs in single-
arm studies are about 50% [1913]. Observational studies have demonstrated that multiple biopsies yield a
higher chance of sperm retrieval [1913, 1932]. Conventional TESE has been associated with a higher rate
of complications compared with other techniques [1913]. A total of 51.7% of patients have been found with
intratesticular haematoma at scrotal US 3 months after surgery, with testicular fibrosis observed in up to 30% of
patients at 6-months’ assessment [1933]. However, the functional clinical significance of this in the longer term
remains unclear.

mTESE is performed with an operative optical microscope to inspect seminiferous tubules at a magnification
of 20-25x and it allows to find and extract those tubules which were larger, dilated and opaque as these were
more likely to harbour sperm [1931]. The rationale of this technique is to increase the probability of retrieving
sperm with a lower amount of tissue sampled and a subsequent lower risk of complications. Lower rates of
complications have been observed with mTESE compared to cTESE, both in terms of haematoma and fibrosis
[1934]. Both procedures have shown a recovery of baseline testosterone levels after long-term follow-up [1935,
1936]. Therefore, it would be reasonable to provide long-term endocrinological follow-up after TESE (any type) to
detect hypogonadism.

A meta-analysis that pooled data of case-control studies comparing cTESE with mTESE showed a lower
unadjusted SRR of 35% (95% CI: 30-40) for TESE and 52% (95% CI: 47-58) for mTESE [1914]. A meta-analysis
comparing cTESE and mTESE in patients with NOA showed a mean overall SRR of 47% (95% CI: 45;49%).
No differences were observed when mTESE was compared with cTESE (46 [range 43-49] % for cTESE vs. 46
[range 42-49] % for mTESE, respectively) [1923]. Meta-regression analysis demonstrated that the SRR per cycle
was independent of age and hormonal parameters at enrolment. However, the SRR increased as a function of
testicular volume. Retrieved sperms resulted in a live-birth rate of up to 28% per ICSI cycle [1912]. The difference
in surgical sperm retrieval outcomes between the two meta-analyses may be explained by the data studied; one
analysed only case control studies [1914] whilst the other also included the single RCT [1912]; however, it is
important to note that all studies directly comparing cTESE and mTESE have shown that the latter is superior in
retrieving sperm.

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In this context, studies showed a higher chance of sperm retrieval with mTESE only for patients with a
histological diagnosis of SCOS [1934]. In such cases, results ranged from 22.5 to 41% and from 6.3 to 29% for
mTESE vs. cTESE, respectively [1934]. Conversely, no difference between the two techniques has been found
when comparing patients with a histology suggestive of maturation arrest [1934]. A single study showed a small
advantage of mTESE when hypospermatogenesis was found [1936].

In a study assessing the role of salvage mTESE after a previously failed cTESE or TESA, sperm were
successfully retrieved in 46.5% of cases [1937]. In studies reporting SSR by mTESE for men who had failed TESE
or cTESE the SRR was 39.1% (range 18.4-57.1%) [1938, 1939]. Hypospermatogenesis might be a predictor for
successful salvage mTESE after a failed cTESE, but this is based on retrospective studies with a limited number
of patients [1940]. Similarly, a variable SRR has been reported for salvage mTESE after a previously failed
mTESE (ranging from 18.4% to 42.8%) [1941, 1942].

A recent meta-analysis investigated the risk of hypogonadism after TESE due to testicular atrophy [1943];
patients with NOA experienced a mean 2.7 nmol/L decrease in total testosterone 6 months after cTESE, which
recovered to baseline within 18-26 months. Lower rates of complications have been observed with mTESE
compared to cTESE, both in terms of haematoma and fibrosis [1934]. Both procedures have shown a recovery of
baseline testosterone levels after long-term follow-up [1935, 1936].

To date only one RCT has investigated surgical sperm retrieval in 100 men with NOA, mTESE was compared to a
modified TESA using a large biopsy needle (18G) with multiple needle passes [1944]. The SRR was significantly
higher in mTESE compared to multiple needle pass TESA (43% vs. 22%; rate difference -0.21; 95% Cl -0.39 to –
0.03; p = 0.02). A salvage mTESE was offered to men who failed multiple needle-pass TESA and the combined
SRR from the two procedures was 29%. This was not significantly different from the SRR achieved by mTESE,
but the study was not powered for this comparison. Taken together this study shows that the SRR from mTESE
is superior to TESA.

Most available studies on surgical sperm retrieval in men with NOA are limited by their observational designs,
heterogeneity in NOA diagnostic criteria, surgical techniques, and reporting of outcomes. However, the main
limitation to contemporary literature is the paucity of randomised controlled studies comparing cTESE and
mTESE. Although no difference in SSR was observed between cTESE/mTESE techniques in patients with NOA
in the latest and most comprehensive meta-analysis [1923], it is important to note that in all the individual
trials comparing cTESE and mTESE the latter was superior in retrieving sperm. Furthermore, the current data
suggests that mTESE has less complications than cTESE and therefore the consensus opinion of the guidelines
panel is that mTESE is the optimum approach for surgical sperm retrieval procedures. However, this is based
on low-quality evidence and larger RCTs comparing SSR, risks and costs between the two techniques are
urgently needed. Such trials should report the specifics of the surgical technique, the procedure followed by the
embryologists, clinical outcomes including quantity and quality of retrieved sperm, and detailed ART outcomes
including live birth rates [1945].

Hormonal therapy prior to surgical sperm retrieval approaches

Stimulating spermatogenesis by optimising intratesticular testosterone (ITT) has been proposed to increase the
chance of SSR in men with NOA. Similarly, increasing FSH serum levels could stimulate spermatogenesis. To
this aim, several treatment options are available, thus including hCG and/or FSH [1859, 1946, 1947] or SERMs
[1948], but a standardized protocol is lacking.

No RCT has shown a benefit of hormonal treatment to enhance the chances of sperm retrieval among patients
with idiopathic NOA [1949]. A meta-analysis has suggested that hormone stimulation prior to TESE might
improve SRR in eugonadal but not in hypergonadotropic hypogonadal patients [1950]; however, the included
studies had moderate or severe risk of bias and randomised studies are needed to confirm these findings.

Hormonal therapy has also been proposed to increase the chance of sperm retrieval at salvage surgery after
previously failed cTESE or mTESE. Only small retrospective studies with conflicting results have been conducted
[1859, 1950-1952]. The histological finding of hypo-spermatogenesis emerged as a predictor of sperm retrieval
at salvage surgery after hormonal treatment [1952]. Patients should be counselled that the evidence for the role
of hormone stimulation prior to sperm retrieval surgery in men with idiopathic NOA is limited [1953]. Currently, it
is not recommended in routine practice.

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 157

11.6.2.4 Recommendations for Non-Obstructive Azoospermia

Summary of evidence LE
Patients with NOA are at increased risk of long-term cardio-metabolic diseases, cancer and mortality. 3
Hypogonadism is present in about one third of men with non-obstructive azoospermia (NOA), before 3
surgical for sperm retrieval.
Surgery for sperm retrieval is mandatory in NOA men before ART. 1b
Fine needle aspiration (FNA) and testicular sperm aspiration (TESA) have lower sperm retrieval rates 1b
compared to TESE in patients with NOA.
FNA requires a secondary therapeutic surgical approach, which may increase the risk of testicular 2a
damage, and without appropriate cost-benefit analysis it is not justifiable.
No definitive predictors of positive sperm retrieval before TESE have been identified. 1b
Microdissection TESE has been associated with higher rates of sperm retrieval and lower 2a
complications than conventional TESE.
No conclusive data are available regarding the benefit of use of medical therapy before TESE (e.g., 2a
recombinant follicle-stimulating hormone [rFSH]; highly purified FSH; human chorionic gonadotrophin;
aromatase inhibitors or selective oestrogen receptor modulators [SERMs]) in patients with NOA.

Recommendations Strength rating

Confirm a diagnosis of non-obstructive azoospermia (NOA) in two consecutive semen Strong
analyses, when no sperm are found after centrifugation.
Perform a comprehensive assessment, including detailed medical history, hormonal profile, Strong
genetic tests and scrotal ultrasound to investigate the underlying aetiology and associated
co-morbidity in patients with NOA.
Genetic counselling is mandatory in couples with genetic abnormalities prior to any assisted Strong
reproductive technology.
Perform surgery for sperm retrieval in men who are candidates for assisted reproductive Strong
technology (i.e., ICSI).
Do not perform surgery for sperm retrieval in patients with complete AZFa and AZFb Strong
microdeletions, since the chance of sperm retrieval is zero.
Do not perform fine needle aspiration (FNA) and testicular sperm aspiration (TESA) in Strong
patients with NOA.
Do not perform FNA mapping as a prognostic procedure prior to definitive testicular sperm Weak
extraction (any type) in patients with NOA.
Use microdissection TESE as the treatment of choice to retrieve sperm in patients with NOA. Weak
Do not consider pre-operative biochemical and clinical variables as sufficient and reliable Weak
predictors of sperm retrieval outcome at surgery in patients with NOA.
Do not routinely use medical therapy, e.g. hormonal stimulation in men with NOA and Weak
hypergonadotrophic hypogonadism before c/mTESE to improve sperm recovery.

11.7 Assisted Reproductive Technologies

Assisted reproductive technology consists of procedures that involve the in vitro handling of both human
oocytes and sperm, or of embryos, with the objective of establishing pregnancy. A limited summary of ARTs
including a discussion on safety can be found in Appendix 7 online supplementary evidence.

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11.8 Psychosocial aspects in men’s infertility
Male infertility impacts men’s psychological well-being resulting in emotional distress and challenges men’s
sense of identity. Is worth noting that a failed treatment often results in a prolonged grief response, requiring
post-treatment psychological support [1954]. The mental health expert is thus regarded as part of the infertility
intervention team, acting in all intervention stages, using strategies that may range from psycho-education
techniques to more comprehensive psycho-therapeutic approaches [1955]. Furthermore, there should be a
deeper focus on preventive policies; It has been recognised that men, such as women, want to become parents.
Yet, they have very limited knowledge on infertility related risk factors, including a lack of awareness on the age-
related decline in fertility, and tend to overestimate the chance of spontaneous conception [1956, 1957].

12. LATE EFFECTS, SURVIVORSHIP AND

MEN’S HEALTH
The EAU Guidelines Panel of Sexual and Reproductive Health have extensively reviewed the literature to provide
guidance on: (i) late effects of urological diseases (both occurring during childhood and adulthood) on male
sexual and reproductive health; (ii) late and long-term effects of cancers on male sexual and reproductive health;
and, (iii) future directions to support personalised medicine strategies for promotion and raising the awareness
of male sexual and reproductive health overall.

A systematic literature search for original English-language publications and review articles published up to
December 2019 and a further search up to December 2020 were performed using both Pubmed and Google,
yielding only a limited number of papers addressing the role of health care professionals in supporting male
patients who have suffered from cancers in terms of sexual and reproductive health, or the concept of Men’s
Health programmes.

Despite considerable public health initiatives over the past few decades, the Panel has observed that there is
still a significant gender gap between male and female in life expectancy [1958]. The main contributors to male
mortality in Europe are non-communicable diseases (namely CVDs), cancer, diabetes and respiratory disease)
and injuries [1679], as highlighted in a recent WHO report disproving the prevailing misconception that the higher
rate of premature mortality among men is a natural phenomenon [1958, 1959]. The recent pandemic situation
linked with SARS-CoV-2 infection associated diseased (COVID-19) further demonstrates how the development
of strategies dedicated to male health is of fundamental importance [1960].

The WHO report also addresses male sexual and reproductive health which is considered under-reported, linking
in particular male infertility, as a proxy for overall health, to serious diseases in men [1902, 1903, 1961-1964].
These data suggest that health care policies should redirect their focus to preventive strategies and in particular
pay attention to follow-up of men with sexual and reproductive complaints [1905, 1965]. [1965]. Considering
that infertile men seem to be at greater risk of death, simply because of their inability to become fathers, is
unacceptable [1906]. The Panel aims to develop a concept of a more streamlined and holistic approach to men’s
health.

For these guidelines, the Panel aimed to challenge clinicians to look beyond the pathology of disorders alone
and consider the potential associations with other health disorders. Men with varicoceles have a higher
incidence of heart disease and higher risk of diabetes and hyperlipidaemia following diagnosis [1965]. A
diagnosis of infertility may have a profound psychological impact on men (and their partners), potentially
resulting in anxiety, enduring sadness, anger, and a sense of personal inadequacy and “unmet masculinity”
[1966]. A combination of factors, personality, sociocultural background, and specific treatments/professional
support, will determine how men cope with this diagnosis [1955].

The most common cancer among European men (excluding non-melanoma skin cancer) is PCa [1967]. Due to
new therapeutic approaches, survival rates have improved significantly [1968] and as men live longer, health-
related quality of life and related sexual well-being will become increasingly important [295]. Regardless of the
type of treatment used [1692], sexual dysfunction and distress are common post-treatment complications [296,
1969-1971].

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 159

Furthermore, little is known about the relevance of fertility and fertility-preservation strategies in cancer
survivors [1972-1976]. In PCa, it has been documented that the psychological consequences persist, even after
complete remission or cure and erectile function is restored [1977]. In addition, special attention must be given
to gay and bisexual men with PCa; these men present specific sexual concerns steaming from heteronormativity
standards that have a negative impact in health care quality [1978]. Therefore, urologists dealing with sexual and
reproductive health are primed to act as a vanguard for cancer survivorship programmes.

Finally, the relationship between ED and heart disease has been firmly established for well over two decades
[1979-1985]. Cadiovascular disease is the leading cause of both male mortality and premature mortality
[1986-1989]. Studies indicate that all major risk factors for CVD, including hypertension, smoking and elevated
cholesterol are more prevalent in men than women [1990-1996]. Given that ED is an established early sign
of atherosclerotic disease and predicts cardiovascular events as an independent factor [1981], it provides
urologists with the unique opportunity for CVD screening and health modification and optimise CVD risk factors,
while treating men’s primary complaint (e.g., ED). Currently, both the EAU and AUA guidelines recommend
screening for CVD risk factors in men with ED and late onset hypogonadism [1997-1999] (see Sections 3.5.5 and
5.2).

There is clearly a need to prospectively collect data addressing all aspects of male health, including CVD
screening protocols and assess the impact of primary and secondary preventive strategies. The EAU Sexual and
Reproductive Health Guidelines Panel aims to promote and develop a long-term strategy to raise men’s health at
a global level.

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13. REFERENCES
1. Phillips, B. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by Jeremy
Howick March 2009. 1998.
https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-
medicine-levels-of-evidence-march-2009
2. Guyatt, G.H., et al. Going from evidence to recommendations. BMJ, 2008. 336: 1049.
https://www.ncbi.nlm.nih.gov/pubmed/18467413
3. Salonia, A., et al. Paediatric and adult-onset male hypogonadism. Nat Rev Dis Primers, 2019. 5: 38.
https://www.ncbi.nlm.nih.gov/pubmed/31147553
4. Nieschlag, E., et al., Andrology: male reproductive health and dysfunction. 3rd edn. 2010, Heidelberg.
5. Wu, F.C., et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked
to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab, 2008.
93: 2737.
https://www.ncbi.nlm.nih.gov/pubmed/18270261
6. Araujo, A.B., et al. Clinical review: Endogenous testosterone and mortality in men: a systematic
review and meta-analysis. J Clin Endocrinol Metab, 2011. 96: 3007.
https://www.ncbi.nlm.nih.gov/pubmed/21816776
7. Haring, R., et al. Low serum testosterone levels are associated with increased risk of mortality in a
population-based cohort of men aged 20-79. Eur Heart J, 2010. 31: 1494.
https://www.ncbi.nlm.nih.gov/pubmed/20164245
8. Wu, F.C., et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J
Med, 2010. 363: 123.
https://www.ncbi.nlm.nih.gov/pubmed/20554979
9. Zarotsky, V., et al. Systematic literature review of the risk factors, comorbidities, and consequences
of hypogonadism in men. Andrology, 2014. 2: 819.
https://www.ncbi.nlm.nih.gov/pubmed/25269643
10. Ding, E.L., et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a
systematic review and meta-analysis. JAMA, 2006. 295: 1288.
https://www.ncbi.nlm.nih.gov/pubmed/16537739
11. Corona, G., et al. Testosterone therapy in diabetes and pre-diabetes. Andrology, 2023. 11: 204.
https://www.ncbi.nlm.nih.gov/pubmed/36542412
12. Bonomi, M., et al. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J
Endocrinol Invest, 2017. 40: 123.
https://www.ncbi.nlm.nih.gov/pubmed/27644703
13. Kanakis, G.A., et al. Klinefelter syndrome: more than hypogonadism. Metabolism, 2018. 86: 135.
https://www.ncbi.nlm.nih.gov/pubmed/29382506
14. Aksglaede, L., et al. 47,XXY Klinefelter syndrome: clinical characteristics and age-specific
recommendations for medical management. Am J Med Genet C Semin Med Genet, 2013. 163C: 55.
https://www.ncbi.nlm.nih.gov/pubmed/23345262
15. Pizzocaro, A., et al. Testosterone treatment in male patients with Klinefelter syndrome: a systematic
review and meta-analysis. J Endocrinol Invest, 2020. 43: 1675.
https://www.ncbi.nlm.nih.gov/pubmed/32567016
16. Bojesen, A., et al. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry
study. J Clin Endocrinol Metab, 2003. 88: 622.
https://www.ncbi.nlm.nih.gov/pubmed/12574191
17. Santi, D., et al., Primary and Secondary Hypogonadism, in Endocrinology of the Testis and Male
Reproduction 2017, Springer International Publishing: Cham.
18. Giannetta, E., et al. Subclinical male hypogonadism. Best Pract Res Clin Endocrinol Metab, 2012. 26:
539.
https://www.ncbi.nlm.nih.gov/pubmed/22863395
19. Tajar, A., et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men:
evidence from the European Male Ageing Study. J Clin Endocrinol Metab, 2010. 95: 1810.
https://www.ncbi.nlm.nih.gov/pubmed/20173018
20. Corona, G., et al. Subclinical male hypogonadism. Minerva Endocrinol (Torino), 2021. 46: 252.
https://www.ncbi.nlm.nih.gov/pubmed/32969626
21. Isidori, A.M., et al. Adult- and late-onset male hypogonadism: the clinical practice guidelines of the
Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology
(SIE). J Endocrinol Invest, 2022. 45: 2385.
https://www.ncbi.nlm.nih.gov/pubmed/36018454

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 161

22. Rastrelli, G., et al. Pharmacotherapy of male hypogonadism. Curr Opin Pharmacol, 2023. 68: 102323.
https://www.ncbi.nlm.nih.gov/pubmed/36525815
23. Giagulli, V.A., et al. Critical evaluation of different available guidelines for late-onset hypogonadism.
Andrology, 2020. 8: 1628.
https://www.ncbi.nlm.nih.gov/pubmed/32593233
24. Morelli, A., et al. Which patients with sexual dysfunction are suitable for testosterone replacement
therapy? J Endocrinol Invest, 2007. 30: 880.
https://www.ncbi.nlm.nih.gov/pubmed/18075293
25. Kelly, D.M., et al. Testosterone and obesity. Obes Rev, 2015. 16: 581.
https://www.ncbi.nlm.nih.gov/pubmed/25982085
26. Wittert, G., et al. Obesity, type 2 diabetes, and testosterone in ageing men. Rev Endocr Metab Disord,
2022. 23: 1233.
https://www.ncbi.nlm.nih.gov/pubmed/35834069
27. Ken-Dror, G., et al. Meta-analysis and construction of simple-to-use nomograms for approximating
testosterone levels gained from weight loss in obese men. Andrology, 2024. 12: 297.
https://www.ncbi.nlm.nih.gov/pubmed/37345263
28. Muller, M., et al. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol
Metab, 2005. 90: 2618.
https://www.ncbi.nlm.nih.gov/pubmed/15687322
29. Dhindsa, S., et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin
Endocrinol Metab, 2004. 89: 5462.
https://www.ncbi.nlm.nih.gov/pubmed/15531498
30. Jones, T.H., et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or
metabolic syndrome (the TIMES2 study). Diabetes Care, 2011. 34: 828.
https://www.ncbi.nlm.nih.gov/pubmed/21386088
31. Kalinchenko, S.Y., et al. Effects of testosterone supplementation on markers of the metabolic
syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded
placebo-controlled Moscow study. Clin Endocrinol (Oxf), 2010. 73: 602.
https://www.ncbi.nlm.nih.gov/pubmed/20718771
32. Groti, K., et al. The impact of testosterone replacement therapy on glycemic control, vascular
function, and components of the metabolic syndrome in obese hypogonadal men with type 2
diabetes. Aging Male, 2018. 21: 158.
https://www.ncbi.nlm.nih.gov/pubmed/29708829
33. Hackett, G., et al. Testosterone replacement therapy improves metabolic parameters in hypogonadal
men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med,
2014. 11: 840.
https://www.ncbi.nlm.nih.gov/pubmed/24308723
34. Wittert, G., et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a
lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.
Lancet Diabetes Endocrinol, 2021. 9: 32.
https://www.ncbi.nlm.nih.gov/pubmed/33338415
35. Yassin, A., et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From
Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care, 2019. 42:
1104.
https://www.ncbi.nlm.nih.gov/pubmed/30862651
36. Kapoor, D., et al. Testosterone replacement therapy improves insulin resistance, glycaemic control,
visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J
Endocrinol, 2006. 154: 899.
https://www.ncbi.nlm.nih.gov/pubmed/16728551
37. Hackett, G., et al. Long-term testosterone therapy in type 2 diabetes is associated with reduced
mortality without improvement in conventional cardiovascular risk factors. BJU Int, 2019. 123: 519.
https://www.ncbi.nlm.nih.gov/pubmed/30216622
38. Muraleedharan, V., et al. Testosterone deficiency is associated with increased risk of mortality and
testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol, 2013. 169:
725.
https://www.ncbi.nlm.nih.gov/pubmed/23999642
39. Hackett, G., et al. Testosterone undecanoate improves sexual function in men with type 2 diabetes
and severe hypogonadism: results from a 30-week randomized placebo-controlled study. BJU Int,
2016. 118: 804.
https://www.ncbi.nlm.nih.gov/pubmed/27124889

162 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

40. Corona, G., et al. The Role of testosterone treatment in patients with metabolic disorders. Expert Rev
Clin Pharmacol, 2021. 14: 1091.
https://www.ncbi.nlm.nih.gov/pubmed/34085587
41. Corona, G., et al. THERAPY OF ENDOCRINE DISEASE: Testosterone supplementation and body
composition: results from a meta-analysis study. Eur J Endocrinol, 2016. 174: R99.
https://www.ncbi.nlm.nih.gov/pubmed/26537862
42. Saad, F., et al. Differential effects of 11 years of long-term injectable testosterone undecanoate
therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight,
overweight and obesity in comparison with untreated controls: real-world data from a controlled
registry study. Int J Obes (Lond), 2020. 44: 1264.
https://www.ncbi.nlm.nih.gov/pubmed/32060355
43. Rastrelli, G., et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2
pneumonia patients. Andrology, 2021. 9: 88.
https://www.ncbi.nlm.nih.gov/pubmed/32436355
44. Salciccia, S., et al. Interplay between male testosterone levels and the risk for subsequent invasive
respiratory assistance among COVID-19 patients at hospital admission. Endocrine, 2020. 70: 206.
https://www.ncbi.nlm.nih.gov/pubmed/33030665
45. Cinislioglu, A.E., et al. The relationship of serum testosterone levels with the clinical course and
prognosis of COVID-19 disease in male patients: A prospective study. Andrology, 2022. 10: 24.
https://www.ncbi.nlm.nih.gov/pubmed/34288536
46. Kadihasanoglu, M., et al. SARS-CoV-2 Pneumonia Affects Male Reproductive Hormone Levels: A
Prospective, Cohort Study. J Sex Med, 2021. 18: 256.
https://www.ncbi.nlm.nih.gov/pubmed/33468445
47. Salonia, A., et al. Severely low testosterone in males with COVID-19: A case-control study. Andrology,
2021. 9: 1043.
https://www.ncbi.nlm.nih.gov/pubmed/33635589
48. Dhindsa, S., et al. Association of Circulating Sex Hormones With Inflammation and Disease Severity
in Patients With COVID-19. JAMA Netw Open, 2021. 4: e2111398.
https://www.ncbi.nlm.nih.gov/pubmed/34032853
49. Lanser, L., et al. Testosterone Deficiency Is a Risk Factor for Severe COVID-19. Front Endocrinol
(Lausanne), 2021. 12: 694083.
https://www.ncbi.nlm.nih.gov/pubmed/34226825
50. Nie, X., et al. Multi-organ proteomic landscape of COVID-19 autopsies. Cell, 2021. 184: 775.
https://www.ncbi.nlm.nih.gov/pubmed/33503446
51. Dhindsa, S., et al. Association of Male Hypogonadism With Risk of Hospitalization for COVID-19.
JAMA Netw Open, 2022. 5: e2229747.
https://www.ncbi.nlm.nih.gov/pubmed/36053534
52. Corona, G., et al. Andrological effects of SARS-Cov-2 infection: a systematic review and meta-
analysis. J Endocrinol Invest, 2022. 45: 2207.
https://www.ncbi.nlm.nih.gov/pubmed/35527294
53. Turner, H.E., et al. Gonadal function in men with chronic illness. Clin Endocrinol (Oxf), 1997. 47: 379.
https://www.ncbi.nlm.nih.gov/pubmed/9404435
54. Corona, G., et al. Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or
merely an epiphenomenon caused by accumulating disease-burden? Minerva Endocrinol, 2016. 41:
196.
https://www.ncbi.nlm.nih.gov/pubmed/26883937
55. Temiz, M.Z., et al. Investigation of SARS-CoV-2 in semen samples and the effects of COVID-19 on
male sexual health by using semen analysis and serum male hormone profile: A cross-sectional, pilot
study. Andrologia, 2021. 53: e13912.
https://www.ncbi.nlm.nih.gov/pubmed/33244788
56. Salonia, A., et al. Testosterone in males with COVID-19: a 12-month cohort study. Andrology, 2023.
11: 17.
https://www.ncbi.nlm.nih.gov/pubmed/36251583
57. Salonia, A., et al. Testosterone in males with COVID-19: A 7-month cohort study. Andrology, 2022. 10:
34.
https://www.ncbi.nlm.nih.gov/pubmed/34409772
58. Mohr, B.A., et al. Normal, bound and nonbound testosterone levels in normally ageing men: results
from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf), 2005. 62: 64.
https://www.ncbi.nlm.nih.gov/pubmed/15638872

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 163

59. Grossmann, M., et al. A Perspective on Middle-Aged and Older Men With Functional Hypogonadism:
Focus on Holistic Management. J Clin Endocrinol Metab, 2017. 102: 1067.
https://www.ncbi.nlm.nih.gov/pubmed/28359097
60. Millar, A.C., et al. Predicting low testosterone in aging men: a systematic review. CMAJ, 2016. 188:
E321.
https://www.ncbi.nlm.nih.gov/pubmed/27325129
61. Cayan, S., et al. Effect of serum total testosterone and its relationship with other laboratory
parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male
patients: a cohort study. Aging Male, 2020. 23: 1493.
https://www.ncbi.nlm.nih.gov/pubmed/32883151
62. Rastrelli, G., et al. Testosterone and Benign Prostatic Hyperplasia. Sex Med Rev, 2019. 7: 259.
https://www.ncbi.nlm.nih.gov/pubmed/30803920
63. Guay, A., et al. Does early morning versus late morning draw time influence apparent testosterone
concentration in men aged > or =45 years? Data from the Hypogonadism In Males study. Int J Impot
Res, 2008. 20: 162.
https://www.ncbi.nlm.nih.gov/pubmed/17637790
64. Travison, T.G., et al. Harmonized Reference Ranges for Circulating Testosterone Levels in Men of
Four Cohort Studies in the United States and Europe. J Clin Endocrinol Metab, 2017. 102: 1161.
https://www.ncbi.nlm.nih.gov/pubmed/28324103
65. Gagliano-Juca, T., et al. Oral glucose load and mixed meal feeding lowers testosterone levels in
healthy eugonadal men. Endocrine, 2019. 63: 149.
https://www.ncbi.nlm.nih.gov/pubmed/30191441
66. Huhtaniemi, I.T., et al. Comparison of serum testosterone and estradiol measurements in 3174
European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in
aging men. Eur J Endocrinol, 2012. 166: 983.
https://www.ncbi.nlm.nih.gov/pubmed/22423144
67. Rosner, W., et al. Toward excellence in testosterone testing: a consensus statement. J Clin Endocrinol
Metab, 2010. 95: 4542.
https://www.ncbi.nlm.nih.gov/pubmed/20926540
68. Fiers, T., et al. Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass
Spectrometry Direct Equilibrium Dialysis. J Clin Endocrinol Metab, 2018. 103: 2167.
https://www.ncbi.nlm.nih.gov/pubmed/29618085
69. Vermeulen, A., et al. A critical evaluation of simple methods for the estimation of free testosterone in
serum. J Clin Endocrinol Metab, 1999. 84: 3666.
https://www.ncbi.nlm.nih.gov/pubmed/10523012
70. Corona, G., et al. Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on
International Index of Erectile Function Scores. Eur Urol, 2017. 72: 1000.
https://www.ncbi.nlm.nih.gov/pubmed/28434676
71. Boeri, L., et al. Does Calculated Free Testosterone Overcome Total Testosterone in Protecting From
Sexual Symptom Impairment? Findings of a Cross-Sectional Study. J Sex Med, 2017. 14: 1549.
https://www.ncbi.nlm.nih.gov/pubmed/29198510
72. Antonio, L., et al. Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in
Men with Normal Total Testosterone. J Clin Endocrinol Metab, 2016. 101: 2647.
https://www.ncbi.nlm.nih.gov/pubmed/26909800
73. Rastrelli, G., et al. Symptomatic androgen deficiency develops only when both total and free
testosterone decline in obese men who may have incident biochemical secondary hypogonadism:
Prospective results from the EMAS. Clin Endocrinol (Oxf), 2018. 89: 459.
https://www.ncbi.nlm.nih.gov/pubmed/29855071
74. Ferlin, A., et al. Management of male factor infertility: position statement from the Italian Society
of Andrology and Sexual Medicine (SIAMS) : Endorsing Organization: Italian Society of Embryology,
Reproduction, and Research (SIERR). J Endocrinol Invest, 2022. 45: 1085.
https://www.ncbi.nlm.nih.gov/pubmed/35075609
75. Dalvi, M., et al. The prevalence of structural pituitary abnormalities by MRI scanning in men
presenting with isolated hypogonadotrophic hypogonadism. Clin Endocrinol (Oxf), 2016. 84: 858.
https://www.ncbi.nlm.nih.gov/pubmed/26733239
76. Molitch, M.E. Diagnosis and Treatment of Pituitary Adenomas: A Review. JAMA, 2017. 317: 516.
https://www.ncbi.nlm.nih.gov/pubmed/28170483

164 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

77. Cipriani, S., et al. Biochemical predictors of structural hypothalamus-pituitary abnormalities detected
by magnetic resonance imaging in men with secondary hypogonadism. J Endocrinol Invest, 2021. 44:
2785.
https://www.ncbi.nlm.nih.gov/pubmed/33970435
78. Lincoff, A.M., et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med, 2023.
389: 107.
https://www.ncbi.nlm.nih.gov/pubmed/37326322
79. Corona, G., et al. Testosterone treatment and cardiovascular and venous thromboembolism risk:
what is 'new'? J Investig Med, 2017. 65: 964.
https://www.ncbi.nlm.nih.gov/pubmed/28495861
80. Champigneulle, B., et al. Are coagulation profiles in Andean highlanders with excessive erythrocytosis
favouring hypercoagulability? Exp Physiol, 2024. 109: 899.
https://www.ncbi.nlm.nih.gov/pubmed/38554124
81. Gagnon, D.R., et al. Hematocrit and the risk of cardiovascular disease--the Framingham study: a
34-year follow-up. Am Heart J, 1994. 127: 674.
https://www.ncbi.nlm.nih.gov/pubmed/8122618
82. Corona, G., et al. Consequences of Anabolic-Androgenic Steroid Abuse in Males; Sexual and
Reproductive Perspective. World J Mens Health, 2022. 40: 165.
https://www.ncbi.nlm.nih.gov/pubmed/34169679
83. Colpi, G.M., et al. European Academy of Andrology guideline Management of oligo-astheno-
teratozoospermia. Andrology, 2018. 6: 513.
https://www.ncbi.nlm.nih.gov/pubmed/30134082
84. Corona, G., et al. The pharmacotherapy of male hypogonadism besides androgens. Expert Opin
Pharmacother, 2015. 16: 369.
https://www.ncbi.nlm.nih.gov/pubmed/25523084
85. Mirone, V., et al. European Association of Urology Position Statement on the Role of the Urologist in
the Management of Male Hypogonadism and Testosterone Therapy. Eur Urol, 2017. 72: 164.
https://www.ncbi.nlm.nih.gov/pubmed/28249799
86. Nieschlag, E. Late-onset hypogonadism: a concept comes of age. Andrology, 2020. 8: 1506.
https://www.ncbi.nlm.nih.gov/pubmed/31639279
87. Isidori, A.M., et al. A critical analysis of the role of testosterone in erectile function: from
pathophysiology to treatment-a systematic review. Eur Urol, 2014. 65: 99.
https://www.ncbi.nlm.nih.gov/pubmed/24050791
88. Huo, S., et al. Treatment of Men for "Low Testosterone": A Systematic Review. PLoS One, 2016. 11:
e0162480.
https://www.ncbi.nlm.nih.gov/pubmed/27655114
89. Rastrelli, G., et al. Testosterone Replacement Therapy for Sexual Symptoms. Sex Med Rev, 2019. 7:
464.
https://www.ncbi.nlm.nih.gov/pubmed/30803919
90. Elliott, J., et al. Testosterone therapy in hypogonadal men: a systematic review and network meta-
analysis. BMJ Open, 2017. 7: e015284.
https://www.ncbi.nlm.nih.gov/pubmed/29150464
91. Corona, G., et al. Androgens and male sexual function. Best Pract Res Clin Endocrinol Metab, 2022.
36: 101615.
https://www.ncbi.nlm.nih.gov/pubmed/35153145
92. Pencina, K.M., et al. Effect of Testosterone Replacement Therapy on Sexual Function and
Hypogonadal Symptoms in Men with Hypogonadism. J Clin Endocrinol Metab, 2024. 109: 569.
https://www.ncbi.nlm.nih.gov/pubmed/37589949
93. Corona, G., et al. The role of testosterone in male sexual function. Rev Endocr Metab Disord, 2022.
23: 1159.
https://www.ncbi.nlm.nih.gov/pubmed/35999483
94. Zhu, J., et al. Do testosterone supplements enhance response to phosphodiesterase 5 inhibitors in
men with erectile dysfunction and hypogonadism: a systematic review and meta-analysis. Transl
Androl Urol, 2020. 9: 591.
https://www.ncbi.nlm.nih.gov/pubmed/32420164
95. Snyder, P.J., et al. Lessons From the Testosterone Trials. Endocr Rev, 2018. 39: 369.
https://www.ncbi.nlm.nih.gov/pubmed/29522088
96. Cunningham, G.R., et al. Testosterone Treatment and Sexual Function in Older Men With Low
Testosterone Levels. J Clin Endocrinol Metab, 2016. 101: 3096.
https://www.ncbi.nlm.nih.gov/pubmed/27355400

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 165

97. Nieschlag, E., et al. MECHANISMS IN ENDOCRINOLOGY: Medical consequences of doping with
anabolic androgenic steroids: effects on reproductive functions. Eur J Endocrinol, 2015. 173: R47.
https://www.ncbi.nlm.nih.gov/pubmed/25805894
98. Steeves, J.A., et al. Cross-sectional association between physical activity and serum testosterone
levels in US men: results from NHANES 1999-2004. Andrology, 2016. 4: 465.
https://www.ncbi.nlm.nih.gov/pubmed/26991734
99. Lee, T.W., et al. Effects of Testosterone Replacement Therapy on Muscle Strength in Older Men with
Low to Low-Normal Testosterone Levels: A Systematic Review and Meta-Analysis. Gerontology,
2023. 69: 1157.
https://www.ncbi.nlm.nih.gov/pubmed/37494893
100. Rosen, R.C., et al. Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment:
Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med, 2017. 14:
1104.
https://www.ncbi.nlm.nih.gov/pubmed/28781213
101. Smith, J.B., et al. Low Serum Testosterone in Outpatient Psychiatry Clinics: Addressing Challenges to
the Screening and Treatment of Hypogonadism. Sex Med Rev, 2018. 6: 69.
https://www.ncbi.nlm.nih.gov/pubmed/29128270
102. Walther, A., et al. Association of Testosterone Treatment With Alleviation of Depressive Symptoms in
Men: A Systematic Review and Meta-analysis. JAMA Psychiatry, 2019. 76: 31.
https://www.ncbi.nlm.nih.gov/pubmed/30427999
103. Bhasin, S., et al. Depressive Syndromes in Men With Hypogonadism in the TRAVERSE Trial: Response
to Testosterone-Replacement Therapy. J Clin Endocrinol Metab, 2024. 109: 1814.
https://www.ncbi.nlm.nih.gov/pubmed/38205962
104. Nian, Y., et al. Testosterone replacement therapy improves health-related quality of life for patients
with late-onset hypogonadism: a meta-analysis of randomized controlled trials. Andrologia, 2017. 49.
https://www.ncbi.nlm.nih.gov/pubmed/27389320
105. Corona, G., et al. Testosterone Deficiency and Risk of Cognitive Disorders in Aging Males. World J
Mens Health, 2021. 39: 9.
https://www.ncbi.nlm.nih.gov/pubmed/32378366
106. Isidori, A.M., et al. Outcomes of androgen replacement therapy in adult male hypogonadism:
recommendations from the Italian society of endocrinology. J Endocrinol Invest, 2015. 38: 103.
https://www.ncbi.nlm.nih.gov/pubmed/25384570
107. Corona, G., et al. Testosterone supplementation and body composition: results from a meta-analysis
of observational studies. J Endocrinol Invest, 2016. 39: 967.
https://www.ncbi.nlm.nih.gov/pubmed/27241317
108. Traish, A.M. Testosterone and weight loss: the evidence. Curr Opin Endocrinol Diabetes Obes, 2014.
21: 313.
https://www.ncbi.nlm.nih.gov/pubmed/25105998
109. Saad, F., et al. Effects of long-term treatment with testosterone on weight and waist size in 411
hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes
(Lond), 2016. 40: 162.
https://www.ncbi.nlm.nih.gov/pubmed/26219417
110. Bhasin, S., et al. Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With
Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial. JAMA Intern Med, 2024.
184: 353.
https://www.ncbi.nlm.nih.gov/pubmed/38315466
111. Rochira, V., et al. EAA clinical guideline on management of bone health in the andrological outpatient
clinic. Andrology, 2018. 6: 272.
https://www.ncbi.nlm.nih.gov/pubmed/29499097
112. Isidori, A.M., et al. Effects of testosterone on body composition, bone metabolism and serum lipid
profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf), 2005. 63: 280.
https://www.ncbi.nlm.nih.gov/pubmed/16117815
113. Tracz, M.J., et al. Testosterone use in men and its effects on bone health. A systematic review and
meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab, 2006. 91: 2011.
https://www.ncbi.nlm.nih.gov/pubmed/16720668
114. Corona, G., et al. Testosterone supplementation and bone parameters: a systematic review and meta-
analysis study. J Endocrinol Invest, 2022. 45: 911.
https://www.ncbi.nlm.nih.gov/pubmed/35041193

166 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

115. Fan, Y., et al. Diabetes mellitus and risk of hip fractures: a meta-analysis. Osteoporos Int, 2016. 27:
219.
https://www.ncbi.nlm.nih.gov/pubmed/26264604
116. Wang, J., et al. Increased risk of vertebral fracture in patients with diabetes: a meta-analysis of cohort
studies. Int Orthop, 2016. 40: 1299.
https://www.ncbi.nlm.nih.gov/pubmed/27029481
117. Ng Tang Fui, M., et al. Effect of Testosterone Treatment on Bone Microarchitecture and Bone Mineral
Density in Men: A 2-Year RCT. J Clin Endocrinol Metab, 2021. 106: e3143.
https://www.ncbi.nlm.nih.gov/pubmed/33693907
118. Snyder, P.J., et al. Testosterone Treatment and Fractures in Men with Hypogonadism. N Engl J Med,
2024. 390: 203.
https://www.ncbi.nlm.nih.gov/pubmed/38231621
119. Grossmann, M. Hypogonadism and male obesity: Focus on unresolved questions. Clin Endocrinol
(Oxf), 2018. 89: 11.
https://www.ncbi.nlm.nih.gov/pubmed/29683196
120. Corona, G., et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a
systematic review and meta-analysis. Eur J Endocrinol, 2013. 168: 829.
https://www.ncbi.nlm.nih.gov/pubmed/23482592
121. Corona, G., et al. Treatment of Functional Hypogonadism Besides Pharmacological Substitution.
World J Mens Health, 2020. 38: 256.
https://www.ncbi.nlm.nih.gov/pubmed/31496147
122. Pasquali R, et al. ESE Clinical Practice Guideline on Endocrine Work-up in Obesity. Eur J Endocrinol
2019.
https://academic.oup.com/ejendo/article/182/1/G1/6653910
123. Rastrelli, G., et al. Pharmacological management of late-onset hypogonadism. Expert Rev Clin
Pharmacol, 2018. 11: 439.
https://www.ncbi.nlm.nih.gov/pubmed/29505313
124. Miller, J.A., et al. Oral testosterone therapy: past, present, and future. Sex Med Rev, 2023. 11: 124.
https://www.ncbi.nlm.nih.gov/pubmed/36779549
125. Ohlander, S.J., et al. Erythrocytosis Following Testosterone Therapy. Sex Med Rev, 2018. 6: 77.
https://www.ncbi.nlm.nih.gov/pubmed/28526632
126. Rastrelli, G., et al. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a
meta-analytic study. Andrology, 2014. 2: 794.
https://www.ncbi.nlm.nih.gov/pubmed/25271205
127. Rogol, A.D., et al. Natesto , a novel testosterone nasal gel, normalizes androgen levels in hypogonadal
men. Andrology, 2016. 4: 46.
https://www.ncbi.nlm.nih.gov/pubmed/26695758
128. Awouters, M., et al. Aromatase inhibitors and selective estrogen receptor modulators:
Unconventional therapies for functional hypogonadism? Andrology, 2020. 8: 1590.
https://www.ncbi.nlm.nih.gov/pubmed/31696669
129. Rambhatla, A., et al. The Role of Estrogen Modulators in Male Hypogonadism and Infertility. Rev Urol,
2016. 18: 66.
https://www.ncbi.nlm.nih.gov/pubmed/27601965
130. Fentiman, I.S. The endocrinology of male breast cancer. Endocr Relat Cancer, 2018. 25: R365.
https://www.ncbi.nlm.nih.gov/pubmed/29752333
131. Okada, K., et al. Improved Lower Urinary Tract Symptoms Associated With Testosterone
Replacement Therapy in Japanese Men With Late-Onset Hypogonadism. Am J Mens Health, 2018.
12: 1403.
https://www.ncbi.nlm.nih.gov/pubmed/27256990
132. Rastrelli, G., et al. Testosterone does not affect lower urinary tract symptoms while improving
markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial. J
Endocrinol Invest, 2022. 45: 1413.
https://www.ncbi.nlm.nih.gov/pubmed/35298833
133. Permpongkosol, S., et al. Effects of 8-Year Treatment of Long-Acting Testosterone Undecanoate on
Metabolic Parameters, Urinary Symptoms, Bone Mineral Density, and Sexual Function in Men With
Late-Onset Hypogonadism. J Sex Med, 2016. 13: 1199.
https://www.ncbi.nlm.nih.gov/pubmed/27436076

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 167

134. Debruyne, F.M., et al. Testosterone treatment is not associated with increased risk of prostate
cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of
Hypogonadism in Men. BJU Int, 2017. 119: 216.
https://www.ncbi.nlm.nih.gov/pubmed/27409523
135. Rastrelli, G., et al. Predictors and clinical consequences of starting androgen therapy in men with low
testosterone: results from the SIAMO-NOI registry. J Endocrinol Invest, 2016. 39: 695.
https://www.ncbi.nlm.nih.gov/pubmed/27037688
136. Calof, O.M., et al. Adverse events associated with testosterone replacement in middle-aged and older
men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci, 2005.
60: 1451.
https://www.ncbi.nlm.nih.gov/pubmed/16339333
137. Boyle, P., et al. Endogenous and exogenous testosterone and the risk of prostate cancer and
increased prostate-specific antigen (PSA) level: a meta-analysis. BJU Int, 2016. 118: 731.
https://www.ncbi.nlm.nih.gov/pubmed/26779889
138. Cui, Y., et al. The effect of androgen-replacement therapy on prostate growth: a systematic review
and meta-analysis. Eur Urol, 2013. 64: 811.
https://www.ncbi.nlm.nih.gov/pubmed/23567065
139. Cui, Y., et al. The effect of testosterone replacement therapy on prostate cancer: a systematic review
and meta-analysis. Prostate Cancer Prostatic Dis, 2014. 17: 132.
https://www.ncbi.nlm.nih.gov/pubmed/24445948
140. Fernandez-Balsells, M.M., et al. Clinical review 1: Adverse effects of testosterone therapy in adult
men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 2010. 95: 2560.
https://www.ncbi.nlm.nih.gov/pubmed/20525906
141. Guo, C., et al. Efficacy and safety of testosterone replacement therapy in men with hypogonadism: A
meta-analysis study of placebo-controlled trials. Exp Ther Med, 2016. 11: 853.
https://www.ncbi.nlm.nih.gov/pubmed/26998003
142. Kang, D.Y., et al. The effect of testosterone replacement therapy on prostate-specific antigen (PSA)
levels in men being treated for hypogonadism: a systematic review and meta-analysis. Medicine
(Baltimore), 2015. 94: e410.
https://www.ncbi.nlm.nih.gov/pubmed/25621688
143. Lopez, D.S., et al. Endogenous and exogenous testosterone and prostate cancer: decreased-,
increased- or null-risk? Transl Androl Urol, 2017. 6: 566.
https://www.ncbi.nlm.nih.gov/pubmed/28725600
144. Watts, E.L., et al. Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20
Prospective Studies. Eur Urol, 2018. 74: 585.
https://www.ncbi.nlm.nih.gov/pubmed/30077399
145. Haider, A., et al. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy:
observations from 5-year median followup of 3 registries. J Urol, 2015. 193: 80.
https://www.ncbi.nlm.nih.gov/pubmed/24980615
146. Wallis, C.J., et al. Survival and cardiovascular events in men treated with testosterone replacement
therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol, 2016. 4: 498.
https://www.ncbi.nlm.nih.gov/pubmed/27165609
147. Gray, H., et al. Recurrence of prostate cancer in patients receiving testosterone supplementation for
hypogonadism. Am J Health Syst Pharm, 2015. 72: 536.
https://www.ncbi.nlm.nih.gov/pubmed/25788507
148. Teeling, F., et al. Testosterone Therapy for High-risk Prostate Cancer Survivors: A Systematic Review
and Meta-analysis. Urology, 2019. 126: 16.
https://www.ncbi.nlm.nih.gov/pubmed/30244116
149. Kardoust Parizi, M., et al. Oncological safety of testosterone replacement therapy in prostate cancer
survivors after definitive local therapy: A systematic literature review and meta-analysis. Urol Oncol,
2019. 37: 637.
https://www.ncbi.nlm.nih.gov/pubmed/31296421
150. Valderrabano, R.J., et al. Testosterone replacement in prostate cancer survivors with testosterone
deficiency: Study protocol of a randomized controlled trial. Andrology, 2023. 11: 93.
https://www.ncbi.nlm.nih.gov/pubmed/36181480
151. Corona, G., et al. Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of
Observational Studies. J Sex Med, 2018. 15: 1260.
https://www.ncbi.nlm.nih.gov/pubmed/30145097

168 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

152. Malkin, C.J., et al. Low serum testosterone and increased mortality in men with coronary heart
disease. Heart, 2010. 96: 1821.
https://www.ncbi.nlm.nih.gov/pubmed/20959649
153. Kapoor, D., et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes:
correlations with bioavailable testosterone and visceral adiposity. Diabetes Care, 2007. 30: 911.
https://www.ncbi.nlm.nih.gov/pubmed/17392552
154. Khaw, K.T., et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease,
and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk)
Prospective Population Study. Circulation, 2007. 116: 2694.
https://www.ncbi.nlm.nih.gov/pubmed/18040028
155. Laughlin, G.A., et al. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab,
2008. 93: 68.
https://www.ncbi.nlm.nih.gov/pubmed/17911176
156. Shores, M.M., et al. Low serum testosterone and mortality in male veterans. Arch Intern Med, 2006.
166: 1660.
https://www.ncbi.nlm.nih.gov/pubmed/16908801
157. Vikan, T., et al. Endogenous sex hormones and the prospective association with cardiovascular
disease and mortality in men: the Tromso Study. Eur J Endocrinol, 2009. 161: 435.
https://www.ncbi.nlm.nih.gov/pubmed/19542243
158. Corona, G., et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic
study. Eur J Endocrinol, 2011. 165: 687.
https://www.ncbi.nlm.nih.gov/pubmed/21852391
159. Keating, N.L., et al. Diabetes and cardiovascular disease during androgen deprivation therapy for
prostate cancer. J Clin Oncol, 2006. 24: 4448.
https://www.ncbi.nlm.nih.gov/pubmed/16983113
160. Ohlsson, C., et al. High serum testosterone is associated with reduced risk of cardiovascular events
in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol, 2011.
58: 1674.
https://www.ncbi.nlm.nih.gov/pubmed/21982312
161. Soisson, V., et al. A J-shaped association between plasma testosterone and risk of ischemic arterial
event in elderly men: the French 3C cohort study. Maturitas, 2013. 75: 282.
https://www.ncbi.nlm.nih.gov/pubmed/23706278
162. Snyder, P.J., et al. Effects of Testosterone Treatment in Older Men. N Engl J Med, 2016. 374: 611.
https://www.ncbi.nlm.nih.gov/pubmed/26886521
163. Srinivas-Shankar, U., et al. Effects of testosterone on muscle strength, physical function, body
composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind,
placebo-controlled study. J Clin Endocrinol Metab, 2010. 95: 639.
https://www.ncbi.nlm.nih.gov/pubmed/20061435
164. English, K.M., et al. Low-dose transdermal testosterone therapy improves angina threshold in men
with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation, 2000.
102: 1906.
https://www.ncbi.nlm.nih.gov/pubmed/11034937
165. Malkin, C.J., et al. Testosterone therapy in men with moderate severity heart failure: a double-blind
randomized placebo controlled trial. Eur Heart J, 2006. 27: 57.
https://www.ncbi.nlm.nih.gov/pubmed/16093267
166. Mathur, A., et al. Long-term benefits of testosterone replacement therapy on angina threshold and
atheroma in men. Eur J Endocrinol, 2009. 161: 443.
https://www.ncbi.nlm.nih.gov/pubmed/19542238
167. Shores, M.M., et al. Association Between Testosterone Treatment and Risk of Incident
Cardiovascular Events Among US Male Veterans With Low Testosterone Levels and Multiple Medical
Comorbidities. J Am Heart Assoc, 2021. 10: e020562.
https://www.ncbi.nlm.nih.gov/pubmed/34423650
168. EMA. No consistent evidence of an increased risk of heart problems with testosterone medicines.
2014.
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Testosterone_31/
Position_provided_by_CMDh/WC500177617.pdf.
169. Ayele, H.T., et al. Testosterone replacement therapy and the risk of venous thromboembolism: A
systematic review and meta-analysis of randomized controlled trials. Thromb Res, 2021. 199: 123.
https://www.ncbi.nlm.nih.gov/pubmed/33486321

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 169

170. Rastrelli, G., et al. Cardiovascular impact of testosterone therapy for hypogonadism. Expert Rev
Cardiovasc Ther, 2018. 16: 617.
https://www.ncbi.nlm.nih.gov/pubmed/30099911
171. Handelsman, D.J., et al. Long-term Outcomes of Testosterone Treatment in Men: A T4DM
Postrandomization Observational Follow-up Study. J Clin Endocrinol Metab, 2023. 109: e25.
https://www.ncbi.nlm.nih.gov/pubmed/37623257
172. FDA. Briefing Information for the September 17, 2014 Joint Meeting of the Bone, Reproductive and
Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM)
Advisory Committee Meeting.
http://www.fda.gov/AdvisoryCommittees/ucm404905.htm
173. Alexander, G.C., et al. Cardiovascular Risks of Exogenous Testosterone Use Among Men: A
Systematic Review and Meta-Analysis. Am J Med, 2017. 130: 293.
https://www.ncbi.nlm.nih.gov/pubmed/27751897
174. Corona, G., et al. Cardiovascular risk associated with testosterone-boosting medications: a
systematic review and meta-analysis. Expert Opin Drug Saf, 2014. 13: 1327.
https://www.ncbi.nlm.nih.gov/pubmed/25139126
175. Corona, G., et al. Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies. J
Sex Med, 2018. 15: 820.
https://www.ncbi.nlm.nih.gov/pubmed/29803351
176. Hudson, J., et al. Adverse cardiovascular events and mortality in men during testosterone treatment:
an individual patient and aggregate data meta-analysis. Lancet Healthy Longev, 2022. 3: e381.
https://www.ncbi.nlm.nih.gov/pubmed/35711614
177. Basaria, S., et al. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis
Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial.
JAMA, 2015. 314: 570.
https://www.ncbi.nlm.nih.gov/pubmed/26262795
178. Budoff, M.J., et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With
Low Testosterone. JAMA, 2017. 317: 708.
https://www.ncbi.nlm.nih.gov/pubmed/28241355
179. Caminiti, G., et al. Effect of long-acting testosterone treatment on functional exercise capacity,
skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with
chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol, 2009.
54: 919.
https://www.ncbi.nlm.nih.gov/pubmed/19712802
180. Pugh, P.J., et al. Testosterone treatment for men with chronic heart failure. Heart, 2004. 90: 446.
https://www.ncbi.nlm.nih.gov/pubmed/15020527
181. Sharma, R., et al. Normalization of testosterone level is associated with reduced incidence of
myocardial infarction and mortality in men. Eur Heart J, 2015. 36: 2706.
https://www.ncbi.nlm.nih.gov/pubmed/26248567
182. Brown, D.W., et al. Hematocrit and the risk of coronary heart disease mortality. Am Heart J, 2001.
142: 657.
https://www.ncbi.nlm.nih.gov/pubmed/11579356
183. Puddu, P.E., et al. Red blood cell count in short-term prediction of cardiovascular disease incidence in
the Gubbio population study. Acta Cardiol, 2002. 57: 177.
https://www.ncbi.nlm.nih.gov/pubmed/12088175
184. Boffetta, P., et al. A U-shaped relationship between haematocrit and mortality in a large prospective
cohort study. Int J Epidemiol, 2013. 42: 601.
https://www.ncbi.nlm.nih.gov/pubmed/23569195
185. Baillargeon, J., et al. Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy.
Mayo Clin Proc, 2015. 90: 1038.
https://www.ncbi.nlm.nih.gov/pubmed/26205547
186. Sharma, R., et al. Association Between Testosterone Replacement Therapy and the Incidence of DVT
and Pulmonary Embolism: A Retrospective Cohort Study of the Veterans Administration Database.
Chest, 2016. 150: 563.
https://www.ncbi.nlm.nih.gov/pubmed/27179907
187. Martinez, C., et al. Testosterone treatment and risk of venous thromboembolism: population based
case-control study. BMJ, 2016. 355: i5968.
https://www.ncbi.nlm.nih.gov/pubmed/27903495

170 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

188. Glueck, C.J., et al. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events.
Metabolism, 2014. 63: 989.
https://www.ncbi.nlm.nih.gov/pubmed/24930993
189. Smith, A.M., et al. Testosterone does not adversely affect fibrinogen or tissue plasminogen activator
(tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina. Eur J
Endocrinol, 2005. 152: 285.
https://www.ncbi.nlm.nih.gov/pubmed/15745938
190. Zitzmann, M., et al. The HEAT-Registry (HEmatopoietic Affection by Testosterone): comparison of a
transdermal gel vs long-acting intramuscular testosterone undecanoate in hypogonadal men. Aging
Male, 2022. 25: 134.
https://www.ncbi.nlm.nih.gov/pubmed/35467476
191. Madaeva, I.M., et al. [Obstructive sleep apnea syndrome and age-related hypohonadism]. Zh Nevrol
Psikhiatr Im S S Korsakova, 2017. 117: 79.
https://www.ncbi.nlm.nih.gov/pubmed/28777369
192. Hoyos, C.M., et al. Body compositional and cardiometabolic effects of testosterone therapy in obese
men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur J Endocrinol,
2012. 167: 531.
https://www.ncbi.nlm.nih.gov/pubmed/22848006
193. Barbui, T., et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised
management recommendations from European LeukemiaNet. Leukemia, 2018. 32: 1057.
https://www.ncbi.nlm.nih.gov/pubmed/29515238
194. Ory, J., et al. Secondary Polycythemia in Men Receiving Testosterone Therapy Increases Risk of
Major Adverse Cardiovascular Events and Venous Thromboembolism in the First Year of Therapy. J
Urol, 2022. 207: 1295.
https://www.ncbi.nlm.nih.gov/pubmed/35050717
195. Mottet, N., et al. Updated Guidelines for Metastatic Hormone-sensitive Prostate Cancer: Abiraterone
Acetate Combined with Castration Is Another Standard. Eur Urol, 2018. 73: 316.
https://www.ncbi.nlm.nih.gov/pubmed/29103760
196. Eardley, I. The Incidence, Prevalence, and Natural History of Erectile Dysfunction. Sex Med Rev, 2013.
1: 3.
https://www.ncbi.nlm.nih.gov/pubmed/27784558
197. Feldman, H.A., et al. Impotence and its medical and psychosocial correlates: results of the
Massachusetts Male Aging Study. J Urol, 1994. 151: 54.
https://www.ncbi.nlm.nih.gov/pubmed/8254833
198. Braun, M., et al. Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey'. Int J Impot
Res, 2000. 12: 305.
https://www.ncbi.nlm.nih.gov/pubmed/11416833
199. Johannes, C.B., et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results
from the Massachusetts male aging study. J Urol, 2000. 163: 460.
https://www.ncbi.nlm.nih.gov/pubmed/10647654
200. Schouten, B.W., et al. Incidence rates of erectile dysfunction in the Dutch general population. Effects
of definition, clinical relevance and duration of follow-up in the Krimpen Study. Int J Impot Res, 2005.
17: 58.
https://www.ncbi.nlm.nih.gov/pubmed/15510192
201. Capogrosso, P., et al. One patient out of four with newly diagnosed erectile dysfunction is a young
man--worrisome picture from the everyday clinical practice. J Sex Med, 2013. 10: 1833.
https://www.ncbi.nlm.nih.gov/pubmed/23651423
202. Laumann, E.O., et al. Sexual dysfunction in the United States: prevalence and predictors. JAMA, 1999.
281: 537.
https://www.ncbi.nlm.nih.gov/pubmed/10022110
203. Porst, H., et al. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence,
comorbidities, and professional help-seeking. Eur Urol, 2007. 51: 816.
https://www.ncbi.nlm.nih.gov/pubmed/16934919
204. Serefoglu, E.C., et al. Prevalence of the complaint of ejaculating prematurely and the four premature
ejaculation syndromes: results from the Turkish Society of Andrology Sexual Health Survey. J Sex
Med, 2011. 8: 540.
https://www.ncbi.nlm.nih.gov/pubmed/21054799

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 171

205. Gao, J., et al. Prevalence and factors associated with the complaint of premature ejaculation and the
four premature ejaculation syndromes: a large observational study in China. J Sex Med, 2013. 10:
1874.
https://www.ncbi.nlm.nih.gov/pubmed/23651451
206. Waldinger, M.D., et al. The use of old and recent DSM definitions of premature ejaculation in
observational studies: a contribution to the present debate for a new classification of PE in the DSM-
V. J Sex Med, 2008. 5: 1079.
https://www.ncbi.nlm.nih.gov/pubmed/18331260
207. Perelman, M. Retarded Ejaculation. Curr Sex Hlth Rep, 2004. 1: 95.
https://link.springer.com/article/10.1007/s11930-004-0023-2
208. Simons, J.S., et al. Prevalence of sexual dysfunctions: results from a decade of research. Arch Sex
Behav, 2001. 30: 177.
https://www.ncbi.nlm.nih.gov/pubmed/11329727
209. Mercer, C.H., et al. Who reports sexual function problems? Empirical evidence from Britain's 2000
National Survey of Sexual Attitudes and Lifestyles. Sex Transm Infect, 2005. 81: 394.
https://www.ncbi.nlm.nih.gov/pubmed/16199738
210. Laumann, E.O., et al. Sexual problems among women and men aged 40-80 y: prevalence and
correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res, 2005. 17:
39.
https://www.ncbi.nlm.nih.gov/pubmed/15215881
211. Lindau, S.T., et al. A study of sexuality and health among older adults in the United States. N Engl J
Med, 2007. 357: 762.
https://www.ncbi.nlm.nih.gov/pubmed/17715410
212. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition. 2013, Arlington, VA. Access date: 1 June 2013.
https://psychiatryonline.org/dsm
213. Di Sante, S., et al. Epidemiology of delayed ejaculation. Transl Androl Urol, 2016. 5: 541.
https://www.ncbi.nlm.nih.gov/pubmed/27652226
214. Kinsey, A.C., et al. Sexual behavior in the human male. 1948. Am J Public Health, 2003. 93: 894.
https://www.ncbi.nlm.nih.gov/pubmed/12773346
215. Chehensse, C., et al. The spinal control of ejaculation revisited: a systematic review and meta-
analysis of anejaculation in spinal cord injured patients. Hum Reprod Update, 2013. 19: 507.
https://www.ncbi.nlm.nih.gov/pubmed/23820516
216. Jefferys, A., et al. The management of retrograde ejaculation: a systematic review and update. Fertil
Steril, 2012. 97: 306.
https://www.ncbi.nlm.nih.gov/pubmed/22177462
217. Gandhi, J., et al. The Role of Diabetes Mellitus in Sexual and Reproductive Health: An Overview of
Pathogenesis, Evaluation, and Management. Curr Diabetes Rev, 2017. 13: 573.
https://www.ncbi.nlm.nih.gov/pubmed/27875946
218. Yavetz, H., et al. Retrograde ejaculation. Hum Reprod, 1994. 9: 381.
https://www.ncbi.nlm.nih.gov/pubmed/8006123
219. Fedder, J., et al. Retrograde ejaculation and sexual dysfunction in men with diabetes mellitus: a
prospective, controlled study. Andrology, 2013. 1: 602.
https://www.ncbi.nlm.nih.gov/pubmed/23606485
220. Hylmarova, S., et al. The impact of type 1 diabetes mellitus on male sexual functions and sex
hormone levels. Endocr J, 2020. 67: 59.
https://www.ncbi.nlm.nih.gov/pubmed/31619592
221. Emberton, M., et al. The effect of prostatectomy on symptom severity and quality of life. Br J Urol,
1996. 77: 233.
https://www.ncbi.nlm.nih.gov/pubmed/8800892
222. Woo, H.H., et al. Preservation of sexual function with the prostatic urethral lift: a novel treatment for
lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med, 2012. 9: 568.
https://www.ncbi.nlm.nih.gov/pubmed/22172161
223. Talab, S.S., et al. V403 the Impact of Ejaculation-Preserving Photo-Selective Vaporization of
the Prostate (Ep-Pvp) on Lower Urinary Tract Symptoms and Ejaculatory Function: Results of a
Multicenter Study. Journal of Urology, 2013. 189.
https://www.auajournals.org/doi/full/10.1016/j.juro.2013.02.1792

172 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

224. Liu, Y., et al. Impact on Sexual Function of Endoscopic Enucleation vs Transurethral Resection of
the Prostate for Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: A Systematic
Review and Meta-Analysis. J Endourol, 2020. 34: 1064.
https://www.ncbi.nlm.nih.gov/pubmed/32242462
225. Suarez-Ibarrola, R., et al. Efficacy and safety of aquablation of the prostate for patients with
symptomatic benign prostatic enlargement: a systematic review. World J Urol, 2020. 38: 1147.
https://www.ncbi.nlm.nih.gov/pubmed/31559476
226. Bebi, C., et al. Sexual and ejaculatory function after holmium laser enucleation of the prostate and
bipolar transurethral enucleation of the prostate: a single-center experience. Int J Impot Res, 2022.
34: 71.
https://www.ncbi.nlm.nih.gov/pubmed/33082545
227. Lindal, E., et al. The lifetime prevalence of psychosexual dysfunction among 55 to 57-year-olds in
Iceland. Soc Psychiatry Psychiatr Epidemiol, 1993. 28: 91.
https://www.ncbi.nlm.nih.gov/pubmed/8511669
228. Blanker, M.H., et al. Erectile and ejaculatory dysfunction in a community-based sample of men 50 to
78 years old: prevalence, concern, and relation to sexual activity. Urology, 2001. 57: 763.
https://www.ncbi.nlm.nih.gov/pubmed/11306400
229. Roberts, R.O., et al. Prevalence of prostatitis-like symptoms in a community based cohort of older
men. J Urol, 2002. 168: 2467.
https://www.ncbi.nlm.nih.gov/pubmed/12441942
230. Sonmez, N.C., et al. Sexual dysfunction in type III chronic prostatitis (CP) and chronic pelvic pain
syndrome (CPPS) observed in Turkish patients. Int Urol Nephrol, 2011. 43: 309.
https://www.ncbi.nlm.nih.gov/pubmed/20680450
231. Nickel, J.C., et al. Benign prostatic hyperplasia (BPH) and prostatitis: prevalence of painful
ejaculation in men with clinical BPH. BJU Int, 2005. 95: 571.
https://www.ncbi.nlm.nih.gov/pubmed/15705082
232. Mo, M.Q., et al. Sexual dysfunctions and psychological disorders associated with type IIIa chronic
prostatitis: a clinical survey in China. Int Urol Nephrol, 2014. 46: 2255.
https://www.ncbi.nlm.nih.gov/pubmed/25158893
233. Wagenlehner, F.M., et al. National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI)
symptom evaluation in multinational cohorts of patients with chronic prostatitis/chronic pelvic pain
syndrome. Eur Urol, 2013. 63: 953.
https://www.ncbi.nlm.nih.gov/pubmed/23141933
234. Shoskes, D.A., et al. Impact of post-ejaculatory pain in men with category III chronic prostatitis/
chronic pelvic pain syndrome. J Urol, 2004. 172: 542.
https://www.ncbi.nlm.nih.gov/pubmed/15247725
235. Ng, Y.H., et al. Haematospermia as a presenting symptom: outcomes of investigation in 300 men.
Surgeon, 2013. 11: 35.
https://www.ncbi.nlm.nih.gov/pubmed/22682581
236. Mulhall, J.P., et al. Hemospermia: diagnosis and management. Urology, 1995. 46: 463.
https://www.ncbi.nlm.nih.gov/pubmed/7571212
237. Han, M., et al. Association of hemospermia with prostate cancer. J Urol, 2004. 172: 2189.
https://www.ncbi.nlm.nih.gov/pubmed/15538229
238. Fugl-Meyer, A., et al. Sexual disabilities, problems and satisfaction in 18-74 year old Swedes. Scand J
Sexol, 1999. 2: 79.
https://www.researchgate.net/publication/10980828_Sexual_disabilities_are_not_singularities
239. Quinta Gomes, A.L., et al. Prevalence of sexual problems in Portugal: results of a population-based
study using a stratified sample of men aged 18 to 70 years. J Sex Res, 2014. 51: 13.
https://www.ncbi.nlm.nih.gov/pubmed/23573897
240. Martin, S., et al. Clinical and biopsychosocial determinants of sexual dysfunction in middle-aged and
older Australian men. J Sex Med, 2012. 9: 2093.
https://www.ncbi.nlm.nih.gov/pubmed/22759388
241. Hirshfield, S., et al. Sexual dysfunction in an Internet sample of U.S. men who have sex with men. J
Sex Med, 2010. 7: 3104.
https://www.ncbi.nlm.nih.gov/pubmed/19968773
242. Peixoto, M.M., et al. Prevalence of sexual problems and associated distress among gay and
heterosexual men. Sexual and Relationship Therapy, 2014. 30: 211.
https://www.tandfonline.com/doi/abs/10.1080/14681994.2014.986084

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 173

243. Najman, J.M., et al. Sexual dysfunction in the Australian population. Aust Fam Physician, 2003. 32:
951.
https://www.ncbi.nlm.nih.gov/pubmed/14650796
244. Traeen, B., et al. Sexual problems in 18-67-year-old Norwegians. Scand J Public Health, 2010. 38:
445.
https://www.ncbi.nlm.nih.gov/pubmed/20494944
245. NIH, C.D.P.o.I. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on
Impotence. JAMA, 1993. 270: 83.
https://www.ncbi.nlm.nih.gov/pubmed/8510302
246. Fisher, W.A., et al. Erectile dysfunction (ED) is a shared sexual concern of couples I: couple
conceptions of ED. J Sex Med, 2009. 6: 2746.
https://www.ncbi.nlm.nih.gov/pubmed/19694926
247. Salonia, A., et al. Is erectile dysfunction a reliable proxy of general male health status? The case for
the International Index of Erectile Function-Erectile Function domain. J Sex Med, 2012. 9: 2708.
https://www.ncbi.nlm.nih.gov/pubmed/22897643
248. Corona, G., et al. Assessment of the relational factor in male patients consulting for sexual
dysfunction: the concept of couple sexual dysfunction. J Androl, 2006. 27: 795.
https://www.ncbi.nlm.nih.gov/pubmed/16809271
249. Wright, L.N., et al. Erectile Dysfunction and Treatment: An Analysis of Associated Chronic Health
Conditions. Urology, 2021. 157: 148.
https://www.ncbi.nlm.nih.gov/pubmed/34428539
250. Besiroglu, H., et al. The relationship between metabolic syndrome, its components, and erectile
dysfunction: a systematic review and a meta-analysis of observational studies. J Sex Med, 2015. 12:
1309.
https://pubmed.ncbi.nlm.nih.gov/25872648/
251. Jackson, G., et al. Cardiovascular aspects of sexual medicine. J Sex Med, 2010. 7: 1608.
https://www.ncbi.nlm.nih.gov/pubmed/20388161
252. Cao, S., et al. Association of quantity and duration of smoking with erectile dysfunction: a dose-
response meta-analysis. J Sex Med, 2014. 11: 2376.
https://www.ncbi.nlm.nih.gov/pubmed/25052869
253. Gandaglia, G., et al. A systematic review of the association between erectile dysfunction and
cardiovascular disease. Eur Urol, 2014. 65: 968.
https://www.ncbi.nlm.nih.gov/pubmed/24011423
254. Binmoammar, T.A., et al. The impact of poor glycaemic control on the prevalence of erectile
dysfunction in men with type 2 diabetes mellitus: a systematic review. JRSM Open, 2016. 7:
2054270415622602.
https://www.ncbi.nlm.nih.gov/pubmed/26981254
255. Glina, F.P.A., et al. What Is the Impact of Bariatric Surgery on Erectile Function? A Systematic Review
and Meta-Analysis. Sex Med Rev, 2017. 5: 393.
https://www.ncbi.nlm.nih.gov/pubmed/28526630
256. Sansone, A., et al. Serum Homocysteine Levels in Men with and without Erectile Dysfunction: A
Systematic Review and Meta-Analysis. Int J Endocrinol, 2018. 2018: 7424792.
https://www.ncbi.nlm.nih.gov/pubmed/30158975
257. Corona, G., et al. Sexual dysfunction at the onset of type 2 diabetes: the interplay of depression,
hormonal and cardiovascular factors. J Sex Med, 2014. 11: 2065.
https://www.ncbi.nlm.nih.gov/pubmed/25041930
258. Pizzol, D., et al. Associations between body mass index, waist circumference and erectile
dysfunction: a systematic review and META-analysis. Rev Endocr Metab Disord, 2020. 21: 657.
https://www.ncbi.nlm.nih.gov/pubmed/32002782
259. Sivaratnam, L., et al. Behavior-Related Erectile Dysfunction: A Systematic Review and Meta-Analysis.
J Sex Med, 2021. 18: 121.
https://www.ncbi.nlm.nih.gov/pubmed/33223424
260. El-Shahawy, O., et al. Association of E-Cigarettes With Erectile Dysfunction: The Population
Assessment of Tobacco and Health Study. Am J Prev Med, 2022. 62: 26.
https://www.ncbi.nlm.nih.gov/pubmed/34922653
261. Trinchieri, M., et al. Erectile and Ejaculatory Dysfunction Associated with Use of Psychotropic Drugs:
A Systematic Review. J Sex Med, 2021. 18: 1354.
https://www.ncbi.nlm.nih.gov/pubmed/34247952

174 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

262. Alberti, L., et al. Erectile dysfunction in heart failure patients: a critical reappraisal. Andrology, 2013. 1:
177.
https://www.ncbi.nlm.nih.gov/pubmed/23339018
263. Baumhakel, M., et al. Cardiovascular risk, drugs and erectile function--a systematic analysis. Int J Clin
Pract, 2011. 65: 289.
https://www.ncbi.nlm.nih.gov/pubmed/21314866
264. Lin, W.Y., et al. Atrial fibrillation is associated with increased risk of erectile dysfunction: A nationwide
population-based cohort study. Int J Cardiol, 2015. 190: 106.
https://www.ncbi.nlm.nih.gov/pubmed/25918058
265. Corona, G., et al. Endocrinologic Control of Men's Sexual Desire and Arousal/Erection. J Sex Med,
2016. 13: 317.
https://www.ncbi.nlm.nih.gov/pubmed/26944463
266. Farag, Y.M.K., et al. Vitamin D deficiency is independently associated with greater prevalence of
erectile dysfunction: The National Health and Nutrition Examination Survey (NHANES) 2001-2004.
Atherosclerosis, 2016. 252: 61.
https://www.ncbi.nlm.nih.gov/pubmed/27505344
267. Caretta, N., et al. Hypovitaminosis D is associated with erectile dysfunction in type 2 diabetes.
Endocrine, 2016. 53: 831.
https://www.ncbi.nlm.nih.gov/pubmed/26758995
268. Salem, S., et al. Serum uric acid as a risk predictor for erectile dysfunction. J Sex Med, 2014. 11:
1118.
https://www.ncbi.nlm.nih.gov/pubmed/24621054
269. Zhang, Y., et al. Serum Folic Acid and Erectile Dysfunction: A Systematic Review and Meta-Analysis.
Sex Med, 2021. 9: 100356.
https://www.ncbi.nlm.nih.gov/pubmed/34051538
270. Liu, Q., et al. Erectile Dysfunction and Depression: A Systematic Review and Meta-Analysis. J Sex
Med, 2018. 15: 1073.
https://www.ncbi.nlm.nih.gov/pubmed/29960891
271. Velurajah, R., et al. Erectile dysfunction in patients with anxiety disorders: a systematic review. Int J
Impot Res, 2022. 34: 177.
https://www.ncbi.nlm.nih.gov/pubmed/33603242
272. Perez-Garcia, L.F., et al. Sexual function and reproduction can be impaired in men with rheumatic
diseases: A systematic review. Semin Arthritis Rheum, 2020. 50: 557.
https://www.ncbi.nlm.nih.gov/pubmed/32165034
273. Luo, L., et al. Association between chronic obstructive pulmonary disease and risk of erectile
dysfunction: a systematic review and meta-analysis. Int J Impot Res, 2020. 32: 159.
https://www.ncbi.nlm.nih.gov/pubmed/31263249
274. He, W., et al. Migraine Is Associated With High Risk of Erectile Dysfunction: A Systematic Review and
Cumulative Analysis. J Sex Med, 2022. 19: 430.
https://www.ncbi.nlm.nih.gov/pubmed/35082102
275. Wu, X., et al. The Prevalence and Associated Risk Factors of Erectile Dysfunction in Patients With
Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Sex Med, 2022. 19: 950.
https://www.ncbi.nlm.nih.gov/pubmed/35491378
276. Xu, J., et al. Risk of osteoporosis in patients with erectile dysfunction: A PRISMA-compliant
systematic review and meta-analysis. Medicine (Baltimore), 2021. 100: e26326.
https://www.ncbi.nlm.nih.gov/pubmed/34128874
277. Agrawal, P., et al. Sleep disorders are associated with testosterone deficiency and erectile
dysfunction-a U.S. claims database analysis. Int J Impot Res, 2024. 36: 78.
https://www.ncbi.nlm.nih.gov/pubmed/36473958
278. Donovan, J.L., et al. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for
Prostate Cancer. N Engl J Med, 2016. 375: 1425.
https://www.ncbi.nlm.nih.gov/pubmed/27626365
279. Sanda, M.G., et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N
Engl J Med, 2008. 358: 1250.
https://www.ncbi.nlm.nih.gov/pubmed/18354103
280. Tal, R., et al. Erectile function recovery rate after radical prostatectomy: a meta-analysis. J Sex Med,
2009. 6: 2538.
https://www.ncbi.nlm.nih.gov/pubmed/19515209

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 175

281. Schauer, I., et al. Have rates of erectile dysfunction improved within the past 17 years after radical
prostatectomy? A systematic analysis of the control arms of prospective randomized trials on penile
rehabilitation. Andrology, 2015. 3: 661.
https://pubmed.ncbi.nlm.nih.gov/26198796/
282. Seftel, A.D., et al. Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic
review of epidemiological data. Int J Clin Pract, 2013. 67: 32.
https://www.ncbi.nlm.nih.gov/pubmed/23082930
283. Rosen, R., et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey
of the aging male (MSAM-7). Eur Urol, 2003. 44: 637.
https://www.ncbi.nlm.nih.gov/pubmed/14644114
284. Verze, P., et al. The impact of surgery for lower urinary tract symptoms/benign prostatic enlargement
on both erectile and ejaculatory function: a systematic review. Int J Impot Res, 2019. 31: 319.
https://www.ncbi.nlm.nih.gov/pubmed/30996268
285. Li, H.J., et al. Prevalence of sexual dysfunction in men with chronic prostatitis/chronic pelvic pain
syndrome: a meta-analysis. World J Urol, 2016. 34: 1009.
https://www.ncbi.nlm.nih.gov/pubmed/26546073
286. Chung, S.D., et al. A nationwide population-based study on bladder pain syndrome/interstitial cystitis
and ED. Int J Impot Res, 2013. 25: 224.
https://www.ncbi.nlm.nih.gov/pubmed/23552579
287. van der Poel, H.G., et al. Focal Therapy in Primary Localised Prostate Cancer: The European
Association of Urology Position in 2018. Eur Urol, 2018. 74: 84.
https://www.ncbi.nlm.nih.gov/pubmed/29373215
288. Feng, C., et al. The relationship between erectile dysfunction and open urethroplasty: a systematic
review and meta-analysis. J Sex Med, 2013. 10: 2060.
https://www.ncbi.nlm.nih.gov/pubmed/23656595
289. Gratzke, C., et al. Anatomy, physiology, and pathophysiology of erectile dysfunction. J Sex Med, 2010.
7: 445.
https://www.ncbi.nlm.nih.gov/pubmed/20092448
290. Rasmussen, L., et al. Cardiovascular drugs and erectile dysfunction - a symmetry analysis. Br J Clin
Pharmacol, 2015. 80: 1219.
https://www.ncbi.nlm.nih.gov/pubmed/26094913
291. Emanu, J.C., et al. Erectile dysfunction after radical prostatectomy: prevalence, medical treatments,
and psychosocial interventions. Curr Opin Support Palliat Care, 2016. 10: 102.
https://www.ncbi.nlm.nih.gov/pubmed/26808052
292. Modh, R.A., et al. Sexual dysfunction after cystectomy and urinary diversion. Nat Rev Urol, 2014. 11:
445.
https://www.ncbi.nlm.nih.gov/pubmed/24980191
293. Celentano, V., et al. Sexual dysfunction following rectal cancer surgery. Int J Colorectal Dis, 2017. 32:
1523.
https://www.ncbi.nlm.nih.gov/pubmed/28497404
294. Wittmann, D., et al. Guidelines for Sexual Health Care for Prostate Cancer Patients:
Recommendations of an International Panel. J Sex Med, 2022. 19: 1655.
https://www.ncbi.nlm.nih.gov/pubmed/36192299
295. Capogrosso, P., et al. Erectile Recovery After Radical Pelvic Surgery: Methodological Challenges and
Recommendations for Data Reporting. J Sex Med, 2020. 17: 7.
https://www.ncbi.nlm.nih.gov/pubmed/31668729
296. Salonia, A., et al. Sexual Rehabilitation After Treatment For Prostate Cancer-Part 2:
Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J
Sex Med, 2017. 14: 297.
https://www.ncbi.nlm.nih.gov/pubmed/28262100
297. Hunt, A.A., et al. Risk of erectile dysfunction after modern radiotherapy for intact prostate cancer.
Prostate Cancer Prostatic Dis, 2021. 24: 128.
https://www.ncbi.nlm.nih.gov/pubmed/32647352
298. Nolsoe, A.B., et al. Neglected side effects to curative prostate cancer treatments. Int J Impot Res,
2021. 33: 428.
https://www.ncbi.nlm.nih.gov/pubmed/33318637
299. van As, N., et al. Radical Prostatectomy Versus Stereotactic Radiotherapy for Clinically Localised
Prostate Cancer: Results of the PACE-A Randomised Trial. Eur Urol, 2024. 86: 566.
https://www.ncbi.nlm.nih.gov/pubmed/39266383

176 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

300. Capogrosso, P., et al. Are We Improving Erectile Function Recovery After Radical Prostatectomy?
Analysis of Patients Treated over the Last Decade. Eur Urol, 2019. 75: 221.
https://www.ncbi.nlm.nih.gov/pubmed/30237021
301. Salonia, A., et al. Prevention and management of postprostatectomy sexual dysfunctions. Part 1:
choosing the right patient at the right time for the right surgery. Eur Urol, 2012. 62: 261.
https://www.ncbi.nlm.nih.gov/pubmed/22575909
302. Khoder, W.Y., et al. Do we need the nerve sparing radical prostatectomy techniques (intrafascial vs.
interfascial) in men with erectile dysfunction? Results of a single-centre study. World J Urol, 2015.
33: 301.
https://www.ncbi.nlm.nih.gov/pubmed/24752607
303. Ju, I.E., et al. Surgeon Experience and Erectile Function After Radical Prostatectomy: A Systematic
Review. Sex Med Rev, 2021. 9: 650.
https://www.ncbi.nlm.nih.gov/pubmed/34219004
304. Ficarra, V., et al. Systematic review and meta-analysis of studies reporting potency rates after robot-
assisted radical prostatectomy. Eur Urol, 2012. 62: 418.
https://www.ncbi.nlm.nih.gov/pubmed/22749850
305. Haglind, E., et al. Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical
Prostatectomy: A Prospective, Controlled, Nonrandomised Trial. Eur Urol, 2015. 68: 216.
https://www.ncbi.nlm.nih.gov/pubmed/25770484
306. Yaxley, J.W., et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic
prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet, 2016. 388:
1057.
https://www.ncbi.nlm.nih.gov/pubmed/27474375
307. Stember, D.S., et al. The concept of erectile function preservation (penile rehabilitation) in the patient
after brachytherapy for prostate cancer. Brachytherapy, 2012. 11: 87.
https://www.ncbi.nlm.nih.gov/pubmed/22330103
308. Gaither, T.W., et al. The Natural History of Erectile Dysfunction After Prostatic Radiotherapy: A
Systematic Review and Meta-Analysis. J Sex Med, 2017. 14: 1071.
https://www.ncbi.nlm.nih.gov/pubmed/28859870
309. Loi, M., et al. Sexual Function in Patients Treated With Stereotactic Radiotherapy For Prostate Cancer:
A Systematic Review of the Current Evidence. J Sex Med, 2019. 16: 1409.
https://www.ncbi.nlm.nih.gov/pubmed/31303575
310. Fallara, G., et al. Erectile function after focal therapy for localized prostate cancer: a systematic
review. Int J Impot Res, 2021. 33: 418.
https://www.ncbi.nlm.nih.gov/pubmed/32999435
311. Hatzichristou, D., et al. Diagnosing Sexual Dysfunction in Men and Women: Sexual History Taking and
the Role of Symptom Scales and Questionnaires. J Sex Med, 2016. 13: 1166.
https://www.ncbi.nlm.nih.gov/pubmed/27436074
312. Cilio, S., et al. Unrecognised orgasmic phase disorders in men presenting with new-onset erectile
dysfunction-Findings from a real-life, cross-sectional study. Andrology, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37555487
313. The Process of Care Consensus Panel. The process of care model for evaluation and treatment of
erectile dysfunction. The Process of Care Consensus Panel. Int J Impot Res, 1999. 11: 59.
https://www.ncbi.nlm.nih.gov/pubmed/10356665
314. Althof, S.E., et al. Standard operating procedures for taking a sexual history. J Sex Med, 2013. 10: 26.
https://www.ncbi.nlm.nih.gov/pubmed/22970717
315. Rosen, R.C., et al. The international index of erectile function (IIEF): a multidimensional scale for
assessment of erectile dysfunction. Urology, 1997. 49: 822.
https://www.ncbi.nlm.nih.gov/pubmed/9187685
316. Rosen, R.C., et al. Development and evaluation of an abridged, 5-item version of the International
Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res, 1999.
11: 319.
https://www.ncbi.nlm.nih.gov/pubmed/10637462
317. Petrone, L., et al. Structured interview on erectile dysfunction (SIEDY): a new, multidimensional
instrument for quantification of pathogenetic issues on erectile dysfunction. Int J Impot Res, 2003.
15: 210.
https://www.ncbi.nlm.nih.gov/pubmed/12904808
318. Mulhall, J.P., et al. Validation of the erection hardness score. J Sex Med, 2007. 4: 1626.
https://www.ncbi.nlm.nih.gov/pubmed/17888069

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 177

319. Davis-Joseph, B., et al. Accuracy of the initial history and physical examination to establish the
etiology of erectile dysfunction. Urology, 1995. 45: 498.
https://www.ncbi.nlm.nih.gov/pubmed/7879338
320. Ghanem, H.M., et al. SOP: physical examination and laboratory testing for men with erectile
dysfunction. J Sex Med, 2013. 10: 108.
https://www.ncbi.nlm.nih.gov/pubmed/22524416
321. Morgado, A., et al. Can we rely on total testosterone measurement to exclude hypogonadism in
erectile dysfunction? Int J Impot Res, 2023. 35: 454.
https://www.ncbi.nlm.nih.gov/pubmed/35347299
322. Heidenreich, A., et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local
treatment with curative intent-update 2013. Eur Urol, 2014. 65: 124.
https://www.ncbi.nlm.nih.gov/pubmed/24207135
323. Maggi, M., et al. Hormonal causes of male sexual dysfunctions and their management
(hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). J Sex Med, 2013. 10: 661.
https://www.ncbi.nlm.nih.gov/pubmed/22524444
324. Tanaka, Y., et al. Association of Erectile Dysfunction with Incident Atrial Fibrillation: The Multi-Ethnic
Study of Atherosclerosis (MESA). Am J Med, 2020. 133: 613.
https://www.ncbi.nlm.nih.gov/pubmed/31743659
325. Fang, S.C., et al. Changes in erectile dysfunction over time in relation to Framingham cardiovascular
risk in the Boston Area Community Health (BACH) Survey. J Sex Med, 2015. 12: 100.
https://www.ncbi.nlm.nih.gov/pubmed/25293632
326. Gazzaruso, C., et al. Erectile dysfunction can improve the effectiveness of the current guidelines for
the screening for asymptomatic coronary artery disease in diabetes. Endocrine, 2011. 40: 273.
https://www.ncbi.nlm.nih.gov/pubmed/21861245
327. Turek, S.J., et al. Sexual dysfunction as a marker of cardiovascular disease in males with 50 or more
years of type 1 diabetes. Diabetes Care, 2013. 36: 3222.
https://www.ncbi.nlm.nih.gov/pubmed/23780949
328. Adam, A., et al. Is the History of Erectile Dysfunction a Reliable Risk Factor for New Onset Acute
Myocardial Infarction? A Systematic Review and Meta-Analysis. Curr Urol, 2020. 14: 122.
https://www.ncbi.nlm.nih.gov/pubmed/33224004
329. Kloner, R.A., et al. Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health. J Sex Med,
2023.
https://www.ncbi.nlm.nih.gov/pubmed/38148297
330. Nehra, A., et al. The Princeton III Consensus recommendations for the management of erectile
dysfunction and cardiovascular disease. Mayo Clin Proc, 2012. 87: 766.
https://www.ncbi.nlm.nih.gov/pubmed/22862865
331. DeBusk, R., et al. Management of sexual dysfunction in patients with cardiovascular disease:
recommendations of The Princeton Consensus Panel. Am J Cardiol, 2000. 86: 175.
https://www.ncbi.nlm.nih.gov/pubmed/10913479
332. Kostis, J.B., et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference).
Am J Cardiol, 2005. 96: 313.
https://www.ncbi.nlm.nih.gov/pubmed/16018863
333. Rosen, R.C., et al. Proceedings of PRINCETON IV: PDE5 inhibitors and cardiac health symposium. Sex
Med Rev, 2024. 12: 681.
https://www.ncbi.nlm.nih.gov/pubmed/38936840
334. Kloner, R.A., et al. Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health. J Sex Med,
2024. 21: 90.
https://www.ncbi.nlm.nih.gov/pubmed/38148297
335. Kohler, T.S., et al. The Princeton IV Consensus Recommendations for the Management of Erectile
Dysfunction and Cardiovascular Disease. Mayo Clin Proc, 2024. 99: 1500.
https://www.ncbi.nlm.nih.gov/pubmed/39115509
336. Arnett, D.K., et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease:
A Report of the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines. Circulation, 2019. 140: e596.
https://www.ncbi.nlm.nih.gov/pubmed/30879355
337. Reiter-Brennan, C., et al. ACC/AHA lipid guidelines: Personalized care to prevent cardiovascular
disease. Cleve Clin J Med, 2020. 87: 231.
https://www.ncbi.nlm.nih.gov/pubmed/32238379

178 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

338. Zou, Z., et al. The Role of Nocturnal Penile Tumescence and Rigidity (NPTR) Monitoring in the
Diagnosis of Psychogenic Erectile Dysfunction: A Review. Sex Med Rev, 2019. 7: 442.
https://www.ncbi.nlm.nih.gov/pubmed/30612976
339. Qin, F., et al. Advantages and limitations of sleep-related erection and rigidity monitoring: a review. Int
J Impot Res, 2018. 30: 192.
https://www.ncbi.nlm.nih.gov/pubmed/29855552
340. Hatzichristou, D.G., et al. Hemodynamic characterization of a functional erection. Arterial and
corporeal veno-occlusive function in patients with a positive intracavernosal injection test. Eur Urol,
1999. 36: 60.
https://www.ncbi.nlm.nih.gov/pubmed/10364657
341. Sikka, S.C., et al. Standardization of vascular assessment of erectile dysfunction: standard operating
procedures for duplex ultrasound. J Sex Med, 2013. 10: 120.
https://www.ncbi.nlm.nih.gov/pubmed/22970798
342. Pathak, R.A., et al. Novel Evidence-Based Classification of Cavernous Venous Occlusive Disease. J
Urol, 2016. 196: 1223.
https://www.ncbi.nlm.nih.gov/pubmed/27164516
343. Capogrosso, P., et al. Low-Intensity Shock Wave Therapy in Sexual Medicine-Clinical
Recommendations from the European Society of Sexual Medicine (ESSM). J Sex Med, 2019. 16:
1490.
https://www.ncbi.nlm.nih.gov/pubmed/31447380
344. Morgado, A., et al. Is There a Point to Performing a Penile Duplex Ultrasound? J Sex Med, 2019. 16:
1574.
https://www.ncbi.nlm.nih.gov/pubmed/31405766
345. Nascimento, B., et al. A Critical Analysis of Methodology Pitfalls in Duplex Doppler Ultrasound in the
Evaluation of Patients With Erectile Dysfunction: Technical and Interpretation Deficiencies. J Sex
Med, 2020. 17: 1416.
https://www.ncbi.nlm.nih.gov/pubmed/32631763
346. Nashed, A., et al. The Efficacy of Penile Duplex Ultrasound in Erectile Dysfunction Management
Decision-Making: A Systematic Review. Sex Med Rev, 2021. 9: 472.
https://www.ncbi.nlm.nih.gov/pubmed/33250351
347. Silva, A.C., et al. Erection hardness score or penile Doppler ultrasound: which is a better predictor of
failure of nonsurgical treatment of erectile dysfunction? Sex Med, 2023. 11: qfad009.
https://www.ncbi.nlm.nih.gov/pubmed/36960301
348. Carneiro, F., et al. Audiovisual Sexual Stimulation Improves Diagnostic Accuracy of Penile Doppler
Ultrasound in Patients With Erectile Dysfunction. J Sex Med, 2020. 17: 249.
https://www.ncbi.nlm.nih.gov/pubmed/31836300
349. Said, S.Z., et al. Evaluation of the sensitivity of different doses of vasoactive drugs in diagnosing
erectile dysfunction in impotent patients: a prospective case-control study. Cent European J Urol,
2021. 74: 109.
https://www.ncbi.nlm.nih.gov/pubmed/33976925
350. Zhang, Y., et al. A novel strategy to induce penile erection during penile doppler ultrasound: oral
sildenafil administration plus alprostadil injection. Aging Male, 2024. 27: 2339352.
https://www.ncbi.nlm.nih.gov/pubmed/38590113
351. Glina, S., et al. SOP: corpus cavernosum assessment (cavernosography/cavernosometry). J Sex Med,
2013. 10: 111.
https://www.ncbi.nlm.nih.gov/pubmed/22971225
352. Hoppe, H., et al. Erectile dysfunction: role of computed tomography cavernosography in the
diagnosis and treatment planning of venous leak. CVIR Endovasc, 2023. 6: 56.
https://www.ncbi.nlm.nih.gov/pubmed/37975993
353. Li, K., et al. The Relationships of Dehydroepiandrosterone Sulfate, Erectile Function and General
Psychological Health. Sex Med, 2021. 9: 100386.
https://www.ncbi.nlm.nih.gov/pubmed/34273785
354. Nguyen, H.M.T., et al. Erectile Dysfunction in Young Men-A Review of the Prevalence and Risk
Factors. Sex Med Rev, 2017. 5: 508.
https://www.ncbi.nlm.nih.gov/pubmed/28642047
355. Carvalho, J., et al. The Relationship Between COVID-19 Confinement, Psychological Adjustment, and
Sexual Functioning, in a Sample of Portuguese Men and Women. J Sex Med, 2021. 18: 1191.
https://www.ncbi.nlm.nih.gov/pubmed/34116985

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 179

356. McCabe, M.P., et al. A systematic review of the psychosocial outcomes associated with erectile
dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex? J
Sex Med, 2014. 11: 347.
https://www.ncbi.nlm.nih.gov/pubmed/24251371
357. Rosen, R.C., et al. Men with Sexual Problems and Their Partners: Findings from the International
Survey of Relationships. Arch Sex Behav, 2016. 45: 159.
https://www.ncbi.nlm.nih.gov/pubmed/26228991
358. Walther, A., et al. Psychobiological Protective Factors Modifying the Association Between Age and
Sexual Health in Men: Findings From the Men's Health 40+ Study. Am J Mens Health, 2017. 11: 737.
https://www.ncbi.nlm.nih.gov/pubmed/28413941
359. Brotto, L., et al. Psychological and Interpersonal Dimensions of Sexual Function and Dysfunction. J
Sex Med, 2016. 13: 538.
https://www.ncbi.nlm.nih.gov/pubmed/27045257
360. Derogatis, L.R., et al. The Brief Symptom Inventory: an introductory report. Psychol Med, 1983. 13:
595.
https://www.ncbi.nlm.nih.gov/pubmed/6622612
361. Parent, M.C., et al. Heterosexual Self-Presentation, Identity Management, and Sexual Functioning
Among Men Who Have Sex with Men. Arch Sex Behav, 2021. 50: 3155.
https://www.ncbi.nlm.nih.gov/pubmed/34462841
362. Montorsi, F., et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med,
2010. 7: 3572.
https://www.ncbi.nlm.nih.gov/pubmed/21040491
363. Williams, P., et al. Men's beliefs about treatment for erectile dysfunction-what influences treatment
use? A systematic review. Int J Impot Res, 2021. 33: 16.
https://www.ncbi.nlm.nih.gov/pubmed/32231275
364. Fruhauf, S., et al. Efficacy of psychological interventions for sexual dysfunction: a systematic review
and meta-analysis. Arch Sex Behav, 2013. 42: 915.
https://www.ncbi.nlm.nih.gov/pubmed/23559141
365. Gupta, B.P., et al. The effect of lifestyle modification and cardiovascular risk factor reduction on
erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med, 2011. 171: 1797.
https://www.ncbi.nlm.nih.gov/pubmed/21911624
366. Hatzimouratidis, K., et al. Pharmacotherapy for Erectile Dysfunction: Recommendations From the
Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med, 2016. 13: 465.
https://www.ncbi.nlm.nih.gov/pubmed/27045254
367. Vlachopoulos, C., et al. Erectile dysfunction in the cardiovascular patient. Eur Heart J, 2013. 34: 2034.
https://www.ncbi.nlm.nih.gov/pubmed/23616415
368. Glina, S., et al. Modifying risk factors to prevent and treat erectile dysfunction. J Sex Med, 2013. 10:
115.
https://www.ncbi.nlm.nih.gov/pubmed/22971247
369. Allen, M.S. Physical activity as an adjunct treatment for erectile dysfunction. Nat Rev Urol, 2019. 16:
553.
https://www.ncbi.nlm.nih.gov/pubmed/31239541
370. Khera, M., et al. Effect of aerobic exercise on erectile function: systematic review and meta-analysis
of randomized controlled trials. J Sex Med, 2023. 20: 1369.
https://www.ncbi.nlm.nih.gov/pubmed/37814532
371. Liu, S., et al. The relationships between bariatric surgery and sexual function: current evidence based
medicine. BMC Urol, 2020. 20: 150.
https://www.ncbi.nlm.nih.gov/pubmed/33008406
372. Cai, X., et al. The role of statins in erectile dysfunction: a systematic review and meta-analysis. Asian
J Androl, 2014. 16: 461.
https://www.ncbi.nlm.nih.gov/pubmed/24556747
373. Cui, Y., et al. The effect of statins on erectile dysfunction: a systematic review and meta-analysis. J
Sex Med, 2014. 11: 1367.
https://www.ncbi.nlm.nih.gov/pubmed/24628781
374. Yuan, J., et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for
erectile dysfunction: a systematic review and network meta-analysis. Eur Urol, 2013. 63: 902.
https://www.ncbi.nlm.nih.gov/pubmed/23395275
375. Chen, L., et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off
network meta-analysis. Eur Urol, 2015. 68: 674.
https://www.ncbi.nlm.nih.gov/pubmed/25817916

180 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

376. Zhou, Z., et al. Meta-Analysis of the Long-Term Efficacy and Tolerance of Tadalafil Daily Compared
With Tadalafil On-Demand in Treating Men With Erectile Dysfunction. Sex Med, 2019. 7: 282.
https://www.ncbi.nlm.nih.gov/pubmed/31307951
377. Goldstein, I., et al. Efficacy and Safety of Sildenafil by Age in Men With Erectile Dysfunction. J Sex
Med, 2016. 13: 852.
https://www.ncbi.nlm.nih.gov/pubmed/27114196
378. Giuliano, F., et al. Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and
the postmarketing safety database. Int J Clin Pract, 2010. 64: 240.
https://www.ncbi.nlm.nih.gov/pubmed/19900167
379. Tsertsvadze, A., et al. Oral sildenafil citrate (viagra) for erectile dysfunction: a systematic review and
meta-analysis of harms. Urology, 2009. 74: 831.
https://www.ncbi.nlm.nih.gov/pubmed/19592078
380. Chung, E., et al. A state of art review on vardenafil in men with erectile dysfunction and associated
underlying diseases. Expert Opin Pharmacother, 2011. 12: 1341.
https://www.ncbi.nlm.nih.gov/pubmed/21548725
381. Wang, R., et al. Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction:
implications for clinical safety and improved tolerability. J Sex Med, 2012. 9: 2122.
https://www.ncbi.nlm.nih.gov/pubmed/22759639
382. Goldstein, I., et al. A randomized, double-blind, placebo-controlled evaluation of the safety and
efficacy of avanafil in subjects with erectile dysfunction. J Sex Med, 2012. 9: 1122.
https://www.ncbi.nlm.nih.gov/pubmed/22248153
383. Madeira, C.R., et al. Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile
dysfunction: a network meta-analysis and multicriteria decision analysis. World J Urol, 2021. 39: 953.
https://www.ncbi.nlm.nih.gov/pubmed/32388784
384. Stridh, A., et al. Placebo Responses Among Men With Erectile Dysfunction Enrolled in
Phosphodiesterase 5 Inhibitor Trials: A Systematic Review and Meta-analysis. JAMA Netw Open,
2020. 3: e201423.
https://www.ncbi.nlm.nih.gov/pubmed/32196105
385. Goldstein, I., et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N
Engl J Med, 1998. 338: 1397.
https://www.ncbi.nlm.nih.gov/pubmed/9580646
386. Moncada, I., et al. Efficacy of sildenafil citrate at 12 hours after dosing: re-exploring the therapeutic
window. Eur Urol, 2004. 46: 357.
https://www.ncbi.nlm.nih.gov/pubmed/15306108
387. Goldstein, I., et al. Oral sildenafil in the treatment of erectile dysfunction. 1998. J Urol, 2002. 167:
1197.
https://www.ncbi.nlm.nih.gov/pubmed/11905901
388. Sangkum, P., et al. Efficacy of the Orally Disintegrating Strip Sildenafil for the Treatment of Erectile
Dysfunction: A Prospective, Randomized Trial. Sex Med, 2021. 9: 100453.
https://www.ncbi.nlm.nih.gov/pubmed/34710784
389. Curran, M., et al. Tadalafil. Drugs, 2003. 63: 2203.
https://www.ncbi.nlm.nih.gov/pubmed/14498756
390. Ventimiglia, E., et al. The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction.
Expert Opin Drug Saf, 2016. 15: 141.
https://www.ncbi.nlm.nih.gov/pubmed/26752541
391. Paduch, D.A., et al. Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic
dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated
analysis of 17 placebo-controlled studies. BJU Int, 2013. 111: 334.
https://www.ncbi.nlm.nih.gov/pubmed/23356749
392. Roehrborn, C.G., et al. Erectile dysfunction and lower urinary tract symptoms associated with benign
prostatic hyperplasia (LUTS/BPH) combined responders to tadalafil after 12 weeks of treatment. BJU
Int, 2016. 118: 153.
https://www.ncbi.nlm.nih.gov/pubmed/26765325
393. Gacci, M., et al. Latest Evidence on the Use of Phosphodiesterase Type 5 Inhibitors for the Treatment
of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. Eur Urol, 2016. 70: 124.
https://www.ncbi.nlm.nih.gov/pubmed/26806655
394. Keating, G.M., et al. Vardenafil: a review of its use in erectile dysfunction. Drugs, 2003. 63: 2673.
https://www.ncbi.nlm.nih.gov/pubmed/14636086

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 181

395. Capogrosso, P., et al. Time of onset of vardenafil orodispersible tablet in a real-life setting - looking
beyond randomized clinical trials. Expert Rev Clin Pharmacol, 2017. 10: 339.
https://www.ncbi.nlm.nih.gov/pubmed/28129714
396. Sanford, M. Vardenafil orodispersible tablet. Drugs, 2012. 72: 87.
https://www.ncbi.nlm.nih.gov/pubmed/22191797
397. Debruyne, F.M., et al. Time to onset of action of vardenafil: a retrospective analysis of the pivotal
trials for the orodispersible and film-coated tablet formulations. J Sex Med, 2011. 8: 2912.
https://www.ncbi.nlm.nih.gov/pubmed/21883954
398. Gittelman, M., et al. The POTENT II randomised trial: efficacy and safety of an orodispersible
vardenafil formulation for the treatment of erectile dysfunction. Int J Clin Pract, 2010. 64: 594.
https://www.ncbi.nlm.nih.gov/pubmed/20456213
399. Sperling, H., et al. The POTENT I randomized trial: efficacy and safety of an orodispersible vardenafil
formulation for the treatment of erectile dysfunction. J Sex Med, 2010. 7: 1497.
https://www.ncbi.nlm.nih.gov/pubmed/20233275
400. Hellstrom, W.J., et al. Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A
Randomized, Double-Blind, Placebo Controlled Study. J Urol, 2015. 194: 485.
https://www.ncbi.nlm.nih.gov/pubmed/25591992
401. Corona, G., et al. The safety and efficacy of Avanafil, a new 2^nd generation PDE5i:
Comprehensive review and meta-analysis. Expert Opin Drug Saf, 2016. 15(2): 237.
https://pubmed.ncbi.nlm.nih.gov/26646748/
402. Brock, G., et al. Efficacy of Continuous Dosing of Tadalafil Once Daily vs Tadalafil On Demand in
Clinical Subgroups of Men With Erectile Dysfunction: A Descriptive Comparison Using the Integrated
Tadalafil Databases. J Sex Med, 2016. 13: 860.
https://www.ncbi.nlm.nih.gov/pubmed/27114197
403. Porst, H., et al. Tadalafil once daily in men with erectile dysfunction: an integrated analysis of data
obtained from 1913 patients from six randomized, double-blind, placebo-controlled, clinical studies.
Eur Urol, 2014. 65: 455.
https://www.ncbi.nlm.nih.gov/pubmed/24119319
404. Burns, P.R., et al. - Treatment satisfaction of men and partners following switch from on-demand
phosphodiesterase type 5 inhibitor therapy to tadalafil 5mg once daily. J Sex Med, 2015. 12:720.
https://pubmed.ncbi.nlm.nih.gov/25615445/
405. Jiang, H., et al. Long-term tadalafil once daily in Chinese men with erectile dysfunction: a 2-year final
analysis of a post-marketing, multicenter, randomized, open-label trial. Asian J Androl, 2024. 26: 282.
https://www.ncbi.nlm.nih.gov/pubmed/38284776
406. Andersson, D.P., et al. Association of Phosphodiesterase-5 Inhibitors Versus Alprostadil With Survival
in Men With Coronary Artery Disease. J Am Coll Cardiol, 2021. 77: 1535.
https://www.ncbi.nlm.nih.gov/pubmed/33766260
407. Kloner, R.A., et al. Cardiovascular Safety of Phosphodiesterase Type 5 Inhibitors After Nearly 2
Decades on the Market. Sex Med Rev, 2018. 6: 583.
https://www.ncbi.nlm.nih.gov/pubmed/29960874
408. Swearingen, D., et al. Hemodynamic effect of avanafil and glyceryl trinitrate coadministration. Drugs
Context, 2013. 2013: 212248.
https://www.ncbi.nlm.nih.gov/pubmed/24432037
409. Gur, S., et al. Update on drug interactions with phosphodiesterase-5 inhibitors prescribed as first-line
therapy for patients with erectile dysfunction or pulmonary hypertension. Curr Drug Metab, 2013. 14:
265.
https://www.ncbi.nlm.nih.gov/pubmed/23140258
410. Corona, G., et al. The use of phosphodiesterase 5 inhibitors with concomitant medications. J
Endocrinol Invest, 2008. 31: 799.
https://www.ncbi.nlm.nih.gov/pubmed/18997493
411. Kloner, R.A. Novel phosphodiesterase type 5 inhibitors: assessing hemodynamic effects and safety
parameters. Clin Cardiol, 2004. 27: I20.
https://www.ncbi.nlm.nih.gov/pubmed/15115192
412. Satake, N., et al. Potentiating effect of nicorandil, an antianginal agent, on relaxation induced
by isoproterenol in isolated rat aorta: involvement of cyclic GMP-inhibitable cyclic AMP
phosphodiesterase. J Cardiovasc Pharmacol, 1995. 25: 489.
https://www.ncbi.nlm.nih.gov/pubmed/7769818
413. Pickering, T.G., et al. Sildenafil citrate for erectile dysfunction in men receiving multiple
antihypertensive agents: a randomized controlled trial. Am J Hypertens, 2004. 17: 1135.
https://www.ncbi.nlm.nih.gov/pubmed/15607620

182 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

414. Kloner, R.A., et al. Analysis of integrated clinical safety data of tadalafil in patients receiving
concomitant antihypertensive medications. J Clin Hypertens (Greenwich), 2022. 24: 167.
https://www.ncbi.nlm.nih.gov/pubmed/35099113
415. Nunes, A.P., et al. Retrospective Observational Real-World Outcome Study to Evaluate Safety Among
Patients With Erectile Dysfunction (ED) With Co-Possession of Tadalafil and Anti-Hypertensive
Medications (anti-HTN). J Sex Med, 2022. 19: 74.
https://www.ncbi.nlm.nih.gov/pubmed/34872842
416. Adamou, C., et al. The hemodynamic interactions of combination therapy with alpha-blockers and
phosphodiesterase-5 inhibitors compared to monotherapy with alpha-blockers: a systematic review
and meta-analysis. Int Urol Nephrol, 2020. 52: 1407.
https://www.ncbi.nlm.nih.gov/pubmed/32240459
417. Hatzichristou, D., et al. Sildenafil failures may be due to inadequate patient instructions and follow-
up: a study on 100 non-responders. Eur Urol, 2005. 47: 518.
https://www.ncbi.nlm.nih.gov/pubmed/15774252
418. Rajagopalan, P., et al. Effect of high-fat breakfast and moderate-fat evening meal on the
pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile
dysfunction. J Clin Pharmacol, 2003. 43: 260.
https://www.ncbi.nlm.nih.gov/pubmed/12638394
419. Kyle, J.A., et al. Avanafil for erectile dysfunction. Ann Pharmacother, 2013. 47: 1312.
https://www.ncbi.nlm.nih.gov/pubmed/24259695
420. Wang, H., et al. The effectiveness and safety of avanafil for erectile dysfunction: a systematic review
and meta-analysis. Curr Med Res Opin, 2014. 30: 1565.
https://www.ncbi.nlm.nih.gov/pubmed/24701971
421. Gruenwald, I., et al. Positive effect of counseling and dose adjustment in patients with erectile
dysfunction who failed treatment with sildenafil. Eur Urol, 2006. 50: 134.
https://www.ncbi.nlm.nih.gov/pubmed/16527391
422. Hatzimouratidis, K., et al. Treatment strategy for "non-responders" to tadalafil and vardenafil: a real-
life study. Eur Urol, 2006. 50: 126.
https://www.ncbi.nlm.nih.gov/pubmed/16564127
423. Park, N.C., et al. Treatment Strategy for Non-Responders to PDE5 Inhibitors. World J Mens Health,
2013. 31: 31.
https://www.ncbi.nlm.nih.gov/pubmed/23658863
424. Porst, H., et al. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J Sex
Med, 2013. 10: 130.
https://www.ncbi.nlm.nih.gov/pubmed/23343170
425. Corona, G., et al. Testosterone supplementation and sexual function: a meta-analysis study. J Sex
Med, 2014. 11: 1577.
https://www.ncbi.nlm.nih.gov/pubmed/24697970
426. Eardley, I., et al. Factors associated with preference for sildenafil citrate and tadalafil for treating
erectile dysfunction in men naive to phosphodiesterase 5 inhibitor therapy: post hoc analysis of data
from a multicentre, randomized, open-label, crossover study. BJU Int, 2007. 100: 122.
https://www.ncbi.nlm.nih.gov/pubmed/17552960
427. Hatzimouratidis, K., et al. Psychosocial outcomes after initial treatment of erectile dysfunction with
tadalafil once daily, tadalafil on demand or sildenafil citrate on demand: results from a randomized,
open-label study. Int J Impot Res, 2014. 26: 223.
https://www.ncbi.nlm.nih.gov/pubmed/24784894
428. Liao, X., et al. Comparative efficacy and safety of phosphodiesterase type 5 inhibitors for erectile
dysfunction in diabetic men: a Bayesian network meta-analysis of randomized controlled trials. World
J Urol, 2019. 37: 1061.
https://www.ncbi.nlm.nih.gov/pubmed/30523399
429. Mykoniatis, I., et al. Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction:
A Systematic Review and Meta-analysis. JAMA Netw Open, 2021. 4: e2036337.
https://www.ncbi.nlm.nih.gov/pubmed/33599772
430. Cui, H., et al. Efficacy and safety of long-term tadalafil 5 mg once daily combined with sildenafil 50
mg as needed at the early stage of treatment for patients with erectile dysfunction. Andrologia, 2015.
47: 20.
https://pubmed.ncbi.nlm.nih.gov/24387078/
431. Tao, R., et al. The Efficacy of Li-ESWT Combined With VED in Diabetic ED Patients Unresponsive to
PDE5is: A Single-Center, Randomized Clinical Trial. Front Endocrinol (Lausanne), 2022. 13: 937958.
https://www.ncbi.nlm.nih.gov/pubmed/35813628

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 183

432. Garrido-Abad, P., et al. Combination therapy with topical alprostadil and phosphodiesterase-5
inhibitors after failure of oral therapy in patients with erectile dysfunction: a prospective, two-arm,
open-label, non-randomized study. Int J Impot Res, 2022. 34: 164.
https://www.ncbi.nlm.nih.gov/pubmed/33483603
433. Anaissie, J., et al. Clinical use of alprostadil topical cream in patients with erectile dysfunction: a
review. Res Rep Urol, 2016. 8: 123.
https://www.ncbi.nlm.nih.gov/pubmed/27536559
434. Rooney, M., et al. Long-term, multicenter study of the safety and efficacy of topical alprostadil cream
in male patients with erectile dysfunction. J Sex Med, 2009. 6: 520.
https://www.ncbi.nlm.nih.gov/pubmed/19138370
435. Padma-Nathan, H., et al. An integrated analysis of alprostadil topical cream for the treatment of
erectile dysfunction in 1732 patients. Urology, 2006. 68: 386.
https://www.ncbi.nlm.nih.gov/pubmed/16904458
436. Cai, T., et al. The intra-meatal application of alprostadil cream (Vitaros(R)) improves drug efficacy and
patient's satisfaction: results from a randomized, two-administration route, cross-over clinical trial.
Int J Impot Res, 2019. 31: 119.
https://www.ncbi.nlm.nih.gov/pubmed/30323234
437. Padma-Nathan, H., et al. Treatment of men with erectile dysfunction with transurethral alprostadil.
Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med, 1997. 336: 1.
https://www.ncbi.nlm.nih.gov/pubmed/8970933
438. Costa, P., et al. Intraurethral alprostadil for erectile dysfunction: a review of the literature. Drugs, 2012.
72: 2243.
https://www.ncbi.nlm.nih.gov/pubmed/23170913
439. Mulhall, J.P., et al. Analysis of the consistency of intraurethral prostaglandin E(1) (MUSE) during
at-home use. Urology, 2001. 58: 262.
https://www.ncbi.nlm.nih.gov/pubmed/11489714
440. Shabsigh, R., et al. Intracavernous alprostadil alfadex is more efficacious, better tolerated, and
preferred over intraurethral alprostadil plus optional actis: a comparative, randomized, crossover,
multicenter study. Urology, 2000. 55: 109.
https://www.ncbi.nlm.nih.gov/pubmed/10654905
441. Han, M., et al. Efficacy of online cognitive behavioral therapy for nonorganic erectile dysfunction in
reproductive-age males during the COVID-19 pandemic: a randomized wait list-controlled trial. J Sex
Med, 2023. 20: 1325.
https://www.ncbi.nlm.nih.gov/pubmed/37740951
442. Dewitte, M., et al. A Psychosocial Approach to Erectile Dysfunction: Position Statements from the
European Society of Sexual Medicine (ESSM). Sex Med, 2021. 9: 100434.
https://www.ncbi.nlm.nih.gov/pubmed/34626919
443. Saad, F., et al. Long-term treatment with testosterone undecanoate injections in men with
hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular
events, prostate cancer, and mortality. Aging Male, 2020. 23: 81.
https://www.ncbi.nlm.nih.gov/pubmed/30782054
444. Taniguchi, H., et al. Testosterone Therapy for Late-Onset Hypogonadism Improves Erectile Function:
A Systematic Review and Meta-Analysis. Urol Int, 2022. 106: 539.
https://www.ncbi.nlm.nih.gov/pubmed/34856556
445. Alwani, M., et al. Cardiovascular Disease, Hypogonadism and Erectile Dysfunction: Early
Detection, Prevention and the Positive Effects of Long-Term Testosterone Treatment: Prospective
Observational, Real-Life Data. Vasc Health Risk Manag, 2021. 17: 497.
https://www.ncbi.nlm.nih.gov/pubmed/34465997
446. Levine, L.A., et al. Vacuum constriction and external erection devices in erectile dysfunction. Urol Clin
North Am, 2001. 28: 335.
https://www.ncbi.nlm.nih.gov/pubmed/11402585
447. Yuan, J., et al. Vacuum therapy in erectile dysfunction--science and clinical evidence. Int J Impot Res,
2010. 22: 211.
https://www.ncbi.nlm.nih.gov/pubmed/20410903
448. Cookson, M.S., et al. Long-term results with vacuum constriction device. J Urol, 1993. 149: 290.
https://www.ncbi.nlm.nih.gov/pubmed/8426404
449. Lewis, R.W., et al. External vacuum therapy for erectile dysfunction: use and results. World J Urol,
1997. 15: 78.
https://www.ncbi.nlm.nih.gov/pubmed/9066099

184 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

450. Trost, L.W., et al. External Mechanical Devices and Vascular Surgery for Erectile Dysfunction. J Sex
Med, 2016. 13: 1579.
https://www.ncbi.nlm.nih.gov/pubmed/27770853
451. Pajovic, B., et al. Vacuum erection device in treatment of organic erectile dysfunction and penile
vascular differences between patients with DM type I and DM type II. Aging Male, 2017. 20: 49.
https://www.ncbi.nlm.nih.gov/pubmed/27690728
452. Eardley, I., et al. Pharmacotherapy for erectile dysfunction. J Sex Med, 2010. 7: 524.
https://www.ncbi.nlm.nih.gov/pubmed/20092451
453. Kattan, S., et al. Double-blind, cross-over study comparing prostaglandin E1 and papaverine in
patients with vasculogenic impotence. Urology, 1991. 37: 516.
https://www.ncbi.nlm.nih.gov/pubmed/2038782
454. Lakin, M.M., et al. Intracavernous injection therapy: analysis of results and complications. J Urol,
1990. 143: 1138.
https://www.ncbi.nlm.nih.gov/pubmed/2342174
455. Moriel, E.Z., et al. Sodium bicarbonate alleviates penile pain induced by intracavernous injections for
erectile dysfunction. J Urol, 1993. 149: 1299.
https://www.ncbi.nlm.nih.gov/pubmed/8386779
456. Gupta, R., et al. Predictors of success and risk factors for attrition in the use of intracavernous
injection. J Urol, 1997. 157: 1681.
https://www.ncbi.nlm.nih.gov/pubmed/9112505
457. Sundaram, C.P., et al. Long-term follow-up of patients receiving injection therapy for erectile
dysfunction. Urology, 1997. 49: 932.
https://www.ncbi.nlm.nih.gov/pubmed/9187703
458. Vardi, Y., et al. Logistic regression and survival analysis of 450 impotent patients treated with
injection therapy: long-term dropout parameters. J Urol, 2000. 163: 467.
https://www.ncbi.nlm.nih.gov/pubmed/10647656
459. Porst, H., et al. Intracavernous Alprostadil Alfadex--an effective and well tolerated treatment for
erectile dysfunction. Results of a long-term European study. Int J Impot Res, 1998. 10: 225.
https://www.ncbi.nlm.nih.gov/pubmed/9884918
460. Duncan, C., et al. Erectile dysfunction: a global review of intracavernosal injectables. World J Urol,
2019. 37: 1007.
https://www.ncbi.nlm.nih.gov/pubmed/30895359
461. Buvat, J., et al. Double-blind multicenter study comparing alprostadil alpha-cyclodextrin with
moxisylyte chlorhydrate in patients with chronic erectile dysfunction. J Urol, 1998. 159: 116.
https://www.ncbi.nlm.nih.gov/pubmed/9400450
462. Mulhall, J.P., et al. Intracavernosal forskolin: role in management of vasculogenic impotence resistant
to standard 3-agent pharmacotherapy. J Urol, 1997. 158: 1752.
https://www.ncbi.nlm.nih.gov/pubmed/9334594
463. Bechara, A., et al. Comparative study of papaverine plus phentolamine versus prostaglandin E1 in
erectile dysfunction. J Urol, 1997. 157: 2132.
https://www.ncbi.nlm.nih.gov/pubmed/9146599
464. McMahon CG, et al. A comparison of the response to the intracavernosal injection of papaverine
and phentolamine, prostaglandin E1 and a combination of all three agents in the management of
impotence. J Urol, 1999. 162.
465. Dinsmore, W.W., et al. Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in
erectile dysfunction. BJU Int, 2008. 102: 933.
https://www.ncbi.nlm.nih.gov/pubmed/18485029
466. Kim, J.H., et al. Mesenchymal stem cell-based gene therapy for erectile dysfunction. Int J Impot Res,
2016. 28: 81.
https://www.ncbi.nlm.nih.gov/pubmed/26888355
467. Patel, D.P., et al. Emerging Treatments for Erectile Dysfunction: a Review of Novel, Non-surgical
Options. Curr Urol Rep, 2019. 20: 44.
https://www.ncbi.nlm.nih.gov/pubmed/31214818
468. Matz, E.L., et al. Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev, 2019. 7: 321.
https://www.ncbi.nlm.nih.gov/pubmed/29631980
469. Yu, B., et al. Advances in Gene Therapy for Erectile Dysfunction: Promises and Challenges. Curr Gene
Ther, 2018. 18: 351.
https://www.ncbi.nlm.nih.gov/pubmed/30289066

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 185

470. Scott, S., et al. Platelet-Rich Plasma and Treatment of Erectile Dysfunction: Critical Review of
Literature and Global Trends in Platelet-Rich Plasma Clinics. Sex Med Rev, 2019. 7: 306.
https://www.ncbi.nlm.nih.gov/pubmed/30833169
471. Epifanova, M.V., et al. Platelet-Rich Plasma Therapy for Male Sexual Dysfunction: Myth or Reality? Sex
Med Rev, 2020. 8: 106.
https://www.ncbi.nlm.nih.gov/pubmed/30898594
472. Chung, E., et al. Evaluation of clinical efficacy, safety and patient satisfaction rate after low-intensity
extracorporeal shockwave therapy for the treatment of male erectile dysfunction: an Australian first
open-label single-arm prospective clinical trial. BJU Int, 2015. 115 Suppl 5: 46.
https://www.ncbi.nlm.nih.gov/pubmed/25828173
473. Gruenwald, I., et al. Shockwave treatment of erectile dysfunction. Ther Adv Urol, 2013. 5: 95.
https://www.ncbi.nlm.nih.gov/pubmed/23554844
474. Gruenwald, I., et al. Low-intensity extracorporeal shock wave therapy--a novel effective treatment for
erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. J Sex Med,
2012. 9: 259.
https://www.ncbi.nlm.nih.gov/pubmed/22008059
475. Olsen, A.B., et al. Can low-intensity extracorporeal shockwave therapy improve erectile
dysfunction?hA prospective, randomized, double-blind, placebo-controlled study. Scand J Urol, 2015.
49: 329.
https://pubmed.ncbi.nlm.nih.gov/25470423/
476. Vardi, Y., et al. Can low-intensity extracorporeal shockwave therapy improve erectile function? A
6-month follow-up pilot study in patients with organic erectile dysfunction. Eur Urol, 2010. 58: 243.
https://www.ncbi.nlm.nih.gov/pubmed/20451317
477. Kitrey, N.D., et al. Penile Low Intensity Shock Wave Treatment is Able to Shift PDE5i Nonresponders
to Responders: A Double-Blind, Sham Controlled Study. J Urol, 2016. 195: 1550.
https://www.ncbi.nlm.nih.gov/pubmed/26694904
478. Hisasue, S., et al. Impact of aging and comorbidity on the efficacy of low-intensity shock wave
therapy for erectile dysfunction. Int J Urol, 2016. 23: 80.
https://www.ncbi.nlm.nih.gov/pubmed/26501992
479. Young Academic Urologists Men's Health, G., et al. Low-intensity shockwave therapy for erectile
dysfunction: is the evidence strong enough? Nat Rev Urol, 2017. 14: 593.
https://www.ncbi.nlm.nih.gov/pubmed/28741629
480. Sokolakis, I., et al. Clinical studies on low intensity extracorporeal shockwave therapy for erectile
dysfunction: a systematic review and meta-analysis of randomised controlled trials. Int J Impot Res,
2019. 31: 177.
https://www.ncbi.nlm.nih.gov/pubmed/30664671
481. Porst, H. Review of the Current Status of Low Intensity Extracorporeal Shockwave Therapy (Li-ESWT)
in Erectile Dysfunction (ED), Peyronie's Disease (PD), and Sexual Rehabilitation After Radical
Prostatectomy With Special Focus on Technical Aspects of the Different Marketed ESWT Devices
Including Personal Experiences in 350 Patients. Sex Med Rev, 2021. 9: 93.
https://www.ncbi.nlm.nih.gov/pubmed/32499189
482. Kalyvianakis, D., et al. Low-intensity shockwave therapy (LiST) for erectile dysfunction: a randomized
clinical trial assessing the impact of energy flux density (EFD) and frequency of sessions. Int J Impot
Res, 2020. 32: 329.
https://www.ncbi.nlm.nih.gov/pubmed/31474753
483. Sandoval-Salinas, C., et al. Are Radial Pressure Waves Effective for the Treatment of Moderate or
Mild to Moderate Erectile Dysfunction? A Randomized Sham Therapy Controlled Clinical Trial. J Sex
Med, 2022. 19: 738.
https://www.ncbi.nlm.nih.gov/pubmed/35341724
484. Kalyvianakis, D., et al. Low-Intensity Shockwave Therapy Improves Hemodynamic Parameters in
Patients With Vasculogenic Erectile Dysfunction: A Triplex Ultrasonography-Based Sham-Controlled
Trial. J Sex Med, 2017. 14: 891.
https://www.ncbi.nlm.nih.gov/pubmed/28673433
485. Bechara, A., et al. Twelve-Month Efficacy and Safety of Low-Intensity Shockwave Therapy for Erectile
Dysfunction in Patients Who Do Not Respond to Phosphodiesterase Type 5 Inhibitors. Sex Med,
2016. 4: e225.
https://www.ncbi.nlm.nih.gov/pubmed/27444215
486. Vinay, J., et al. Penile low intensity shock wave treatment for PDE5I refractory erectile dysfunction: a
randomized double-blind sham-controlled clinical trial. World J Urol, 2021. 39: 2217.
https://www.ncbi.nlm.nih.gov/pubmed/32696128

186 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

487. Lu, Z., et al. Low-intensity Extracorporeal Shock Wave Treatment Improves Erectile Function: A
Systematic Review and Meta-analysis. Eur Urol, 2017. 71: 223.
https://www.ncbi.nlm.nih.gov/pubmed/27321373
488. Chung, E., et al. Evaluation of Long-Term Clinical Outcomes and Patient Satisfaction Rate Following
Low Intensity Shock Wave Therapy in Men With Erectile Dysfunction: A Minimum 5-Year Follow-Up on
a Prospective Open-Label Single-Arm Clinical Study. Sex Med, 2021. 9: 100384.
https://www.ncbi.nlm.nih.gov/pubmed/34126432
489. Kaynak, Y., et al. Long-term effects of combination treatment comprising low-intensity extracorporeal
shockwave therapy and tadalafil for patients with erectile dysfunction: a retrospective study. Int J
Impot Res, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37644168
490. Mykoniatis, I., et al. The Effect of Combination Treatment With Low-Intensity Shockwave Therapy and
Tadalafil on Mild and Mild-To-Moderate Erectile Dysfunction: A Double-Blind, Randomized, Placebo-
Controlled Clinical Trial. J Sex Med, 2022. 19: 106.
https://www.ncbi.nlm.nih.gov/pubmed/34866029
491. Rho, B.Y., et al. Efficacy of Low-Intensity Extracorporeal Shock Wave Treatment in Erectile
Dysfunction Following Radical Prostatectomy: A Systematic Review and Meta-Analysis. J Clin Med,
2022. 11.
https://www.ncbi.nlm.nih.gov/pubmed/35628901
492. Sighinolfi, M.C., et al. Low-intensity Extracorporeal Shockwave Therapy for the Management of
Postprostatectomy Erectile Dysfunction: A Systematic Review of the Literature. Eur Urol Open Sci,
2022. 43: 45.
https://www.ncbi.nlm.nih.gov/pubmed/35928730
493. Matthew, A.N., et al. The use of low-intensity extracorporeal shockwave therapy in management of
erectile dysfunction following prostate cancer treatment: a review of the current literature. Transl
Androl Urol, 2023. 12: 1023.
https://www.ncbi.nlm.nih.gov/pubmed/37426598
494. Epifanova M, et al. Combined therapy for treating erectile dysfunction: First results on the use of low
intensity extracorporeal shock wave therapy and platelet-rich plasma. BJU Int, 2019. 123.

495. Banno JJ, et al. The efficacy of platelet-rich plasma (PRP) as a supplemental therapy for the
treatment of erectile dysfunction (ED): Initial outcomes. J Sex Med, 2017. 14.
496. Chalyj, M.E., et al. [the Effectiveness of Intracavernous Autologous Platelet-Rich Plasma in the
Treatment of Erectile Dysfunction]. Urologiia, 2015: 76.
https://www.ncbi.nlm.nih.gov/pubmed/26665770
497. Ruffo, A., et al. Effectiveness and safety of Platelet rich Plasma (PrP) cavernosal injections plus
external shock wave treatment for penile erectile dysfunction: First results from a prospective,
randomized, controlled, interventional study. European Urology Supplements, 2019. 18: e1622.
https://urosource.uroweb.org/resource-centres/EAU19/187172/abstract
498. Matz, E.L., et al. Safety and feasibility of platelet rich fibrin matrix injections for treatment of common
urologic conditions. Investig Clin Urol, 2018. 59: 61.
https://www.ncbi.nlm.nih.gov/pubmed/29333517
499. Alkhayal, S., et al. PO-01-091 Platelet Rich Plasma Penile Rejuvenation as a Treatment for Erectile
Dysfunction: An Update. The Journal of Sexual Medicine, 2019. 16: S71.
https://doi.org/10.1016/j.jsxm.2019.03.228
500. Poulios, E., et al. Platelet-Rich Plasma (PRP) Improves Erectile Function: A Double-Blind, Randomized,
Placebo-Controlled Clinical Trial. J Sex Med, 2021. 18: 926.
https://www.ncbi.nlm.nih.gov/pubmed/33906807
501. Oudelaar, B.W., et al. Concentrations of Blood Components in Commercial Platelet-Rich Plasma
Separation Systems: A Review of the Literature. Am J Sports Med, 2019. 47: 479.
https://www.ncbi.nlm.nih.gov/pubmed/29337592
502. Shaher, H., et al. Is Platelet Rich Plasma Safe and Effective in Treatment of Erectile Dysfunction?
Randomized Controlled Study. Urology, 2023. 175: 114.
https://www.ncbi.nlm.nih.gov/pubmed/36736914
503. Masterson, T.A., et al. Platelet-rich Plasma for the Treatment of Erectile Dysfunction: A Prospective,
Randomized, Double-blind, Placebo-controlled Clinical Trial. Reply. J Urol, 2023. 210: 734.
https://www.ncbi.nlm.nih.gov/pubmed/37811758

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 187

504. Panunzio, A., et al. Platelet-rich plasma intracavernosal injections for the treatment of primary
organic erectile dysfunction: a systematic review and meta-analysis of contemporary controlled
studies. Int J Impot Res, 2024. 36: 562.
https://www.ncbi.nlm.nih.gov/pubmed/37993601
505. Panunzio, A., et al. Platelet-rich plasma intracavernosal injections for the treatment of primary
organic erectile dysfunction: a systematic review and meta-analysis of contemporary controlled
studies. Int J Impot Res, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37993601
506. Khodamoradi, K., et al. Platelet Rich Plasma (PRP) Growth Factor Concentration Varies in Men With
Erectile Dysfunction. J Sex Med, 2022. 19: 1488.
https://www.ncbi.nlm.nih.gov/pubmed/35817715
507. Furtado, T.P., et al. Stem cell therapy for erectile dysfunction: a systematic review. Sex Med Rev, 2023.
12: 87.
https://www.ncbi.nlm.nih.gov/pubmed/37758225
508. Reddy, A.G., et al. Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We
Now? Sex Med Rev, 2021. 9: 320.
https://www.ncbi.nlm.nih.gov/pubmed/32641225
509. Abdelrahman, I.F.S., et al. Safety and efficacy of botulinum neurotoxin in the treatment of erectile
dysfunction refractory to phosphodiesterase inhibitors: Results of a randomized controlled trial.
Andrology, 2022. 10: 254.
https://www.ncbi.nlm.nih.gov/pubmed/34618409
510. El-Shaer, W., et al. Intra-cavernous injection of BOTOX((R)) (50 and 100 Units) for treatment of
vasculogenic erectile dysfunction: Randomized controlled trial. Andrology, 2021. 9: 1166.
https://www.ncbi.nlm.nih.gov/pubmed/33784020
511. Giuliano, F., et al. Long Term Effectiveness and Safety of Intracavernosal Botulinum Toxin A as an
Add-on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 Injections for Erectile
Dysfunction. J Sex Med, 2022. 19: 83.
https://www.ncbi.nlm.nih.gov/pubmed/34937674
512. Giuliano, F., et al. Safety and Efficacy of Intracavernosal Injections of AbobotulinumtoxinA
(Dysport((R))) as Add on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 for
Erectile Dysfunction-Case Studies. Toxins (Basel), 2019. 11.
https://www.ncbi.nlm.nih.gov/pubmed/31117236
513. Lee, H.W., et al. Ginseng for Erectile Dysfunction: A Cochrane Systematic Review. World J Mens
Health, 2022. 40: 264.
https://www.ncbi.nlm.nih.gov/pubmed/34169686
514. Su, L., et al. Effect of Antioxidants Supplementation on Erectile Dysfunction: A Systematic Review
and Meta-Analysis of Randomized Controlled Trials. Sex Med Rev, 2022. 10: 754.
https://www.ncbi.nlm.nih.gov/pubmed/35246405
515. Baunacke, M., et al. Urologist communication is a primary factor leading to erectile dysfunction
treatment postprostatectomy. J Sex Med, 2024. 21: 904.
https://www.ncbi.nlm.nih.gov/pubmed/39214554
516. Jo, J.K., et al. Effect of Starting Penile Rehabilitation with Sildenafil Immediately after Robot-Assisted
Laparoscopic Radical Prostatectomy on Erectile Function Recovery: A Prospective Randomized Trial.
J Urol, 2018. 199: 1600.
https://www.ncbi.nlm.nih.gov/pubmed/29307683
517. Montorsi, F., et al. Effect of nightly versus on-demand vardenafil on recovery of erectile function in
men following bilateral nerve-sparing radical prostatectomy. Eur Urol, 2008. 54: 924.
https://www.ncbi.nlm.nih.gov/pubmed/18640769
518. Montorsi, F., et al. Effects of tadalafil treatment on erectile function recovery following bilateral nerve-
sparing radical prostatectomy: a randomised placebo-controlled study (REACTT). Eur Urol, 2014. 65:
587.
https://www.ncbi.nlm.nih.gov/pubmed/24169081
519. Noh, T.I., et al. Efficacy of Tadalafil in Penile Rehabilitation Started Before Nerve-Sparing Robot-
Assisted Radical Prostatectomy: A Double-Blind Pilot Study. Sex Med, 2022. 10: 100508.
https://www.ncbi.nlm.nih.gov/pubmed/35395569
520. Montorsi, F., et al. Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial
of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing
Radical Prostatectomy. Eur Urol, 2016. 70: 529.
https://www.ncbi.nlm.nih.gov/pubmed/26947602

188 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

521. Philippou, Y.A., et al. Penile rehabilitation for postprostatectomy erectile dysfunction. Cochrane
Database Syst Rev, 2018. 10: CD012414.
https://www.ncbi.nlm.nih.gov/pubmed/30352488
522. Sari Motlagh, R., et al. Penile Rehabilitation Strategy after Nerve Sparing Radical Prostatectomy: A
Systematic Review and Network Meta-Analysis of Randomized Trials. J Urol, 2021. 205: 1018.
https://www.ncbi.nlm.nih.gov/pubmed/33443457
523. Sridhar, A.N., et al. Recovery of Baseline Erectile Function in Men Following Radical Prostatectomy
for High-Risk Prostate Cancer: A Prospective Analysis Using Validated Measures. J Sex Med, 2016.
13: 435.
https://www.ncbi.nlm.nih.gov/pubmed/26944466
524. Qin, F., et al. The Early Use of Vacuum Therapy for Penile Rehabilitation After Radical Prostatectomy:
Systematic Review and Meta-Analysis. Am J Mens Health, 2018. 12: 2136.
https://www.ncbi.nlm.nih.gov/pubmed/30182794
525. Feng, D., et al. Generating comprehensive comparative evidence on various interventions for penile
rehabilitation in patients with erectile dysfunction after radical prostatectomy: a systematic review
and network meta-analysis. Transl Androl Urol, 2021. 10: 109.
https://www.ncbi.nlm.nih.gov/pubmed/33532301
526. Toussi, A., et al. Efficacy of a Novel Penile Traction Device in Improving Penile Length and Erectile
Function Post Prostatectomy: Results from a Single-Center Randomized, Controlled Trial. J Urol,
2021. 206: 416.
https://www.ncbi.nlm.nih.gov/pubmed/34060339
527. Wong, C., et al. A Systematic Review of Pelvic Floor Muscle Training for Erectile Dysfunction After
Prostatectomy and Recommendations to Guide Further Research. J Sex Med, 2020. 17: 737.
https://www.ncbi.nlm.nih.gov/pubmed/32029399
528. Sohn, M., et al. Standard operating procedures for vascular surgery in erectile dysfunction:
revascularization and venous procedures. J Sex Med, 2013. 10: 172.
https://www.ncbi.nlm.nih.gov/pubmed/23171072
529. Antonini, G., et al. Minimally invasive infrapubic inflatable penile prosthesis implant for erectile
dysfunction: evaluation of efficacy, satisfaction profile and complications. Int J Impot Res, 2016. 28:
4.
https://www.ncbi.nlm.nih.gov/pubmed/26657316
530. Hellstrom, W.J., et al. Implants, mechanical devices, and vascular surgery for erectile dysfunction. J
Sex Med, 2010. 7: 501.
https://www.ncbi.nlm.nih.gov/pubmed/20092450
531. Martinez-Salamanca, J.I., et al. Penile prosthesis surgery in patients with corporal fibrosis: a state of
the art review. J Sex Med, 2011. 8: 1880.
https://www.ncbi.nlm.nih.gov/pubmed/21492405
532. Montague, D.K. Penile prosthesis implantation in the era of medical treatment for erectile
dysfunction. Urol Clin North Am, 2011. 38: 217.
https://www.ncbi.nlm.nih.gov/pubmed/21621088
533. Casabe, A.R., et al. Satisfaction assessment with malleable prosthetic implant of Spectra (AMS) and
Genesis (Coloplast) models. Int J Impot Res, 2016. 28: 228.
https://www.ncbi.nlm.nih.gov/pubmed/27557609
534. Atri, E., et al. A Comparison Between AMS 700 and Coloplast Titan: A Systematic Literature Review.
Cureus, 2020. 12: e11350.
https://www.ncbi.nlm.nih.gov/pubmed/33304685
535. Mulcahy, J.J., et al. The penile implant for erectile dysfunction. J Sex Med, 2004. 1: 98.
https://www.ncbi.nlm.nih.gov/pubmed/16422990
536. Montague, D.K., et al. Penile prosthesis implantation. Urol Clin North Am, 2001. 28: 355.
https://www.ncbi.nlm.nih.gov/pubmed/11402587
537. Palmisano, F., et al. Comparison of Infrapubic vs Penoscrotal Approaches for 3-Piece Inflatable
Penile Prosthesis Placement: Do We Have a Winner? Sex Med Rev, 2018. 6: 631.
https://www.ncbi.nlm.nih.gov/pubmed/29730314
538. Bettocchi, C., et al. Patient and partner satisfaction after AMS inflatable penile prosthesis implant. J
Sex Med, 2010. 7: 304.
https://www.ncbi.nlm.nih.gov/pubmed/19758282
539. Chung, E., et al. Penile prosthesis implantation for the treatment for male erectile dysfunction: clinical
outcomes and lessons learnt after 955 procedures. World J Urol, 2013. 31: 591.
https://www.ncbi.nlm.nih.gov/pubmed/22457032

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 189

540. Falcone, M., et al. Prospective analysis of the surgical outcomes and patients' satisfaction rate after
the AMS Spectra penile prosthesis implantation. Urology, 2013. 82: 373.
https://www.ncbi.nlm.nih.gov/pubmed/23791218
541. Henry, G.D., et al. A survey of patients with inflatable penile prostheses: assessment of timing and
frequency of intercourse and analysis of implant durability. J Sex Med, 2012. 9: 1715.
https://www.ncbi.nlm.nih.gov/pubmed/22568579
542. Kim, D.S., et al. AMS 700CX/CXM inflatable penile prosthesis has high mechanical reliability at long-
term follow-up. J Sex Med, 2010. 7: 2602.
https://www.ncbi.nlm.nih.gov/pubmed/20384938
543. Lux, M., et al. Outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. J Urol,
2007. 177: 262.
https://www.ncbi.nlm.nih.gov/pubmed/17162061
544. Natali, A., et al. Penile implantation in Europe: successes and complications with 253 implants in Italy
and Germany. J Sex Med, 2008. 5: 1503.
https://www.ncbi.nlm.nih.gov/pubmed/18410306
545. Otero, J.R., et al. Comparison of the patient and partner satisfaction with 700CX and Titan penile
prostheses. Asian J Androl, 2017. 19: 321.
https://www.ncbi.nlm.nih.gov/pubmed/26806085
546. Chierigo, F., et al. Long-Term Follow-Up After Penile Prosthesis Implantation-Survival and Quality of
Life Outcomes. J Sex Med, 2019. 16: 1827.
https://www.ncbi.nlm.nih.gov/pubmed/31501062
547. Pisano, F., et al. The importance of psychosexual counselling in the re-establishment of organic and
erotic functions after penile prosthesis implantation. Int J Impot Res, 2015. 27: 197.
https://www.ncbi.nlm.nih.gov/pubmed/26268774
548. Akakpo, W., et al. Critical Analysis of Satisfaction Assessment After Penile Prosthesis Surgery. Sex
Med Rev, 2017. 5: 244.
https://www.ncbi.nlm.nih.gov/pubmed/28143706
549. Carson, C.C., et al. Efficacy, safety and patient satisfaction outcomes of the AMS 700CX inflatable
penile prosthesis: results of a long-term multicenter study. AMS 700CX Study Group. J Urol, 2000.
164: 376.
https://www.ncbi.nlm.nih.gov/pubmed/10893589
550. Wilson, S.K., et al. Comparison of mechanical reliability of original and enhanced Mentor Alpha I
penile prosthesis. J Urol, 1999. 162: 715.
https://www.ncbi.nlm.nih.gov/pubmed/10458350
551. Miller, L.E., et al. Long-Term Survival Rates of Inflatable Penile Prostheses: Systematic Review and
Meta-Analysis. Urology, 2022. 166: 6.
https://www.ncbi.nlm.nih.gov/pubmed/35421510
552. Mandava, S.H., et al. Infection retardant coated inflatable penile prostheses decrease the incidence
of infection: a systematic review and meta-analysis. J Urol, 2012. 188: 1855.
https://www.ncbi.nlm.nih.gov/pubmed/22999690
553. Trost, L.W., et al. Long-term outcomes of penile prostheses for the treatment of erectile dysfunction.
Expert Rev Med Devices, 2013. 10: 353.
https://www.ncbi.nlm.nih.gov/pubmed/23668707
554. Chung, E., et al. A Worldwide Survey on Peyronie's Disease Surgical Practice Patterns Among
Surgeons. J Sex Med, 2018. 15: 568.
https://www.ncbi.nlm.nih.gov/pubmed/29550462
555. Mahon, J., et al. Infectious Adverse Events Following the Placement of a Penile Prosthesis: A
Systematic Review. Sex Med Rev, 2020. 8: 348.
https://www.ncbi.nlm.nih.gov/pubmed/31519461
556. Carson, C.C., 3rd, et al. Long-term infection outcomes after original antibiotic impregnated inflatable
penile prosthesis implants: up to 7.7 years of followup. J Urol, 2011. 185: 614.
https://www.ncbi.nlm.nih.gov/pubmed/21168870
557. Darouiche, R.O., et al. North American consensus document on infection of penile prostheses.
Urology, 2013. 82: 937.
https://www.ncbi.nlm.nih.gov/pubmed/23958508
558. Serefoglu, E.C., et al. Long-term revision rate due to infection in hydrophilic-coated inflatable penile
prostheses: 11-year follow-up. J Sex Med, 2012. 9: 2182.
https://www.ncbi.nlm.nih.gov/pubmed/22759917

190 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

559. Zargaroff, S., et al. National trends in the treatment of penile prosthesis infections by explantation
alone vs. immediate salvage and reimplantation. J Sex Med, 2014. 11: 1078.
https://www.ncbi.nlm.nih.gov/pubmed/24628707
560. Pineda, M., et al. Penile Prosthesis Infections-A Review of Risk Factors, Prevention, and Treatment.
Sex Med Rev, 2016. 4: 389.
https://www.ncbi.nlm.nih.gov/pubmed/27872031
561. Dropkin, B.M., et al. Antibiotics and Inflatable Penile Prosthesis Insertion: A Literature Review. Sex
Med Rev, 2021. 9: 174.
https://www.ncbi.nlm.nih.gov/pubmed/32631811
562. Bode, L.G., et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N
Engl J Med, 2010. 362: 9.
https://www.ncbi.nlm.nih.gov/pubmed/20054045
563. Lipsky, M.J., et al. Diabetes Is a Risk Factor for Inflatable Penile Prosthesis Infection: Analysis of a
Large Statewide Database. Sex Med, 2019. 7: 35.
https://www.ncbi.nlm.nih.gov/pubmed/30674445
564. Towe, M., et al. Impact of Antimicrobial Dipping Solutions on Postoperative Infection Rates
in Patients With Diabetes Undergoing Primary Insertion of a Coloplast Titan Inflatable Penile
Prosthesis. J Sex Med, 2020. 17: 2077.
https://www.ncbi.nlm.nih.gov/pubmed/32807707
565. Patel, D.P., et al. Hypogonadism Associated With Higher Rate of Penile Prosthesis Infection: An
Analysis of United States Claims Data. Urology, 2022. 167: 132.
https://www.ncbi.nlm.nih.gov/pubmed/35768026
566. Pang, K.H., et al. A Systematic Review of Penile Prosthesis Insertion in Patients With Spinal Cord
Injury. Sex Med Rev, 2022. 10: 468.
https://www.ncbi.nlm.nih.gov/pubmed/35221231
567. Mulcahy, J.J. Long-term experience with salvage of infected penile implants. J Urol, 2000. 163: 481.
https://www.ncbi.nlm.nih.gov/pubmed/10647660
568. Henry, G.D., et al. An outcomes analysis of over 200 revision surgeries for penile prosthesis
implantation: a multicenter study. J Sex Med, 2012. 9: 309.
https://www.ncbi.nlm.nih.gov/pubmed/22082149
569. Gross, M.S., et al. The Malleable Implant Salvage Technique: Infection Outcomes after Mulcahy
Salvage Procedure and Replacement of Infected Inflatable Penile Prosthesis with Malleable
Prosthesis. J Urol, 2016. 195: 694.
https://www.ncbi.nlm.nih.gov/pubmed/26343986
570. Scherzer, N.D., et al. Penile Prosthesis Complications: Planning, Prevention, and Decision Making.
Sex Med Rev, 2019. 7: 349.
https://www.ncbi.nlm.nih.gov/pubmed/30033128
571. Clavell-Hernandez, J., et al. Non-Infectious Reservoir-Related Complications During and After Penile
Prosthesis Placement. Sex Med Rev, 2019. 7: 521.
https://www.ncbi.nlm.nih.gov/pubmed/30786958
572. Hebert, K., et al. Acute Post-Inflatable Penile Prosthesis Glans Ischemia: Review of Incidence,
Pathophysiology, and Management Recommendations. J Sex Med, 2019. 16: 1.
https://www.ncbi.nlm.nih.gov/pubmed/30509507
573. Clement, P., et al. Physiology and Pharmacology of Ejaculation. Basic Clin Pharmacol Toxicol, 2016.
119 Suppl 3: 18.
https://www.ncbi.nlm.nih.gov/pubmed/26709195
574. Waldinger, M.D. The neurobiological approach to premature ejaculation. J Urol, 2002. 168: 2359.
https://www.ncbi.nlm.nih.gov/pubmed/12441918
575. Gao, J., et al. The impact of intravaginal ejaculatory latency time and erectile function on anxiety
and depression in the four types of premature ejaculation: a large cross-sectional study in a Chinese
population. J Sex Med, 2014. 11: 521.
https://www.ncbi.nlm.nih.gov/pubmed/24274171
576. Kempeneers, P., et al. Sexual Cognitions, Trait Anxiety, Sexual Anxiety, and Distress in Men With
Different Subtypes of Premature Ejaculation and in Their Partners. J Sex Marital Ther, 2018. 44: 319.
https://www.ncbi.nlm.nih.gov/pubmed/29161211
577. Ventus, D., et al. No Evidence for Long-Term Causal Associations Between Symptoms of Premature
Ejaculation and Symptoms of Anxiety, Depression, and Sexual Distress in a Large, Population-Based
Longitudinal Sample. J Sex Res, 2017. 54: 264.
https://www.ncbi.nlm.nih.gov/pubmed/27982691

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 191

578. Yang, Y., et al. Correlations and stratification analysis between premature ejaculation and
psychological disorders. Andrologia, 2019. 51: e13315.
https://www.ncbi.nlm.nih.gov/pubmed/31090231
579. Wiggins, A., et al. The Penile Sensitivity Ratio: A Novel Application of Biothesiometry to Assess
Changes in Penile Sensitivity. J Sex Med, 2019. 16: 447.
https://www.ncbi.nlm.nih.gov/pubmed/30773499
580. Chen, X., et al. Penile sensory thresholds in subtypes of premature ejaculation: implications of
comorbid erectile dysfunction. Asian J Androl, 2018. 20: 330.
https://www.ncbi.nlm.nih.gov/pubmed/29405168
581. Guo, L., et al. Significance of penile hypersensitivity in premature ejaculation. Sci Rep, 2017. 7: 10441.
https://www.ncbi.nlm.nih.gov/pubmed/28874780
582. Xia, J.D., et al. A reassessment of penile sensory pathways and effects of prilocaine-lidocaine cream
in primary premature ejaculation. Int J Impot Res, 2014. 26: 186.
https://www.ncbi.nlm.nih.gov/pubmed/24572995
583. Salonia, A., et al. Quantitative sensory testing of peripheral thresholds in patients with lifelong
premature ejaculation: a case-controlled study. J Sex Med, 2009. 6: 1755.
https://www.ncbi.nlm.nih.gov/pubmed/19453912
584. Xin, Z.C., et al. Somatosensory evoked potentials in patients with primary premature ejaculation. J
Urol, 1997. 158: 451.
https://www.ncbi.nlm.nih.gov/pubmed/9224321
585. Xin, Z.C., et al. Penile sensitivity in patients with primary premature ejaculation. J Urol, 1996. 156:
979.
https://www.ncbi.nlm.nih.gov/pubmed/8709378
586. Sun, Z., et al. A Study of Differences in Penile Dorsal Nerve Somatosensory Evoked Potential Testing
Among Healthy Controls and Patients With Primary and Secondary Premature Ejaculation. J Sex
Med, 2021. 18: 732.
https://www.ncbi.nlm.nih.gov/pubmed/33744179
587. Khan, H.L., et al. Serotonin transporter (5-HTTLPR) genotypes and trinucleotide repeats of androgen
receptor exert a combinatorial effect on hormonal milieu in patients with lifelong premature
ejaculation. Andrology, 2018. 6: 916.
https://www.ncbi.nlm.nih.gov/pubmed/30019487
588. Roaiah, M.F., et al. Study of the prevalence of 5 HT-2C receptor gene polymorphisms in Egyptian
patients with lifelong premature ejaculation. Andrologia, 2018. 50.
https://www.ncbi.nlm.nih.gov/pubmed/28730747
589. Janssen, P.K., et al. The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal
ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. Asian J Androl,
2014. 16: 607.
https://www.ncbi.nlm.nih.gov/pubmed/24799636
590. Janssen, P.K., et al. The 5-HT(1)A receptor C(1019)G polymorphism influences the intravaginal
ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. Pharmacol
Biochem Behav, 2014. 121: 184.
https://www.ncbi.nlm.nih.gov/pubmed/24440118
591. Hsieh, J.T., et al. The activation of peripheral 5-HT1A receptors can inhibit seminal vesicle
contraction: an in vivo animal study. Urology, 2011. 78: 376.
https://www.ncbi.nlm.nih.gov/pubmed/21676447
592. Janssen, P.K., et al. Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated
with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation. J Sex
Med, 2009. 6: 276.
https://www.ncbi.nlm.nih.gov/pubmed/19170855
593. Waldinger, M.D., et al. Changing paradigms from a historical DSM-III and DSM-IV view toward an
evidence-based definition of premature ejaculation. Part I--validity of DSM-IV-TR. J Sex Med, 2006. 3:
682.
https://www.ncbi.nlm.nih.gov/pubmed/16839325
594. Waldinger, M.D., et al. Changing paradigms from a historical DSM-III and DSM-IV view toward an
evidence-based definition of premature ejaculation. Part II--proposals for DSM-V and ICD-11. J Sex
Med, 2006. 3: 693.
https://www.ncbi.nlm.nih.gov/pubmed/16839326

192 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

595. Waldinger, M.D., et al. Method and design of drug treatment research of subjective premature
ejaculation in men differs from that of lifelong premature ejaculation in males: proposal for a new
objective measure (part 1). Int J Impot Res, 2019. 31: 328.
https://www.ncbi.nlm.nih.gov/pubmed/30647430
596. Waldinger, M.D. The pathophysiology of lifelong premature ejaculation. Transl Androl Urol, 2016. 5:
424.
https://www.ncbi.nlm.nih.gov/pubmed/27652215
597. Carani, C., et al. Multicenter study on the prevalence of sexual symptoms in male hypo- and
hyperthyroid patients. J Clin Endocrinol Metab, 2005. 90: 6472.
https://www.ncbi.nlm.nih.gov/pubmed/16204360
598. Corona, G., et al. Psycho-biological correlates of rapid ejaculation in patients attending an andrologic
unit for sexual dysfunctions. Eur Urol, 2004. 46: 615.
https://www.ncbi.nlm.nih.gov/pubmed/15474272
599. McMahon, C.G., et al. The pathophysiology of acquired premature ejaculation. Transl Androl Urol,
2016. 5: 434.
https://www.ncbi.nlm.nih.gov/pubmed/27652216
600. Zhang, W., et al. Poor Sleep Quality is an Independent Risk Factor for Acquired Premature Ejaculation.
Nat Sci Sleep, 2022. 14: 255.
https://www.ncbi.nlm.nih.gov/pubmed/35228824
601. Murray, K.S., et al. A prospective study of erectile function after transrectal ultrasonography-guided
prostate biopsy. BJU Int, 2015. 116: 190.
https://www.ncbi.nlm.nih.gov/pubmed/25430505
602. Verze, P., et al. Premature Ejaculation Among Italian Men: Prevalence and Clinical Correlates From an
Observational, Non-Interventional, Cross-Sectional, Epidemiological Study (IPER). Sex Med, 2018. 6:
193.
https://www.ncbi.nlm.nih.gov/pubmed/29803639
603. Carson, C., et al. Premature ejaculation: definition and prevalence. Int J Impot Res, 2006. 18 Suppl 1:
S5.
https://www.ncbi.nlm.nih.gov/pubmed/16953247
604. Richardson, D., et al. Premature ejaculation--does country of origin tell us anything about etiology? J
Sex Med, 2005. 2: 508.
https://www.ncbi.nlm.nih.gov/pubmed/16422845
605. Waldinger, M.D., et al. Familial occurrence of primary premature ejaculation. Psychiatr Genet, 1998. 8:
37.
https://www.ncbi.nlm.nih.gov/pubmed/9564687
606. Janssen, P.K., et al. Measurement errors in polymerase chain reaction are a confounding factor for a
correct interpretation of 5-HTTLPR polymorphism effects on lifelong premature ejaculation: a critical
analysis of a previously published meta-analysis of six studies. PLoS One, 2014. 9: e88031.
https://www.ncbi.nlm.nih.gov/pubmed/24595335
607. Jern, P., et al. A reassessment of the possible effects of the serotonin transporter gene linked
polymorphism 5-HTTLPR on premature ejaculation. Arch Sex Behav, 2013. 42: 45.
https://www.ncbi.nlm.nih.gov/pubmed/22810993
608. Jern, P., et al. Preliminary Evidence for an Association Between Variants of the Catechol-O-
Methyltransferase (COMT) Gene and Premature Ejaculation. J Sex Med, 2017. 14: 1558.
https://www.ncbi.nlm.nih.gov/pubmed/29198511
609. Kim, M., et al. Erectile dysfunction in patients with liver disease related to chronic hepatitis B. Clin
Mol Hepatol, 2015. 21: 352.
https://www.ncbi.nlm.nih.gov/pubmed/26770923
610. Screponi, E., et al. Prevalence of chronic prostatitis in men with premature ejaculation. Urology, 2001.
58: 198.
https://www.ncbi.nlm.nih.gov/pubmed/11489699
611. Shamloul, R., et al. Chronic prostatitis in premature ejaculation: a cohort study in 153 men. J Sex
Med, 2006. 3: 150.
https://www.ncbi.nlm.nih.gov/pubmed/16409229
612. Chierigo, F., et al. Lower urinary tract symptoms and depressive symptoms among patients
presenting for distressing early ejaculation. Int J Impot Res, 2020. 32: 207.
https://www.ncbi.nlm.nih.gov/pubmed/31024115
613. Culha, M.G., et al. Frequency of etiological factors among patients with acquired premature
ejaculation: prospective, observational, single-center study. Int J Impot Res, 2020. 32: 352.
https://www.ncbi.nlm.nih.gov/pubmed/31477853

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 193

614. Corona, G., et al. Hypoprolactinemia: a new clinical syndrome in patients with sexual dysfunction. J
Sex Med, 2009. 6: 1457.
https://www.ncbi.nlm.nih.gov/pubmed/19210705
615. Corona, G., et al. Premature and delayed ejaculation: two ends of a single continuum influenced by
hormonal milieu. Int J Androl, 2011. 34: 41.
https://www.ncbi.nlm.nih.gov/pubmed/20345874
616. Kadihasanoglu, M., et al. Relation between blood vitamin B12 levels with premature ejaculation: case-
control study. Andrologia, 2017. 49.
https://www.ncbi.nlm.nih.gov/pubmed/27681841
617. Abd El Aal, A.M., et al. Serum vitamin D level may be a novel potential risk factor for premature
ejaculation: a comparative study. Int Urol Nephrol, 2018. 50: 1975.
https://www.ncbi.nlm.nih.gov/pubmed/30155606
618. Majzoub, A., et al. Premature ejaculation in type II diabetes mellitus patients: association with
glycemic control. Transl Androl Urol, 2016. 5: 248.
https://www.ncbi.nlm.nih.gov/pubmed/27141454
619. Bellastella, G., et al. Premature ejaculation is associated with glycemic control in Type 1 diabetes. J
Sex Med, 2015. 12: 93.
https://www.ncbi.nlm.nih.gov/pubmed/25424355
620. Jeh, S.U., et al. Metabolic Syndrome Is an Independent Risk Factor for Acquired Premature
Ejaculation. World J Mens Health, 2019. 37: 226.
https://www.ncbi.nlm.nih.gov/pubmed/30588783
621. Bolat, D., et al. The relationship between acquired premature ejaculation and metabolic syndrome: a
prospective, comparative study. Int J Impot Res, 2017. 29: 105.
https://www.ncbi.nlm.nih.gov/pubmed/28179637
622. Ventus, D., et al. Lifestyle Factors and Premature Ejaculation: Are Physical Exercise, Alcohol
Consumption, and Body Mass Index Associated With Premature Ejaculation and Comorbid Erectile
Problems? J Sex Med, 2016. 13: 1482.
https://www.ncbi.nlm.nih.gov/pubmed/27590186
623. Dunn, K.M., et al. Association of sexual problems with social, psychological, and physical problems in
men and women: a cross sectional population survey. J Epidemiol Community Health, 1999. 53: 144.
https://www.ncbi.nlm.nih.gov/pubmed/10396490
624. Xia, Y., et al. Relationship between premature ejaculation and depression: A PRISMA-compliant
systematic review and meta-analysis. Medicine (Baltimore), 2016. 95: e4620.
https://www.ncbi.nlm.nih.gov/pubmed/27583879
625. Rowland, D., et al. Self-reported premature ejaculation and aspects of sexual functioning and
satisfaction. J Sex Med, 2004. 1: 225.
https://www.ncbi.nlm.nih.gov/pubmed/16429622
626. Rowland, D.L., et al. The psychological burden of premature ejaculation. J Urol, 2007. 177: 1065.
https://www.ncbi.nlm.nih.gov/pubmed/17296413
627. Hanafy, S., et al. Prevalence of premature ejaculation and its impact on the quality of life: Results
from a sample of Egyptian patients. Andrologia, 2019. 51: e13298.
https://www.ncbi.nlm.nih.gov/pubmed/31025424
628. Abdo, C.H. The impact of ejaculatory dysfunction upon the sufferer and his partner. Transl Androl
Urol, 2016. 5: 460.
https://www.ncbi.nlm.nih.gov/pubmed/27652218
629. Burri, A., et al. Female partner's perception of premature ejaculation and its impact on relationship
breakups, relationship quality, and sexual satisfaction. J Sex Med, 2014. 11: 2243.
https://www.ncbi.nlm.nih.gov/pubmed/24774717
630. Byers, E.S., et al. Premature or rapid ejaculation: heterosexual couples' perceptions of men's
ejaculatory behavior. Arch Sex Behav, 2003. 32: 261.
https://www.ncbi.nlm.nih.gov/pubmed/12807298
631. Canat, L., et al. The relationship between female sexual function index domains and premature
ejaculation. Int Urol Nephrol, 2018. 50: 633.
https://www.ncbi.nlm.nih.gov/pubmed/29497891
632. Limoncin, E., et al. Premature ejaculation results in female sexual distress: standardization and
validation of a new diagnostic tool for sexual distress. J Urol, 2013. 189: 1830.
https://www.ncbi.nlm.nih.gov/pubmed/23142691
633. Zucker, I., et al. Majority of men with premature ejaculation do not receive pharmacotherapy. Int J
Impot Res, 2023. 35: 544.
https://www.ncbi.nlm.nih.gov/pubmed/35840677

194 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

634. Solursh, D.S., et al. The human sexuality education of physicians in North American medical schools.
Int J Impot Res, 2003. 15 Suppl 5: S41.
https://www.ncbi.nlm.nih.gov/pubmed/14551576
635. Sotomayor, M. The burden of premature ejaculation: the patient's perspective. J Sex Med, 2005. 2
Suppl 2: 110.
https://www.ncbi.nlm.nih.gov/pubmed/16422797
636. Cilio, S., et al. Premature ejaculation among men with erectile dysfunction-findings from a real-life
cross-sectional study. Int J Impot Res, 2023. 35: 558.
https://www.ncbi.nlm.nih.gov/pubmed/35915329
637. Parnham, A., et al. Classification and definition of premature ejaculation. Transl Androl Urol, 2016. 5:
416.
https://www.ncbi.nlm.nih.gov/pubmed/27652214
638. World Health Organisation. International Classification of Diseases 11th Revision for Mortality and
Morbidity Statistics (ICD- 11-MMS). The global standard for diagnostic health information. 2018.
https://www.who.int/standards/classifications/classification-of-diseases
639. Serefoglu, E.C., et al. An evidence-based unified definition of lifelong and acquired premature
ejaculation: report of the second International Society for Sexual Medicine Ad Hoc Committee for the
Definition of Premature Ejaculation. J Sex Med, 2014. 11: 1423.
https://www.ncbi.nlm.nih.gov/pubmed/24848805
640. Waldinger, M.D., et al. Differences between ICD-11 MMS and DSM-5 definition of premature
ejaculation: a continuation of historical inadequacies and a source of serious misinterpretation by
some European Regulatory Agencies (PART 2). Int J Impot Res, 2019. 31: 310.
https://www.ncbi.nlm.nih.gov/pubmed/30659291
641. Shabsigh, R. Diagnosing premature ejaculation: a review. J Sex Med, 2006. 3 Suppl 4: 318.
https://www.ncbi.nlm.nih.gov/pubmed/16939476
642. Sharlip, I. Diagnosis and treatment of premature ejaculation: the physician's perspective. J Sex Med,
2005. 2 Suppl 2: 103.
https://www.ncbi.nlm.nih.gov/pubmed/16422796
643. Althof, S.E., et al. An update of the International Society of Sexual Medicine's guidelines for the
diagnosis and treatment of premature ejaculation (PE). J Sex Med, 2014. 11: 1392.
https://www.ncbi.nlm.nih.gov/pubmed/24848686
644. Shindel, A.W., et al. Disorders of Ejaculation: An AUA/SMSNA Guideline. J Urol, 2022. 207: 504.
https://www.ncbi.nlm.nih.gov/pubmed/34961344
645. Rowland, D.L., et al. Premature ejaculation: psychophysiological considerations in theory, research,
and treatment. Annu Rev Sex Res, 1997. 8: 224.
https://www.ncbi.nlm.nih.gov/pubmed/10051895
646. Waldinger, M.D., et al. Relevance of methodological design for the interpretation of efficacy of drug
treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res, 2004.
16: 369.
https://www.ncbi.nlm.nih.gov/pubmed/14961051
647. Waldinger, M.D. Towards evidence-based drug treatment research on premature ejaculation: a critical
evaluation of methodology. Int J Impot Res, 2003. 15: 309.
https://www.ncbi.nlm.nih.gov/pubmed/14562129
648. Giuliano, F., et al. Premature ejaculation: results from a five-country European observational study.
Eur Urol, 2008. 53: 1048.
https://www.ncbi.nlm.nih.gov/pubmed/17950985
649. Patrick, D.L., et al. Premature ejaculation: an observational study of men and their partners. J Sex
Med, 2005. 2: 358.
https://www.ncbi.nlm.nih.gov/pubmed/16422867
650. McNabney, S.M., et al. Are the Criteria for the Diagnosis of Premature Ejaculation Applicable to Gay
Men or Sexual Activities Other than Penile-Vaginal Intercourse? Sex Med, 2022. 10: 100516.
https://www.ncbi.nlm.nih.gov/pubmed/35477122
651. Shindel, A.W., et al. Erectile dysfunction and premature ejaculation in men who have sex with men. J
Sex Med, 2012. 9: 576.
https://www.ncbi.nlm.nih.gov/pubmed/22214402
652. Barbonetti, A., et al. Erectile Dysfunction and Premature Ejaculation in Homosexual and Heterosexual
Men: A Systematic Review and Meta-Analysis of Comparative Studies. J Sex Med, 2019. 16: 624.
https://www.ncbi.nlm.nih.gov/pubmed/30926517

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 195

653. Rowland, D.L., et al. Do the diagnostic criteria for premature ejaculation apply to non-straight men
and to sexual activities other than penile-vaginal intercourse? Int J Impot Res, 2022. 34: 730.
https://www.ncbi.nlm.nih.gov/pubmed/34504313
654. Althof, S.E., et al. International Society for Sexual Medicine's guidelines for the diagnosis and
treatment of premature ejaculation. J Sex Med, 2010. 7: 2947.
https://www.ncbi.nlm.nih.gov/pubmed/21050394
655. Rosen, R.C., et al. Correlates to the clinical diagnosis of premature ejaculation: results from a large
observational study of men and their partners. J Urol, 2007. 177: 1059.
https://www.ncbi.nlm.nih.gov/pubmed/17296411
656. Waldinger, M.D., et al. Geometric mean IELT and premature ejaculation: appropriate statistics to avoid
overestimation of treatment efficacy. J Sex Med, 2008. 5: 492.
https://www.ncbi.nlm.nih.gov/pubmed/18179458
657. Symonds, T., et al. Development and validation of a premature ejaculation diagnostic tool. Eur Urol,
2007. 52: 565.
https://www.ncbi.nlm.nih.gov/pubmed/17275165
658. Arafa, M., et al. Development and evaluation of the Arabic Index of Premature Ejaculation (AIPE). J
Sex Med, 2007. 4: 1750.
https://www.ncbi.nlm.nih.gov/pubmed/17970977
659. Althof, S., et al. Development and validation of a new questionnaire to assess sexual satisfaction,
control, and distress associated with premature ejaculation. J Sex Med, 2006. 3: 465.
https://www.ncbi.nlm.nih.gov/pubmed/16681472
660. Rosen, R.C., et al. Development and validation of four-item version of Male Sexual Health
Questionnaire to assess ejaculatory dysfunction. Urology, 2007. 69: 805.
https://www.ncbi.nlm.nih.gov/pubmed/17482908
661. Xi, Y., et al. The masturbatory premature ejaculation diagnostic tool (MPEDT): A novel psychometric
tool to evaluate premature ejaculation during masturbation. Andrology, 2022. 10: 333.
https://www.ncbi.nlm.nih.gov/pubmed/34825515
662. Rowland, D.L., et al. Premature Ejaculation Measures During Partnered Sex and Masturbation: What
These Findings Tell Us About the Nature and Rigidity of Premature Ejaculation. J Sex Marital Ther,
2022. 48: 680.
https://www.ncbi.nlm.nih.gov/pubmed/35253608
663. Althof, S.E. Psychosexual therapy for premature ejaculation. Transl Androl Urol, 2016. 5: 475.
https://www.ncbi.nlm.nih.gov/pubmed/27652220
664. Cormio, L., et al. The Combination of Dapoxetine and Behavioral Treatment Provides Better Results
than Dapoxetine Alone in the Management of Patients with Lifelong Premature Ejaculation. J Sex
Med, 2015. 12: 1609.
https://www.ncbi.nlm.nih.gov/pubmed/26077706
665. Pavone, C., et al. Premature ejaculation: Pharmacotherapy vs group psychotherapy alone or in
combination. Arch Ital Urol Androl, 2017. 89: 114.
https://www.ncbi.nlm.nih.gov/pubmed/28679182
666. Melnik, T., et al. Psychosocial interventions for premature ejaculation. Cochrane Database Syst Rev,
2011: CD008195.
https://www.ncbi.nlm.nih.gov/pubmed/21833964
667. Porst, H., et al. Baseline characteristics and treatment outcomes for men with acquired or lifelong
premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3
dapoxetine trials. J Sex Med, 2010. 7: 2231.
https://www.ncbi.nlm.nih.gov/pubmed/20412423
668. EMA. Fortacin: Summary of product characteristics. 2014.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002693/
human_med_001704.jsp&mid=WC0b01ac058001d124
669. Gul, M., et al. Current and emerging treatment options for premature ejaculation. Nat Rev Urol, 2022.
19: 659.
https://www.ncbi.nlm.nih.gov/pubmed/36008555
670. Qin, Z., et al. Safety and efficacy characteristics of oral drugs in patients with premature ejaculation:
a Bayesian network meta-analysis of randomized controlled trials. Int J Impot Res, 2019. 31: 356.
https://www.ncbi.nlm.nih.gov/pubmed/31024113
671. Jian, Z., et al. Pharmacotherapy of premature ejaculation: a systematic review and network meta-
analysis. Int Urol Nephrol, 2018. 50: 1939.
https://www.ncbi.nlm.nih.gov/pubmed/30225547

196 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

672. Sridharan, K., et al. Pharmacological interventions for premature ejaculation: a mixed-treatment
comparison network meta-analysis of randomized clinical trials. Int J Impot Res, 2018. 30: 215.
https://www.ncbi.nlm.nih.gov/pubmed/29921893
673. Castiglione, F., et al. Current Pharmacological Management of Premature Ejaculation: A Systematic
Review and Meta-analysis. Eur Urol, 2016. 69: 904.
https://www.ncbi.nlm.nih.gov/pubmed/26749092
674. Martin-Tuite, P., et al. Management Options for Premature Ejaculation and Delayed Ejaculation in
Men. Sex Med Rev, 2020. 8: 473.
https://www.ncbi.nlm.nih.gov/pubmed/31668585
675. Ventus, D., et al. Vibrator-Assisted Start-Stop Exercises Improve Premature Ejaculation Symptoms: A
Randomized Controlled Trial. Arch Sex Behav, 2020. 49: 1559.
https://www.ncbi.nlm.nih.gov/pubmed/31741252
676. Stephenson, K.R., et al. Statistical Mediators of the Association Between Mindfulness and Sexual
Experiences in Men with Impaired Sexual Function. Arch Sex Behav, 2020. 49: 1545.
https://www.ncbi.nlm.nih.gov/pubmed/31713094
677. Optale, G., et al. Smartphone-Based Therapeutic Exercises for Men Affected by Premature
Ejaculation: A Pilot Study. Sex Med, 2020. 8: 461.
https://www.ncbi.nlm.nih.gov/pubmed/32565067
678. Pryor, J.L., et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an
integrated analysis of two double-blind, randomised controlled trials. Lancet, 2006. 368: 929.
https://www.ncbi.nlm.nih.gov/pubmed/16962882
679. Modi, N.B., et al. Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel
agent for the treatment of premature ejaculation. J Clin Pharmacol, 2006. 46: 301.
https://www.ncbi.nlm.nih.gov/pubmed/16490806
680. McMahon, C.G. Dapoxetine: a new option in the medical management of premature ejaculation. Ther
Adv Urol, 2012. 4: 233.
https://www.ncbi.nlm.nih.gov/pubmed/23024705
681. Li, J., et al. Dapoxetine for the treatment of premature ejaculation: a meta-analysis of randomized
controlled trials with trial sequential analysis. Ann Saudi Med, 2018. 38: 366.
https://www.ncbi.nlm.nih.gov/pubmed/30284992
682. Peng, J., et al. Safety and Effectiveness of Dapoxetine On Demand in Chinese Men With Premature
Ejaculation: Results of a Multicenter, Prospective, Open-Label Phase IV Study. Sex Med, 2021. 9:
100296.
https://www.ncbi.nlm.nih.gov/pubmed/33529810
683. Verze, P., et al. Comparison of Treatment Emergent Adverse Events in Men With Premature
Ejaculation Treated With Dapoxetine and Alternate Oral Treatments: Results From a Large
Multinational Observational Trial. J Sex Med, 2016. 13: 194.
https://www.ncbi.nlm.nih.gov/pubmed/26805941
684. Kowey, P.R., et al. Cardiovascular safety profile of dapoxetine during the premarketing evaluation.
Drugs R D, 2011. 11: 1.
https://www.ncbi.nlm.nih.gov/pubmed/21410293
685. European Medicines Agency. Priligy - Article 29 referral - Annex III - Summary of Product
Characteristics, Labelling and Package Leaflet. 2012.
686. European Medicines Agency. Priligy - Article 29 referral - Assessment Report for Priligy and
Associated Names. 2012.
https://www.ema.europa.eu/en/documents/referral/questions-and-answers-referral-priligy_en.pdf
687. Mirone, V., et al. Results from a prospective observational study of men with premature ejaculation
treated with dapoxetine or alternative care: the PAUSE study. Eur Urol, 2014. 65: 733.
https://www.ncbi.nlm.nih.gov/pubmed/23993257
688. Dresser, M.J., et al. Dapoxetine, a novel treatment for premature ejaculation, does not have
pharmacokinetic interactions with phosphodiesterase-5 inhibitors. Int J Impot Res, 2006. 18: 104.
https://www.ncbi.nlm.nih.gov/pubmed/16307008
689. McMahon, C.G., et al. Efficacy and safety of dapoxetine in men with premature ejaculation and
concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized,
placebo-controlled, phase III study. J Sex Med, 2013. 10: 2312.
https://www.ncbi.nlm.nih.gov/pubmed/23845016
690. Abu El-Hamd, M., et al. Comparison of the clinical efficacy and safety of the on-demand use of
paroxetine, dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients
with premature ejaculation: A randomised placebo-controlled clinical trial. Andrologia, 2018. 50.
https://www.ncbi.nlm.nih.gov/pubmed/28497478

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 197

691. Tuken, M., et al. Efficacy and safety of dapoxetine/sildenafil combination tablets in the treatment of
men with premature ejaculation and concomitant erectile dysfunction-DAP-SPEED Study. Int J Impot
Res, 2019. 31: 92.
https://www.ncbi.nlm.nih.gov/pubmed/30705437
692. Zhong, C., et al. Reasons and treatment strategy for discontinuation of dapoxetine treatment in
premature ejaculation patients in China: A retrospective observational study. Andrologia, 2022. 54:
1598.
https://www.ncbi.nlm.nih.gov/pubmed/35324028
693. Park, H.J., et al. Discontinuation of Dapoxetine Treatment in Patients With Premature Ejaculation: A
2-Year Prospective Observational Study. Sex Med, 2017. 5: e99.
https://www.ncbi.nlm.nih.gov/pubmed/28395997
694. Jern, P., et al. Antidepressant treatment of premature ejaculation: discontinuation rates and
prevalence of side effects for dapoxetine and paroxetine in a naturalistic setting. Int J Impot Res,
2015. 27: 75.
https://www.ncbi.nlm.nih.gov/pubmed/25410962
695. Peng, J., et al. Efficacy of dapoxetine treatment in Chinese patients with premature ejaculation and
possible factors affecting efficacy in the real-world practice. BMC Urol, 2020. 20: 11.
https://www.ncbi.nlm.nih.gov/pubmed/32013958
696. Giuliano, F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention.
Trends Neurosci, 2007. 30: 79.
https://www.ncbi.nlm.nih.gov/pubmed/17169440
697. Olivier, B., et al. Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual
behaviour. Int Clin Psychopharmacol, 1998. 13 Suppl 6: S9.
https://www.ncbi.nlm.nih.gov/pubmed/9728669
698. Waldinger, M.D., et al. Paroxetine treatment of premature ejaculation: a double-blind, randomized,
placebo-controlled study. Am J Psychiatry, 1994. 151: 1377.
https://www.ncbi.nlm.nih.gov/pubmed/8067497
699. Zhang, D., et al. Paroxetine in the treatment of premature ejaculation: a systematic review and meta-
analysis. BMC Urol, 2019. 19: 2.
https://www.ncbi.nlm.nih.gov/pubmed/30606186
700. Waldinger, M.D. Emerging drugs for premature ejaculation. Expert Opin Emerg Drugs, 2006. 11: 99.
https://www.ncbi.nlm.nih.gov/pubmed/16503829
701. Migliorini, F., et al. A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of
a Single Oral Dose of 5-HT1A Antagonist GSK958108 on Ejaculation Latency Time in Male Patients
Suffering From Premature Ejaculation. J Sex Med, 2021. 18: 63.
https://www.ncbi.nlm.nih.gov/pubmed/33223426
702. Waldinger, M.D. Premature ejaculation: definition and drug treatment. Drugs, 2007. 67: 547.
https://www.ncbi.nlm.nih.gov/pubmed/17352514
703. Goodman, R.E. An assessment of clomipramine (Anafranil) in the treatment of premature ejaculation.
J Int Med Res, 1980. 8 Suppl 3: 53.
https://www.ncbi.nlm.nih.gov/pubmed/7193614
704. Choi, J.B., et al. Efficacy and Safety of On Demand Clomipramine for the Treatment of Premature
Ejaculation: A Multicenter, Randomized, Double-Blind, Phase III Clinical Trial. J Urol, 2019. 201: 147.
https://www.ncbi.nlm.nih.gov/pubmed/30086277
705. Kim, S.W., et al. Tolerability and adequate therapeutic dosage of oral clomipramine for the treatment
of premature ejaculation: A randomized, double-blind, placebo-controlled, fixed-dose, parallel-
grouped clinical study. Int J Impot Res, 2018. 30: 65.
https://www.ncbi.nlm.nih.gov/pubmed/29203842
706. Sathianathen, N.J., et al. Selective Serotonin Re-Uptake Inhibitors for Premature Ejaculation in Adult
Men: A Cochrane Systematic Review. World J Mens Health, 2022. 40: 257.
https://www.ncbi.nlm.nih.gov/pubmed/35021307
707. Zhou, Z., et al. The network meta-analysis of "on-demand" and "daily" use of paroxetine in treating
men with premature ejaculation from randomized controlled trials. Andrologia, 2022. 54: e14388.
https://www.ncbi.nlm.nih.gov/pubmed/35122448
708. Liu, Q., et al. Comparison of fluoxetine with other selective serotonin reuptake inhibitors in the
treatment of premature ejaculation: A systematic review and meta-analysis. Andrologia, 2022. 54:
e14500.
https://www.ncbi.nlm.nih.gov/pubmed/35760074

198 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

709. McMahon, C.G., et al. Efficacy and safety of dapoxetine for the treatment of premature ejaculation:
integrated analysis of results from five phase 3 trials. J Sex Med, 2011. 8: 524.
https://www.ncbi.nlm.nih.gov/pubmed/21059176
710. Norr, L., et al. Use of selective serotonin reuptake inhibitors reduces fertility in men. Andrology, 2016.
4: 389.
https://www.ncbi.nlm.nih.gov/pubmed/27019308
711. Tanrikut, C., et al. Antidepressant-associated changes in semen parameters. Urology, 2007. 69: 185
e5.
https://www.ncbi.nlm.nih.gov/pubmed/17270655
712. Tanrikut, C., et al. Adverse effect of paroxetine on sperm. Fertil Steril, 2010. 94: 1021.
https://www.ncbi.nlm.nih.gov/pubmed/19515367
713. Koyuncu, H., et al. Escitalopram treatment for premature ejaculation has a negative effect on semen
parameters. Int J Impot Res, 2011. 23: 257.
https://www.ncbi.nlm.nih.gov/pubmed/21776003
714. Koyuncu, H., et al. Deleterious effects of selective serotonin reuptake inhibitor treatment on semen
parameters in patients with lifelong premature ejaculation. Int J Impot Res, 2012. 24: 171.
https://www.ncbi.nlm.nih.gov/pubmed/22573230
715. Morales, A., et al. A review of the current status of topical treatments for premature ejaculation. BJU
Int, 2007. 100: 493.
https://www.ncbi.nlm.nih.gov/pubmed/17608824
716. Sachs, B.D., et al. Maintenance of erection of penile glans, but not penile body, after transection of rat
cavernous nerves. J Urol, 1991. 146: 900.
https://www.ncbi.nlm.nih.gov/pubmed/1875517
717. Wieder, J.A., et al. Anesthetic block of the dorsal penile nerve inhibits vibratory-induced ejaculation in
men with spinal cord injuries. Urology, 2000. 55: 915.
https://www.ncbi.nlm.nih.gov/pubmed/10840108
718. Liu, H., et al. Comparative efficacy and safety of drug treatment for premature ejaculation: A
systemic review and Bayesian network meta-analysis. Andrologia, 2020. 52: e13806.
https://www.ncbi.nlm.nih.gov/pubmed/32892379
719. Atikeler, M.K., et al. Optimum usage of prilocaine-lidocaine cream in premature ejaculation.
Andrologia, 2002. 34: 356.
https://www.ncbi.nlm.nih.gov/pubmed/12472618
720. Busato, W., et al. Topical anaesthetic use for treating premature ejaculation: a double-blind,
randomized, placebo-controlled study. BJU Int, 2004. 93: 1018.
https://www.ncbi.nlm.nih.gov/pubmed/15142155
721. Sutton, M., et al. Promescent Has a Cytotoxic Impact on Fresh Human Sperm In Vitro. Urology, 2018.
114: 95.
https://www.ncbi.nlm.nih.gov/pubmed/29307732
722. Porst, H., et al. Fortacin Spray for the Treatment of Premature Ejaculation. Urologia, 2017. 84: 1.
https://www.ncbi.nlm.nih.gov/pubmed/30047847
723. Henry, R., et al. TEMPE: Topical Eutectic-Like Mixture for Premature Ejaculation. Expert Opin Drug
Deliv, 2008. 5: 251.
https://www.ncbi.nlm.nih.gov/pubmed/18248322
724. Dinsmore, W.W., et al. Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-
delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int, 2007. 99: 369.
https://www.ncbi.nlm.nih.gov/pubmed/17129234
725. Boeri, L., et al. Real-life use of the eutectic mixture lidocaine/prilocaine spray in men with premature
ejaculation. Int J Impot Res, 2022. 34: 289.
https://www.ncbi.nlm.nih.gov/pubmed/33828264
726. Cai, T., et al. Prilocaine/lidocaine spray for the treatment of premature ejaculation: a dose- and time-
finding study for clinical practice use. Int J Impot Res, 2023. 35: 378.
https://www.ncbi.nlm.nih.gov/pubmed/35314817
727. Wyllie, M.G., et al. The role of local anaesthetics in premature ejaculation. BJU Int, 2012. 110: E943.
https://www.ncbi.nlm.nih.gov/pubmed/22758648
728. ECCR, Fortacin 150 mg/ml + 50 mg/ml cutaneous spray solution - Summary of Product
Characteristcs. 2015.
https://ec.europa.eu/health/documents/community-register/2015/20151015133209/anx_133209_
en.pdf

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 199

729. Morales, A. Evolving therapeutic strategies for premature ejaculation: The search for on-demand
treatment - topical versus systemic. Can Urol Assoc J, 2012. 6: 380.
https://www.ncbi.nlm.nih.gov/pubmed/23093633
730. Alghobary, M., et al. Oral dapoxetine versus topical lidocaine as on-demand treatment for lifelong
premature ejaculation: A randomised controlled trial. Andrologia, 2020. 52: e13558.
https://www.ncbi.nlm.nih.gov/pubmed/32153050
731. Abu El-Hamd, M. Effectiveness and tolerability of lidocaine 5% spray in the treatment of lifelong
premature ejaculation patients: a randomized single-blind placebo-controlled clinical trial. Int J Impot
Res, 2021. 33: 96.
https://www.ncbi.nlm.nih.gov/pubmed/31896832
732. Frink, M.C., et al. Influence of tramadol on neurotransmitter systems of the rat brain.
Arzneimittelforschung, 1996. 46: 1029.
https://www.ncbi.nlm.nih.gov/pubmed/8955860
733. Bar-Or, D., et al. A randomized double-blind, placebo-controlled multicenter study to evaluate the
efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of
premature ejaculation within less than 2 minutes. Eur Urol, 2012. 61: 736.
https://www.ncbi.nlm.nih.gov/pubmed/21889833
734. Lu, Y., et al. The Influence of Tramadol on Intravaginal Ejaculatory Latency Time and Sexual
Satisfaction Score in Treating Patients With Premature Ejaculation: A Network Meta-Analysis. Am J
Mens Health, 2021. 15: 15579883211057713.
https://www.ncbi.nlm.nih.gov/pubmed/34911381
735. Tan, H., et al. A systematic review and meta-analysis of randomized controlled trials of "on-demand"
use of tramadol vs "on-demand" use of paroxetine in the management of patients with premature
ejaculation. Int J Clin Pract, 2021. 75: e14825.
https://www.ncbi.nlm.nih.gov/pubmed/34492139
736. Food and Drug Administration. Warning letter to William Weldon, CEO & Chairman of Johnson &
Johnson, regarding Ultram-ER web advertisement. 2009.
737. Hamidi-Madani, A., et al. The Efficacy and Safety of On-demand Tramadol and Paroxetine Use in
Treatment of Life Long Premature Ejaculation: A Randomized Double-blind Placebo-controlled
Clinical Trial. J Reprod Infertil, 2018. 19: 10.
https://www.ncbi.nlm.nih.gov/pubmed/29850442
738. Mohamed Gharib, T., et al. Short- and long-term follow-up results of daily 5-mg tadalafil as a
treatment for erectile dysfunction and premature ejaculation. Arab J Urol, 2022. 20: 49.
https://www.ncbi.nlm.nih.gov/pubmed/35223110
739. Abou Faddan, A.H., et al. Effect of a tadalafil 5-mg single daily dose on lifelong premature
ejaculation: A single-blinded placebo-controlled study. Arab J Urol, 2022. 20: 100.
https://www.ncbi.nlm.nih.gov/pubmed/35530567
740. Zhang, X., et al. Phosphodiesterase-5 Inhibitors for Premature Ejaculation: Systematic Review and
Meta-Analysis of Placebo-Controlled Trials. Am J Mens Health, 2020. 14: 1557988320916406.
https://www.ncbi.nlm.nih.gov/pubmed/32375542
741. Bhat, G.S., et al. Effectiveness of 'on demand' silodosin in the treatment of premature ejaculation in
patients dissatisfied with dapoxetine: a randomized control study. Cent European J Urol, 2016. 69:
280.
https://www.ncbi.nlm.nih.gov/pubmed/27729995
742. Sato, Y., et al. Silodosin versus naftopidil in the treatment of premature ejaculation: A prospective
multicenter trial. Int J Urol, 2017. 24: 626.
https://www.ncbi.nlm.nih.gov/pubmed/28627033
743. Sato, Y., et al. Silodosin and its potential for treating premature ejaculation: a preliminary report. Int J
Urol, 2012. 19: 268.
https://www.ncbi.nlm.nih.gov/pubmed/22188258
744. Tuken, M., et al. On-demand Modafinil Improves Ejaculation Time and Patient-reported Outcomes in
Men With Lifelong Premature Ejaculation. Urology, 2016. 94: 139.
https://www.ncbi.nlm.nih.gov/pubmed/27151339
745. Kim, J.J., et al. Effects of glans penis augmentation using hyaluronic acid gel for premature
ejaculation. Int J Impot Res, 2004. 16: 547.
https://www.ncbi.nlm.nih.gov/pubmed/15057258
746. Ahn, S.T., et al. Efficacy and Safety of Penile Girth Enhancement Using Hyaluronic Acid Filler and
the Clinical Impact on Ejaculation: A Multi-Center, Patient/Evaluator-Blinded, Randomized Active-
Controlled Trial. World J Mens Health, 2022. 40: 299.
https://www.ncbi.nlm.nih.gov/pubmed/33988002

200 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

747. Zhang, C., et al. Efficacy and safety assessment of glandular augmentation with hyaluronic acid for
premature ejaculation. Andrologia, 2022. 54: e14435.
https://www.ncbi.nlm.nih.gov/pubmed/35523761
748. Ahn, S.T., et al. Complications of glans penis augmentation. Int J Impot Res, 2019. 31: 245.
https://www.ncbi.nlm.nih.gov/pubmed/30478264
749. Yang, J., et al. Correlation between age and curative effects of selective dorsal neurectomy for
primary premature ejaculation. Adv Clin Exp Med, 2022. 31: 837.
https://www.ncbi.nlm.nih.gov/pubmed/35438850
750. Liu, Q., et al. Anatomic Basis and Clinical Effect of Selective Dorsal Neurectomy for Patients with
Lifelong Premature Ejaculation: A Randomized Controlled Trial. J Sex Med, 2019. 16: 522.
https://www.ncbi.nlm.nih.gov/pubmed/30935469
751. Tang, Q.L., et al. The application of intraoperative neurophysiological monitoring in selective dorsal
neurotomy for primary premature ejaculation: a prospective single-center study. Asian J Androl,
2023. 25: 137.
https://www.ncbi.nlm.nih.gov/pubmed/35488667
752. David Prologo, J., et al. Percutaneous CT-guided cryoablation of the dorsal penile nerve for treatment
of symptomatic premature ejaculation. J Vasc Interv Radiol, 2013. 24: 214.
https://www.ncbi.nlm.nih.gov/pubmed/23182939
753. Zhang, G.X., et al. Selective resection of dorsal nerves of penis for premature ejaculation. Int J
Androl, 2012. 35: 873.
https://www.ncbi.nlm.nih.gov/pubmed/22882515
754. Basal, S., et al. A novel treatment modality in patients with premature ejaculation resistant to
conventional methods: the neuromodulation of dorsal penile nerves by pulsed radiofrequency. J
Androl, 2010. 31: 126.
https://www.ncbi.nlm.nih.gov/pubmed/19395368
755. Shi, W.G., et al. [Selective resection of the branches of the two dorsal penile nerves for primary
premature ejaculation]. Zhonghua Nan Ke Xue, 2008. 14: 436.
https://www.ncbi.nlm.nih.gov/pubmed/18572864
756. Clement, P., et al. Inhibition of ejaculation by the non-peptide oxytocin receptor antagonist
GSK557296: a multi-level site of action. Br J Pharmacol, 2013. 169: 1477.
https://www.ncbi.nlm.nih.gov/pubmed/23530818
757. Shinghal, R., et al. Safety and efficacy of epelsiban in the treatment of men with premature
ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study. J Sex Med, 2013. 10:
2506.
https://www.ncbi.nlm.nih.gov/pubmed/23937679
758. Osterloh, I.H., et al. Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel
Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three
Randomized Clinical Trials in Healthy Subjects. J Sex Med, 2018. 15: 1547.
https://www.ncbi.nlm.nih.gov/pubmed/30341006
759. Wayman, C., et al. Cligosiban, A Novel Brain-Penetrant, Selective Oxytocin Receptor Antagonist,
Inhibits Ejaculatory Physiology in Rodents. J Sex Med, 2018. 15: 1698.
https://www.ncbi.nlm.nih.gov/pubmed/30527053
760. McMahon, C., et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency
and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a
Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med, 2019. 16:
1178.
https://www.ncbi.nlm.nih.gov/pubmed/31351659
761. Althof, S., et al. The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency
in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-
Controlled Phase IIb trial (PEDRIX). J Sex Med, 2019. 16: 1188.
https://www.ncbi.nlm.nih.gov/pubmed/31351660
762. El Najjar, M.R., et al. A Double Blind, Placebo Controlled, Randomized Trial to Evaluate the Efficacy
and Tolerability of On-Demand Oral Pregablin (150 mg and 75 mg) in Treatment of Premature
Ejaculation. J Sex Med, 2020. 17: 442.
https://www.ncbi.nlm.nih.gov/pubmed/31982359
763. Jiang, M., et al. The efficacy of regular penis-root masturbation, versus Kegel exercise in the
treatment of primary premature ejaculation: A quasi-randomised controlled trial. Andrologia, 2020.
52: e13473.
https://www.ncbi.nlm.nih.gov/pubmed/31746051

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 201

764. Shechter, A., et al. A novel on-demand therapy for lifelong premature ejaculation using a miniature
transperineal electrical stimulator-the vPatch: an as-treated analysis. J Sex Med, 2023. 20: 22.
https://www.ncbi.nlm.nih.gov/pubmed/36897239
765. Shechter, A., et al. Transcutaneous functional electrical stimulation-a novel therapy for premature
ejaculation: results of a proof of concept study. Int J Impot Res, 2020. 32: 440.
https://www.ncbi.nlm.nih.gov/pubmed/31570825
766. Uribe, O.L., et al. Transcutaneous electric nerve stimulation to treat patients with premature
ejaculation: phase II clinical trial. Int J Impot Res, 2020. 32: 434.
https://www.ncbi.nlm.nih.gov/pubmed/31551577
767. Sahin, S., et al. A Prospective Randomized Controlled Study to Compare Acupuncture and Dapoxetine
for the Treatment of Premature Ejaculation. Urol Int, 2016. 97: 104.
https://www.ncbi.nlm.nih.gov/pubmed/27049323
768. Lu, X., et al. Study on the Efficacy of Electric Acupuncture in the Treatment of Premature Ejaculation
Based on Testosterone Level. J Healthc Eng, 2022. 2022: 8331688.
https://www.ncbi.nlm.nih.gov/pubmed/35360482
769. Sunay, D., et al. Acupuncture versus paroxetine for the treatment of premature ejaculation: a
randomized, placebo-controlled clinical trial. Eur Urol, 2011. 59: 765.
https://www.ncbi.nlm.nih.gov/pubmed/21256670
770. Joshi, A.M., et al. Role of Yoga in the Management of Premature Ejaculation. World J Mens Health,
2020. 38: 495.
https://www.ncbi.nlm.nih.gov/pubmed/31496152
771. Rowland, D.L., et al. Moving Toward Empirically Based Standardization in the Diagnosis of Delayed
Ejaculation. J Sex Med, 2020. 17: 1896.
https://www.ncbi.nlm.nih.gov/pubmed/32828700
772. Rowland, D.L., et al. Similarities and differences between men with self-reported lifelong and
acquired difficulty reaching ejaculation. Int J Impot Res, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37592174
773. Shin, D.H., et al. The Evaluation and Treatment of Delayed Ejaculation. Sex Med Rev, 2014. 2: 121.
https://www.ncbi.nlm.nih.gov/pubmed/27784563
774. Abdel-Hamid, I.A., et al. Delayed Ejaculation: Pathophysiology, Diagnosis, and Treatment. World J
Mens Health, 2018. 36: 22.
https://www.ncbi.nlm.nih.gov/pubmed/29299903
775. Corona, G., et al. The hormonal control of ejaculation. Nat Rev Urol, 2012. 9: 508.
https://www.ncbi.nlm.nih.gov/pubmed/22869001
776. Morgentaler, A., et al. Delayed Ejaculation and Associated Complaints: Relationship to Ejaculation
Times and Serum Testosterone Levels. J Sex Med, 2017. 14: 1116.
https://www.ncbi.nlm.nih.gov/pubmed/28807505
777. Paduch, D.A., et al. Clinical and Demographic Correlates of Ejaculatory Dysfunctions Other Than
Premature Ejaculation: A Prospective, Observational Study. J Sex Med, 2015. 12: 2276.
https://www.ncbi.nlm.nih.gov/pubmed/26511106
778. Perelman, M.A. Regarding ejaculation: delayed and otherwise. J Androl., 2003. 24: 496.
https://pubmed.ncbi.nlm.nih.gov/12826687/
779. Perelman, M.A., et al., Evaluation and Treatment of Ejaculatory Disorders, in Atlas of Male Sexual
Dysfunction, 2004, Current Medicine LLC: Philadelphia.
780. Perelman, M.A., et al. Retarded ejaculation. World J Urol, 2006. 24: 645.
https://www.ncbi.nlm.nih.gov/pubmed/17082938
781. Butcher, M.J., et al., Treatment of Delayed Ejaculation, in The Textbook of Clinical Sexual Medicine,
W.W. IsHak, Editor. 2017, Springer International Publishing: Cham.
https://doi.org/10.1007/978-3-319-52539-6_17
782. Mulloy, E., et al. Diagnoses and medications associated with delayed ejaculation. Sex Med, 2023. 11:
qfad040.
https://www.ncbi.nlm.nih.gov/pubmed/37547871
783. Rowland, D.L., et al. Characteristics of men who report symptoms of delayed ejaculation: providing
support for empirically derived diagnostic criteria. J Sex Med, 2023. 20: 426.
https://www.ncbi.nlm.nih.gov/pubmed/36781403
784. Rowland, D.L., et al. Self-reported reasons for having difficulty reaching orgasm in men with diverse
etiologies. Sex Med, 2023. 11: qfad030.
https://www.ncbi.nlm.nih.gov/pubmed/37408873

202 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

785. Carvalheira, A., et al. Individual and Relationship Factors Associated With the Self-Identified Inability
to Experience Orgasm in a Community Sample of Heterosexual Men From Three European Countries.
J Sex Marital Ther, 2016. 42: 257.
https://www.ncbi.nlm.nih.gov/pubmed/25650656
786. Althof, S.E. Psychological interventions for delayed ejaculation/orgasm. Int J Impot Res, 2012. 24:
131.
https://www.ncbi.nlm.nih.gov/pubmed/22378496
787. Butcher, M.J., et al. How is delayed ejaculation defined and treated in North America? Andrology,
2015. 3: 626.
https://www.ncbi.nlm.nih.gov/pubmed/26013106
788. Nelson, C.J., et al. Assessment of penile vibratory stimulation as a management strategy in men with
secondary retarded orgasm. Urology, 2007. 69: 552.
https://www.ncbi.nlm.nih.gov/pubmed/17382163
789. Soler, J.M., et al. Midodrine improves orgasm in spinal cord-injured men: the effects of autonomic
stimulation. J Sex Med, 2008. 5: 2935.
https://www.ncbi.nlm.nih.gov/pubmed/18422493
790. Geboes, K., et al. Primary anejaculation: diagnosis and therapy. Fertil Steril, 1975. 26: 1018.
https://www.ncbi.nlm.nih.gov/pubmed/1081053
791. Ohl, D.A., et al. Anejaculation and retrograde ejaculation. Urol Clin North Am, 2008. 35: 211.
https://www.ncbi.nlm.nih.gov/pubmed/18423241
792. Brindley, G.S. Reflex ejaculation under vibratory stimulation in paraplegic men. Paraplegia, 1981. 19:
299.
https://www.ncbi.nlm.nih.gov/pubmed/7279433
793. Schatte, E.C., et al. Treatment of Infertility Due to Anejaculation in the Male with Electroejaculation
and Intracytoplasmic Sperm Injection. Journal of Urology, 2000. 163: 1717.
https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967527-1
794. Esteves, S.C., et al. An update on sperm retrieval techniques for azoospermic males. Clinics (Sao
Paulo), 2013. 68 Suppl 1: 99.
https://www.ncbi.nlm.nih.gov/pubmed/23503959
795. Maurer, C.A., et al. Total mesorectal excision preserves male genital function compared with
conventional rectal cancer surgery. Br J Surg, 2001. 88: 1501.
https://www.ncbi.nlm.nih.gov/pubmed/11683749
796. Parnham, A., et al. Retrograde ejaculation, painful ejaculation and hematospermia. Transl Androl Urol,
2016. 5: 592.
https://www.ncbi.nlm.nih.gov/pubmed/27652230
797. Edwards, A. Chronic Disease of the Colliculus Seminalis. Br Med J, 1909. 2: 1672.
https://www.ncbi.nlm.nih.gov/pubmed/20764794
798. Grosse, A.B. Remarks on Impotentia Cocundi and Sexual Neurasthenia and Their Treatment.
California State Journal of Medicine, 1911. 9: 25.
http://www.ncbi.nlm.nih.gov/pubmed/18735133
799. Irwin, W.K. PAIN IN GENITO-URINARY AFFECTIONS: Its Variations and their Interpretation. Br Med J,
1922. 2: 457.
https://www.ncbi.nlm.nih.gov/pubmed/20770853
800. Tran, C.N., et al. Sexual dysfunction in chronic prostatitis/chronic pelvic pain syndrome. World J Urol,
2013. 31: 741.
https://www.ncbi.nlm.nih.gov/pubmed/23579441
801. Kleinberg, L., et al. Treatment-related symptoms during the first year following transperineal 125I
prostate implantation. Int J Radiat Oncol Biol Phys, 1994. 28: 985.
https://www.ncbi.nlm.nih.gov/pubmed/8138452
802. Walz, J., et al. Ejaculatory disorders may affect screening for prostate cancer. J Urol, 2007. 178: 232.
https://www.ncbi.nlm.nih.gov/pubmed/17499807
803. Koeman, M., et al. Orgasm after radical prostatectomy. Br J Urol, 1996. 77: 861.
https://www.ncbi.nlm.nih.gov/pubmed/8705222
804. Matsushita, K., et al. The evolution of orgasmic pain (dysorgasmia) following radical prostatectomy.
J Sex Med, 2012. 9: 1454.
https://www.ncbi.nlm.nih.gov/pubmed/22458302
805. Merrick, G.S., et al. Short-term sexual function after prostate brachytherapy. Int J Cancer, 2001. 96:
313.
https://www.ncbi.nlm.nih.gov/pubmed/11582584

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 203

806. Butler, J.D., et al. Painful ejaculation after inguinal hernia repair. J R Soc Med, 1998. 91: 432.
https://www.ncbi.nlm.nih.gov/pubmed/9816362
807. Aizenberg, D., et al. Painful ejaculation associated with antidepressants in four patients. J Clin
Psychiatry, 1991. 52: 461.
https://www.ncbi.nlm.nih.gov/pubmed/1744063
808. Kulik, F.A., et al. Case report of painful ejaculation as a side effect of amoxapine. Am J Psychiatry,
1982. 139: 234.
https://www.ncbi.nlm.nih.gov/pubmed/7055299
809. Michael, A. Venlafaxine-induced painful ejaculation. Br J Psychiatry, 2000. 177: 282.
https://www.ncbi.nlm.nih.gov/pubmed/11040898
810. Lange, W.R., et al. Can ciguatera be a sexually transmitted disease? Journal of Toxicology. Clinical
Toxicology, 1989. 27: 193.
http://www.ncbi.nlm.nih.gov/pubmed/2810444
811. Senthilkumaran, S., et al. Painful ejaculation. Something fishy. Saudi Med J, 2010. 31: 451.
https://www.ncbi.nlm.nih.gov/pubmed/20383428
812. Kaplan, H.S. Post-ejaculatory pain syndrome. J Sex Marital Ther, 1993. 19: 91.
https://www.ncbi.nlm.nih.gov/pubmed/8336348
813. Demyttenaere, K., et al. Painful ejaculation and urinary hesitancy in association with antidepressant
therapy: relief with tamsulosin. Eur Neuropsychopharmacol, 2002. 12: 337.
https://www.ncbi.nlm.nih.gov/pubmed/12126873
814. Jordi, P., et al. Management of ejaculation pain with topiramate: a case report. Clin J Pain, 2004. 20:
368.
https://www.ncbi.nlm.nih.gov/pubmed/15322446
815. Cornel, E.B., et al. The effect of biofeedback physical therapy in men with Chronic Pelvic Pain
Syndrome Type III. Eur Urol, 2005. 47: 607.
https://www.ncbi.nlm.nih.gov/pubmed/15826751
816. Tuhkanen, K., et al. Sexual function of LUTS patients before and after neodymium laser
prostatectomy and transurethral resection of prostate. A prospective, randomized trial. Urol Int, 2004.
73: 137.
https://www.ncbi.nlm.nih.gov/pubmed/15331898
817. Krause, W. Transurethral resection of the ejaculatory ducts for treating ejaculatory symptoms. BJU
Int, 2005. 96: 1145.
https://www.ncbi.nlm.nih.gov/pubmed/16225549
818. Giuliano, F., et al. Physiology of ejaculation: emphasis on serotonergic control. Eur Urol, 2005. 48:
408.
https://www.ncbi.nlm.nih.gov/pubmed/15996810
819. Proctor, K.G., et al. The effect of sympathomimetic drugs on post-lymphadenectomy aspermia. J
Urol, 1983. 129: 837.
https://www.ncbi.nlm.nih.gov/pubmed/6842716
820. Gilja, I., et al. Retrograde ejaculation and loss of emission: possibilities of conservative treatment. Eur
Urol, 1994. 25: 226.
https://www.ncbi.nlm.nih.gov/pubmed/8200405
821. Hotchkiss, R.S., et al. Artificial insemination with semen recovered from the bladder. Fertil Steril,
1954. 6: 37.
https://www.ncbi.nlm.nih.gov/pubmed/13220644
822. Templeton, A., et al. Successful circumvention of retrograde ejaculation in an infertile diabetic man.
Case report. Br J Obstet Gynaecol, 1982. 89: 1064.
https://www.ncbi.nlm.nih.gov/pubmed/7171519
823. Crich, J.P., et al. Infertility in men with retrograde ejaculation: the action of urine on sperm motility,
and a simple method for achieving antegrade ejaculation. Fertil Steril, 1978. 30: 572.
https://www.ncbi.nlm.nih.gov/pubmed/720646
824. Jenkins, L.C., et al. Delayed orgasm and anorgasmia. Fertil Steril, 2015. 104: 1082.
https://www.ncbi.nlm.nih.gov/pubmed/26439762
825. Calabro, R.S., et al. Anorgasmia during pregabalin add-on therapy for partial seizures. Epileptic
Disord, 2013. 15: 358.
https://www.ncbi.nlm.nih.gov/pubmed/23906723
826. McMahon, C.G., et al. Standard operating procedures in the disorders of orgasm and ejaculation. J
Sex Med, 2013. 10: 204.
https://www.ncbi.nlm.nih.gov/pubmed/22970767

204 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

827. McCormick, S., et al. Reversal of fluoxetine-induced anorgasmia by cyproheptadine in two patients. J
Clin Psychiatry, 1990. 51: 383.
https://www.ncbi.nlm.nih.gov/pubmed/2211550
828. Balon, R. Intermittent amantadine for fluoxetine-induced anorgasmia. J Sex Marital Ther, 1996. 22:
290.
https://www.ncbi.nlm.nih.gov/pubmed/9018655
829. Balogh, S., et al. Treatment of fluoxetine-induced anorgasmia with amantadine. J Clin Psychiatry,
1992. 53: 212.
https://www.ncbi.nlm.nih.gov/pubmed/1607353
830. Price, J., et al. Treatment of clomipramine-induced anorgasmia with yohimbine: a case report. J Clin
Psychiatry, 1990. 51: 32.
https://www.ncbi.nlm.nih.gov/pubmed/2295589
831. Jacobsen, F.M. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin
Psychiatry, 1992. 53: 119.
https://www.ncbi.nlm.nih.gov/pubmed/1564046
832. Ashton, A.K., et al. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual
dysfunction. The Journal of Clinical Psychiatry, 1998. 59: 112.
http://www.ncbi.nlm.nih.gov/pubmed/9541153
833. Kumar, P., et al. Haematospermia - a systematic review. Ann R Coll Surg Engl, 2006. 88: 339.
https://www.ncbi.nlm.nih.gov/pubmed/16834849
834. Pozzi, E., et al. Haemospermia in the Real- Life Setting: A New High-Risk Stratification. Urology, 2023.
171: 146.
https://www.ncbi.nlm.nih.gov/pubmed/36241064
835. Hakam, N., et al. Hematospermia is rarely associated with urologic malignancy: Analysis of United
States claims data. Andrology, 2022. 10: 919.
https://www.ncbi.nlm.nih.gov/pubmed/35483126
836. Drury, R.H., et al. Hematospermia Etiology, Diagnosis, Treatment, and Sexual Ramifications: A
Narrative Review. Sex Med Rev, 2022. 10: 669.
https://www.ncbi.nlm.nih.gov/pubmed/34538619
837. Ahmad, I., et al. Hemospermia. J Urol, 2007. 177: 1613.
https://www.ncbi.nlm.nih.gov/pubmed/17437771
838. Efesoy, O., et al. Hematospermia is rarely related to genitourinary cancer: lessons learned from 15
years of experience with 342 cases. Int J Impot Res, 2021. 33: 627.
https://www.ncbi.nlm.nih.gov/pubmed/32704074
839. Akhter, W., et al. Should every patient with hematospermia be investigated? A critical review. Cent
European J Urol, 2013. 66: 79.
https://www.ncbi.nlm.nih.gov/pubmed/24578999
840. Expert Panel on Urologic, I., et al. ACR Appropriateness Criteria((R)) Hematospermia. J Am Coll
Radiol, 2017. 14: S154.
https://www.ncbi.nlm.nih.gov/pubmed/28473071
841. Bhaduri, S., et al. Haematospermia associated with malignant hypertension. Sex Transm Infect, 1999.
75: 200.
https://www.ncbi.nlm.nih.gov/pubmed/10448405
842. Close, C.F., et al. The association between haemospermia and severe hypertension. Postgrad Med J,
1991. 67: 157.
https://www.ncbi.nlm.nih.gov/pubmed/2041846
843. Bamberger, E., et al. Detection of sexually transmitted pathogens in patients with hematospermia. Isr
Med Assoc J, 2005. 7: 224.
https://www.ncbi.nlm.nih.gov/pubmed/15849868
844. Munkel witz, R., et al. Current perspectives on hematospermia: a review. J Androl, 1997. 18: 6.
https://www.ncbi.nlm.nih.gov/pubmed/9089062
845. Cho, I.R., et al. Magnetic resonance imaging in hemospermia. J Urol, 1997. 157: 258.
https://www.ncbi.nlm.nih.gov/pubmed/8976266
846. Lencioni, R., et al. Endorectal coil MR imaging findings in hemospermia. MAGMA, 1999. 8: 91.
https://www.ncbi.nlm.nih.gov/pubmed/10456371
847. Li, Y.F., et al. Imaging diagnosis, transurethral endoscopic observation, and management of 43 cases
of persistent and refractory hematospermia. J Androl, 2012. 33: 906.
https://www.ncbi.nlm.nih.gov/pubmed/22323622

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 205

848. Cui, Z.Q., et al. [Transurethral seminal vesiculoscopy combined with finasteride for recurrent
hematospermia]. Zhonghua Nan Ke Xue, 2014. 20: 536.
https://www.ncbi.nlm.nih.gov/pubmed/25029861
849. Liu, Z.Y., et al. Transurethral seminal vesiculoscopy in the diagnosis and treatment of persistent or
recurrent hemospermia: a single-institution experience. Asian J Androl, 2009. 11: 566.
https://www.ncbi.nlm.nih.gov/pubmed/19701221
850. Xing, C., et al. Prospective trial comparing transrectal ultrasonography and transurethral seminal
vesiculoscopy for persistent hematospermia. Int J Urol, 2012. 19: 437.
https://www.ncbi.nlm.nih.gov/pubmed/22221075
851. Lowell, D.M., et al. Melanospermia: a hitherto undescribed entity. J Urol, 1966. 95: 407.
https://www.ncbi.nlm.nih.gov/pubmed/5906009
852. Smith, G.W., et al. Melanospermia: an unusual presentation of malignant melanoma. J Urol, 1973.
110: 314.
https://www.ncbi.nlm.nih.gov/pubmed/4725737
853. Manohar, T., et al. Transrectal ultrasound- and fluoroscopic-assisted transurethral incision of
ejaculatory ducts: a problem-solving approach to nonmalignant hematospermia due to ejaculatory
duct obstruction. J Endourol, 2008. 22: 1531.
https://www.ncbi.nlm.nih.gov/pubmed/18690817
854. Fuse, H., et al. Transurethral incision for hematospermia caused by ejaculatory duct obstruction. Arch
Androl, 2003. 49: 433.
https://www.ncbi.nlm.nih.gov/pubmed/14555325
855. Mittal, P.K., et al. Hematospermia Evaluation at MR Imaging. Radiographics, 2016. 36: 1373.
https://www.ncbi.nlm.nih.gov/pubmed/27517360
856. Suh, Y., et al. Etiologic classification, evaluation, and management of hematospermia. Transl Androl
Urol, 2017. 6: 959.
https://www.ncbi.nlm.nih.gov/pubmed/29184797
857. World Health Organisation, International statistical classification of diseases and related health
problems. Vol. 1. 2004.
858. McCabe, M.P., et al. Definitions of Sexual Dysfunctions in Women and Men: A Consensus Statement
From the Fourth International Consultation on Sexual Medicine 2015. J Sex Med, 2016. 13: 135.
https://www.ncbi.nlm.nih.gov/pubmed/26953828
859. Meissner, V.H., et al. Factors Associated with Low Sexual Desire in 45-Year-Old Men: Findings from
the German Male Sex-Study. J Sex Med, 2019. 16: 981.
https://www.ncbi.nlm.nih.gov/pubmed/31196838
860. Levine, S.B. The nature of sexual desire: a clinician's perspective. Arch Sex Behav, 2003. 32: 279.
https://www.ncbi.nlm.nih.gov/pubmed/12807300
861. Rubio-Aurioles, E., et al. Standard operational procedures for low sexual desire in men. J Sex Med,
2013. 10: 94.
https://www.ncbi.nlm.nih.gov/pubmed/22971157
862. Nimbi, F.M., et al. Male Sexual Desire: An Overview of Biological, Psychological, Sexual, Relational,
and Cultural Factors Influencing Desire. Sex Med Rev, 2020. 8: 59.
https://www.ncbi.nlm.nih.gov/pubmed/30803921
863. Carvalho, J., et al. Predictors of men's sexual desire: the role of psychological, cognitive-emotional,
relational, and medical factors. J Sex Res, 2011. 48: 254.
https://www.ncbi.nlm.nih.gov/pubmed/20191421
864. Carvalho, J., et al. Gender issues and sexual desire: the role of emotional and relationship variables. J
Sex Med, 2010. 7: 2469.
https://www.ncbi.nlm.nih.gov/pubmed/20102479
865. Vowels, L.M., et al. Uncovering the Most Important Factors for Predicting Sexual Desire Using
Explainable Machine Learning. J Sex Med, 2021. 18: 1198.
https://www.ncbi.nlm.nih.gov/pubmed/34183292
866. Mark, K.P., et al. Maintaining Sexual Desire in Long-Term Relationships: A Systematic Review and
Conceptual Model. J Sex Res, 2018. 55: 563.
https://www.ncbi.nlm.nih.gov/pubmed/29521522
867. Deziel, J., et al. Anxiety, Dispositional Mindfulness, and Sexual Desire in Men Consulting in Clinical
Sexology: A Mediational Model. J Sex Marital Ther, 2018. 44: 513.
https://www.ncbi.nlm.nih.gov/pubmed/29281564
868. Marieke, D., et al. Sexual Desire Discrepancy: A Position Statement of the European Society for
Sexual Medicine. Sex Med, 2020. 8: 121.
https://www.ncbi.nlm.nih.gov/pubmed/32192965

206 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

869. Zitzmann, M., et al. Association of specific symptoms and metabolic risks with serum testosterone in
older men. J Clin Endocrinol Metab, 2006. 91: 4335.
https://www.ncbi.nlm.nih.gov/pubmed/16926258
870. Meuleman, E.J., et al. Hypoactive sexual desire disorder: an underestimated condition in men. BJU
Int, 2005. 95: 291.
https://www.ncbi.nlm.nih.gov/pubmed/15679780
871. Dei, M., et al. Sex steroids and libido. Eur J Contracept Reprod Health Care, 1997. 2: 253.
https://www.ncbi.nlm.nih.gov/pubmed/9678082
872. Spector, I.P., et al. The sexual desire inventory: development, factor structure, and evidence of
reliability. J Sex Marital Ther, 1996. 22: 175.
https://www.ncbi.nlm.nih.gov/pubmed/8880651
873. Kennedy, S.H., et al. Sexual dysfunction before antidepressant therapy in major depression. J Affect
Disord, 1999. 56: 201.
https://www.ncbi.nlm.nih.gov/pubmed/10701478
874. Isidori, A.M., et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin
Endocrinol (Oxf), 2005. 63: 381.
https://www.ncbi.nlm.nih.gov/pubmed/16181230
875. Corona, G., et al. Effect of hyperprolactinemia in male patients consulting for sexual dysfunction. J
Sex Med, 2007. 4: 1485.
https://www.ncbi.nlm.nih.gov/pubmed/17655655
876. Nobre, P.J., et al., Principles and Practice of Sex Therapy: Sixth Edition - Low sexual desire in men,
2020. New York.
877. Jannini, E.A., et al. Couplepause: A New Paradigm in Treating Sexual Dysfunction During Menopause
and Andropause. Sex Med Rev, 2018. 6: 384.
https://www.ncbi.nlm.nih.gov/pubmed/29371146
878. Wang, A.T., et al. Treatment of hyperprolactinemia: a systematic review and meta-analysis. Syst Rev,
2012. 1: 33.
https://www.ncbi.nlm.nih.gov/pubmed/22828169
879. Cuijpers, P., et al. The contribution of active medication to combined treatments of psychotherapy
and pharmacotherapy for adult depression: a meta-analysis. Acta Psychiatr Scand, 2010. 121: 415.
https://www.ncbi.nlm.nih.gov/pubmed/19922522
880. Yachia, D., et al. The incidence of congenital penile curvature. J Urol, 1993. 150: 1478.
https://www.ncbi.nlm.nih.gov/pubmed/8411431
881. Montag, S., et al. Abnormalities of penile curvature: chordee and penile torsion.
ScientificWorldJournal, 2011. 11: 1470.
https://www.ncbi.nlm.nih.gov/pubmed/21805016
882. Baskin, L.S., et al. Penile curvature. Urology, 1996. 48: 347.
https://www.ncbi.nlm.nih.gov/pubmed/8804484
883. Menon, V., et al. Do adult men with untreated ventral penile curvature have adverse outcomes? J
Pediatr Urol, 2016. 12: 31 e1.
https://www.ncbi.nlm.nih.gov/pubmed/26776946
884. Hayashi, Y., et al. Can spongioplasty prevent fistula formation and correct penile curvature in TIP
urethroplasty for hypospadias? Urology, 2013. 81: 1330.
https://www.ncbi.nlm.nih.gov/pubmed/23453651
885. Akbulut, F., et al. Neurovascular bundle dissection for Nesbit procedure in congenital penile curvature
patients: medial or lateral? Asian J Androl, 2014. 16: 442.
https://www.ncbi.nlm.nih.gov/pubmed/24625879
886. Alei, G., et al. New surgical technique for ventral penile curvature without circumcision. BJU Int, 2014.
113: 968.
https://www.ncbi.nlm.nih.gov/pubmed/25035866
887. Bhat, A., et al. Correlation of severity of penile torsion with type of hypospadias & ventral penile
curvature and their management. African Journal of Urology, 2015. 21: 111.
https://www.sciencedirect.com/science/article/pii/S1110570415000168
888. Cantoro, U., et al. Plication corporoplasty for congenital penile curvature: our results with long-term
follow-up. Int Urol Nephrol, 2014. 46: 1741.
https://www.ncbi.nlm.nih.gov/pubmed/24818593
889. Chung, P.H., et al. Dorsal plication without degloving is safe and effective for correcting ventral penile
deformities. Urology, 2014. 84: 1228.
https://www.ncbi.nlm.nih.gov/pubmed/25443939

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 207

890. Golomb, D., et al. Long-term Results of Ventral Penile Curvature Repair in Childhood. Urology, 2018.
112: 161.
https://www.ncbi.nlm.nih.gov/pubmed/29051007
891. Perdzynski, W., et al. Three anatomical levels: possibilities to decrease invasiveness of reconstructive
surgery for congenital penile curvature. Cent European J Urol, 2017. 70: 280.
https://www.ncbi.nlm.nih.gov/pubmed/29104792
892. Schlomer, B.J. Correction of Residual Ventral Penile Curvature After Division of the Urethral Plate in
the First Stage of a 2-Stage Proximal Hypospadias Repair. Curr Urol Rep, 2017. 18: 13.
https://www.ncbi.nlm.nih.gov/pubmed/28213855
893. Seo, S., et al. Correction of penile ventral curvature in patients with minor or no hypospadias: a single
surgeon's experience of 43 cases. Pediatr Surg Int, 2016. 32: 975.
https://www.ncbi.nlm.nih.gov/pubmed/27488311
894. Shaeer, O., et al. Shaeer's Corporal Rotation III: Shortening-Free Correction of Congenital Penile
Curvature-The Noncorporotomy Technique. Eur Urol, 2016. 69: 129.
https://www.ncbi.nlm.nih.gov/pubmed/26298209
895. Shaeer, O. Shaeer's corporal rotation for length-preserving correction of penile curvature:
modifications and 3-year experience. J Sex Med, 2008. 5: 2716.
https://www.ncbi.nlm.nih.gov/pubmed/18624969
896. Shaeer, O. Trans-corporal incision of Peyronie's plaques. J Sex Med, 2011. 8: 589.
https://www.ncbi.nlm.nih.gov/pubmed/20955315
897. Shaeer, O. Shaeer's Corporal Rotation. J Sex Med, 2010. 7: 16.
https://www.ncbi.nlm.nih.gov/pubmed/20092460
898. Chung, E., et al. Prevalence of penile curvature: a population-based cross-sectional study in
metropolitan and rural cities in Australia. BJU Int, 2018. 122 Suppl 5: 42.
https://www.ncbi.nlm.nih.gov/pubmed/30387224
899. Arafa, M., et al. The prevalence of Peyronie's disease in diabetic patients with erectile dysfunction. Int
J Impot Res, 2007. 19: 213.
https://www.ncbi.nlm.nih.gov/pubmed/16915304
900. Kumar, B., et al. A clinico-aetiological and ultrasonographic study of Peyronie's disease. Sex Health,
2006. 3: 113.
https://www.ncbi.nlm.nih.gov/pubmed/16800397
901. La Pera, G., et al. Peyronie's disease: prevalence and association with cigarette smoking. A
multicenter population-based study in men aged 50-69 years. Eur Urol, 2001. 40: 525.
https://www.ncbi.nlm.nih.gov/pubmed/11752860
902. Lindsay, M.B., et al. The incidence of Peyronie's disease in Rochester, Minnesota, 1950 through 1984.
J Urol, 1991. 146: 1007.
https://www.ncbi.nlm.nih.gov/pubmed/1895413
903. Mulhall, J.P., et al. Subjective and objective analysis of the prevalence of Peyronie's disease in a
population of men presenting for prostate cancer screening. J Urol, 2004. 171: 2350.
https://www.ncbi.nlm.nih.gov/pubmed/15126819
904. Rhoden, E.L., et al. Prevalence of Peyronie's disease in men over 50-y-old from Southern Brazil. Int J
Impot Res, 2001. 13: 291.
https://www.ncbi.nlm.nih.gov/pubmed/11890516
905. Schwarzer, U., et al. The prevalence of Peyronie's disease: results of a large survey. BJU Int, 2001. 88:
727.
https://www.ncbi.nlm.nih.gov/pubmed/11890244
906. Sommer, F., et al. Epidemiology of Peyronie's disease. Int J Impot Res, 2002. 14: 379.
https://www.ncbi.nlm.nih.gov/pubmed/12454689
907. Stuntz, M., et al. The Prevalence of Peyronie's Disease in the United States: A Population-Based
Study. PLoS One, 2016. 11: e0150157.
https://www.ncbi.nlm.nih.gov/pubmed/26907743
908. Tefekli, A., et al. Peyronie's disease in men under age 40: characteristics and outcome. Int J Impot
Res, 2001. 13: 18.
https://www.ncbi.nlm.nih.gov/pubmed/11313836
909. Levine, L.A., et al. Peyronie disease in younger men: characteristics and treatment results. J Androl,
2003. 24: 27.
https://www.ncbi.nlm.nih.gov/pubmed/12514077
910. Hellstrom, W.J., et al. Bother and distress associated with Peyronie's disease: validation of the
Peyronie's disease questionnaire. J Urol, 2013. 190: 627.
https://www.ncbi.nlm.nih.gov/pubmed/23376705

208 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

911. Russo, G.I., et al. Clinical Efficacy of Injection and Mechanical Therapy for Peyronie's Disease: A
Systematic Review of the Literature. Eur Urol, 2018. 74: 767.
https://www.ncbi.nlm.nih.gov/pubmed/30237020
912. Masterson, T.A., et al. Characteristics predictive of response to collagenase clostridium histolyticum
for Peyronie's disease: a review of the literature. World J Urol, 2020. 38: 279.
https://www.ncbi.nlm.nih.gov/pubmed/31250098
913. Chung, E., et al. Evidence-Based Management Guidelines on Peyronie's Disease. J Sex Med, 2016. 13:
905.
https://www.ncbi.nlm.nih.gov/pubmed/27215686
914. Mulhall, J.P., et al. An analysis of the natural history of Peyronie's disease. J Urol, 2006. 175: 2115.
https://www.ncbi.nlm.nih.gov/pubmed/16697815
915. Bekos, A., et al. The natural history of Peyronie's disease: an ultrasonography-based study. Eur Urol,
2008. 53: 644.
https://www.ncbi.nlm.nih.gov/pubmed/17673362
916. Greenfield, J.M., et al. Factors affecting the loss of length associated with tunica albuginea plication
for correction of penile curvature. J Urol, 2006. 175: 238.
https://www.ncbi.nlm.nih.gov/pubmed/16406919
917. Liguori, G., et al. Objective measurements of the penile angulation are significantly different than self-
estimated magnitude among patients with penile curvature. Int Braz J Urol, 2018. 44: 555.
https://www.ncbi.nlm.nih.gov/pubmed/29570261
918. Habous, M., et al. Outcomes of variation in technique and variation in accuracy of measurement in
penile length measurement. Int J Impot Res, 2018. 30: 21.
https://www.ncbi.nlm.nih.gov/pubmed/29180797
919. Levine, L.A., et al. Establishing a standardized evaluation of the man with Peyronie's disease. Int J
Impot Res, 2003. 15 Suppl 5: S103.
https://www.ncbi.nlm.nih.gov/pubmed/14551586
920. Ozmez, A., et al. The Effectiveness of 3-D Computed Tomography in the Evaluation of Penile
Deformities in Patients With Peyronie's Disease: A Pilot Study. Sex Med, 2019. 7: 311.
https://www.ncbi.nlm.nih.gov/pubmed/31324507
921. Hauck, E.W., et al. Diagnostic value of magnetic resonance imaging in Peyronie's disease--a
comparison both with palpation and ultrasound in the evaluation of plaque formation. Eur Urol, 2003.
43: 293.
https://www.ncbi.nlm.nih.gov/pubmed/12600434
922. Nguyen, H.M.T., et al. Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of
Acute-Phase Peyronie's Disease. J Sex Med, 2017. 14: 1220.
https://www.ncbi.nlm.nih.gov/pubmed/28874331
923. Gholami, S.S., et al. Peyronie's disease: a review. J Urol, 2003. 169: 1234.
https://www.ncbi.nlm.nih.gov/pubmed/12629334
924. Kadioglu, A., et al. Color Doppler ultrasound assessment of penile vascular system in men with
Peyronie's disease. Int J Impot Res, 2000. 12: 263.
https://www.ncbi.nlm.nih.gov/pubmed/11424963
925. Serefoglu, E.C., et al. Factors Associated With Erectile Dysfunction and the Peyronie's Disease
Questionnaire in Patients With Peyronie Disease. Urology, 2017. 107: 155.
https://www.ncbi.nlm.nih.gov/pubmed/28554517
926. McCauley, J.F., et al. Diagnostic utility of penile ultrasound in Peyronie's disease. World J Urol, 2020.
38: 263.
https://www.ncbi.nlm.nih.gov/pubmed/31606787
927. Porst, H., et al. Standards for clinical trials in male sexual dysfunctions. J Sex Med, 2010. 7: 414.
https://www.ncbi.nlm.nih.gov/pubmed/20092447
928. Muller, A., et al. Peyronie's disease intervention trials: methodological challenges and issues. J Sex
Med, 2009. 6: 848.
https://www.ncbi.nlm.nih.gov/pubmed/19138374
929. Nehra, A., et al. Peyronie's Disease: AUA Guideline. J Urol, 2015. 194: 745.
https://www.ncbi.nlm.nih.gov/pubmed/26066402
930. Bella, A.J., et al. 2018 Canadian Urological Association guideline for Peyronie's disease and
congenital penile curvature. Can Urol Assoc J, 2018. 12: E197.
https://www.ncbi.nlm.nih.gov/pubmed/29792593
931. Dahm, P., et al. Moving from Consensus- to Evidence-Based Clinical Practice Guidelines for Peyronie's
Disease. J Sex Med, 2017. 14: 170.
https://www.ncbi.nlm.nih.gov/pubmed/28065352

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 209

932. Safarinejad, M.R., et al. A double-blind placebo-controlled study of the efficacy and safety of
pentoxifylline in early chronic Peyronie's disease. BJU Int, 2010. 106: 240.
https://www.ncbi.nlm.nih.gov/pubmed/19863517
933. Safarinejad, M.R., et al. Retraction statement: A double-blind placebo-controlled study of the efficacy
and safety of pentoxifylline in early chronic Peyronie's disease. BJU Int, 2015. 115: E10.
https://www.ncbi.nlm.nih.gov/pubmed/25830185
934. Ferrini, M.G., et al. Effects of long-term vardenafil treatment on the development of fibrotic plaques in
a rat model of Peyronie's disease. BJU Int, 2006. 97: 625.
https://www.ncbi.nlm.nih.gov/pubmed/16469038
935. Valente, E.G., et al. L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the
Peyronie's fibrotic plaque and related fibroblast cultures. Nitric Oxide, 2003. 9: 229.
https://www.ncbi.nlm.nih.gov/pubmed/14996430
936. Ilg, M.M., et al. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can
Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med, 2020. 17:
1848.
https://www.ncbi.nlm.nih.gov/pubmed/32771352
937. Chung, E., et al. The role of PDE5 inhibitors in penile septal scar remodeling: assessment of clinical
and radiological outcomes. J Sex Med, 2011. 8: 1472.
https://www.ncbi.nlm.nih.gov/pubmed/21324095
938. Ozturk, U., et al. Effects of sildenafil treatment on patients with Peyronie's disease and erectile
dysfunction. Ir J Med Sci, 2014. 183: 449.
https://www.ncbi.nlm.nih.gov/pubmed/24190613
939. Spirito, L., et al. Daily low-dose tadalafil may reduce the penile curvature progression rate in patients
with acute Peyronie's disease: a retrospective comparative analysis. Int J Impot Res, 2022.
https://www.ncbi.nlm.nih.gov/pubmed/36513814
940. Mulhall, J.P., et al. Peyronie's disease cell culture models: phenotypic, genotypic and functional
analyses. Int J Impot Res, 2002. 14: 397.
https://www.ncbi.nlm.nih.gov/pubmed/12454692
941. Roth, M., et al. Ca2+ channel blockers modulate metabolism of collagens within the extracellular
matrix. Proc Natl Acad Sci U S A, 1996. 93: 5478.
https://www.ncbi.nlm.nih.gov/pubmed/8643600
942. Favilla, V., et al. Evaluation of intralesional injection of hyaluronic acid compared with verapamil
in Peyronie's disease: preliminary results from a prospective, double-blinded, randomized study.
Andrology, 2017. 5: 771.
https://www.ncbi.nlm.nih.gov/pubmed/28718527
943. Abern, M.R., et al. Combination of penile traction, intralesional verapamil, and oral therapies for
Peyronie's disease. J Sex Med, 2012. 9: 288.
https://www.ncbi.nlm.nih.gov/pubmed/22024053
944. Rehman, J., et al. Use of intralesional verapamil to dissolve Peyronie's disease plaque: a long-term
single-blind study. Urology, 1998. 51: 620.
https://www.ncbi.nlm.nih.gov/pubmed/9586617
945. Soh, J., et al. Nicardipine vs. saline injection as treatment for Peyronie's disease: a prospective,
randomized, single-blind trial. J Sex Med, 2010. 7: 3743.
https://www.ncbi.nlm.nih.gov/pubmed/20584114
946. Toscano, L., Jr., et al. A prospective, randomized, single - blind study comparing intraplaque injection
of thiocolchicine and verapamil in Peyronie's Disease: a pilot study. Int Braz J Urol, 2016. 42: 1005.
https://www.ncbi.nlm.nih.gov/pubmed/24893912
947. Shirazi, M., et al. Effect of intralesional verapamil for treatment of Peyronie's disease: a randomized
single-blind, placebo-controlled study. Int Urol Nephrol, 2009. 41: 467.
https://www.ncbi.nlm.nih.gov/pubmed/19199072
948. Gelbard, M.K., et al. The use of collagenase in the treatment of Peyronie's disease. J Urol, 1985. 134:
280.
https://www.ncbi.nlm.nih.gov/pubmed/2991611
949. Ehrlich, H.P. Scar contracture: cellular and connective tissue aspects in Peyronie's disease. J Urol,
1997. 157: 316.
https://www.ncbi.nlm.nih.gov/pubmed/8976288
950. Gelbard, M.K., et al. Collagenase versus placebo in the treatment of Peyronie's disease: a double-
blind study. J Urol, 1993. 149: 56.
https://www.ncbi.nlm.nih.gov/pubmed/8417217

210 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

951. Jordan, G.H. The use of intralesional clostridial collagenase injection therapy for Peyronie's disease:
a prospective, single-center, non-placebo-controlled study. J Sex Med, 2008. 5: 180.
https://www.ncbi.nlm.nih.gov/pubmed/18173766
952. EMA, Assessement Report - Xiapex (Collagenase Clostridium Histolyticum). 2014.
https://www.ema.europa.eu/en/documents/variation-report/xiapex-h-c-2048-ii-0044-epar-
assessment-report-variation_en.pdf
953. Russo, G.I., et al. Comparative Effectiveness of Intralesional Therapy for Peyronie's Disease in
Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis. J Sex Med, 2019. 16:
289.
https://www.ncbi.nlm.nih.gov/pubmed/30692028
954. Lipshultz, L.I., et al. Clinical efficacy of collagenase Clostridium histolyticum in the treatment of
Peyronie's disease by subgroup: results from two large, double-blind, randomized, placebo-controlled,
phase III studies. BJU Int, 2015. 116: 650.
https://www.ncbi.nlm.nih.gov/pubmed/25711400
955. Gelbard, M., et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for
the treatment of peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3
studies. J Urol, 2013. 190: 199.
https://www.ncbi.nlm.nih.gov/pubmed/23376148
956. Abdel Raheem, A., et al. Safety and effectiveness of collagenase clostridium histolyticum in the
treatment of Peyronie's disease using a new modified shortened protocol. BJU Int, 2017. 120: 717.
https://www.ncbi.nlm.nih.gov/pubmed/28612401
957. Cocci, A., et al. Predictors of treatment success after collagenase Clostridium histolyticum injection
for Peyronie's disease: development of a nomogram from a multicentre single-arm, non-placebo
controlled clinical study. BJU Int, 2018. 122: 680.
https://www.ncbi.nlm.nih.gov/pubmed/29791971
958. Carson, C.C., 3rd, et al. Analysis of the clinical safety of intralesional injection of collagenase
Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD). BJU Int, 2015. 116: 815.
https://www.ncbi.nlm.nih.gov/pubmed/25818264
959. El-Khatib, F.M., et al. Management of Peyronie's disease with collagenase Clostridium histolyticum in
the acute phase. World J Urol, 2020. 38: 299.
https://www.ncbi.nlm.nih.gov/pubmed/31093703
960. Cocci, A., et al. Efficacy of Collagenase Clostridium histolyticum (Xiapex((R))) in Patients with the
Acute Phase of Peyronie's Disease. Clin Drug Investig, 2020. 40: 583.
https://www.ncbi.nlm.nih.gov/pubmed/32342279
961. Nguyen, H.M.T., et al. Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of
Acute Phase Peyronie's Disease: A Multi-institutional Analysis. Urology, 2020. 145: 147.
https://www.ncbi.nlm.nih.gov/pubmed/32777367
962. Ziegelmann, M.J., et al. Restoration of Penile Function and Patient Satisfaction with Intralesional
Collagenase Clostridium Histolyticum Injection for Peyronie's Disease. J Urol, 2016. 195: 1051.
https://www.ncbi.nlm.nih.gov/pubmed/26476353
963. Yang, K.K., et al. Peyronie's Disease and Injectable Collagenase Clostridium histolyticum: Safety,
Efficacy, and Improvements in Subjective Symptoms. Urology, 2016. 94: 143.
https://www.ncbi.nlm.nih.gov/pubmed/27211926
964. Hellstrom, W.J., et al. Single-blind, multicenter, placebo controlled, parallel study to assess the safety
and efficacy of intralesional interferon alpha-2B for minimally invasive treatment for Peyronie's
disease. J Urol, 2006. 176: 394.
https://www.ncbi.nlm.nih.gov/pubmed/16753449
965. Kendirci, M., et al. The impact of intralesional interferon alpha-2b injection therapy on penile
hemodynamics in men with Peyronie's disease. J Sex Med, 2005. 2: 709.
https://www.ncbi.nlm.nih.gov/pubmed/16422829
966. Stewart, C.A., et al. Intralesional Injection of Interferon-alpha2b Improves Penile Curvature in Men
with Peyronie's Disease Independent of Plaque Location. J Urol, 2015. 194: 1704.
https://www.ncbi.nlm.nih.gov/pubmed/26144333
967. Cipollone, G., et al. [Betamethasone versus placebo in Peyronie's disease]. Arch Ital Urol Androl, 1998.
70: 165.
https://www.ncbi.nlm.nih.gov/pubmed/9823662
968. Desanctis, P.N., et al. Steroid injection therapy for Peyronie's disease: a 10-year summary and review
of 38 cases. J Urol, 1967. 97: 114.
https://www.ncbi.nlm.nih.gov/pubmed/6016195

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 211

969. Cocci, A., et al. Comparison of Intralesional Hyaluronic Acid vs. Verapamil for the Treatment of Acute
Phase Peyronie's Disease: A Prospective, Open-Label Non-Randomized Clinical Study. World J Mens
Health, 2021. 39: 352.
https://www.ncbi.nlm.nih.gov/pubmed/32009312
970. Cai, T., et al. Oral Administration and Intralesional Injection of Hyaluronic Acid Versus Intralesional
Injection Alone in Peyronie's Disease: Results from a Phase III Study. World J Mens Health, 2021. 39:
526.
https://www.ncbi.nlm.nih.gov/pubmed/33151042
971. Munoz-Rangel, C.A., et al. Minimally Invasive Therapy Using Intralesional OnabotulinumtoxinA in
Peyronie's Disease. Urol J, 2015. 12: 2105.
https://www.ncbi.nlm.nih.gov/pubmed/25923158
972. Virag, R., et al. A New Treatment of Lapeyronie’s Disease by Local Injections of Plasma Rich Platelets
(PRP) and Hyaluronic Acid. Preliminary Results. e-Mémoires de l'Académie Nationale de Chirurgie,
2014. 13: 96.
https://www3.biusante.parisdescartes.fr/acadchir/sean/index.las
973. Virag R, et al. Evaluation of the benefit of using a combination of autologous platelet rich- plasma
and hyaluronic acid for the treatment of Peyronie’s disease. Sex Health Issues, 2017. 1: 1.
https://www.oatext.com/evaluation-of-the-benefit-of-using-a-combination-of-autologous-platelet-rich-
plasma-and-hyaluronic-acid-for-the-treatment-of-Peyronies-disease.php
974. Marcovici, I. PRP and Correction of Penile Curvature (Peyronie’s Disease). The American Journal of
Cosmetic Surgery, 2018. 36: 117.
https://journals.sagepub.com/doi/abs/10.1177/0748806818798280
975. Notsek, M., et al. PO-01-083 Platelet-rich Plasma Therapy of Peyronie's Disease. The Journal of
Sexual Medicine, 2019. 16: S70.
https://doi.org/10.1016/j.jsxm.2019.03.225
976. Schirmann, A., et al. Tolerance and efficacy of platelet-rich plasma injections in Peyronie's disease:
Pilot study. Prog Urol, 2022. 32: 856.
https://www.ncbi.nlm.nih.gov/pubmed/35778315
977. Achraf, C., et al. Platelet-rich plasma in patients affected with Peyronie's disease. Arab J Urol, 2023.
21: 69.
https://www.ncbi.nlm.nih.gov/pubmed/37234679
978. Chu, K.Y., et al. A Phase 2 Randomized, Placebo-controlled Crossover Trial to Evaluate Safety and
Efficacy of Platelet-rich Plasma Injections for Peyronie's Disease: Clinical Trial Update. Eur Urol
Focus, 2023. 9: 11.
https://www.ncbi.nlm.nih.gov/pubmed/36100520
979. Montorsi, F., et al. Transdermal electromotive multi-drug administration for Peyronie's disease:
preliminary results. J Androl, 2000. 21: 85.
https://www.ncbi.nlm.nih.gov/pubmed/10670523
980. Di Stasi, S.M., et al. Transdermal electromotive administration of verapamil and dexamethasone for
Peyronie's disease. BJU Int, 2003. 91: 825.
https://www.ncbi.nlm.nih.gov/pubmed/12780842
981. Greenfield, J.M., et al. Verapamil versus saline in electromotive drug administration for Peyronie's
disease: a double-blind, placebo controlled trial. J Urol, 2007. 177: 972.
https://www.ncbi.nlm.nih.gov/pubmed/17296390
982. Twidwell, J., et al. Topical treatment for acute phase Peyronie's disease utilizing a new gel, H-100: a
randomized, prospective, placebo-controlled pilot study. Int J Impot Res, 2016. 28: 41.
https://www.ncbi.nlm.nih.gov/pubmed/26700214
983. Palmieri, A., et al. A first prospective, randomized, double-blind, placebo-controlled clinical trial
evaluating extracorporeal shock wave therapy for the treatment of Peyronie's disease. Eur Urol, 2009.
56: 363.
https://www.ncbi.nlm.nih.gov/pubmed/19473751
984. Chitale, S., et al. Limited shock wave therapy vs sham treatment in men with Peyronie's disease:
results of a prospective randomized controlled double-blind trial. BJU Int, 2010. 106: 1352.
https://www.ncbi.nlm.nih.gov/pubmed/20438568
985. Palmieri, A., et al. Tadalafil once daily and extracorporeal shock wave therapy in the management
of patients with Peyronie's disease and erectile dysfunction: results from a prospective randomized
trial. Int J Androl, 2012. 35: 190.
https://www.ncbi.nlm.nih.gov/pubmed/22085227

212 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

986. Hatzichristodoulou, G., et al. Extracorporeal shock wave therapy in Peyronie's disease: results of a
placebo-controlled, prospective, randomized, single-blind study. J Sex Med, 2013. 10: 2815.
https://www.ncbi.nlm.nih.gov/pubmed/23898925
987. Gao, L., et al. A meta-analysis of extracorporeal shock wave therapy for Peyronie's disease. Int J
Impot Res, 2016. 28: 161.
https://www.ncbi.nlm.nih.gov/pubmed/27250868
988. Husain, J., et al. Extracorporeal shock wave therapy in the management of Peyronie's disease: initial
experience. BJU Int, 2000. 86: 466.
https://www.ncbi.nlm.nih.gov/pubmed/10971273
989. Gelbard, M. Myofibroblasts and mechanotransduction: do forces in the tunica albuginea contribute to
Peyronie's disease? J Sex Med, 2008. 5: 2974.
https://www.ncbi.nlm.nih.gov/pubmed/19090949
990. Chung, E., et al. Peyronie's disease and mechanotransduction: an in vitro analysis of the cellular
changes to Peyronie's disease in a cell-culture strain system. J Sex Med, 2013. 10: 1259.
https://www.ncbi.nlm.nih.gov/pubmed/23421851
991. Gontero, P., et al. Use of penile extender device in the treatment of penile curvature as a result of
Peyronie's disease. Results of a phase II prospective study. J Sex Med, 2009. 6: 558.
https://www.ncbi.nlm.nih.gov/pubmed/19138361
992. Levine, L.A., et al. Penile traction therapy for treatment of Peyronie's disease: a single-center pilot
study. J Sex Med, 2008. 5: 1468.
https://www.ncbi.nlm.nih.gov/pubmed/18373527
993. Martinez-Salamanca, J.I., et al. Acute phase Peyronie's disease management with traction device: a
nonrandomized prospective controlled trial with ultrasound correlation. J Sex Med, 2014. 11: 506.
https://www.ncbi.nlm.nih.gov/pubmed/24261900
994. Wymer, K., et al. Comparative Cost-effectiveness of Surgery, Collagenase Clostridium Histolyticum,
and Penile Traction Therapy in Men with Peyronie's Disease in an Era of Effective Clinical Treatment.
J Sex Med, 2019. 16: 1421.
https://www.ncbi.nlm.nih.gov/pubmed/31351851
995. Ziegelmann, M., et al. Outcomes of a Novel Penile Traction Device in Men with Peyronie's Disease: A
Randomized, Single-Blind, Controlled Trial. J Urol, 2019. 202: 599.
https://www.ncbi.nlm.nih.gov/pubmed/30916626
996. Moncada, I., et al. Penile traction therapy with the new device 'Penimaster PRO' is effective and safe
in the stable phase of Peyronie's disease: a controlled multicentre study. BJU Int, 2019. 123: 694.
https://www.ncbi.nlm.nih.gov/pubmed/30365247
997. Garcia-Gomez, B., et al. The Use of Penile Traction Devices for Peyronie's Disease: Position
Statements from the European Society for Sexual Medicine. Sex Med, 2021. 9: 100387.
https://www.ncbi.nlm.nih.gov/pubmed/34273788
998. Broderick, G.A., et al. The hemodynamics of vacuum constriction erections: assessment by color
Doppler ultrasound. J Urol, 1992. 147: 57.
https://www.ncbi.nlm.nih.gov/pubmed/1729552
999. Paulis, G., et al. Long-term multimodal therapy (verapamil associated with propolis, blueberry, vitamin
E and local diclofenac) on patients with Peyronie's disease (chronic inflammation of the tunica
albuginea). Results of a controlled study. Inflamm Allergy Drug Targets, 2013. 12: 403.
https://www.ncbi.nlm.nih.gov/pubmed/24304332
1000. Raheem, A.A., et al. The role of vacuum pump therapy to mechanically straighten the penis in
Peyronie's disease. BJU Int, 2010. 106: 1178.
https://www.ncbi.nlm.nih.gov/pubmed/20438558
1001. MacDonald, L.P., et al. Outcome analysis of patients with Peyronie's disease who elect for vacuum
erection device therapy. Can Urol Assoc J, 2020. 14: E428.
https://www.ncbi.nlm.nih.gov/pubmed/32223874
1002. Avant, R.A., et al. Penile Traction Therapy and Vacuum Erection Devices in Peyronie's Disease. Sex
Med Rev, 2019. 7: 338.
https://www.ncbi.nlm.nih.gov/pubmed/29631979
1003. Yafi, F.A., et al. The Effect of Duration of Penile Traction Therapy in Patients Undergoing Intralesional
Injection Therapy for Peyronie's Disease. J Urol, 2015. 194: 754.
https://www.ncbi.nlm.nih.gov/pubmed/25804087
1004. Ziegelmann, M.J., et al. Clinical Experience With Penile Traction Therapy Among Men Undergoing
Collagenase Clostridium histolyticum for Peyronie Disease. Urology, 2017. 104: 102.
https://www.ncbi.nlm.nih.gov/pubmed/28347795

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 213

1005. Haney, N.M., et al. The Effect of Adjunct Mechanical Traction on Penile Length in Men Undergoing
Primary Treatment for Peyronie's Disease: A Systematic Review and Meta-analysis. Urology, 2018.
122: 110.
https://www.ncbi.nlm.nih.gov/pubmed/30099127
1006. Cocci, A., et al. Sildenafil 25 mg ODT + Collagenase Clostridium hystoliticum vs Collagenase
Clostridium hystoliticum Alone for the Management of Peyronie's Disease: A Matched-Pair
Comparison Analysis. J Sex Med, 2018. 15: 1472.
https://www.ncbi.nlm.nih.gov/pubmed/30245025
1007. Ralph, D., et al. The management of Peyronie's disease: evidence-based 2010 guidelines. J Sex Med,
2010. 7: 2359.
https://www.ncbi.nlm.nih.gov/pubmed/20497306
1008. Matsushita, K., et al. Concordance between patient and physician assessment of the magnitude of
Peyronie's disease curvature. J Sex Med, 2014. 11: 205.
https://www.ncbi.nlm.nih.gov/pubmed/24119178
1009. Smith, J.F., et al. Peyronie's disease: a critical appraisal of current diagnosis and treatment. Int J
Impot Res, 2008. 20: 445.
https://www.ncbi.nlm.nih.gov/pubmed/18650828
1010. Kadioglu, A., et al. Current status of the surgical management of Peyronie's disease. Nat Rev Urol,
2011. 8: 95.
https://www.ncbi.nlm.nih.gov/pubmed/21304544
1011. Carson, C.C., et al. Outcomes of surgical treatment of Peyronie's disease. BJU Int, 2014. 113: 704.
https://www.ncbi.nlm.nih.gov/pubmed/24219080
1012. Taylor, F.L., et al. Surgical correction of Peyronie's disease via tunica albuginea plication or partial
plaque excision with pericardial graft: long-term follow up. J Sex Med, 2008. 5: 2221.
https://www.ncbi.nlm.nih.gov/pubmed/18637996
1013. Langston, J.P., et al. Peyronie disease: plication or grafting. Urol Clin North Am, 2011. 38: 207.
https://www.ncbi.nlm.nih.gov/pubmed/21621087
1014. Mulhall, J., et al. A surgical algorithm for men with combined Peyronie's disease and erectile
dysfunction: functional and satisfaction outcomes. J Sex Med, 2005. 2: 132.
https://www.ncbi.nlm.nih.gov/pubmed/16422916
1015. Garaffa, G., et al. Circumcision is not mandatory in penile surgery. BJU Int, 2010. 105: 222.
https://www.ncbi.nlm.nih.gov/pubmed/19594732
1016. Adibi, M., et al. Penile plication without degloving enables effective correction of complex Peyronie's
deformities. Urology, 2012. 79: 831.
https://www.ncbi.nlm.nih.gov/pubmed/22365444
1017. Clavell-Hernandez, J., et al. Penile Size Restoration With Nondegloving Approach for Peyronie's
Disease: Initial Experience. J Sex Med, 2018. 15: 1506.
https://www.ncbi.nlm.nih.gov/pubmed/30177471
1018. Kendirci, M., et al. Critical analysis of surgery for Peyronie's disease. Curr Opin Urol, 2004. 14: 381.
https://www.ncbi.nlm.nih.gov/pubmed/15626883
1019. Nesbit, R.M. Congenital Curvature of the Phallus: Report of Three Cases with Description of
Corrective Operation. J Urol, 1965. 93: 230.
https://www.ncbi.nlm.nih.gov/pubmed/14260875
1020. Pryor, J.P., et al. A new approach to the correction of the penile deformity in Peyronie's disease. J
Urol, 1979. 122: 622.
https://www.ncbi.nlm.nih.gov/pubmed/501814
1021. Lemberger, R.J., et al. Nesbit's operation for Peyronie's disease. Br J Urol, 1984. 56: 721.
https://www.ncbi.nlm.nih.gov/pubmed/6534497
1022. Sassine, A.M., et al. Modified corporoplasty for penile curvature: 10 years' experience. Urology, 1994.
44: 419.
https://www.ncbi.nlm.nih.gov/pubmed/8073558
1023. Daitch, J.A., et al. Modified corporoplasty for penile curvature: long-term results and patient
satisfaction. J Urol, 1999. 162: 2006.
https://www.ncbi.nlm.nih.gov/pubmed/10569557
1024. Licht, M.R., et al. Modified Nesbit procedure for the treatment of Peyronie's disease: a comparative
outcome analysis. J Urol, 1997. 158: 460.
https://www.ncbi.nlm.nih.gov/pubmed/9224323
1025. Yachia, D. Modified corporoplasty for the treatment of penile curvature. J Urol, 1990. 143: 80.
https://www.ncbi.nlm.nih.gov/pubmed/2294269

214 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1026. Lopes, I., et al. Penile corporoplasty with Yachia's technique for Peyronie's disease: Single center
experience with 117 patients. Urol Ann, 2013. 5: 167.
https://www.ncbi.nlm.nih.gov/pubmed/24049379
1027. Nooter, R.I., et al. Peyronie's disease and congenital penile curvature: long-term results of operative
treatment with the plication procedure. Br J Urol, 1994. 74: 497.
https://www.ncbi.nlm.nih.gov/pubmed/7820430
1028. Klevmark, B., et al. Congenital and acquired curvature of the penis treated surgically by plication of
the tunica albuginea. Br J Urol, 1994. 74: 501.
https://www.ncbi.nlm.nih.gov/pubmed/7820431
1029. Kummerling, S., et al. Peyronie's disease. Investigation of staging, erectile failure and operative
management. Int Urol Nephrol, 1995. 27: 629.
https://www.ncbi.nlm.nih.gov/pubmed/8775049
1030. Thiounn, N., et al. Corporeal plication for surgical correction of penile curvature. Experience with 60
patients. Eur Urol, 1998. 33: 401.
https://www.ncbi.nlm.nih.gov/pubmed/9612685
1031. Schultheiss, D., et al. Congenital and acquired penile deviation treated with the essed plication
method. Eur Urol, 2000. 38: 167.
https://www.ncbi.nlm.nih.gov/pubmed/10895008
1032. Chahal, R., et al. Corporal plication for penile curvature caused by Peyronie's disease: the patients'
perspective. BJU Int, 2001. 87: 352.
https://www.ncbi.nlm.nih.gov/pubmed/11251529
1033. Cormio, L., et al. Tunica albuginea plication for the correction of penile curvature. Scand J Urol
Nephrol, 2002. 36: 307.
https://www.ncbi.nlm.nih.gov/pubmed/12201925
1034. van der Drift, D.G., et al. The plication procedure for penile curvature: surgical outcome and
postoperative sexual functioning. Urol Int, 2002. 69: 120.
https://www.ncbi.nlm.nih.gov/pubmed/12187042
1035. Van Der Horst, C., et al. Treatment of penile curvature with Essed-Schroder tunical plication: aspects
of quality of life from the patients' perspective. BJU Int, 2004. 93: 105.
https://www.ncbi.nlm.nih.gov/pubmed/14678379
1036. Geertsen, U.A., et al. Peyronie curvature treated by plication of the penile fasciae. Br J Urol, 1996. 77:
733.
https://www.ncbi.nlm.nih.gov/pubmed/8689121
1037. Kim, D.H., et al. Subjective patient-reported experiences after surgery for Peyronie's disease:
corporeal plication versus plaque incision with vein graft. Urology, 2008. 71: 698.
https://www.ncbi.nlm.nih.gov/pubmed/18387398
1038. Cantoro, U., et al. Penile plication for Peyronie's disease: our results with mean follow-up of 103
months on 89 patients. Int J Impot Res, 2014. 26: 156.
https://www.ncbi.nlm.nih.gov/pubmed/24572996
1039. Iacono, F., et al. Tunical plication in the management of penile curvature due La Peyronie's disease.
Our experience on 47 cases. BMC Surg, 2012. 12 Suppl 1: S25.
https://www.ncbi.nlm.nih.gov/pubmed/23173735
1040. Kadirov, R., et al. Penile Plication With or Without Degloving of the Penis Results in Similar Outcomes.
Sex Med, 2017. 5: e142.
https://www.ncbi.nlm.nih.gov/pubmed/28711404
1041. Hudak, S.J., et al. Favorable patient reported outcomes after penile plication for wide array of
peyronie disease abnormalities. J Urol, 2013. 189: 1019.
https://www.ncbi.nlm.nih.gov/pubmed/23017514
1042. Reddy, R.S., et al. Plication for Severe Peyronie's Deformities Has Similar Long-Term Outcomes to
Milder Cases. J Sex Med, 2018. 15: 1498.
https://www.ncbi.nlm.nih.gov/pubmed/30228083
1043. Seveso, M., et al. Surgical correction of Peyronie's disease via tunica albuginea plication: long-term
follow-up. Andrology, 2018. 6: 47.
https://www.ncbi.nlm.nih.gov/pubmed/29195031
1044. Cayan, S., et al. Comparison of Patient's Satisfaction and Long-term Results of 2 Penile Plication
Techniques: Lessons Learned From 387 Patients With Penile Curvature. Urology, 2019. 129: 106.
https://www.ncbi.nlm.nih.gov/pubmed/30954611
1045. Gholami, S.S., et al. Correction of penile curvature using the 16-dot plication technique: a review of
132 patients. J Urol, 2002. 167: 2066.
https://www.ncbi.nlm.nih.gov/pubmed/11956440

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 215

1046. Salem, E.A. Modified 16-Dot plication technique for correction of penile curvature: prevention of knot-
related complications. Int J Impot Res, 2018. 30: 117.
https://www.ncbi.nlm.nih.gov/pubmed/29736012
1047. Ismail, H.R., et al. Non-tensile tunica albuginea plication for the correction of penile curvature. Afr J
Urol, 2009. 15:88.
https://link.springer.com/article/10.1007%2Fs12301-009-0019-2#citeas
1048. Rehman, J., et al. Results of surgical treatment for abnormal penile curvature: Peyronie's disease and
congenital deviation by modified Nesbit plication (tunical shaving and plication). J Urol, 1997. 157:
1288.
https://www.ncbi.nlm.nih.gov/pubmed/9120923
1049. Kuehhas, F.E., et al. Superficial tunica albuginea excision, using geometric principles, for the
correction of congenital penile curvature. BJU Int, 2012. 110: E949.
https://www.ncbi.nlm.nih.gov/pubmed/22788740
1050. Vicini, P., et al. Geometrical modified nesbit corporoplasty to correct different types of penile
curvature: description of the surgical procedure based on geometrical principles and long-term
results. Int J Impot Res, 2016. 28: 209.
https://www.ncbi.nlm.nih.gov/pubmed/27511302
1051. Schwarzer, J.U., et al. Tunica albuginea underlap--a new modification of the Nesbit procedure:
description of the technique and preliminary results. J Sex Med, 2012. 9: 2970.
https://www.ncbi.nlm.nih.gov/pubmed/22925461
1052. Zaid, U.B., et al. Surgical management of Peyronie's disease. Curr Urol Rep, 2014. 15: 446.
https://www.ncbi.nlm.nih.gov/pubmed/25118854
1053. Dalkin, B.L., et al. Venogenic impotence following dermal graft repair for Peyronie's disease. J Urol,
1991. 146: 849.
https://www.ncbi.nlm.nih.gov/pubmed/1843616
1054. Flores, S., et al. Erectile dysfunction after plaque incision and grafting: short-term assessment of
incidence and predictors. J Sex Med, 2011. 8: 2031.
https://www.ncbi.nlm.nih.gov/pubmed/21595832
1055. Garcia-Gomez, B., et al. Grafts for Peyronie's disease: a comprehensive review. Andrology, 2018. 6:
117.
https://www.ncbi.nlm.nih.gov/pubmed/29266877
1056. Egydio, P.H., et al. A single relaxing incision to correct different types of penile curvature: surgical
technique based on geometrical principles. BJU Int, 2004. 94: 1147.
https://www.ncbi.nlm.nih.gov/pubmed/15541152
1057. Gelbard, M.K., et al. The natural history of Peyronie's disease. J Urol, 1990. 144: 1376.
https://www.ncbi.nlm.nih.gov/pubmed/2231932
1058. Devine, C.J., Jr., et al. Surgical treatment of Peyronie's disease with a dermal graff. J Urol, 1974. 111:
44.
https://www.ncbi.nlm.nih.gov/pubmed/4273261
1059. De Rose, A.F., et al. Dermal graft surgery for Peyronie's disease: Long term results at a 15 years
follow-up. Arch Esp Urol, 2019. 72: 415.
https://www.ncbi.nlm.nih.gov/pubmed/31070138
1060. Hicks, C.C., et al. Experience with the Horton-Devine dermal graft in the treatment of Peyronie's
disease. J Urol, 1978. 119: 504.
https://www.ncbi.nlm.nih.gov/pubmed/349174
1061. Wild, R.M., et al. Dermal graft repair of Peyronie's disease: survey of 50 patients. J Urol, 1979. 121:
47.
https://www.ncbi.nlm.nih.gov/pubmed/366185
1062. Alferez-Villalobos, C., et al. [Surgery of Peyronie's disease using a skin graft]. Actas Urol Esp, 1981. 5:
105.
https://www.ncbi.nlm.nih.gov/pubmed/7023198
1063. Austoni, E., et al. [Radical surgery and conservation of erection in Peyronie's disease]. Arch Ital Urol
Androl, 1995. 67: 359.
https://www.ncbi.nlm.nih.gov/pubmed/8589753
1064. Kondas, J., et al. Plaque excision and dermal graft in the surgical treatment of plastic induration of
the penis (Peyronie's disease). Int Urol Nephrol, 1998. 30: 321.
https://www.ncbi.nlm.nih.gov/pubmed/9696341
1065. Chun, J.L., et al. A comparison of dermal and cadaveric pericardial grafts in the modified Horton-
Devine procedure for Peyronie's disease. J Urol, 2001. 166: 185.
https://www.ncbi.nlm.nih.gov/pubmed/11435853

216 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1066. Irani, D., et al. Results of dermal patch graft in the treatment of Peyronie's disease. Urol J, 2004. 1:
103.
https://www.ncbi.nlm.nih.gov/pubmed/17874395
1067. Nikoobakht, M.R., et al. Management of Peyronie's disease by dermal grafting. Urol J, 2004. 1: 99.
https://www.ncbi.nlm.nih.gov/pubmed/17874394
1068. Kovac, J.R., et al. Surgical outcomes and patient satisfaction after dermal, pericardial, and small
intestinal submucosal grafting for Peyronie's disease. J Sex Med, 2007. 4: 1500.
https://www.ncbi.nlm.nih.gov/pubmed/17433088
1069. Goyal, N.K., et al. Experience with plaque excision and dermal grafting in the surgical treatment of
Peyronie's disease. Singapore Med J, 2008. 49: 805.
https://www.ncbi.nlm.nih.gov/pubmed/18946615
1070. Kim, E.D., et al. Long-term followup of treatment of Peyronie's disease with plaque incision, carbon
dioxide laser plaque ablation and placement of a deep dorsal vein patch graft. J Urol, 1995. 153:
1843.
https://www.ncbi.nlm.nih.gov/pubmed/7752331
1071. El-Sakka, A.I., et al. Venous patch graft for Peyronie's disease. Part II: outcome analysis. J Urol, 1998.
160: 2050.
https://www.ncbi.nlm.nih.gov/pubmed/9817321
1072. Chalouhy, E., et al. Vein grafting of tunical incisions in the treatment of Peyronie's disease. J Med
Liban, 1998. 46: 251.
https://www.ncbi.nlm.nih.gov/pubmed/10349258
1073. Arena, F., et al. Peyronie's disease--incision and dorsal vein grafting combined with contralateral
plication in straightening the penis. Scand J Urol Nephrol, 1999. 33: 181.
https://www.ncbi.nlm.nih.gov/pubmed/10452294
1074. De Stefani, S., et al. Saphenous vein harvesting by 'stripping' technique and 'W'-shaped patch covering
after plaque incision in treatment of Peyronie's disease. Int J Impot Res, 2000. 12: 299.
https://www.ncbi.nlm.nih.gov/pubmed/11416831
1075. Akkus, E., et al. Incision and venous patch graft in the surgical treatment of penile curvature in
Peyronie's disease. Eur Urol, 2001. 40: 531.
https://www.ncbi.nlm.nih.gov/pubmed/11752861
1076. Yurkanin, J.P., et al. Effect of incision and saphenous vein grafting for Peyronie's disease on penile
length and sexual satisfaction. J Urol, 2001. 166: 1769.
https://www.ncbi.nlm.nih.gov/pubmed/11586221
1077. Adeniyi, A.A., et al. The Lue procedure: an analysis of the outcome in Peyronie's disease. BJU Int,
2002. 89: 404.
https://www.ncbi.nlm.nih.gov/pubmed/11872033
1078. Metin, A., et al. Plaque incision and venous patch grafting for Peyronie's disease. Int Urol Nephrol,
2002. 34: 223.
https://www.ncbi.nlm.nih.gov/pubmed/12775100
1079. Porena, M., et al. Peyronie's disease: corporoplasty using saphenous vein patch graft. Urol Int, 2002.
68: 91.
https://www.ncbi.nlm.nih.gov/pubmed/11834897
1080. Montorsi, F., et al. 1256: Five Year Followup of Plaque Incision and Vein Grafting for Peyronie's
Disease. Journal of Urology, 2004. 171: 331.
http://www.sciencedirect.com/science/article/pii/S0022534718384817
1081. Kalsi, J., et al. The results of plaque incision and venous grafting (Lue procedure) to correct the penile
deformity of Peyronie's disease. BJU Int, 2005. 95: 1029.
https://www.ncbi.nlm.nih.gov/pubmed/15839925
1082. Hsu, G.L., et al. Long-term results of autologous venous grafts for penile morphological
reconstruction. J Androl, 2007. 28: 186.
https://www.ncbi.nlm.nih.gov/pubmed/16988328
1083. Kadioglu, A., et al. Surgical treatment of Peyronie's disease: a single center experience with 145
patients. Eur Urol, 2008. 53: 432.
https://www.ncbi.nlm.nih.gov/pubmed/17467161
1084. Wimpissinger, F., et al. 10 Years' Plaque Incision and Vein Grafting for Peyronie's Disease: Does Time
Matter? J Sex Med, 2016. 13: 120.
https://www.ncbi.nlm.nih.gov/pubmed/26755094
1085. Kayigil, O., et al. The comparison of an acellular matrix graft with an autologous venous graft in the
surgical treatment of Peyronie's disease. Andrologia, 2019. 51: e13168.
https://www.ncbi.nlm.nih.gov/pubmed/30298592

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 217

1086. Teloken, C., et al. Penile straightening with crural graft of the corpus cavernosum. J Urol, 2000. 164:
107.
https://www.ncbi.nlm.nih.gov/pubmed/10840434
1087. Da Ros, C.T., et al. Long-term follow-up of penile curvature correction utilizing autologous albugineal
crural graft. Int Braz J Urol, 2012. 38: 242.
https://www.ncbi.nlm.nih.gov/pubmed/22555030
1088. Schwarzer, J.U., et al. Penile corporoplasty using tunica albuginea free graft from proximal corpus
cavernosum: a new technique for treatment of penile curvature in Peyronie's disease. Eur Urol, 2003.
44: 720.
https://www.ncbi.nlm.nih.gov/pubmed/14644126
1089. Das, S. Peyronie's disease: excision and autografting with tunica vaginalis. J Urol, 1980. 124: 818.
https://www.ncbi.nlm.nih.gov/pubmed/7441830
1090. O'Donnell, P.D. Results of surgical management of Peyronie's disease. J Urol, 1992. 148: 1184.
https://www.ncbi.nlm.nih.gov/pubmed/1404633
1091. Helal, M.A., et al. Tunica vaginalis flap for the management of disabling Peyronie's disease: surgical
technique, results, and complications. Urology, 1995. 46: 390.
https://www.ncbi.nlm.nih.gov/pubmed/7660515
1092. Yuanyuan, M., et al. Testicular tunica vaginalis patch grafting for the treatment of Peyronie's disease.
Cell Biochem Biophys, 2015. 71: 1117.
https://www.ncbi.nlm.nih.gov/pubmed/25486902
1093. Liu, B., et al. Surgical treatment of Peyronie's disease with autologous tunica vaginalis of testis. BMC
Urol, 2016. 16: 1.
https://www.ncbi.nlm.nih.gov/pubmed/26762220
1094. Shioshvili, T.J., et al. The surgical treatment of Peyronie's disease: replacement of plaque by free
autograft of buccal mucosa. Eur Urol, 2005. 48: 129.
https://www.ncbi.nlm.nih.gov/pubmed/15967262
1095. Liu, B., et al. [Replacement of plaque by buccal mucosa in the treatment of Peyronies disease: a
report of 27 cases]. Zhonghua Nan Ke Xue, 2009. 15: 45.
https://www.ncbi.nlm.nih.gov/pubmed/19288749
1096. Cormio, L., et al. Surgical treatment of Peyronie's disease by plaque incision and grafting with buccal
mucosa. Eur Urol, 2009. 55: 1469.
https://www.ncbi.nlm.nih.gov/pubmed/19084325
1097. Salem, E.A., et al. Lingual mucosal graft in treatment of Peyronie disease. Urology, 2014. 84: 1374.
https://www.ncbi.nlm.nih.gov/pubmed/25283703
1098. Zucchi, A., et al. Corporoplasty using buccal mucosa graft in Peyronie disease: is it a first choice?
Urology, 2015. 85: 679.
https://www.ncbi.nlm.nih.gov/pubmed/25582815
1099. Molina-Escudero, R., et al. Cavernoplasty with oral mucosa graft for the surgical treatment of
Peyronie's disease. Actas Urol Esp, 2016. 40: 328.
https://www.ncbi.nlm.nih.gov/pubmed/26874924
1100. Fabiani, A., et al. Buccal mucosa is a promising graft in Peyronie's disease surgery. Our experience
and a brief literature review on autologous grafting materials. Arch Ital Urol Androl, 2016. 88: 115.
https://www.ncbi.nlm.nih.gov/pubmed/27377087
1101. Collins, J.P. Experience with lyophilized human dura for treatment of Peyronie disease. Urology, 1988.
31: 379.
https://www.ncbi.nlm.nih.gov/pubmed/3363774
1102. Sampaio, J.S., et al. Peyronie's disease: surgical correction of 40 patients with relaxing incision and
duramater graft. Eur Urol, 2002. 41: 551.
https://www.ncbi.nlm.nih.gov/pubmed/12074798
1103. Leungwattanakij, S., et al. Long-term follow-up on use of pericardial graft in the surgical management
of Peyronie's disease. Int J Impot Res, 2001. 13: 183.
https://www.ncbi.nlm.nih.gov/pubmed/11525318
1104. Levine, L.A., et al. Human cadaveric pericardial graft for the surgical correction of Peyronie's disease.
J Urol, 2003. 170: 2359.
https://www.ncbi.nlm.nih.gov/pubmed/14634416
1105. Kalsi, J.S., et al. Plaque incision and fascia lata grafting in the surgical management of Peyronie's
disease. BJU Int, 2006. 98: 110.
https://www.ncbi.nlm.nih.gov/pubmed/16831154

218 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1106. Gelbard, M.K., et al. Expanding contractures of the tunica albuginea due to Peyronie's disease with
temporalis fascia free grafts. J Urol, 1991. 145: 772.
https://www.ncbi.nlm.nih.gov/pubmed/2005698
1107. Kargi, E., et al. Relaxation incision and fascia lata grafting in the surgical correction of penile
curvature in Peyronie's disease. Plast Reconstr Surg, 2004. 113: 254.
https://www.ncbi.nlm.nih.gov/pubmed/14707644
1108. Voytik-Harbin, S.L., et al. Identification of extractable growth factors from small intestinal
submucosa. J Cell Biochem, 1997. 67: 478.
https://www.ncbi.nlm.nih.gov/pubmed/9383707
1109. Breyer, B.N., et al. Complications of porcine small intestine submucosa graft for Peyronie's disease. J
Urol, 2007. 177: 589.
https://www.ncbi.nlm.nih.gov/pubmed/17222639
1110. Knoll, L.D. Use of porcine small intestinal submucosal graft in the surgical management of tunical
deficiencies with penile prosthetic surgery. Urology, 2002. 59: 758.
https://www.ncbi.nlm.nih.gov/pubmed/11992915
1111. Lee, E.W., et al. Small intestinal submucosa for patch grafting after plaque incision in the treatment
of Peyronie's disease. Int Braz J Urol, 2008. 34: 191.
https://www.ncbi.nlm.nih.gov/pubmed/18462517
1112. Staerman, F., et al. Medium-term follow-up of plaque incision and porcine small intestinal
submucosal grafting for Peyronie's disease. Int J Impot Res, 2010. 22: 343.
https://www.ncbi.nlm.nih.gov/pubmed/21124338
1113. Chung, E., et al. Five-year follow-up of Peyronie's graft surgery: outcomes and patient satisfaction. J
Sex Med, 2011. 8: 594.
https://www.ncbi.nlm.nih.gov/pubmed/21054805
1114. Cosentino, M., et al. Surgical treatment of Peyronie's disease with small intestinal submucosa graft
patch. Int J Impot Res, 2016. 28: 106.
https://www.ncbi.nlm.nih.gov/pubmed/27030055
1115. Morgado, A., et al. Penile lengthening with porcine small intestinal submucosa grafting in Peyronie's
disease treatment: long-term surgical outcomes, patients' satisfaction and dissatisfaction predictors.
Andrology, 2018. 6: 909.
https://www.ncbi.nlm.nih.gov/pubmed/30076677
1116. Sayedahmed, K., et al. Bicentric prospective evaluation of corporoplasty with porcine small intestinal
submucosa (SIS) in patients with severe Peyronie's disease. World J Urol, 2017. 35: 1119.
https://www.ncbi.nlm.nih.gov/pubmed/27864619
1117. Valente, P., et al. Small Intestinal Submucosa Grafting for Peyronie Disease: Outcomes and Patient
Satisfaction. Urology, 2017. 100: 117.
https://www.ncbi.nlm.nih.gov/pubmed/27825744
1118. Sansalone, S., et al. Long-term results of the surgical treatment of Peyronie's disease with Egydio's
technique: a European multicentre study. Asian J Androl, 2011. 13: 842.
https://www.ncbi.nlm.nih.gov/pubmed/21743482
1119. Egydio, P.H., et al. Treatment of Peyronie's disease by incomplete circumferential incision of the
tunica albuginea and plaque with bovine pericardium graft. Urology, 2002. 59: 570.
https://www.ncbi.nlm.nih.gov/pubmed/11927316
1120. Otero, J.R., et al. Use of a lyophilized bovine pericardium graft to repair tunical defect in patients with
Peyronie's disease: experience in a clinical setting. Asian J Androl, 2017. 19: 316.
https://www.ncbi.nlm.nih.gov/pubmed/26806077
1121. Silva-Garreton, A., et al. Satisfaction of patients with Peyronie's disease after plaque surgery and
bovine pericardium graft. Actas Urol Esp, 2017. 41: 103.
https://www.ncbi.nlm.nih.gov/pubmed/27468940
1122. Hatzichristodoulou, G., et al. Surgical therapy of Peyronie's disease by partial plaque excision and
grafting with collagen fleece: feasibility study of a new technique. Int J Impot Res, 2013. 25: 183.
https://www.ncbi.nlm.nih.gov/pubmed/23446807
1123. Lahme, S., et al. Collagen fleece for defect coverage following plaque excision in patients with
Peyronie's disease. Eur Urol, 2002. 41: 401.
https://www.ncbi.nlm.nih.gov/pubmed/12074811
1124. Horstmann, M., et al. A self-reported long-term follow-up of patients operated with either shortening
techniques or a TachoSil grafting procedure. Asian J Androl, 2011. 13: 326.
https://www.ncbi.nlm.nih.gov/pubmed/21240293

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 219

1125. Hatzichristodoulou, G. Partial Plaque Excision and Grafting With Collagen Fleece in Peyronie Disease.
J Sex Med, 2016. 13: 277.
https://www.ncbi.nlm.nih.gov/pubmed/26953837
1126. Hatzichristodoulou, G. Introducing the ventral sealing technique using collagen fleece for surgical
therapy of patients with ventral Peyronie's curvature: initial experience. Int J Impot Res, 2018. 30:
306.
https://www.ncbi.nlm.nih.gov/pubmed/29973699
1127. Rosenhammer, B., et al. Long-term outcome after grafting with small intestinal submucosa and
collagen fleece in patients with Peyronie's disease: a matched pair analysis. Int J Impot Res, 2019.
31: 256.
https://www.ncbi.nlm.nih.gov/pubmed/30194372
1128. Schiffman, Z.J., et al. Use of Dacron patch graft in Peyronie disease. Urology, 1985. 25: 38.
https://www.ncbi.nlm.nih.gov/pubmed/3155581
1129. Faerber, G.J., et al. Results of combined Nesbit penile plication with plaque incision and placement of
Dacron patch in patients with severe Peyronie's disease. J Urol, 1993. 149: 1319.
https://www.ncbi.nlm.nih.gov/pubmed/8479026
1130. Ganabathi, K., et al. Peyronie's disease: surgical treatment based on penile rigidity. J Urol, 1995. 153:
662.
https://www.ncbi.nlm.nih.gov/pubmed/7861510
1131. Bokarica, P., et al. Surgical treatment of Peyronie's disease based on penile length and degree of
curvature. Int J Impot Res, 2005. 17: 170.
https://www.ncbi.nlm.nih.gov/pubmed/15215882
1132. Rybak, J., et al. A retrospective comparative study of traction therapy vs. no traction following tunica
albuginea plication or partial excision and grafting for Peyronie's disease: measured lengths and
patient perceptions. J Sex Med, 2012. 9: 2396.
https://www.ncbi.nlm.nih.gov/pubmed/22900621
1133. Levine, L.A., et al. Erectile dysfunction following surgical correction of Peyronie's disease and a pilot
study of the use of sildenafil citrate rehabilitation for postoperative erectile dysfunction. J Sex Med,
2005. 2: 241.
https://www.ncbi.nlm.nih.gov/pubmed/16422892
1134. Fiorillo, A., et al. Long-term outcomes after plaque incision and grafting for Peyronie's disease:
comparison of porcine dermal and bovine pericardium grafts. Andrology, 2021. 9: 269.
https://www.ncbi.nlm.nih.gov/pubmed/32981219
1135. Fernandez-Pascual, E., et al. Multicenter Prospective Study of Grafting With Collagen Fleece TachoSil
in Patients With Peyronie's Disease. J Sex Med, 2020. 17: 2279.
https://www.ncbi.nlm.nih.gov/pubmed/32830078
1136. Ralph, D.J., et al. The Nesbit operation for Peyronie's disease: 16-year experience. J Urol, 1995. 154:
1362.
https://www.ncbi.nlm.nih.gov/pubmed/7658538
1137. Habous, M., et al. Malleable Penile Implant Is an Effective Therapeutic Option in Men With Peyronie's
Disease and Erectile Dysfunction. Sex Med, 2018. 6: 24.
https://www.ncbi.nlm.nih.gov/pubmed/29336942
1138. Yavuz, U., et al. Surgical Treatment of Erectile Dysfunction and Peyronie's Disease Using Malleable
Prosthesis. Urol J, 2015. 12: 2428.
https://www.ncbi.nlm.nih.gov/pubmed/26706740
1139. Chung, E., et al. Comparison between AMS 700 CX and Coloplast Titan inflatable penile prosthesis
for Peyronie's disease treatment and remodeling: clinical outcomes and patient satisfaction. J Sex
Med, 2013. 10: 2855.
https://www.ncbi.nlm.nih.gov/pubmed/23210973
1140. Levine, L.A., et al. Penile Prosthesis Surgery: Current Recommendations From the International
Consultation on Sexual Medicine. J Sex Med, 2016. 13: 489.
https://www.ncbi.nlm.nih.gov/pubmed/27045255
1141. Levine, L.A., et al. A surgical algorithm for penile prosthesis placement in men with erectile failure
and Peyronie's disease. Int J Impot Res, 2000. 12: 147.
https://www.ncbi.nlm.nih.gov/pubmed/11045907
1142. Wilson, S.K., et al. A new treatment for Peyronie's disease: modeling the penis over an inflatable
penile prosthesis. J Urol, 1994. 152: 1121.
https://www.ncbi.nlm.nih.gov/pubmed/8072079

220 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1143. Wilson, S.K. Surgical techniques: modeling technique for penile curvature. J Sex Med, 2007. 4: 231.
https://www.ncbi.nlm.nih.gov/pubmed/17233788
1144. Djordjevic, M.L., et al. Penile prosthesis implantation and tunica albuginea incision without grafting in
the treatment of Peyronie's disease with erectile dysfunction. Asian J Androl, 2013. 15: 391.
https://www.ncbi.nlm.nih.gov/pubmed/23435473
1145. Cormio, L., et al. Long-term results of combined tunica albuginea plication and penile prosthesis
implantation for severe penile curvature and erectile dysfunction. Case Rep Urol, 2014. 2014: 818623.
https://www.ncbi.nlm.nih.gov/pubmed/24790766
1146. Rahman, N.U., et al. Combined penile plication surgery and insertion of penile prosthesis for severe
penile curvature and erectile dysfunction. J Urol, 2004. 171: 2346.
https://www.ncbi.nlm.nih.gov/pubmed/15126818
1147. Garaffa, G., et al. The management of residual curvature after penile prosthesis implantation in men
with Peyronie's disease. BJU Int, 2011. 108: 1152.
https://www.ncbi.nlm.nih.gov/pubmed/21314814
1148. Mulcahy, J.J., et al. Tunica wedge excision to correct penile curvature associated with the inflatable
penile prosthesis. J Urol, 1987. 138: 63.
https://www.ncbi.nlm.nih.gov/pubmed/3599221
1149. Chung, P.H., et al. High patient satisfaction of inflatable penile prosthesis insertion with synchronous
penile plication for erectile dysfunction and Peyronie's disease. J Sex Med, 2014. 11: 1593.
https://www.ncbi.nlm.nih.gov/pubmed/24708140
1150. Falcone, M., et al. A Comparative Study Between 2 Different Grafts Used as Patches After Plaque
Incision and Inflatable Penile Prosthesis Implantation for End-Stage Peyronie's Disease. J Sex Med,
2018. 15: 848.
https://www.ncbi.nlm.nih.gov/pubmed/29753801
1151. Sokolakis, I., et al. Penile Prosthesis Implantation Combined With Grafting Techniques in Patients
With Peyronie's Disease and Erectile Dysfunction: A Systematic Review. Sex Med Rev, 2022. 10: 451.
https://www.ncbi.nlm.nih.gov/pubmed/34219005
1152. Rolle, L., et al. A new, innovative, lengthening surgical procedure for Peyronie's disease by penile
prosthesis implantation with double dorsal-ventral patch graft: the "sliding technique". J Sex Med,
2012. 9: 2389.
https://www.ncbi.nlm.nih.gov/pubmed/22429331
1153. Egydio, P.H., et al. Penile lengthening and widening without grafting according to a modified 'sliding'
technique. BJU Int, 2015. 116: 965.
https://www.ncbi.nlm.nih.gov/pubmed/25644141
1154. Egydio, P.H., et al. The Multiple-Slit Technique (MUST) for Penile Length and Girth Restoration. J Sex
Med, 2018. 15: 261.
https://www.ncbi.nlm.nih.gov/pubmed/29275049
1155. Fernandez-Pascual, E., et al. Surgical Technique for Complex Cases of Peyronie's Disease With
Implantation of Penile Prosthesis, Multiple Corporeal Incisions, and Grafting With Collagen Fleece. J
Sex Med, 2019. 16: 323.
https://www.ncbi.nlm.nih.gov/pubmed/30770074
1156. Rolle, L., et al. A prospective multicentric international study on the surgical outcomes and patients'
satisfaction rates of the 'sliding' technique for end-stage Peyronie's disease with severe shortening of
the penis and erectile dysfunction. BJU Int, 2016. 117: 814.
https://www.ncbi.nlm.nih.gov/pubmed/26688436
1157. Khera, M., et al. Penile Prosthesis Implantation in Patients With Peyronie's Disease: Results of the
PROPPER Study Demonstrates a Decrease in Patient-Reported Depression. J Sex Med, 2018. 15:
786.
https://www.ncbi.nlm.nih.gov/pubmed/29653913
1158. Akin-Olugbade, O., et al. Determinants of patient satisfaction following penile prosthesis surgery. J
Sex Med, 2006. 3: 743.
https://www.ncbi.nlm.nih.gov/pubmed/16839332
1159. Verit, A., et al. The phallus of the greatest archeological finding of the new millenia: an untold story of
Gobeklitepe dated back 12 milleniums. Int J Impot Res, 2021. 33: 504.
https://www.ncbi.nlm.nih.gov/pubmed/32393846
1160. Gul, M., et al. Depictions of penises in historical paintings reflect changing perceptions of the ideal
penis size. BJU Int, 2023. 131: 581.
https://www.ncbi.nlm.nih.gov/pubmed/36308456

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 221

1161. Khan, S.I., et al. Phallus, performance and power: crisis of masculinity. Sexual and Relationship
Therapy, 2009. 23: 37.
https://doi.org/10.1080/14681990701790635
1162. Loos, S., et al. The effect of penis size on partner sexual satisfaction: a literature review. Int J Impot
Res, 2023. 35: 519.
https://www.ncbi.nlm.nih.gov/pubmed/36307732
1163. Soubra, A., et al. Revelations on Men Who Seek Penile Augmentation Surgery: A Review. Sex Med Rev,
2022. 10: 460.
https://www.ncbi.nlm.nih.gov/pubmed/34896063
1164. Sharp, G., et al. Sociocultural Influences on Men's Penis Size Perceptions and Decisions to Undergo
Penile Augmentation: A Qualitative Study. Aesthet Surg J, 2019. 39: 1253.
https://www.ncbi.nlm.nih.gov/pubmed/31107944
1165. Margraf, J., et al. Well-Being From the Knife? Psychological Effects of Aesthetic Surgery. Clinical
Psychological Science, 2013. 1: 239.
https://psycnet.apa.org/record/2014-16940-002
1166. Ferraro, G.A., et al. Self-perception and self-esteem of patients seeking cosmetic surgery. Aesthetic
Plast Surg, 2005. 29: 184.
https://www.ncbi.nlm.nih.gov/pubmed/15959689
1167. Ghanem, H., et al. Position paper: Management of men complaining of a small penis despite an
actually normal size. J Sex Med, 2013. 10: 294.
https://www.ncbi.nlm.nih.gov/pubmed/22512935
1168. Lever, J., et al. Does size matter? Men's and women's views on penis size across the lifespan.
Psychology of Men & Masculinity, 2006. 7: 129.
https://psycnet.apa.org/record/2006-09081-001
1169. King, B.M., et al. Social Desirability and Young Men's Self-Reports of Penis Size. J Sex Marital Ther,
2019. 45: 452.
https://www.ncbi.nlm.nih.gov/pubmed/30681032
1170. Veale, D., et al. A preliminary investigation of a novel method to manipulate penis length to measure
female sexual satisfaction: a single-case experimental design. BJU Int, 2021. 128: 374.
https://www.ncbi.nlm.nih.gov/pubmed/33793040
1171. Grov, C., et al. The association between penis size and sexual health among men who have sex with
men. Arch Sex Behav, 2010. 39: 788.
https://www.ncbi.nlm.nih.gov/pubmed/19139986
1172. Sanches, B.C., et al. Does underestimated penile size impact erectile function in healthy men? Int J
Impot Res, 2018. 30: 158.
https://www.ncbi.nlm.nih.gov/pubmed/29925936
1173. Reis Mde, M., et al. Perceptions about penis size among supposedly healthy 40 to 60-year-old
Brazilian men: a cross-sectional pilot study. Sao Paulo Med J, 2015. 133: 84.
https://www.ncbi.nlm.nih.gov/pubmed/25271878
1174. Nugteren, H.M., et al. 18-year experience in the management of men with a complaint of a small
penis. J Sex Marital Ther, 2010. 36: 109.
https://www.ncbi.nlm.nih.gov/pubmed/20169491
1175. Smith, N.K., et al. Genital Self-Image and Considerations of Elective Genital Surgery. J Sex Marital
Ther, 2017. 43: 169.
https://www.ncbi.nlm.nih.gov/pubmed/26881739
1176. Vardi, Y., et al. A critical analysis of penile enhancement procedures for patients with normal penile
size: surgical techniques, success, and complications. Eur Urol, 2008. 54: 1042.
https://www.ncbi.nlm.nih.gov/pubmed/18760874
1177. Davis, S.N., et al. Male genital image: Measurement and implications for medical conditions and
surgical practice. Sexologies, 2012. 21: 43.
https://www.sciencedirect.com/science/article/pii/S1158136011001538
1178. Veale, D., et al. Am I normal? A systematic review and construction of nomograms for flaccid and
erect penis length and circumference in up to 15,521 men. BJU Int, 2015. 115: 978.
https://www.ncbi.nlm.nih.gov/pubmed/25487360
1179. Kayes, O., et al. Therapeutic strategies for patients with micropenis or penile dysmorphic disorder.
Nat Rev Urol, 2012. 9: 499.
https://www.ncbi.nlm.nih.gov/pubmed/22890302
1180. Greenstein, A., et al. Penile size in adult men-recommendations for clinical and research
measurements. Int J Impot Res, 2020. 32: 153.
https://www.ncbi.nlm.nih.gov/pubmed/31171853

222 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1181. Habous, M., et al. Analysis of the Interobserver Variability in Penile Length Assessment. J Sex Med,
2015. 12: 2031.
https://www.ncbi.nlm.nih.gov/pubmed/26440678
1182. Lee, P.A., et al. Micropenis. I. Criteria, etiologies and classification. Johns Hopkins Med J, 1980. 146:
156.
https://www.ncbi.nlm.nih.gov/pubmed/7366061
1183. Aaronson, I.A. Micropenis: medical and surgical implications. J Urol, 1994. 152: 4.
https://www.ncbi.nlm.nih.gov/pubmed/8201683
1184. Nelson, C.P., et al. The increasing incidence of congenital penile anomalies in the United States. J
Urol, 2005. 174: 1573.
https://www.ncbi.nlm.nih.gov/pubmed/16148654
1185. Gaspari, L., et al. High prevalence of micropenis in 2710 male newborns from an intensive-use
pesticide area of Northeastern Brazil. Int J Androl, 2012. 35: 253.
https://www.ncbi.nlm.nih.gov/pubmed/22372605
1186. Zattoni, F., et al. The impact of COVID-19 pandemic on pornography habits: a global analysis of
Google Trends. Int J Impot Res, 2020. 33: 824.
https://www.ncbi.nlm.nih.gov/pubmed/33249423
1187. Altintas, E., et al. The dark side of the internet regarding sexual education. Int J Impot Res, 2022. 34:
235.
https://www.ncbi.nlm.nih.gov/pubmed/33479471
1188. Maizels, M., et al. Surgical correction of the buried penis: description of a classification system and a
technique to correct the disorder. J Urol, 1986. 136: 268.
https://www.ncbi.nlm.nih.gov/pubmed/2873259
1189. Negm, M., et al. Congenital webbed penis: Surgical outcomes of a simplified technique. J Pediatr
Urol, 2021. 17: 813 e1.
https://www.ncbi.nlm.nih.gov/pubmed/34511377
1190. Tausch, T.J., et al. Classification System for Individualized Treatment of Adult Buried Penis
Syndrome. Plast Reconstr Surg, 2016. 138: 703.
https://www.ncbi.nlm.nih.gov/pubmed/27152580
1191. Keyes, E.L., Urology: diseases of the urinary organs, diseases of the male genital organs, the venereal
diseases. 1921, New York.
//catalog.hathitrust.org/Record/009704977
http://hdl.handle.net/2027/nnc2.ark:/13960/t2g745649 (1921)
1192. Falcone, M., et al. What are the benefits and harms of surgical management options for adult-
acquired buried penis? A systematic review. BJU Int, 2023. 131: 8.
https://www.ncbi.nlm.nih.gov/pubmed/35044046
1193. Alter, G.J. Pubic contouring after massive weight loss in men and women: correction of hidden penis,
mons ptosis, and labia majora enlargement. Plast Reconstr Surg, 2012. 130: 936.
https://www.ncbi.nlm.nih.gov/pubmed/23018703
1194. Cohen, P.R. Adult Acquired Buried Penis: A Hidden Problem in Obese Men. Cureus, 2021. 13: e13067.
https://www.ncbi.nlm.nih.gov/pubmed/33680609
1195. Hampson, L.A., et al. Surgical and Functional Outcomes Following Buried Penis Repair With Limited
Panniculectomy and Split-thickness Skin Graft. Urology, 2017. 110: 234.
https://www.ncbi.nlm.nih.gov/pubmed/28797684
1196. Hughes, D.B., et al. Sexual and Overall Quality of Life Improvements After Surgical Correction of
"Buried Penis". Ann Plast Surg, 2016. 76: 532.
https://www.ncbi.nlm.nih.gov/pubmed/25785378
1197. Knio, Z., et al. Lichen sclerosis: clinicopathological study of 60 cases from Lebanon. Int J Dermatol,
2016. 55: 1076.
https://www.ncbi.nlm.nih.gov/pubmed/27229659
1198. Pariser, J.J., et al. A Simplified Adult Acquired Buried Penis Repair Classification System With an
Analysis of Perioperative Complications and Urethral Stricture Disease. Urology, 2018. 120: 248.
https://www.ncbi.nlm.nih.gov/pubmed/29898381
1199. Husmann, D.A. The androgen insensitive micropenis: long-term follow-up into adulthood. J Pediatr
Endocrinol Metab, 2004. 17: 1037.
https://www.ncbi.nlm.nih.gov/pubmed/15379413
1200. Stuhldreher, P.P., et al. Exstrophy-Epispadias Complex. Current Bladder Dysfunction Reports, 2015.
10: 227.
https://doi.org/10.1007/s11884-015-0306-7

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 223

1201. Ebert, A.K., et al. The exstrophy-epispadias complex. Orphanet J Rare Dis, 2009. 4: 23.
https://www.ncbi.nlm.nih.gov/pubmed/19878548
1202. Ebert, A.K., et al. Association Between Exstrophy-epispadias Complex And Congenital Anomalies: A
German Multicenter Study. Urology, 2019. 123: 210.
https://www.ncbi.nlm.nih.gov/pubmed/30076940
1203. Agopian, A.J., et al. Epidemiologic features of male genital malformations and subtypes in Texas. Am
J Med Genet A, 2014. 164A: 943.
https://www.ncbi.nlm.nih.gov/pubmed/24458943
1204. Han, J.H., et al. Fate of the micropenis and constitutional small penis: do they grow to normalcy in
puberty? J Pediatr Urol, 2019. 15: 526 e1.
https://www.ncbi.nlm.nih.gov/pubmed/31447312
1205. Boas, M., et al. Postnatal penile length and growth rate correlate to serum testosterone levels: a
longitudinal study of 1962 normal boys. Eur J Endocrinol, 2006. 154: 125.
https://www.ncbi.nlm.nih.gov/pubmed/16382001
1206. Maruf, M., et al. Variant Presentations of the Exstrophy-Epispadias Complex: A 40-Year Experience.
Urology, 2019. 125: 184.
https://www.ncbi.nlm.nih.gov/pubmed/30576745
1207. Meyer, K.F., et al. The exstrophy-epispadias complex: is aesthetic appearance important? BJU Int,
2004. 93: 1062.
https://www.ncbi.nlm.nih.gov/pubmed/15142165
1208. Stewart, D., et al. Pediatric surgical complications of major genitourinary reconstruction in the
exstrophy-epispadias complex. J Pediatr Surg, 2015. 50: 167.
https://www.ncbi.nlm.nih.gov/pubmed/25598117
1209. Sujijantararat, P., et al. Surgical reconstruction of exstrophy-epispadias complex: analysis of 13
patients. Int J Urol, 2002. 9: 377.
https://www.ncbi.nlm.nih.gov/pubmed/12165019
1210. Ebert, A., et al. Psychosocial and psychosexual development in childhood and adolescence within the
exstrophy-epispadias complex. J Urol, 2005. 174: 1094.
https://www.ncbi.nlm.nih.gov/pubmed/16094067
1211. Wittmeyer, V., et al. Quality of life in adults with bladder exstrophy-epispadias complex. J Urol, 2010.
184: 2389.
https://www.ncbi.nlm.nih.gov/pubmed/20952009
1212. Zhu, X., et al. Urological, Sexual, and Quality of Life Evaluation of Adult Patients With Exstrophy-
Epispadias Complex: Long-term Results From a Dutch Cohort. Urology, 2020. 136: 272.
https://www.ncbi.nlm.nih.gov/pubmed/31697953
1213. Sinatti, C., et al. Long-term sexual outcomes in patients with exstrophy-epispadias complex. Int J
Impot Res, 2021. 33: 164.
https://www.ncbi.nlm.nih.gov/pubmed/32161399
1214. Ebert, A.K., et al. Genital and reproductive function in males after functional reconstruction of the
exstrophy-epispadias complex--long-term results. Urology, 2008. 72: 566.
https://www.ncbi.nlm.nih.gov/pubmed/18585763
1215. Vasconcelos, J.S., et al. The natural history of penile length after radical prostatectomy: a long-term
prospective study. Urology, 2012. 80: 1293.
https://www.ncbi.nlm.nih.gov/pubmed/23102441
1216. Chung, E. Penile Reconstructive Surgery in Peyronie Disease: Challenges in Restoring Normal Penis
Size, Shape, and Function. World J Mens Health, 2020. 38: 1.
https://www.ncbi.nlm.nih.gov/pubmed/29623703
1217. Ahmed, A., et al. Aetiology and management of injuries to male external genitalia in Nigeria. Injury,
2008. 39: 128.
https://www.ncbi.nlm.nih.gov/pubmed/17572420
1218. Appiah, K.A., et al. Circumcision-related tragedies seen in children at the Komfo Anokye Teaching
Hospital, Kumasi, Ghana. BMC Urol, 2016. 16: 65.
https://www.ncbi.nlm.nih.gov/pubmed/27825332
1219. Hoare, D.T., et al. Prospective Assessment of Patient-perceived Short-term Changes in Penile
Appearance After Urethroplasty. Urology, 2021. 158: 222.
https://www.ncbi.nlm.nih.gov/pubmed/34461146
1220. Maciejewski, C.C., et al. Chordee and Penile Shortening Rather Than Voiding Function Are Associated
With Patient Dissatisfaction After Urethroplasty. Urology, 2017. 103: 234.
https://www.ncbi.nlm.nih.gov/pubmed/28065809

224 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1221. Moriya, K., et al. Factors affecting post-pubertal penile size in patients with hypospadias. World J
Urol, 2016. 34: 1317.
https://www.ncbi.nlm.nih.gov/pubmed/26792579
1222. Wilson, S.K., et al. "Make it as long as you can, Doc." Concomitant surgical treatments with penile
implant to enhance penile size. Int J Impot Res, 2021. 33: 587.
https://www.ncbi.nlm.nih.gov/pubmed/32424302
1223. Kamel, I., et al. Comparing penile measurements in normal and erectile dysfunction subjects. J Sex
Med, 2009. 6: 2305.
https://www.ncbi.nlm.nih.gov/pubmed/19453888
1224. Ziegelmann, M., et al. Conservatively Managed Peyronie's Disease-Long-term Survey Results From
Patients Undergoing Nonsurgical and Noninjection Therapies. Urology, 2018. 113: 99.
https://www.ncbi.nlm.nih.gov/pubmed/29174623
1225. Carlsson, S., et al. Self-perceived penile shortening after radical prostatectomy. Int J Impot Res, 2012.
24: 179.
https://www.ncbi.nlm.nih.gov/pubmed/22573233
1226. Haliloglu, A., et al. Penile length changes in men treated with androgen suppression plus radiation
therapy for local or locally advanced prostate cancer. J Urol, 2007. 177: 128.
https://www.ncbi.nlm.nih.gov/pubmed/17162022
1227. Gontero, P., et al. New insights into the pathogenesis of penile shortening after radical prostatectomy
and the role of postoperative sexual function. J Urol, 2007. 178: 602.
https://www.ncbi.nlm.nih.gov/pubmed/17570431
1228. Burnett, A.L. Does androgen suppression plus radiation therapy lead to changes in penile length in
prostate cancer patients? Nat Clin Pract Urol, 2007. 4: 530.
https://www.ncbi.nlm.nih.gov/pubmed/17712321
1229. Park, K.K., et al. The effects of long-term androgen deprivation therapy on penile length in patients
with prostate cancer: a single-center, prospective, open-label, observational study. J Sex Med, 2011.
8: 3214.
https://www.ncbi.nlm.nih.gov/pubmed/21699669
1230. McCullough, A. Penile change following radical prostatectomy: size, smooth muscle atrophy, and
curve. Curr Urol Rep, 2008. 9: 492.
https://www.ncbi.nlm.nih.gov/pubmed/18947515
1231. Diaz, K.A., et al. Patient-Reported Outcomes in Penile Cancer Patients: Quality of Life, Sexual and
Urinary Function. What do we Know? Urology, 2022. 169: 1.
https://www.ncbi.nlm.nih.gov/pubmed/36037936
1232. American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental
disorders, 2013.
https://psycnet.apa.org/record/2013-14907-000
1233. Veale, D., et al. Penile Dysmorphic Disorder: Development of a Screening Scale. Arch Sex Behav,
2015. 44: 2311.
https://www.ncbi.nlm.nih.gov/pubmed/25731908
1234. Aslan, T.B., et al. Etiological evaluation of patients presenting with isolated micropenis to an
academic health care center. Indian J Pediatr, 2014. 81: 775.
https://www.ncbi.nlm.nih.gov/pubmed/24005879
1235. Wylie, K.R., et al. Penile size and the 'small penis syndrome'. BJU Int, 2007. 99: 1449.
https://www.ncbi.nlm.nih.gov/pubmed/17355371
1236. Veale, D., et al. Body dysmorphic disorder in different settings: A systematic review and estimated
weighted prevalence. Body Image, 2016. 18: 168.
https://www.ncbi.nlm.nih.gov/pubmed/27498379
1237. Salonia, A., et al. European Association of Urology Guidelines on Sexual and Reproductive
Health-2021 Update: Male Sexual Dysfunction. Eur Urol, 2021. 80: 333.
https://www.ncbi.nlm.nih.gov/pubmed/34183196
1238. Santos-Iglesias, P., et al. Preliminary validation of the Sexual Distress Scale-Short Form: Applications
to Women, Men, and Prostate Cancer Survivors. J Sex Marital Ther, 2020. 46: 542.
https://www.ncbi.nlm.nih.gov/pubmed/32393102
1239. Lawrance, K.A., et al. Sexual satisfaction in long‐term heterosexual relationships: The interpersonal
exchange model of sexual satisfaction. Personal Relationships, 2005. 2: 267.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-6811.1995.tb00092.x
1240. Janssen, E., et al. The Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales: I. Measuring sexual
inhibition and excitation proneness in men. J Sex Res, 2002. 39: 114.
https://www.ncbi.nlm.nih.gov/pubmed/12476243

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 225

1241. Nobre, P., et al. Sexual Dysfunctional Beliefs Questionnaire: An instrument to assess sexual
dysfunctional beliefs as vulnerability factors to sexual problems. Sexual and Relationship Therapy,
2003. 18: 171.
https://doi.org/10.1080/1468199031000061281
1242. Blecher, G.A., et al. Penile dimensions: What are surgeons measuring? Int J Impot Res, 2019. 31: 444.
https://www.ncbi.nlm.nih.gov/pubmed/30932028
1243. Joumblat, N.R., et al. Guidelines for the Standardization of Genital Photography. Aesthet Surg J,
2018. 38: 1124.
https://www.ncbi.nlm.nih.gov/pubmed/29420725
1244. Sengezer, M., et al. Accurate method for determining functional penile length in Turkish young men.
Ann Plast Surg, 2002. 48: 381.
https://www.ncbi.nlm.nih.gov/pubmed/12068220
1245. Phillips, K.A., et al. Suicidal ideation and suicide attempts in body dysmorphic disorder. J Clin
Psychiatry, 2005. 66: 717.
https://www.ncbi.nlm.nih.gov/pubmed/15960564
1246. Phillips, K.A., The Broken Mirror: Understanding and Treating Body Dysmorphic Disorder. 2005, New
York, NY.
1247. Herbenick, D., et al. The development and validation of the Male Genital Self-Image Scale: results
from a nationally representative probability sample of men in the United States. J Sex Med, 2013. 10:
1516.
https://www.ncbi.nlm.nih.gov/pubmed/23551571
1248. Davis, S.N., et al. The index of male genital image: a new scale to assess male genital satisfaction. J
Urol, 2013. 190: 1335.
https://www.ncbi.nlm.nih.gov/pubmed/23583534
1249. Veale, D., et al. Beliefs about penis size: validation of a scale for men ashamed about their penis size.
J Sex Med, 2014. 11: 84.
https://www.ncbi.nlm.nih.gov/pubmed/24118940
1250. Spyropoulos, E., et al. Augmentation Phalloplasty Patient Selection and Satisfaction Inventory: a
novel questionnaire to evaluate patients considered for augmentation phalloplasty surgery because
of penile dysmorphophobia. Urology, 2007. 70: 221.
https://www.ncbi.nlm.nih.gov/pubmed/17826474
1251. Rosen, R.C., et al. Male Sexual Health Questionnaire (MSHQ): scale development and psychometric
validation. Urology, 2004. 64: 777.
https://www.ncbi.nlm.nih.gov/pubmed/15491719
1252. Althof, S.E., et al. EDITS: development of questionnaires for evaluating satisfaction with treatments
for erectile dysfunction. Urology, 1999. 53: 793.
https://www.ncbi.nlm.nih.gov/pubmed/10197859
1253. Junior, A.R., et al. The Role of Magnetic Resonance Imaging in the Management of High-Flow
Priapism: An Essential Tool when Everything Else Fails. J Vasc Interv Radiol, 2022. 33: 470.
https://www.ncbi.nlm.nih.gov/pubmed/34968672
1254. Scardino, E., et al. Magnetic resonance imaging combined with artificial erection for local staging of
penile cancer. Urology, 2004. 63: 1158.
https://www.ncbi.nlm.nih.gov/pubmed/15183971
1255. Kirkham, A. MRI of the penis. Br J Radiol, 2012. 85 Spec No 1: S86.
https://www.ncbi.nlm.nih.gov/pubmed/23118102
1256. Lindquist, C.M., et al. MRI of the penis. Abdom Radiol (NY), 2020. 45: 2001.
https://www.ncbi.nlm.nih.gov/pubmed/31701192
1257. Sharp, G., et al. Nonsurgical Medical Penile Girth Augmentation: A Retrospective Study of
Psychological and Psychosexual Outcomes. Aesthet Surg J, 2019. 39: 306.
https://www.ncbi.nlm.nih.gov/pubmed/29741580
1258. Veale, D., et al. Relationship between self-discrepancy and worries about penis size in men with body
dysmorphic disorder. Body Image, 2016. 17: 48.
https://www.ncbi.nlm.nih.gov/pubmed/26952016
1259. Veale, D., et al. Phenomenology of men with body dysmorphic disorder concerning penis size
compared to men anxious about their penis size and to men without concerns: a cohort study. Body
Image, 2015. 13: 53.
https://www.ncbi.nlm.nih.gov/pubmed/25675864
1260. Garcia Gomez, B., et al. Penile length augmentation surgical and non-surgical approaches for
aesthetical purposes. Int J Impot Res, 2022. 34: 332.
https://www.ncbi.nlm.nih.gov/pubmed/34789856

226 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1261. Gontero, P., et al. A pilot phase-II prospective study to test the 'efficacy' and tolerability of a penile-
extender device in the treatment of 'short penis'. BJU Int, 2009. 103: 793.
https://www.ncbi.nlm.nih.gov/pubmed/18990153
1262. Nikoobakht, M., et al. Effect of penile-extender device in increasing penile size in men with shortened
penis: preliminary results. J Sex Med, 2011. 8: 3188.
https://www.ncbi.nlm.nih.gov/pubmed/20102448
1263. Garcia-Gomez, B., et al. Treatment of peyronie's disease with combination of clostridium histolyticum
collagenase and penile traction therapy: a prospective, multicenter, single-arm study. Int J Impot Res,
2021. 33: 325.
https://www.ncbi.nlm.nih.gov/pubmed/32366987
1264. Bole, R., et al. A modern review of penile traction monotherapy and combination therapy for the
treatment of peyronie's disease. Int J Impot Res, 2021. 33: 251.
https://www.ncbi.nlm.nih.gov/pubmed/32152467
1265. Nowroozi, M.R., et al. Applying extender devices in patients with penile dysmorphophobia:
assessment of tolerability, efficacy, and impact on erectile function. J Sex Med, 2015. 12: 1242.
https://www.ncbi.nlm.nih.gov/pubmed/25809129
1266. Aghamir, M.K., et al. A vacuum device for penile elongation: fact or fiction? BJU Int, 2006. 97: 777.
https://www.ncbi.nlm.nih.gov/pubmed/16536772
1267. Antonini, G., et al. Postoperative vacuum therapy following AMS LGX 700(R) inflatable penile
prosthesis placement: penile dimension outcomes and overall satisfaction. Int J Impot Res, 2020. 32:
133.
https://www.ncbi.nlm.nih.gov/pubmed/30745567
1268. Nason, G.J., et al. Efficacy of vacuum erectile devices (VEDs) after radical prostatectomy: the initial
Irish experience of a dedicated VED clinic. Int J Impot Res, 2016. 28: 205.
https://www.ncbi.nlm.nih.gov/pubmed/27225711
1269. Raina, R., et al. Early use of vacuum constriction device following radical prostatectomy facilitates
early sexual activity and potentially earlier return of erectile function. Int J Impot Res, 2006. 18: 77.
https://www.ncbi.nlm.nih.gov/pubmed/16107868
1270. Dalkin, B.L., et al. Preservation of penile length after radical prostatectomy: early intervention with a
vacuum erection device. Int J Impot Res, 2007. 19: 501.
https://www.ncbi.nlm.nih.gov/pubmed/17657210
1271. Lehrfeld, T., et al. The role of vacuum erection devices in penile rehabilitation after radical
prostatectomy. Int J Impot Res, 2009. 21: 158.
https://www.ncbi.nlm.nih.gov/pubmed/19225465
1272. Ben-Galim, E., et al. Topically applied testosterone and phallic growth. Its effects in male children with
hypopituitarism and microphallus. Am J Dis Child, 1980. 134: 296.
https://www.ncbi.nlm.nih.gov/pubmed/7361738
1273. Hatipoglu, N., et al. Micropenis: etiology, diagnosis and treatment approaches. J Clin Res Pediatr
Endocrinol, 2013. 5: 217.
https://www.ncbi.nlm.nih.gov/pubmed/24379029
1274. Main, K.M., et al. Early postnatal treatment of hypogonadotropic hypogonadism with recombinant
human FSH and LH. Eur J Endocrinol, 2002. 146: 75.
https://www.ncbi.nlm.nih.gov/pubmed/11751071
1275. Bougneres, P., et al. Effects of an early postnatal treatment of hypogonadotropic hypogonadism with
a continuous subcutaneous infusion of recombinant follicle-stimulating hormone and luteinizing
hormone. J Clin Endocrinol Metab, 2008. 93: 2202.
https://www.ncbi.nlm.nih.gov/pubmed/18381569
1276. Harris, T.G.W., et al. Pedicled Anterolateral Thigh and Radial Forearm Free Flap Phalloplasty for Penile
Reconstruction in Patients With Bladder Exstrophy. J Urol, 2021. 205: 880.
https://www.ncbi.nlm.nih.gov/pubmed/33026935
1277. Falcone, M., et al. Total Phallic Reconstruction in the Genetic Male. Eur Urol, 2021. 79: 684.
https://www.ncbi.nlm.nih.gov/pubmed/32800729
1278. Li, C.Y., et al. Penile suspensory ligament division for penile augmentation: indications and results.
Eur Urol, 2006. 49: 729.
https://www.ncbi.nlm.nih.gov/pubmed/16473458
1279. Littara, A., et al. Cosmetic penile enhancement surgery: a 3-year single-centre retrospective clinical
evaluation of 355 cases. Sci Rep, 2019. 9: 6323.
https://www.ncbi.nlm.nih.gov/pubmed/31004096

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 227

1280. Xu, J.G., et al. Management of concealed penis with modified penoplasty. Urology, 2015. 85: 698.
https://www.ncbi.nlm.nih.gov/pubmed/25733292
1281. Ghanem, H., et al. Infrapubic Liposuction for Penile Length Augmentation in Patients with Infrapubic
Adiposities. Aesthetic Plast Surg, 2017. 41: 441.
https://www.ncbi.nlm.nih.gov/pubmed/28155063
1282. Shaeer, O.K. Shaeer's Technique: A Minimally Invasive Procedure for Monsplasty and Revealing the
Concealed Penis. Plast Reconstr Surg Glob Open, 2016. 4: e1019.
https://www.ncbi.nlm.nih.gov/pubmed/27622092
1283. Lumen, N., et al. Phalloplasty: a valuable treatment for males with penile insufficiency. Urology, 2008.
71: 272.
https://www.ncbi.nlm.nih.gov/pubmed/18308099
1284. Perovic, S.V., et al. Total phalloplasty using a musculocutaneous latissimus dorsi flap. BJU Int, 2007.
100: 899.
https://www.ncbi.nlm.nih.gov/pubmed/17822468
1285. Garaffa, G., et al. Total phallic reconstruction using radial artery based forearm free flap phalloplasty
in patients with epispadias-exstrophy complex. J Urol, 2014. 192: 814.
https://www.ncbi.nlm.nih.gov/pubmed/24704015
1286. Deveci, S., et al. Penile length alterations following penile prosthesis surgery. Eur Urol, 2007. 51:
1128.
https://www.ncbi.nlm.nih.gov/pubmed/17084508
1287. Negro, C.L., et al. Implantation of AMS 700 LGX penile prosthesis preserves penile length without the
need for penile lengthening procedures. Asian J Androl, 2016. 18: 114.
https://www.ncbi.nlm.nih.gov/pubmed/26112480
1288. Wang, R., et al. Prospective and long-term evaluation of erect penile length obtained with inflatable
penile prosthesis to that induced by intracavernosal injection. Asian J Androl, 2009. 11: 411.
https://www.ncbi.nlm.nih.gov/pubmed/19525974
1289. Osterberg, E.C., et al. Pharmacologically induced erect penile length and stretched penile length are
both good predictors of post-inflatable prosthesis penile length. Int J Impot Res, 2014. 26: 128.
https://www.ncbi.nlm.nih.gov/pubmed/24430278
1290. Perovic, S.V., et al. Penile lengthening. BJU Int, 2000. 86: 1028.
https://www.ncbi.nlm.nih.gov/pubmed/11119096
1291. Falcone, M., et al. Total Phallic Reconstruction Using the Radial Artery Based Forearm Free Flap After
Traumatic Penile Amputation. J Sex Med, 2016. 13: 1119.
https://www.ncbi.nlm.nih.gov/pubmed/27318022
1292. Egydio, P.H. An Innovative Strategy for Non-Grafting Penile Enlargement: A Novel Paradigm for Tunica
Expansion Procedures. J Sex Med, 2020. 17: 2093.
https://www.ncbi.nlm.nih.gov/pubmed/32636162
1293. Zaccaro, C., et al. History and future perspectives of male aesthetic genital surgery. Int J Impot Res,
2022. 34: 327.
https://www.ncbi.nlm.nih.gov/pubmed/35538312
1294. Colombo, F., et al. Penile enlargement. Curr Opin Urol, 2008. 18: 583.
https://www.ncbi.nlm.nih.gov/pubmed/18832943
1295. Manfredi, C., et al. Penile girth enhancement procedures for aesthetic purposes. Int J Impot Res,
2022. 34: 337.
https://www.ncbi.nlm.nih.gov/pubmed/34257403
1296. Steenen, S.A., et al. Head-to-head comparison of 4 hyaluronic acid dermal fillers for lip augmentation:
A multicenter randomized, quadruple-blind, controlled clinical trial. J Am Acad Dermatol, 2023. 88:
932.
https://www.ncbi.nlm.nih.gov/pubmed/36370906
1297. Huang, Y., et al. Application of Cross-Linked and Non-Cross-Linked Hyaluronic Acid Nano-Needles in
Cosmetic Surgery. Int J Anal Chem, 2022. 2022: 4565260.
https://www.ncbi.nlm.nih.gov/pubmed/35651502
1298. Yang, D.Y., et al. A Comparison of the Efficacy and Safety Between Hyaluronic Acid and Polylactic
Acid Filler Injection in Penile Augmentation: A Multicenter, Patient/Evaluator-Blinded, Randomized
Trial. J Sex Med, 2019. 16: 577.
https://www.ncbi.nlm.nih.gov/pubmed/30833149
1299. Kwak, T.I., et al. The effects of penile girth enhancement using injectable hyaluronic acid gel, a filler. J
Sex Med, 2011. 8: 3407.
https://www.ncbi.nlm.nih.gov/pubmed/20233296

228 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1300. Yang, D.Y., et al. A Comparison Between Hyaluronic Acid and Polylactic Acid Filler Injections for
Temporary Penile Augmentation in Patients with Small Penis Syndrome: A Multicenter, Patient/
Evaluator-Blind, Comparative, Randomized Trial. J Sex Med, 2020. 17: 133.
https://www.ncbi.nlm.nih.gov/pubmed/31735613
1301. Yang, D.Y., et al. Comparison of Clinical Outcomes between Hyaluronic and Polylactic Acid Filler
Injections for Penile Augmentation in Men Reporting a Small Penis: A Multicenter, Patient-Blinded/
Evaluator-Blinded, Non-Inferiority, Randomized Comparative Trial with 18 Months of Follow-up. J Clin
Med, 2020. 9.
https://www.ncbi.nlm.nih.gov/pubmed/32260508
1302. Casavantes, L., et al. Penile Girth Enhancement With Polymethylmethacrylate-Based Soft Tissue
Fillers. J Sex Med, 2016. 13: 1414.
https://www.ncbi.nlm.nih.gov/pubmed/27461963
1303. Kim, M.T., et al. Long-Term Safety and Longevity of a Mixture of Polymethyl Methacrylate and Cross-
Linked Dextran (Lipen-10(R)) after Penile Augmentation: Extension Study from Six to 18 Months of
Follow-Up. World J Mens Health, 2015. 33: 202.
https://www.ncbi.nlm.nih.gov/pubmed/26770941
1304. Yang, D.Y., et al. Efficacy and safety of a newly developed polylactic acid microsphere as an
injectable bulking agent for penile augmentation: 18-months follow-up. Int J Impot Res, 2017. 29:
136.
https://www.ncbi.nlm.nih.gov/pubmed/28424498
1305. Dellis, A.E., et al. Paraffinoma, siliconoma and Co: Disastrous consequences of failed penile
augmentation-A single-centre successful surgical management of a challenging entity. Andrologia,
2018. 50: e13109.
https://www.ncbi.nlm.nih.gov/pubmed/29993129
1306. Karakan, T., et al. Injection of Vaseline under Penis Skin for the Purpose of Penis Augmentation. Case
Rep Urol, 2012. 2012: 510612.
https://www.ncbi.nlm.nih.gov/pubmed/23213616
1307. Dellis, A.E., et al. Minimal surgical management of penile paraffinoma after subcutaneous penile
paraffin injection. Arab J Urol, 2017. 15: 387.
https://www.ncbi.nlm.nih.gov/pubmed/29234545
1308. Eandi, J.A., et al. Penile paraffinoma: the delayed presentation. Int Urol Nephrol, 2007. 39: 553.
https://www.ncbi.nlm.nih.gov/pubmed/17308876
1309. Fakin, R., et al. Reconstruction of Penile Shaft Defects Following Silicone Injection by Bipedicled
Anterior Scrotal Flap. J Urol, 2017. 197: 1166.
https://www.ncbi.nlm.nih.gov/pubmed/27871930
1310. Muranyi, M., et al. A New Modified Bipedicle Scrotal Skin Flap Technique for the Reconstruction of
Penile Skin in Patients with Paraffin-Induced Sclerosing Lipogranuloma of the Penis. J Urol, 2022.
208: 171.
https://www.ncbi.nlm.nih.gov/pubmed/35164523
1311. Sedigh, O., et al. Penile injection of aedile silicone: A dangerous shortcut. Urologia, 2022. 89: 456.
https://www.ncbi.nlm.nih.gov/pubmed/34399651
1312. Kang, D.H., et al. Efficacy and safety of penile girth enhancement by autologous fat injection for
patients with thin penises. Aesthetic Plast Surg, 2012. 36: 813.
https://www.ncbi.nlm.nih.gov/pubmed/22527585
1313. Panfilov, D.E. Augmentative phalloplasty. Aesthetic Plast Surg, 2006. 30: 183.
https://www.ncbi.nlm.nih.gov/pubmed/16547638
1314. Mutluoglu, M., et al. Penile Girth Enlargement: do not try it at home. Int J Impot Res, 2022. 34: 108.
https://www.ncbi.nlm.nih.gov/pubmed/33846588
1315. Parodi, P.C., et al. Penis invalidating cicatricial outcomes in an enlargement phalloplasty case with
polyacrylamide gel (Formacryl). Int J Impot Res, 2006. 18: 318.
https://www.ncbi.nlm.nih.gov/pubmed/16281044
1316. Salem, A.M., et al. Effect of Girth Supersizing on Patient Satisfaction After Semi-Rigid Penile Implant
Insertion: A Prospective Case-Control Study. Aesthet Surg J, 2019. 39: NP259.
https://www.ncbi.nlm.nih.gov/pubmed/31220204
1317. Alei, G., et al. Original technique for penile girth augmentation through porcine dermal acellular grafts:
results in a 69-patient series. J Sex Med, 2012. 9: 1945.
https://www.ncbi.nlm.nih.gov/pubmed/22568607
1318. Austoni, E., et al. A new technique for augmentation phalloplasty: albugineal surgery with bilateral
saphenous grafts--three years of experience. Eur Urol, 2002. 42: 245.
https://www.ncbi.nlm.nih.gov/pubmed/12234509

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 229

1319. Mertziotis, N., et al. Is V-Y plasty necessary for penile lengthening? Girth enhancement and increased
length solely through circumcision: description of a novel technique. Asian J Androl, 2013. 15: 819.
https://www.ncbi.nlm.nih.gov/pubmed/23792340
1320. Xu, L., et al. Augmentation Phalloplasty With Autologous Dermal Fat Graft in the Treatment of "Small
Penis". Ann Plast Surg, 2016. 77 Suppl 1: S60.
https://www.ncbi.nlm.nih.gov/pubmed/27070685
1321. Djordjevic, M.L., et al. Repeated penile girth enhancement with biodegradable scaffolds: Microscopic
ultrastructural analysis and surgical benefits. Asian J Androl, 2018. 20: 488.
https://www.ncbi.nlm.nih.gov/pubmed/29862992
1322. Jin, Z., et al. Tissue engineering penoplasty with biodegradable scaffold Maxpol-T cografted
autologous fibroblasts for small penis syndrome. J Androl, 2011. 32: 491.
https://www.ncbi.nlm.nih.gov/pubmed/21164145
1323. Perovic, S.V., et al. New perspectives of penile enhancement surgery: tissue engineering with
biodegradable scaffolds. Eur Urol, 2006. 49: 139.
https://www.ncbi.nlm.nih.gov/pubmed/16310926
1324. Elist, J.J., et al. A Single-Surgeon Retrospective and Preliminary Evaluation of the Safety and
Effectiveness of the Penuma Silicone Sleeve Implant for Elective Cosmetic Correction of the Flaccid
Penis. J Sex Med, 2018. 15: 1216.
https://www.ncbi.nlm.nih.gov/pubmed/30145095
1325. Siegal, A.R., et al. Outcomes of a Single Center's Initial Experience With the Penuma(R) Penile
Implant. Urology, 2023. 171: 236.
https://www.ncbi.nlm.nih.gov/pubmed/36198339
1326. Roos H, et al. Penile lengthening. Int J Aesth Restor Surg. , 1994. 2: 89.
1327. Gaither, T.W., et al. Characterization of Genital Dissatisfaction in a National Sample of U.S. Men. Arch
Sex Behav, 2017. 46: 2123.
https://www.ncbi.nlm.nih.gov/pubmed/27623623
1328. Veale, D., et al. Sexual Functioning and Behavior of Men with Body Dysmorphic Disorder Concerning
Penis Size Compared with Men Anxious about Penis Size and with Controls: A Cohort Study. Sex
Med, 2015. 3: 147.
https://www.ncbi.nlm.nih.gov/pubmed/26468378
1329. Milenkovic, U., et al. Surgical and minimally invasive treatment of ischaemic and non-ischaemic
priapism: a systematic review by the EAU Sexual and Reproductive Health Guidelines panel. Int J
Impot Res, 2022.
https://www.ncbi.nlm.nih.gov/pubmed/36151318
1330. Capogrosso, P., et al. Conservative and medical treatments of non-sickle cell disease-related
ischemic priapism: a systematic review by the EAU Sexual and Reproductive Health Panel. Int J
Impot Res, 2022.
https://www.ncbi.nlm.nih.gov/pubmed/35995858
1331. Gul, M., et al. What is the effectiveness of surgical and non-surgical therapies in the treatment of
ischemic priapism in patients with sickle cell disease? A systematic review by the EAU Sexual and
Reproductive Health Guidelines Panel. Int J Impot Res, 2022.
https://www.ncbi.nlm.nih.gov/pubmed/35941221
1332. Broderick, G.A., et al. Priapism: pathogenesis, epidemiology, and management. J Sex Med, 2010. 7:
476.
https://www.ncbi.nlm.nih.gov/pubmed/20092449
1333. Berger, R., et al. Report of the American Foundation for Urologic Disease (AFUD) Thought Leader
Panel for evaluation and treatment of priapism. Int J Impot Res, 2001. 13 Suppl 5: S39.
https://www.ncbi.nlm.nih.gov/pubmed/11781746
1334. Muneer, A., et al. Investigation of cavernosal smooth muscle dysfunction in low flow priapism using
an in vitro model. Int J Impot Res, 2005. 17: 10.
https://www.ncbi.nlm.nih.gov/pubmed/15071490
1335. Vreugdenhil, S., et al. Ischemic priapism as a model of exhausted metabolism. Physiol Rep, 2019. 7:
e13999.
https://www.ncbi.nlm.nih.gov/pubmed/30916476
1336. El-Bahnasawy, M.S., et al. Low-flow priapism: risk factors for erectile dysfunction. BJU Int, 2002. 89:
285.
https://www.ncbi.nlm.nih.gov/pubmed/11856112
1337. Spycher, M.A., et al. The ultrastructure of the erectile tissue in priapism. J Urol, 1986. 135: 142.
https://www.ncbi.nlm.nih.gov/pubmed/3941454

230 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1338. Zacharakis, E., et al. Penile prosthesis insertion in patients with refractory ischaemic priapism: early
vs delayed implantation. BJU Int, 2014. 114: 576.
https://www.ncbi.nlm.nih.gov/pubmed/25383397
1339. Pohl, J., et al. Priapism: a three-phase concept of management according to aetiology and prognosis.
Br J Urol, 1986. 58: 113.
https://www.ncbi.nlm.nih.gov/pubmed/3516294
1340. Coombs, P.G., et al. A review of outcomes of an intracavernosal injection therapy programme. BJU
Int, 2012. 110: 1787.
https://www.ncbi.nlm.nih.gov/pubmed/22564343
1341. Junemann, K.P., et al. Pathophysiology of erectile dysfunction. Semin Urol, 1990. 8: 80.
https://www.ncbi.nlm.nih.gov/pubmed/2191403
1342. Porst, H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J
Urol, 1996. 155: 802.
https://www.ncbi.nlm.nih.gov/pubmed/8583582
1343. Kilic, M., et al. The actual incidence of papaverine-induced priapism in patients with erectile
dysfunction following penile colour Doppler ultrasonography. Andrologia, 2010. 42: 1.
https://www.ncbi.nlm.nih.gov/pubmed/20078509
1344. Nelson, J.H., 3rd, et al. Priapism: evolution of management in 48 patients in a 22-year series. J Urol,
1977. 117: 455.
https://www.ncbi.nlm.nih.gov/pubmed/15137
1345. Rezaee, M.E., et al. Are We Overstating the Risk of Priapism With Oral Phosphodiesterase Type 5
Inhibitors? J Sex Med, 2020. 17: 1579.
https://www.ncbi.nlm.nih.gov/pubmed/32622767
1346. Schifano, N., et al. Medications mostly associated with priapism events: assessment of the 2015-
2020 Food and Drug Administration (FDA) pharmacovigilance database entries. Int J Impot Res,
2022.
https://www.ncbi.nlm.nih.gov/pubmed/35597798
1347. Bivalacqua, T.J., et al. New insights into the pathophysiology of sickle cell disease-associated
priapism. J Sex Med, 2012. 9: 79.
https://www.ncbi.nlm.nih.gov/pubmed/21554553
1348. Lagoda, G., et al. Molecular analysis of erection regulatory factors in sickle cell disease associated
priapism in the human penis. J Urol, 2013. 189: 762.
https://www.ncbi.nlm.nih.gov/pubmed/22982429
1349. Musicki, B., et al. Mechanisms underlying priapism in sickle cell disease: targeting and key
innovations on the preclinical landscape. Expert Opin Ther Targets, 2020. 24: 439.
https://www.ncbi.nlm.nih.gov/pubmed/32191546
1350. Morrison, B.F., et al. Is testosterone deficiency a possible risk factor for priapism associated with
sickle-cell disease? Int Urol Nephrol, 2015. 47: 47.
https://www.ncbi.nlm.nih.gov/pubmed/25371242
1351. Alwaal, A., et al. Future prospects in the treatment of erectile dysfunction: focus on avanafil. Drug
Des Devel Ther, 2011. 5: 435.
https://www.ncbi.nlm.nih.gov/pubmed/22087063
1352. James Johnson, M., et al. Which patients with ischaemic priapism require further investigation for
malignancy? Int J Impot Res, 2020. 32: 195.
https://www.ncbi.nlm.nih.gov/pubmed/30996267
1353. Kropman, R.F., et al. Hematoma or "partial priapism" in the proximal part of the corpus cavernosum. J
Sex Med, 2014. 11: 2618.
https://www.ncbi.nlm.nih.gov/pubmed/24308665
1354. Weyne, E., et al. Idiopathic Partial Thrombosis (IPT) of the Corpus Cavernosum: A Hypothesis-
Generating Case Series and Review of the Literature. J Sex Med, 2015. 12: 2118.
https://www.ncbi.nlm.nih.gov/pubmed/26553854
1355. Burnett, A.L., et al. Priapism: new concepts in medical and surgical management. Urol Clin North Am,
2011. 38: 185.
https://www.ncbi.nlm.nih.gov/pubmed/21621085
1356. Broderick, G.A. Priapism and sickle-cell anemia: diagnosis and nonsurgical therapy. J Sex Med, 2012.
9: 88.
https://www.ncbi.nlm.nih.gov/pubmed/21699659
1357. Emond, A.M., et al. Priapism and impotence in homozygous sickle cell disease. Arch Intern Med,
1980. 140: 1434.
https://www.ncbi.nlm.nih.gov/pubmed/6159833

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 231

1358. Bertolotto, M., et al. Color Doppler imaging of posttraumatic priapism before and after selective
embolization. Radiographics, 2003. 23: 495.
https://www.ncbi.nlm.nih.gov/pubmed/12640162
1359. Bertolotto, M., et al. Color Doppler appearance of penile cavernosal-spongiosal communications in
patients with high-flow priapism. Acta Radiol, 2008. 49: 710.
https://www.ncbi.nlm.nih.gov/pubmed/18568565
1360. Hakim, L.S., et al. Evolving concepts in the diagnosis and treatment of arterial high flow priapism. J
Urol, 1996. 155: 541.
https://www.ncbi.nlm.nih.gov/pubmed/8558656
1361. von Stempel, C., et al. Mean velocity and peak systolic velocity can help determine ischaemic and
non-ischaemic priapism. Clin Radiol, 2017. 72: 611 e9.
https://www.ncbi.nlm.nih.gov/pubmed/28351471
1362. Ralph, D.J., et al. The use of high-resolution magnetic resonance imaging in the management of
patients presenting with priapism. BJU Int, 2010. 106: 1714.
https://www.ncbi.nlm.nih.gov/pubmed/20438564
1363. Bansal, A.R., et al. Cold saline enema in priapism--a useful tool for underprivileged. Trop Doct, 2004.
34: 227.
https://www.ncbi.nlm.nih.gov/pubmed/15510950
1364. Ateyah, A., et al. Intracavernosal irrigation by cold saline as a simple method of treating iatrogenic
prolonged erection. J Sex Med, 2005. 2: 248.
https://www.ncbi.nlm.nih.gov/pubmed/16422893
1365. Burnett, A.L., et al. Standard operating procedures for priapism. J Sex Med, 2013. 10: 180.
https://www.ncbi.nlm.nih.gov/pubmed/22462660
1366. Montague, D.K., et al. American Urological Association guideline on the management of priapism. J
Urol, 2003. 170: 1318.
https://www.ncbi.nlm.nih.gov/pubmed/14501756
1367. Bodner, D.R., et al. The application of intracavernous injection of vasoactive medications for erection
in men with spinal cord injury. J Urol, 1987. 138: 310.
https://www.ncbi.nlm.nih.gov/pubmed/3599245
1368. Davila, H.H., et al. Subarachnoid hemorrhage as complication of phenylephrine injection for the
treatment of ischemic priapism in a sickle cell disease patient. J Sex Med, 2008. 5: 1025.
https://www.ncbi.nlm.nih.gov/pubmed/18194188
1369. Mantadakis, E., et al. Outpatient penile aspiration and epinephrine irrigation for young patients with
sickle cell anemia and prolonged priapism. Blood, 2000. 95: 78.
https://www.ncbi.nlm.nih.gov/pubmed/10607688
1370. Miller, S.F., et al. Posttraumatic arterial priapism in children: management with embolization.
Radiology, 1995. 196: 59.
https://www.ncbi.nlm.nih.gov/pubmed/7784590
1371. Wen, C.C., et al. Management of ischemic priapism with high-dose intracavernosal phenylephrine:
from bench to bedside. J Sex Med, 2006. 3: 918.
https://www.ncbi.nlm.nih.gov/pubmed/16942536
1372. Muneer, A., et al. Investigating the effects of high-dose phenylephrine in the management of
prolonged ischaemic priapism. J Sex Med, 2008. 5: 2152.
https://www.ncbi.nlm.nih.gov/pubmed/18466270
1373. Muruve, N., et al. Intracorporeal phenylephrine in the treatment of priapism. J Urol, 1996. 155: 141.
https://www.ncbi.nlm.nih.gov/pubmed/7490814
1374. Roberts, J.R., et al. Intracavernous epinephrine: a minimally invasive treatment for priapism in the
emergency department. J Emerg Med, 2009. 36: 285.
https://www.ncbi.nlm.nih.gov/pubmed/18996674
1375. Keskin, D., et al. Intracavernosal adrenalin injection in priapism. Int J Impot Res, 2000. 12: 312.
https://www.ncbi.nlm.nih.gov/pubmed/11416834
1376. Roberts, J., et al. Adrenergic crisis after penile epinephrine injection for priapism. J Emerg Med, 2009.
36: 309.
https://www.ncbi.nlm.nih.gov/pubmed/18353597
1377. Palagiri, R.D.R., et al. A Case Report of Hypertensive Emergency and Intracranial Hemorrhage Due to
Intracavernosal Phenylephrine. Hosp Pharm, 2019. 54: 186.
https://www.ncbi.nlm.nih.gov/pubmed/31205330
1378. Fenwick, M.J., et al. Anaphylaxis and monoamine oxidase inhibitors--the use of adrenaline. J Accid
Emerg Med, 2000. 17: 143.
https://www.ncbi.nlm.nih.gov/pubmed/10718244

232 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1379. Dittrich, A., et al. Treatment of pharmacological priapism with phenylephrine. J Urol, 1991. 146: 323.
https://www.ncbi.nlm.nih.gov/pubmed/1856926
1380. Saffon Cuartas, J.P., et al. Treatment of Priapism Secondary to Drugs for Erectile Dysfunction. Adv
Urol, 2019. 2019: 6214921.
https://www.ncbi.nlm.nih.gov/pubmed/31534452
1381. Serrate, R.G., et al. The usefulness of ethylephrine (Efortil-R) in the treatment of priapism and
intraoperative penile erections. Int Urol Nephrol, 1992. 24: 389.
https://www.ncbi.nlm.nih.gov/pubmed/1281144
1382. Hubler, J., et al. Methylene blue as a means of treatment for priapism caused by intracavernous
injection to combat erectile dysfunction. Int Urol Nephrol, 2003. 35: 519.
https://www.ncbi.nlm.nih.gov/pubmed/15198160
1383. Martinez Portillo, F., et al. Methylene blue as a successful treatment alternative for pharmacologically
induced priapism. Eur Urol, 2001. 39: 20.
https://www.ncbi.nlm.nih.gov/pubmed/11173934
1384. van Driel, M.F., et al. Treatment of priapism by injection of adrenaline into the corpora cavernosa
penis. Scand J Urol Nephrol, 1991. 25: 251.
https://www.ncbi.nlm.nih.gov/pubmed/1780699
1385. Gupta, A., et al. Successful use of terbutaline in persistent priapism in a 12-year-old boy with chronic
myeloid leukemia. Pediatr Hematol Oncol, 2009. 26: 70.
https://www.ncbi.nlm.nih.gov/pubmed/19206011
1386. Lowe, F.C., et al. Placebo-controlled study of oral terbutaline and pseudoephedrine in management of
prostaglandin E1-induced prolonged erections. Urology, 1993. 42: 51.
https://www.ncbi.nlm.nih.gov/pubmed/8392235
1387. Priyadarshi, S. Oral terbutaline in the management of pharmacologically induced prolonged erection.
Int J Impot Res, 2004. 16: 424.
https://www.ncbi.nlm.nih.gov/pubmed/14999218
1388. Govier, F.E., et al. Oral terbutaline for the treatment of priapism. J Urol, 1994. 151: 878.
https://www.ncbi.nlm.nih.gov/pubmed/8126815
1389. Habous, M., et al. Noninvasive treatments for iatrogenic priapism: Do they really work? A prospective
multicenter study. Urol Ann, 2016. 8: 193.
https://www.ncbi.nlm.nih.gov/pubmed/27141191
1390. Bartolucci, P., et al. Clinical management of adult sickle-cell disease. Curr Opin Hematol, 2012. 19:
149.
https://www.ncbi.nlm.nih.gov/pubmed/22357165
1391. Levey, H.R., et al. Medical management of ischemic stuttering priapism: a contemporary review of
the literature. Asian J Androl, 2012. 14: 156.
https://www.ncbi.nlm.nih.gov/pubmed/22057380
1392. Rogers, Z.R. Priapism in sickle cell disease. Hematol Oncol Clin North Am, 2005. 19: 917.
https://www.ncbi.nlm.nih.gov/pubmed/16214652
1393. Morrison, B.F., et al. Priapism in hematological and coagulative disorders: an update. Nat Rev Urol,
2011. 8: 223.
https://www.ncbi.nlm.nih.gov/pubmed/21403660
1394. Ballas, S.K., et al. Safety and efficacy of blood exchange transfusion for priapism complicating sickle
cell disease. J Clin Apher, 2016. 31: 5.
https://www.ncbi.nlm.nih.gov/pubmed/25809639
1395. Marouf, R. Blood transfusion in sickle cell disease. Hemoglobin, 2011. 35: 495.
https://www.ncbi.nlm.nih.gov/pubmed/21981466
1396. Merritt, A.L., et al. Myth: blood transfusion is effective for sickle cell anemia-associated priapism.
CJEM, 2006. 8: 119.
https://www.ncbi.nlm.nih.gov/pubmed/17175874
1397. Howard, J., et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a
randomised, controlled, multicentre clinical trial. Lancet, 2013. 381: 930.
https://www.ncbi.nlm.nih.gov/pubmed/23352054
1398. Johnson, M.J., et al. The surgical management of ischaemic priapism. Int J Impot Res, 2020. 32: 81.
https://www.ncbi.nlm.nih.gov/pubmed/31570823
1399. Burnett, A.L. Surgical management of ischemic priapism. J Sex Med, 2012. 9: 114.
https://www.ncbi.nlm.nih.gov/pubmed/22221308
1400. Bennett, N., et al. Sickle cell disease status and outcomes of African-American men presenting with
priapism. J Sex Med, 2008. 5: 1244.
https://www.ncbi.nlm.nih.gov/pubmed/18312286

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 233

1401. Nixon, R.G., et al. Efficacy of shunt surgery for refractory low flow priapism: a report on the incidence
of failed detumescence and erectile dysfunction. J Urol, 2003. 170: 883.
https://www.ncbi.nlm.nih.gov/pubmed/12913722
1402. Lue, T.F., et al. Distal cavernosum-glans shunts for ischemic priapism. J Sex Med, 2006. 3: 749.
https://www.ncbi.nlm.nih.gov/pubmed/16839333
1403. Ortac, M., et al. Anatomic and Functional Outcome Following Distal Shunt and Tunneling for
Treatment Ischemic Priapism: A Single-Center Experience. J Sex Med, 2019. 16: 1290.
https://www.ncbi.nlm.nih.gov/pubmed/31230939
1404. Yucel, O.B., et al. Penile Prosthesis Implantation in Priapism. Sex Med Rev, 2018. 6: 310.
https://www.ncbi.nlm.nih.gov/pubmed/28916463
1405. Zacharakis, E., et al. The efficacy of the T-shunt procedure and intracavernous tunneling (snake
maneuver) for refractory ischemic priapism. J Urol, 2014. 191: 164.
https://www.ncbi.nlm.nih.gov/pubmed/23892191
1406. Ramstein, J.J., et al. Clinical Outcomes of Periprocedural Antithrombotic Therapy in Ischemic
Priapism Management. J Sex Med, 2020. 17: 2260.
https://www.ncbi.nlm.nih.gov/pubmed/32800740
1407. Winter, C.C. Cure of idiopathic priapism: new procedure for creating fistula between glans penis and
corpora cavernosa. Urology, 1976. 8: 389.
https://www.ncbi.nlm.nih.gov/pubmed/973296
1408. Macaluso, J.N., Jr., et al. Priapism: review of 34 cases. Urology, 1985. 26: 233.
https://www.ncbi.nlm.nih.gov/pubmed/4035837
1409. Ebbehoj, J. A new operation for priapism. Scand J Plast Reconstr Surg, 1974. 8: 241.
https://www.ncbi.nlm.nih.gov/pubmed/4458048
1410. Lund, K., et al. Results of glando-cavernous anastomosis in 18 cases of priapism. Scand J Plast
Reconstr Surg, 1980. 14: 269.
https://www.ncbi.nlm.nih.gov/pubmed/7209413
1411. Brant, W.O., et al. T-shaped shunt and intracavernous tunneling for prolonged ischemic priapism. J
Urol, 2009. 181: 1699.
https://www.ncbi.nlm.nih.gov/pubmed/19233430
1412. Ercole, C.J., et al. Changing surgical concepts in the treatment of priapism. J Urol, 1981. 125: 210.
https://www.ncbi.nlm.nih.gov/pubmed/7206057
1413. Hanafy, H.M., et al. Ancient Egyptian medicine: contribution to urology. Urology, 1974. 4: 114.
https://www.ncbi.nlm.nih.gov/pubmed/21323001
1414. Juskiewenski, S., et al. A study of the arterial blood supply to the penis. Anatomia Clinica, 1982. 4:
101.
https://doi.org/10.1007/BF01800618
1415. Burnett, A.L., et al. Corporal "snake" maneuver: corporoglanular shunt surgical modification for
ischemic priapism. J Sex Med, 2009. 6: 1171.
https://www.ncbi.nlm.nih.gov/pubmed/19207268
1416. Segal, R.L., et al. Corporal Burnett "Snake" surgical maneuver for the treatment of ischemic priapism:
long-term followup. J Urol, 2013. 189: 1025.
https://www.ncbi.nlm.nih.gov/pubmed/23017524
1417. Quackels, R. [Treatment of a Case of Priapism by Cavernospongious Anastomosis]. Acta Urol Belg,
1964. 32: 5.
https://www.ncbi.nlm.nih.gov/pubmed/14111379
1418. Baumgarten, A.S., et al. Favourable multi-institutional experience with penoscrotal decompression for
prolonged ischaemic priapism. BJU Int, 2020. 126: 441.
https://www.ncbi.nlm.nih.gov/pubmed/32501654
1419. Grayhack, J.T., et al. Venous Bypass to Control Priapism. Invest Urol, 1964. 1: 509.
https://www.ncbi.nlm.nih.gov/pubmed/14130594
1420. Kandel, G.L., et al. Pulmonary embolism: a complication of corpus-saphenous shunt for priapism. J
Urol, 1968. 99: 196.
https://www.ncbi.nlm.nih.gov/pubmed/5641077
1421. Kihl, B., et al. Priapsim: evaluation of treatment with special reference to saphenocavernous shunting
in 26 patients. Scand J Urol Nephrol, 1980. 14: 1.
https://www.ncbi.nlm.nih.gov/pubmed/7375831
1422. Ralph, D.J., et al. The immediate insertion of a penile prosthesis for acute ischaemic priapism. Eur
Urol, 2009. 56: 1033.
https://www.ncbi.nlm.nih.gov/pubmed/18930579

234 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1423. Salem, E.A., et al. Management of ischemic priapism by penile prosthesis insertion: prevention of
distal erosion. J Urol, 2010. 183: 2300.
https://www.ncbi.nlm.nih.gov/pubmed/20400140
1424. Sedigh, O., et al. Early insertion of inflatable prosthesis for intractable ischemic priapism: our
experience and review of the literature. Int J Impot Res, 2011. 23: 158.
https://www.ncbi.nlm.nih.gov/pubmed/21654814
1425. Upadhyay, J., et al. Penile implant for intractable priapism associated with sickle cell disease.
Urology, 1998. 51: 638.
https://www.ncbi.nlm.nih.gov/pubmed/9586621
1426. Zacharakis, E., et al. Early insertion of a malleable penile prosthesis in ischaemic priapism allows
later upsizing of the cylinders. Scand J Urol, 2015. 49: 468.
https://www.ncbi.nlm.nih.gov/pubmed/26116193
1427. Bella, A., et al. 1859 3-Piece Inflatable Penile Prosthesis Insertion Post T-Shunt for Priapism with
Dilation/Corporal Snake Maneuver and Comparison to Post Al-Ghorab Shunt Ipp Outcomes. Journal
of Urology, 2012. 187: e751.
https://www.auajournals.org/doi/abs/10.1016/j.juro.2012.02.1971
1428. Tsambarlis, P.N., et al. Successful Placement of Penile Prostheses in Men With Severe Corporal
Fibrosis Following Vacuum Therapy Protocol. J Sex Med, 2017. 14: 44.
https://www.ncbi.nlm.nih.gov/pubmed/27938991
1429. Burnett, A.L., et al. Evaluation of erectile function in men with sickle cell disease. Urology, 1995. 45:
657.
https://www.ncbi.nlm.nih.gov/pubmed/7716848
1430. Datta, N.S. Megalophallus in sickle cell disease. J Urol, 1977. 117: 672.
https://www.ncbi.nlm.nih.gov/pubmed/859210
1431. Broderick, G.A., et al. Pharmacologic erection: time-dependent changes in the corporal environment.
Int J Impot Res, 1994. 6: 9.
https://www.ncbi.nlm.nih.gov/pubmed/8019618
1432. Monga, M., et al. Priapism in sickle cell disease: the case for early implantation of the penile
prosthesis. Eur Urol, 1996. 30: 54.
https://www.ncbi.nlm.nih.gov/pubmed/8854068
1433. Morrison, B.F., et al. Stuttering priapism: insights into pathogenesis and management. Curr Urol Rep,
2012. 13: 268.
https://www.ncbi.nlm.nih.gov/pubmed/22648304
1434. Adeyoju, A.B., et al. Priapism in sickle-cell disease; incidence, risk factors and complications - an
international multicentre study. BJU Int, 2002. 90: 898.
https://www.ncbi.nlm.nih.gov/pubmed/12460353
1435. Virag, R., et al. Preventive treatment of priapism in sickle cell disease with oral and self-administered
intracavernous injection of etilefrine. Urology, 1996. 47: 777.
https://www.ncbi.nlm.nih.gov/pubmed/8650886
1436. Fowler, J.E., Jr., et al. Priapism associated with the sickle cell hemoglobinopathies: prevalence,
natural history and sequelae. J Urol, 1991. 145: 65.
https://www.ncbi.nlm.nih.gov/pubmed/1984102
1437. Mantadakis, E., et al. Prevalence of priapism in children and adolescents with sickle cell anemia. J
Pediatr Hematol Oncol, 1999. 21: 518.
https://www.ncbi.nlm.nih.gov/pubmed/10598664
1438. Roizenblatt, M., et al. Priapism is associated with sleep hypoxemia in sickle cell disease. J Urol, 2012.
188: 1245.
https://www.ncbi.nlm.nih.gov/pubmed/22902014
1439. Champion, H.C., et al. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism
of priapism. Proc Natl Acad Sci U S A, 2005. 102: 1661.
https://www.ncbi.nlm.nih.gov/pubmed/15668387
1440. Bivalacqua, T.J., et al. Attenuated RhoA/Rho-kinase signaling in penis of transgenic sickle cell mice.
Urology, 2010. 76: 510 e7.
https://www.ncbi.nlm.nih.gov/pubmed/20538321
1441. Phatarpekar, P.V., et al. Role of adenosine signaling in penile erection and erectile disorders. J Sex
Med, 2010. 7: 3553.
https://www.ncbi.nlm.nih.gov/pubmed/19889148
1442. Traish, A.M., et al. Are androgens critical for penile erections in humans? Examining the clinical and
preclinical evidence. J Sex Med, 2006. 3: 382.
https://www.ncbi.nlm.nih.gov/pubmed/16681465

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 235

1443. Liguori, G., et al. The management of stuttering priapism. Minerva Urol Nefrol, 2020. 72: 173.
https://www.ncbi.nlm.nih.gov/pubmed/30957473
1444. Mocniak, M., et al. The use of sudafed for priapism in pediatric patients with sickle cell disease. J
Pediatr Nurs, 2012. 27: 82.
https://www.ncbi.nlm.nih.gov/pubmed/22041221
1445. Gbadoe, A.D., et al. Management of sickle cell priapism with etilefrine. Arch Dis Child, 2001. 85: 52.
https://www.ncbi.nlm.nih.gov/pubmed/11420201
1446. Okpala, I., et al. Etilefrine for the prevention of priapism in adult sickle cell disease. Br J Haematol,
2002. 118: 918.
https://www.ncbi.nlm.nih.gov/pubmed/12181066
1447. Olujohungbe, A.B., et al. A prospective diary study of stuttering priapism in adolescents and young
men with sickle cell anemia: report of an international randomized control trial--the priapism in sickle
cell study. J Androl, 2011. 32: 375.
https://www.ncbi.nlm.nih.gov/pubmed/21127308
1448. Yuan, J., et al. Insights of priapism mechanism and rationale treatment for recurrent priapism. Asian
J Androl, 2008. 10: 88.
https://www.ncbi.nlm.nih.gov/pubmed/18087648
1449. Levine, L.A., et al. Gonadotropin-releasing hormone analogues in the treatment of sickle cell anemia-
associated priapism. J Urol, 1993. 150: 475.
https://www.ncbi.nlm.nih.gov/pubmed/8326584
1450. Alshahrani, A. Using cyproterone acetate to treat recurrent ischemic priapism in a patient with sickle
cell anemia as a comorbidity: a case report. J Med Case Rep, 2020. 14: 197.
https://www.ncbi.nlm.nih.gov/pubmed/33081822
1451. Rachid-Filho, D., et al. Treatment of recurrent priapism in sickle cell anemia with finasteride: a new
approach. Urology, 2009. 74: 1054.
https://www.ncbi.nlm.nih.gov/pubmed/19616292
1452. Baker, R.C., et al. Dutasteride in the long-term management of stuttering priapism. Transl Androl Urol,
2020. 9: 87.
https://www.ncbi.nlm.nih.gov/pubmed/32055472
1453. DeCastro, B.J., et al. Oral ketoconazole for prevention of postoperative penile erection: a placebo
controlled, randomized, double-blind trial. J Urol, 2008. 179: 1930.
https://www.ncbi.nlm.nih.gov/pubmed/18353393
1454. Gupta, S., et al. A possible mechanism for alteration of human erectile function by digoxin: inhibition
of corpus cavernosum sodium/potassium adenosine triphosphatase activity. J Urol, 1998. 159:
1529.
https://www.ncbi.nlm.nih.gov/pubmed/9554348
1455. Daoud, A.S., et al. The effect of Vigabatrin, Lamotrigine and Gabapentin on the fertility, weights, sex
hormones and biochemical profiles of male rats. Neuro Endocrinol Lett, 2004. 25: 178.
https://www.ncbi.nlm.nih.gov/pubmed/15349082
1456. Perimenis, P., et al. Gabapentin in the management of the recurrent, refractory, idiopathic priapism.
Int J Impot Res, 2004. 16: 84.
https://www.ncbi.nlm.nih.gov/pubmed/14963477
1457. D'Aleo, G., et al. Favorable response to intrathecal, but not oral, baclofen of priapism in a patient with
spinal cord injury. Spine (Phila Pa 1976), 2009. 34: E127.
https://www.ncbi.nlm.nih.gov/pubmed/19179913
1458. Moreira, D.M., et al. Recurrent priapism in the young patient treated with baclofen. J Pediatr Urol,
2006. 2: 590.
https://www.ncbi.nlm.nih.gov/pubmed/18947688
1459. Vaidyanathan, S., et al. Management of recurrent priapism in a cervical spinal cord injury patient with
oral baclofen therapy. Spinal Cord, 2004. 42: 134.
https://www.ncbi.nlm.nih.gov/pubmed/14765150
1460. Kato, G.J. Priapism in sickle-cell disease: a hematologist's perspective. J Sex Med, 2012. 9: 70.
https://www.ncbi.nlm.nih.gov/pubmed/21554552
1461. Meier, E.R., et al. Sickle cell disease in children. Drugs, 2012. 72: 895.
https://www.ncbi.nlm.nih.gov/pubmed/22519940
1462. Saad, S.T., et al. Follow-up of sickle cell disease patients with priapism treated by hydroxyurea. Am J
Hematol, 2004. 77: 45.
https://www.ncbi.nlm.nih.gov/pubmed/15307105

236 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1463. Bivalacqua, T.J., et al. Establishment of a transgenic sickle-cell mouse model to study the
pathophysiology of priapism. J Sex Med, 2009. 6: 2494.
https://www.ncbi.nlm.nih.gov/pubmed/19523035
1464. Burnett, A.L., et al. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent
priapism. Urology, 2006. 67: 1043.
https://www.ncbi.nlm.nih.gov/pubmed/16698365
1465. Burnett, A.L., et al. Feasibility of the use of phosphodiesterase type 5 inhibitors in a pharmacologic
prevention program for recurrent priapism. J Sex Med, 2006. 3: 1077.
https://www.ncbi.nlm.nih.gov/pubmed/17100941
1466. Pierorazio, P.M., et al. Daily phosphodiesterase type 5 inhibitor therapy as rescue for recurrent
ischemic priapism after failed androgen ablation. J Androl, 2011. 32: 371.
https://www.ncbi.nlm.nih.gov/pubmed/21127306
1467. Hou, L.T., et al. Regimented Phosphodiesterase Type 5 Inhibitor Use Reduces Emergency Department
Visits for Recurrent Ischemic Priapism. J Urol, 2021. 205: 545.
https://www.ncbi.nlm.nih.gov/pubmed/32915079
1468. Rutchik, S., et al. Successful treatment of recalcitrant priapism using intercorporeal injection of tissue
plasminogen activator. J Urol, 2001. 166: 628.
https://www.ncbi.nlm.nih.gov/pubmed/11458096
1469. Welliver, R.C., Jr., et al. Autoinflation leading to failure of two-piece ambicor implantable penile
prosthesis: an outcome from a methodical treatment of recalcitrant stuttering priapism. Case Rep
Urol, 2014. 2014: 529037.
https://www.ncbi.nlm.nih.gov/pubmed/24864222
1470. Anele, U.A., et al. How I treat priapism. Blood, 2015. 125: 3551.
https://www.ncbi.nlm.nih.gov/pubmed/25810489
1471. Burnett, A.L., et al. Priapism: current principles and practice. Urol Clin North Am, 2007. 34: 631.
https://www.ncbi.nlm.nih.gov/pubmed/17983902
1472. Jesus, L.E., et al. Priapism in children: review of pathophysiology and treatment. J Pediatr (Rio J),
2009. 85: 194.
https://www.ncbi.nlm.nih.gov/pubmed/19455267
1473. Donaldson, J.F., et al. Priapism in children: a comprehensive review and clinical guideline. J Pediatr
Urol, 2014. 10: 11.
https://www.ncbi.nlm.nih.gov/pubmed/24135215
1474. Bastuba, M.D., et al. Arterial priapism: diagnosis, treatment and long-term followup. J Urol, 1994. 151:
1231.
https://www.ncbi.nlm.nih.gov/pubmed/8158765
1475. Hatzichristou, D., et al. Management strategy for arterial priapism: therapeutic dilemmas. J Urol,
2002. 168: 2074.
https://www.ncbi.nlm.nih.gov/pubmed/12394712
1476. Witt, M.A., et al. Traumatic laceration of intracavernosal arteries: the pathophysiology of
nonischemic, high flow, arterial priapism. J Urol, 1990. 143: 129.
https://www.ncbi.nlm.nih.gov/pubmed/2294241
1477. Kuefer, R., et al. Changing diagnostic and therapeutic concepts in high-flow priapism. Int J Impot Res,
2005. 17: 109.
https://www.ncbi.nlm.nih.gov/pubmed/15229624
1478. Steers, W.D., et al. Use of methylene blue and selective embolization of the pudendal artery for high
flow priapism refractory to medical and surgical treatments. J Urol, 1991. 146: 1361.
https://www.ncbi.nlm.nih.gov/pubmed/1942293
1479. Ricciardi, R., Jr., et al. Delayed high flow priapism: pathophysiology and management. J Urol, 1993.
149: 119.
https://www.ncbi.nlm.nih.gov/pubmed/8417190
1480. Ingram, A.R., et al. An Update on Non-Ischemic Priapism. Sex Med Rev, 2020. 8: 140.
https://www.ncbi.nlm.nih.gov/pubmed/30987934
1481. Hudnall, M., et al. Advances in the understanding of priapism. Transl Androl Urol, 2017. 6: 199.
https://www.ncbi.nlm.nih.gov/pubmed/28540227
1482. Todd, N.V. Priapism in acute spinal cord injury. Spinal Cord, 2011. 49: 1033.
https://www.ncbi.nlm.nih.gov/pubmed/21647168
1483. Karagiannis, A.A., et al. High flow priapism secondary to internal urethrotomy treated with
embolization. J Urol, 2004. 171: 1631.
https://www.ncbi.nlm.nih.gov/pubmed/15017242

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 237

1484. Liguori, G., et al. High-flow priapism (HFP) secondary to Nesbit operation: management by
percutaneous embolization and colour Doppler-guided compression. Int J Impot Res, 2005. 17: 304.
https://www.ncbi.nlm.nih.gov/pubmed/15690066
1485. Tang, M., et al. Intracavernosal metaraminol bitartrate for treatment of priapism resulting from
circumcision: a case report. Springerplus, 2016. 5: 436.
https://www.ncbi.nlm.nih.gov/pubmed/27104124
1486. Boscolo-Berto, R., et al. Determinism and liabilities in a complicated transrectal prostate biopsy: what
is what. Urologia, 2011. 78: 176.
https://www.ncbi.nlm.nih.gov/pubmed/21786228
1487. Oshima, J., et al. [Nonischemic Priapism Following Brachytherapy : A Case Report and a Review].
Hinyokika Kiyo, 2016. 62: 605.
https://www.ncbi.nlm.nih.gov/pubmed/27919141
1488. Lutz, A., et al. Conversion of low-flow to high-flow priapism: a case report and review (CME). J Sex
Med, 2012. 9: 951.
https://www.ncbi.nlm.nih.gov/pubmed/22462585
1489. McMahon, C.G. High flow priapism due to an arterial-lacunar fistula complicating initial veno-
occlusive priapism. Int J Impot Res, 2002. 14: 195.
https://www.ncbi.nlm.nih.gov/pubmed/12058247
1490. Vagnoni, V., et al. High-flow priapism after T-shunt and tunneling in a patient with ischemic priapism.
Turk J Urol, 2020. 46: 488.
https://www.ncbi.nlm.nih.gov/pubmed/32966205
1491. Ramos, C.E., et al. High flow priapism associated with sickle cell disease. J Urol, 1995. 153: 1619.
https://www.ncbi.nlm.nih.gov/pubmed/7714988
1492. Dubocq, F.M., et al. High flow malignant priapism with isolated metastasis to the corpora cavernosa.
Urology, 1998. 51: 324.
https://www.ncbi.nlm.nih.gov/pubmed/9495721
1493. Inamoto, T., et al. A rare case of penile metastasis of testicular cancer presented with priapism.
Hinyokika Kiyo, 2005. 51: 639.
https://www.ncbi.nlm.nih.gov/pubmed/16229380
1494. Bertolotto, M., et al. Sonography of the penis/erectile dysfunction. Abdom Radiol (NY), 2020. 45:
1973.
https://www.ncbi.nlm.nih.gov/pubmed/32285181
1495. Jung, D.C., et al. Penile Doppler ultrasonography revisited. Ultrasonography, 2018. 37: 16.
https://www.ncbi.nlm.nih.gov/pubmed/28736428
1496. Abdulsattar, O.A., et al. The Role of Color Doppler Ultrasound in Initial Evaluation of Patients with
Priapism: A Cross Sectional Study. Indian Journal of Public Health Research & Development, 2019.
10: 1102.
1497. Kang, B.C., et al. Post-traumatic arterial priapism: colour Doppler examination and superselective
arterial embolization. Clin Radiol, 1998. 53: 830.
https://www.ncbi.nlm.nih.gov/pubmed/9833787
1498. Kolbenstvedt, A., et al. Arterial high flow priapism role of radiology in diagnosis and treatment. Scand
J Urol Nephrol Suppl, 1996. 179: 143.
https://www.ncbi.nlm.nih.gov/pubmed/8908681
1499. Eracleous, E., et al. Use of Doppler ultrasound and 3-dimensional contrast-enhanced MR angiography
in the diagnosis and follow-up of post-traumatic high-flow priapism in a child. Pediatr Radiol, 2000.
30: 265.
https://www.ncbi.nlm.nih.gov/pubmed/10789908
1500. Surgery, B.S.o.A.G., et al. BAUS consensus document for the management of male genital
emergencies: priapism. BJU Int, 2018. 121: 835.
https://www.ncbi.nlm.nih.gov/pubmed/29357203
1501. Arango, O., et al. Complete resolution of post-traumatic high-flow priapism with conservative
treatment. Int J Impot Res, 1999. 11: 115.
https://www.ncbi.nlm.nih.gov/pubmed/10356672
1502. Ilkay, A.K., et al. Conservative management of high-flow priapism. Urology, 1995. 46: 419.
https://www.ncbi.nlm.nih.gov/pubmed/7660524
1503. Mwamukonda, K.B., et al. Androgen blockade for the treatment of high-flow priapism. J Sex Med,
2010. 7: 2532.
https://www.ncbi.nlm.nih.gov/pubmed/20456623

238 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1504. Cakan, M., et al. Is the combination of superselective transcatheter autologous clot embolization and
duplex sonography-guided compression therapy useful treatment option for the patients with high-
flow priapism? Int J Impot Res, 2006. 18: 141.
https://www.ncbi.nlm.nih.gov/pubmed/16079900
1505. Kim, K.R., et al. Treatment of high-flow priapism with superselective transcatheter embolization in 27
patients: a multicenter study. J Vasc Interv Radiol, 2007. 18: 1222.
https://www.ncbi.nlm.nih.gov/pubmed/17911511
1506. Numan, F., et al. Posttraumatic nonischemic priapism treated with autologous blood clot
embolization. J Sex Med, 2008. 5: 173.
https://www.ncbi.nlm.nih.gov/pubmed/18173765
1507. Gorich, J., et al. Interventional treatment of traumatic priapism. J Endovasc Ther, 2002. 9: 614.
https://www.ncbi.nlm.nih.gov/pubmed/12431145
1508. Kerlan, R.K., Jr., et al. Superselective microcoil embolization in the management of high-flow
priapism. J Vasc Interv Radiol, 1998. 9: 85.
https://www.ncbi.nlm.nih.gov/pubmed/9468400
1509. Liu, B.X., et al. High-flow priapism: superselective cavernous artery embolization with microcoils.
Urology, 2008. 72: 571.
https://www.ncbi.nlm.nih.gov/pubmed/18619653
1510. Numan, F., et al. Posttraumatic high-flow priapism treated by N-butyl-cyanoacrylate embolization.
Cardiovasc Intervent Radiol, 1996. 19: 278.
https://www.ncbi.nlm.nih.gov/pubmed/8755084
1511. Sandock, D.S., et al. Perineal abscess after embolization for high-flow priapism. Urology, 1996. 48:
308.
https://www.ncbi.nlm.nih.gov/pubmed/8753749
1512. Shapiro, R.H., et al. Post-traumatic priapism treated with selective cavernosal artery ligation. Urology,
1997. 49: 638.
https://www.ncbi.nlm.nih.gov/pubmed/9111644
1513. De Rose, A.F., et al. Cycling Trauma as a Cause of Arterial Priapism in Children and Teenagers. Rev
Urol, 2017. 19: 273.
https://www.ncbi.nlm.nih.gov/pubmed/29472833
1514. Hacker, H.W., et al. Nonischemic Priapism in Childhood: A Case Series and Review of Literature. Eur J
Pediatr Surg, 2018. 28: 255.
https://www.ncbi.nlm.nih.gov/pubmed/28346955
1515. Corbetta, J.P., et al. High flow priapism: diagnosis and treatment in pediatric population. Pediatr Surg
Int, 2011. 27: 1217.
https://www.ncbi.nlm.nih.gov/pubmed/21544645
1516. Nabinger, G.B., et al. Child non-ischemic priapism, a conservative approach: case report and updated
review. J Pediatr Urol, 2013. 9: e99.
https://www.ncbi.nlm.nih.gov/pubmed/23287647
1517. Cantasdemir, M., et al. Posttraumatic high-flow priapism in children treated with autologous blood
clot embolization: long-term results and review of the literature. Pediatr Radiol, 2011. 41: 627.
https://www.ncbi.nlm.nih.gov/pubmed/21127852
1518. World Health Organisation. WHO Manual for the Standardized Investigation and Diagnosis of the
Infertile Couple. 2000, Cambridge University Press: Cambridge.
1519. Agarwal, A., et al. Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical
Practice Guidelines for Management of Idiopathic Male Infertility. World J Mens Health, 2019. 37:
296.
https://www.ncbi.nlm.nih.gov/pubmed/31081299
1520. Thoma, M.E., et al. Prevalence of infertility in the United States as estimated by the current duration
approach and a traditional constructed approach. Fertil Steril, 2013. 99: 1324.
https://www.ncbi.nlm.nih.gov/pubmed/23290741
1521. Greenhall, E., et al. The prevalence of subfertility: a review of the current confusion and a report of
two new studies. Fertil Steril, 1990. 54: 978.
https://www.ncbi.nlm.nih.gov/pubmed/2245856
1522. Brandt, J.S., et al. Advanced paternal age, infertility, and reproductive risks: A review of the literature.
Prenat Diagn, 2019. 39: 81.
https://www.ncbi.nlm.nih.gov/pubmed/30520056
1523. Avellino, G., et al. Common urologic diseases in older men and their treatment: how they impact
fertility. Fertil Steril, 2017. 107: 305.
https://www.ncbi.nlm.nih.gov/pubmed/28073432

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 239

1524. Jennings, M.O., et al. Management and counseling of the male with advanced paternal age. Fertil
Steril, 2017. 107: 324.
https://www.ncbi.nlm.nih.gov/pubmed/28069174
1525. Ramasamy, R., et al. Male biological clock: a critical analysis of advanced paternal age. Fertil Steril,
2015. 103: 1402.
https://www.ncbi.nlm.nih.gov/pubmed/25881878
1526. Starosta, A., et al. Predictive factors for intrauterine insemination outcomes: a review. Fertil Res
Pract, 2020. 6: 23.
https://www.ncbi.nlm.nih.gov/pubmed/33308319
1527. Van Opstal, J., et al. Male age interferes with embryo growth in IVF treatment. Hum Reprod, 2021. 36:
107.
https://www.ncbi.nlm.nih.gov/pubmed/33164068
1528. Vaughan, D.A., et al. DNA fragmentation of sperm: a radical examination of the contribution of
oxidative stress and age in 16 945 semen samples. Hum Reprod, 2020. 35: 2188.
https://www.ncbi.nlm.nih.gov/pubmed/32976601
1529. du Fosse, N.A., et al. Advanced paternal age is associated with an increased risk of spontaneous
miscarriage: a systematic review and meta-analysis. Hum Reprod Update, 2020. 26: 650.
https://www.ncbi.nlm.nih.gov/pubmed/32358607
1530. Wennberg, A.L., et al. Effect of maternal age on maternal and neonatal outcomes after assisted
reproductive technology. Fertil Steril, 2016. 106: 1142.
https://www.ncbi.nlm.nih.gov/pubmed/27399261
1531. Sunderam, S., et al. Comparing fertilization rates from intracytoplasmic sperm injection to
conventional in vitro fertilization among women of advanced age with non-male factor infertility: a
meta-analysis. Fertil Steril, 2020. 113: 354.
https://www.ncbi.nlm.nih.gov/pubmed/32106989
1532. Guideline Group on Unexplained, I., et al. Evidence-based guideline: unexplained infertilitydagger.
Hum Reprod, 2023. 38: 1881.
https://www.ncbi.nlm.nih.gov/pubmed/37599566
1533. American College of, O., et al. Female age-related fertility decline. Committee Opinion No. 589. Fertil
Steril, 2014. 101: 633.
https://www.ncbi.nlm.nih.gov/pubmed/24559617
1534. Carson, S.A., et al. Diagnosis and Management of Infertility: A Review. JAMA, 2021. 326: 65.
https://www.ncbi.nlm.nih.gov/pubmed/34228062
1535. Nieschlag E, et al., Male reproductive health and dysfunction, in Male reproductive health and
dysfunction. 2010, Springer, Berlin.
1536. Boeri, L., et al. Normal sperm parameters per se do not reliably account for fertility: A case-control
study in the real-life setting. Andrologia, 2021. 53: e13861.
https://www.ncbi.nlm.nih.gov/pubmed/33125742
1537. Campbell, M.J., et al. Distribution of semen examination results 2020 - A follow up of data collated
for the WHO semen analysis manual 2010. Andrology, 2021. 9: 817.
https://www.ncbi.nlm.nih.gov/pubmed/33528873
1538. Fallara, G., et al. A Systematic Review and Meta-analysis on the Impact of Infertility on Men's General
Health. Eur Urol Focus, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37573151
1539. Pozzi, E., et al. Infertile couples still undergo assisted reproductive treatments without initial
andrological evaluation in the real-life setting: A failure to adhere to guidelines? Andrology, 2021. 9:
1843.
https://www.ncbi.nlm.nih.gov/pubmed/34169669
1540. Ferlin, A., et al. Sperm Count and Hypogonadism as Markers of General Male Health. Eur Urol Focus,
2021. 7: 205.
https://www.ncbi.nlm.nih.gov/pubmed/31427194
1541. Fallara, G., et al. A Systematic Review and Meta-analysis on the Impact of Infertility on Men's General
Health. Eur Urol Focus, 2024. 10: 98.
https://www.ncbi.nlm.nih.gov/pubmed/37573151
1542. Bjorndahl, L., et al. Standards in semen examination: publishing reproducible and reliable data based
on high-quality methodology. Hum Reprod, 2022. 37: 2497.
https://www.ncbi.nlm.nih.gov/pubmed/36112046
1543. World Health Organization. WHO Laboratory manual for the examination and processing of human
semen, sixth edition. Geneva: World Health Organization, 2021.
file:///C:/Users/e.smith/Downloads/9789240030787-eng.pdf

240 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1544. Pozzi, E., et al. Initial Andrological Evaluation of the Infertile Male. Eur Urol Focus, 2023. 9: 51.
https://www.ncbi.nlm.nih.gov/pubmed/36210297
1545. Nieschlag E, et al., Andrology: Male Reproductive Health and Dysfunction, 3rd edn. Anamnesis and
physical examination. 2010, Berlin.
1546. Lotti, F., et al. Ultrasound of the male genital tract in relation to male reproductive health. Hum Reprod
Update, 2015. 21: 56.
https://www.ncbi.nlm.nih.gov/pubmed/25038770
1547. Bahk, J.Y., et al. Cut-off value of testes volume in young adults and correlation among testes volume,
body mass index, hormonal level, and seminal profiles. Urology, 2010. 75: 1318.
https://www.ncbi.nlm.nih.gov/pubmed/20299083
1548. Jorgensen, N., et al. East-West gradient in semen quality in the Nordic-Baltic area: a study of men
from the general population in Denmark, Norway, Estonia and Finland. Hum Reprod, 2002. 17: 2199.
https://www.ncbi.nlm.nih.gov/pubmed/12151459
1549. Jensen, T.K., et al. Association of in utero exposure to maternal smoking with reduced semen quality
and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population
in five European countries. Am J Epidemiol, 2004. 159: 49.
https://www.ncbi.nlm.nih.gov/pubmed/14693659
1550. Boeri, L., et al. Testicular volume in infertile versus fertile white-European men: a case-control
investigation in the real-life setting. Asian J Androl, 2021. 23: 501.
https://www.ncbi.nlm.nih.gov/pubmed/33723100
1551. Yifu, P., et al. Sperm DNA fragmentation index with unexplained recurrent spontaneous abortion: A
systematic review and meta-analysis. J Gynecol Obstet Hum Reprod, 2020: 101740.
https://www.ncbi.nlm.nih.gov/pubmed/32348878
1552. McQueen, D.B., et al. Sperm DNA fragmentation and recurrent pregnancy loss: a systematic review
and meta-analysis. Fertil Steril, 2019. 112: 54.
https://www.ncbi.nlm.nih.gov/pubmed/31056315
1553. WHO Laboratory Manual for the Examination and Processing of Human Semen, in 5th edn. 2010.
https://iris.who.int/handle/10665/44261
1554. Grimes, D.A., et al. "Oligozoospermia," "azoospermia," and other semen-analysis terminology: the
need for better science. Fertil Steril, 2007. 88: 1491.
https://www.ncbi.nlm.nih.gov/pubmed/17582404
1555. WHO. WHO laboratory manual for the examination and processing of human semen Sixth edition.
2021.
https://www.who.int/publications/i/item/9789240030787
1556. Agarwal, A., et al. Sperm DNA damage assessment: a test whose time has come. Fertil Steril, 2005.
84: 850.
https://www.ncbi.nlm.nih.gov/pubmed/16213833
1557. Zini, A., et al. Correlations between two markers of sperm DNA integrity, DNA denaturation and DNA
fragmentation, in fertile and infertile men. Fertil Steril, 2001. 75: 674.
https://www.ncbi.nlm.nih.gov/pubmed/11287017
1558. Iommiello, V.M., et al. Ejaculate oxidative stress is related with sperm DNA fragmentation and round
cells. Int J Endocrinol, 2015. 2015: 321901.
https://www.ncbi.nlm.nih.gov/pubmed/25802519
1559. Bisht, S., et al. Oxidative stress and male infertility. Nat Rev Urol, 2017. 14: 470.
https://www.ncbi.nlm.nih.gov/pubmed/28508879
1560. Agarwal, A., et al. Oxidation-reduction potential as a new marker for oxidative stress: Correlation to
male infertility. Investig Clin Urol, 2017. 58: 385.
https://www.ncbi.nlm.nih.gov/pubmed/29124237
1561. Marinaro, J.A. Sperm DNA fragmentation and its interaction with female factors. Fertil Steril, 2023.
120: 715.
https://www.ncbi.nlm.nih.gov/pubmed/37290553
1562. Simon, L., et al. Sperm DNA Fragmentation: Consequences for Reproduction. Adv Exp Med Biol,
2019. 1166: 87.
https://www.ncbi.nlm.nih.gov/pubmed/31301048
1563. Nicopoullos, J., et al. Novel use of COMET parameters of sperm DNA damage may increase its utility
to diagnose male infertility and predict live births following both IVF and ICSI. Hum Reprod, 2019. 34:
1915.
https://www.ncbi.nlm.nih.gov/pubmed/31585464

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 241

1564. Tan, J., et al. Association between sperm DNA fragmentation and idiopathic recurrent pregnancy
loss: a systematic review and meta-analysis. Reprod Biomed Online, 2019. 38: 951.
https://www.ncbi.nlm.nih.gov/pubmed/30979611
1565. Szabo, A., et al. Lifestyle-, environmental-, and additional health factors associated with an increased
sperm DNA fragmentation: a systematic review and meta-analysis. Reprod Biol Endocrinol, 2023. 21:
5.
https://www.ncbi.nlm.nih.gov/pubmed/36653793
1566. Dahan, M.H., et al. Three hour abstinence as a treatment for high sperm DNA fragmentation: a
prospective cohort study. J Assist Reprod Genet, 2021. 38: 227.
https://www.ncbi.nlm.nih.gov/pubmed/33179134
1567. Behdarvandian, P., et al. Sperm chromatin structure assay (SCSA((R))) and flow cytometry-assisted
TUNEL assay provide a concordant assessment of sperm DNA fragmentation as a function of age in
a large cohort of approximately 10,000 patients. Basic Clin Androl, 2023. 33: 33.
https://www.ncbi.nlm.nih.gov/pubmed/38030992
1568. Practice Committee of the American Society for Reproductive, M. The clinical utility of sperm DNA
integrity testing: a guideline. Fertil Steril, 2013. 99: 673.
https://www.ncbi.nlm.nih.gov/pubmed/23391408
1569. Cissen, M., et al. Measuring Sperm DNA Fragmentation and Clinical Outcomes of Medically Assisted
Reproduction: A Systematic Review and Meta-Analysis. PLoS One, 2016. 11: e0165125.
https://www.ncbi.nlm.nih.gov/pubmed/27832085
1570. Kim, G.Y. What should be done for men with sperm DNA fragmentation? Clin Exp Reprod Med, 2018.
45: 101.
https://www.ncbi.nlm.nih.gov/pubmed/30202739
1571. Evenson, D.P. Sperm chromatin structure assay (SCSA(R)). Methods Mol Biol, 2013. 927: 147.
https://www.ncbi.nlm.nih.gov/pubmed/22992911
1572. Evenson, D.P., et al. Sperm chromatin structure assay: its clinical use for detecting sperm DNA
fragmentation in male infertility and comparisons with other techniques. J Androl, 2002. 23: 25.
https://www.ncbi.nlm.nih.gov/pubmed/11780920
1573. Tarozzi, N., et al. Clinical relevance of sperm DNA damage in assisted reproduction. Reprod Biomed
Online, 2007. 14: 746.
https://www.ncbi.nlm.nih.gov/pubmed/17579991
1574. Esteves, S.C., et al. Reproductive outcomes of testicular versus ejaculated sperm for
intracytoplasmic sperm injection among men with high levels of DNA fragmentation in semen:
systematic review and meta-analysis. Fertil Steril, 2017. 108: 456.
https://www.ncbi.nlm.nih.gov/pubmed/28865546
1575. Esteves, S.C., et al. Intracytoplasmic sperm injection for male infertility and consequences for
offspring. Nat Rev Urol, 2018. 15: 535.
https://www.ncbi.nlm.nih.gov/pubmed/29967387
1576. Abhyankar, N., et al. Use of testicular versus ejaculated sperm for intracytoplasmic sperm injection
among men with cryptozoospermia: a meta-analysis. Fertil Steril, 2016. 105: 1469.
https://www.ncbi.nlm.nih.gov/pubmed/26930617
1577. Kendall Rauchfuss, L.M., et al. Testicular sperm extraction vs. ejaculated sperm use for
nonazoospermic male factor infertility. Fertil Steril, 2021. 116: 963.
https://www.ncbi.nlm.nih.gov/pubmed/34233843
1578. Khoo, C.C., et al. Does Testicular Sperm Improve Intracytoplasmic Sperm Injection Outcomes for
Nonazoospermic Infertile Men with Elevated Sperm DNA Fragmentation? A Systematic Review and
Meta-analysis. Eur Urol Focus, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37709593
1579. Martin-du-Pan, R.C., et al. Increased follicle stimulating hormone in infertile men. Is increased plasma
FSH always due to damaged germinal epithelium? Hum Reprod, 1995. 10: 1940.
https://www.ncbi.nlm.nih.gov/pubmed/8567817
1580. Ishikawa, T., et al. Clinical and hormonal findings in testicular maturation arrest. BJU Int, 2004. 94:
1314.
https://www.ncbi.nlm.nih.gov/pubmed/15610112
1581. Ramasamy, R., et al. High serum FSH levels in men with nonobstructive azoospermia does not affect
success of microdissection testicular sperm extraction. Fertil Steril, 2009. 92: 590.
https://www.ncbi.nlm.nih.gov/pubmed/18973887
1582. Zeadna, A., et al. Prediction of sperm extraction in non-obstructive azoospermia patients: a machine-
learning perspective. Hum Reprod, 2020. 35: 1505.
https://www.ncbi.nlm.nih.gov/pubmed/32538428

242 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1583. Pozzi, E., et al. Anti-Mullerian hormone predicts positive sperm retrieval in men with idiopathic non-
obstructive azoospermia-findings from a multi-centric cross-sectional study. Hum Reprod, 2023. 38:
1464.
https://www.ncbi.nlm.nih.gov/pubmed/37322566
1584. Benderradji, H., et al. Contribution of serum anti-Mullerian hormone in the management of
azoospermia and the prediction of testicular sperm retrieval outcomes: a study of 155 adult men.
Basic Clin Androl, 2021. 31: 15.
https://www.ncbi.nlm.nih.gov/pubmed/34134632
1585. Carrell, D.T. The clinical implementation of sperm chromosome aneuploidy testing: pitfalls and
promises. J Androl, 2008. 29: 124.
https://www.ncbi.nlm.nih.gov/pubmed/17881765
1586. Aran, B., et al. Screening for abnormalities of chromosomes X, Y, and 18 and for diploidy in
spermatozoa from infertile men participating in an in vitro fertilization-intracytoplasmic sperm
injection program. Fertil Steril, 1999. 72: 696.
https://www.ncbi.nlm.nih.gov/pubmed/10521113
1587. Kohn, T.P., et al. Genetic counseling for men with recurrent pregnancy loss or recurrent implantation
failure due to abnormal sperm chromosomal aneuploidy. J Assist Reprod Genet, 2016. 33: 571.
https://www.ncbi.nlm.nih.gov/pubmed/27020275
1588. Cheng, X., et al. Preimplantation Genetic Testing for Aneuploidy With Comprehensive Chromosome
Screening in Patients Undergoing In Vitro Fertilization: A Systematic Review and Meta-analysis.
Obstet Gynecol, 2022. 140: 769.
https://www.ncbi.nlm.nih.gov/pubmed/36201787
1589. Zheng, W., et al. Obstetric and neonatal outcomes of pregnancies resulting from preimplantation
genetic testing: a systematic review and meta-analysis. Hum Reprod Update, 2021. 27: 989.
https://www.ncbi.nlm.nih.gov/pubmed/34473268
1590. Dviri, M., et al. Is there an association between paternal age and aneuploidy? Evidence from young
donor oocyte-derived embryos: a systematic review and individual patient data meta-analysis. Hum
Reprod Update, 2021. 27: 486.
https://www.ncbi.nlm.nih.gov/pubmed/33355342
1591. Cornelisse, S., et al. Preimplantation genetic testing for aneuploidies (abnormal number of
chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev, 2020. 9: CD005291.
https://www.ncbi.nlm.nih.gov/pubmed/32898291
1592. Johnson, M.D. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility:
recommendations for genetic counseling and screening. Fertil Steril, 1998. 70: 397.
https://www.ncbi.nlm.nih.gov/pubmed/9757865
1593. Clementini, E., et al. Prevalence of chromosomal abnormalities in 2078 infertile couples referred for
assisted reproductive techniques. Hum Reprod, 2005. 20: 437.
https://www.ncbi.nlm.nih.gov/pubmed/15567875
1594. Vincent, M.C., et al. Cytogenetic investigations of infertile men with low sperm counts: a 25-year
experience. J Androl, 2002. 23: 18.
https://www.ncbi.nlm.nih.gov/pubmed/11780918
1595. Deebel, N.A., et al. Age-related presence of spermatogonia in patients with Klinefelter syndrome: a
systematic review and meta-analysis. Hum Reprod Update, 2020. 26: 58.
https://www.ncbi.nlm.nih.gov/pubmed/31822886
1596. Vockel, M., et al. The X chromosome and male infertility. Hum Genet, 2021. 140: 203.
https://www.ncbi.nlm.nih.gov/pubmed/31875237
1597. Dul, E.C., et al. The prevalence of chromosomal abnormalities in subgroups of infertile men. Hum
Reprod, 2012. 27: 36.
https://www.ncbi.nlm.nih.gov/pubmed/22081244
1598. Davila Garza, S.A., et al. Reproductive outcomes in patients with male infertility because of
Klinefelter's syndrome, Kartagener's syndrome, round-head sperm, dysplasia fibrous sheath, and
'stump' tail sperm: an updated literature review. Curr Opin Obstet Gynecol, 2013. 25: 229.
https://www.ncbi.nlm.nih.gov/pubmed/23587797
1599. Pozzi, E., et al. Rates of hypogonadism forms in Klinefelter patients undergoing testicular sperm
extraction: A multicenter cross-sectional study. Andrology, 2020. 8: 1705.
https://www.ncbi.nlm.nih.gov/pubmed/32558292
1600. Wang, C., et al. Hormonal studies in Klinefelter's syndrome. Clin Endocrinol (Oxf), 1975. 4: 399.
https://www.ncbi.nlm.nih.gov/pubmed/1157343

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 243

1601. Calogero, A.E., et al. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J
Endocrinol Invest, 2017. 40: 705.
https://www.ncbi.nlm.nih.gov/pubmed/28258556
1602. Aksglaede, L., et al. Testicular function and fertility in men with Klinefelter syndrome: a review. Eur J
Endocrinol, 2013. 168: R67.
https://www.ncbi.nlm.nih.gov/pubmed/23504510
1603. Corona, G., et al. Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and
meta-analysis. Hum Reprod Update, 2017. 23: 265.
https://www.ncbi.nlm.nih.gov/pubmed/28379559
1604. Okada, H., et al. Age as a limiting factor for successful sperm retrieval in patients with nonmosaic
Klinefelter's syndrome. Fertil Steril, 2005. 84: 1662.
https://www.ncbi.nlm.nih.gov/pubmed/16359961
1605. Groth, K.A., et al. Clinical review: Klinefelter syndrome--a clinical update. J Clin Endocrinol Metab,
2013. 98: 20.
https://www.ncbi.nlm.nih.gov/pubmed/23118429
1606. Gravholt, C.H., et al. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology.
Endocr Rev, 2018. 39: 389.
https://www.ncbi.nlm.nih.gov/pubmed/29438472
1607. Glueck, C.J., et al. Thrombophilia in Klinefelter Syndrome With Deep Venous Thrombosis, Pulmonary
Embolism, and Mesenteric Artery Thrombosis on Testosterone Therapy: A Pilot Study. Clin Appl
Thromb Hemost, 2017. 23: 973.
https://www.ncbi.nlm.nih.gov/pubmed/27582022
1608. Gies, I., et al. Spermatogonial stem cell preservation in boys with Klinefelter syndrome: to bank or not
to bank, that's the question. Fertil Steril, 2012. 98: 284.
https://www.ncbi.nlm.nih.gov/pubmed/22608314
1609. Franik, S., et al. Klinefelter syndrome and fertility: sperm preservation should not be offered to
children with Klinefelter syndrome. Hum Reprod, 2016. 31: 1952.
https://www.ncbi.nlm.nih.gov/pubmed/27412247
1610. Nguyen, M.H., et al. Balanced complex chromosome rearrangement in male infertility: case report
and literature review. Andrologia, 2015. 47: 178.
https://www.ncbi.nlm.nih.gov/pubmed/24612408
1611. Siffroi, J.P., et al. Assisted reproductive technology and complex chromosomal rearrangements: the
limits of ICSI. Mol Hum Reprod, 1997. 3: 847.
https://www.ncbi.nlm.nih.gov/pubmed/9395262
1612. De Boeck, K. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatr, 2020. 109:
893.
https://www.ncbi.nlm.nih.gov/pubmed/31899933
1613. McBride, J.A., et al. Sperm retrieval and intracytoplasmic sperm injection outcomes in men with
cystic fibrosis disease versus congenital bilateral absence of the vas deferens. Asian J Androl, 2021.
23: 140.
https://www.ncbi.nlm.nih.gov/pubmed/32930103
1614. Donat, R., et al. The incidence of cystic fibrosis gene mutations in patients with congenital bilateral
absence of the vas deferens in Scotland. Br J Urol, 1997. 79: 74.
https://www.ncbi.nlm.nih.gov/pubmed/9043501
1615. Practice Committee of the American Society for Reproductive, M. Diagnostic evaluation of the
infertile male: a committee opinion. Fertil Steril, 2015. 103: e18.
https://www.ncbi.nlm.nih.gov/pubmed/25597249
1616. Oates, R. Evaluation of the azoospermic male. Asian J Androl, 2012. 14: 82.
https://www.ncbi.nlm.nih.gov/pubmed/22179510
1617. Daudin, M., et al. Congenital bilateral absence of the vas deferens: clinical characteristics, biological
parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications
for genetic counseling. Fertil Steril, 2000. 74: 1164.
https://www.ncbi.nlm.nih.gov/pubmed/11119745
1618. Chillon, M., et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas
deferens. N Engl J Med, 1995. 332: 1475.
https://www.ncbi.nlm.nih.gov/pubmed/7739684
1619. De Braekeleer, M., et al. Mutations in the cystic fibrosis gene in men with congenital bilateral absence
of the vas deferens. Mol Hum Reprod, 1996. 2: 669.
https://www.ncbi.nlm.nih.gov/pubmed/9239681

244 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1620. Nathanson, K.L., et al. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum
Genet, 2005. 77: 1034.
https://www.ncbi.nlm.nih.gov/pubmed/16380914
1621. Krausz, C., et al. Genetic risk factors in male infertility. Arch Androl, 2007. 53: 125.
https://www.ncbi.nlm.nih.gov/pubmed/17612870
1622. Augarten, A., et al. Congenital bilateral absence of vas deferens in the absence of cystic fibrosis.
Lancet, 1994. 344: 1473.
https://www.ncbi.nlm.nih.gov/pubmed/7968122
1623. Schlegel, P.N., et al. Urogenital anomalies in men with congenital absence of the vas deferens. J Urol,
1996. 155: 1644.
https://www.ncbi.nlm.nih.gov/pubmed/8627844
1624. Drake, M.J., et al. Absent vas deferens and ipsilateral multicystic dysplastic kidney in a child. Br J
Urol, 1996. 77: 756.
https://www.ncbi.nlm.nih.gov/pubmed/8689131
1625. Vogt, P.H., et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions
in Yq11. Hum Mol Genet, 1996. 5: 933.
https://www.ncbi.nlm.nih.gov/pubmed/8817327
1626. Krausz, C., et al. Spermatogenic failure and the Y chromosome. Hum Genet, 2017. 136: 637.
https://www.ncbi.nlm.nih.gov/pubmed/28456834
1627. Skaletsky, H., et al. The male-specific region of the human Y chromosome is a mosaic of discrete
sequence classes. Nature, 2003. 423: 825.
https://www.ncbi.nlm.nih.gov/pubmed/12815422
1628. Krausz, C., et al. The Y chromosome and male fertility and infertility. Int J Androl, 2003. 26: 70.
https://www.ncbi.nlm.nih.gov/pubmed/12641824
1629. Hinch, A.G., et al. Recombination in the human Pseudoautosomal region PAR1. PLoS Genet, 2014. 10:
e1004503.
https://www.ncbi.nlm.nih.gov/pubmed/25033397
1630. Colaco, S., et al. Genetics of the human Y chromosome and its association with male infertility.
Reprod Biol Endocrinol, 2018. 16: 14.
https://www.ncbi.nlm.nih.gov/pubmed/29454353
1631. Kohn, T.P., et al. The Prevalence of Y-chromosome Microdeletions in Oligozoospermic Men: A
Systematic Review and Meta-analysis of European and North American Studies. Eur Urol, 2019. 76:
626.
https://www.ncbi.nlm.nih.gov/pubmed/31400948
1632. Ferlin, A., et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile
men: a 10-year experience in Italy. J Clin Endocrinol Metab, 2007. 92: 762.
https://www.ncbi.nlm.nih.gov/pubmed/17213277
1633. Hopps, C.V., et al. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb
and AZFc regions. Hum Reprod, 2003. 18: 1660.
https://www.ncbi.nlm.nih.gov/pubmed/12871878
1634. Park, S.H., et al. Success rate of microsurgical multiple testicular sperm extraction and sperm
presence in the ejaculate in korean men with y chromosome microdeletions. Korean J Urol, 2013. 54:
536.
https://www.ncbi.nlm.nih.gov/pubmed/23956830
1635. Abur, U., et al. Chromosomal and Y-chromosome microdeletion analysis in 1,300 infertile males and
the fertility outcome of patients with AZFc microdeletions. Andrologia, 2019. 51: e13402.
https://www.ncbi.nlm.nih.gov/pubmed/31650616
1636. Krausz, C., et al. Y chromosome and male infertility: update, 2006. Front Biosci, 2006. 11: 3049.
https://www.ncbi.nlm.nih.gov/pubmed/16720375
1637. Li, X., et al. Effect of Y Chromosome Microdeletions on the Pregnancy Outcome of Assisted
Reproduction Technology: a Meta-analysis. Reprod Sci, 2021. 28: 2413.
https://www.ncbi.nlm.nih.gov/pubmed/33409872
1638. Krausz, C., et al. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal
microdeletions: state-of-the-art 2013. Andrology, 2014. 2: 5.
https://www.ncbi.nlm.nih.gov/pubmed/24357628
1639. Alhathal, N., et al. A genomics approach to male infertility. Genet Med, 2020. 22: 1967.
https://www.ncbi.nlm.nih.gov/pubmed/32719396
1640. Sieper, M.H., et al. Scrutinizing the human TEX genes in the context of human male infertility.
Andrology, 2024. 12: 570.
https://www.ncbi.nlm.nih.gov/pubmed/37594251

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 245

1641. Cannarella, R., et al. Next-generation sequencing: toward an increase in the diagnostic yield in
patients with apparently idiopathic spermatogenic failure. Asian J Androl, 2021. 23: 24.
https://www.ncbi.nlm.nih.gov/pubmed/32655042
1642. Ignatieva, E.V., et al. A Catalog of Human Genes Associated With Pathozoospermia and Functional
Characteristics of These Genes. Front Genet, 2021. 12: 662770.
https://www.ncbi.nlm.nih.gov/pubmed/34290736
1643. Xavier, M.J., et al. Disease gene discovery in male infertility: past, present and future. Hum Genet,
2021. 140: 7.
https://www.ncbi.nlm.nih.gov/pubmed/32638125
1644. Aliakbari, F., et al. Association of the MTHFR 677C>T and 1298A>C polymorphisms and male
infertility risk: a meta-analysis. Reprod Biol Endocrinol, 2020. 18: 93.
https://www.ncbi.nlm.nih.gov/pubmed/32912251
1645. Garcia Rodriguez, A., et al. Association of polymorphisms in genes coding for antioxidant enzymes
and human male infertility. Ann Hum Genet, 2019. 83: 63.
https://www.ncbi.nlm.nih.gov/pubmed/30191955
1646. Lv, M.Q., et al. Association between X-ray repair cross-complementing group 1 Arg399Gln
polymorphism and male infertility: An update meta-analysis. Andrologia, 2020. 52: e13700.
https://www.ncbi.nlm.nih.gov/pubmed/32535968
1647. Lenz, S., et al. Ultrasonic testicular texture and size in 444 men from the general population:
correlation to semen quality. Eur Urol, 1993. 24: 231.
https://www.ncbi.nlm.nih.gov/pubmed/8104150
1648. Lenz, S., et al. Ultrasonic texture and volume of testicles in infertile men. Hum Reprod, 1994. 9: 878.
https://www.ncbi.nlm.nih.gov/pubmed/7929736
1649. Bieniek, J.M., et al. Prevalence and Management of Incidental Small Testicular Masses Discovered
on Ultrasonographic Evaluation of Male Infertility. J Urol, 2018. 199: 481.
https://www.ncbi.nlm.nih.gov/pubmed/28789946
1650. Tournaye, H., et al. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes
Endocrinol, 2017. 5: 544.
https://www.ncbi.nlm.nih.gov/pubmed/27395771
1651. Behboudi-Gandevani, S., et al. A Systematic Review and Meta-Analysis of Male Infertility and the
Subsequent Risk of Cancer. Front Oncol, 2021. 11: 696702.
https://www.ncbi.nlm.nih.gov/pubmed/34722244
1652. Hanson, H.A., et al. Subfertility increases risk of testicular cancer: evidence from population-based
semen samples. Fertil Steril, 2016. 105: 322.
https://www.ncbi.nlm.nih.gov/pubmed/26604070
1653. Barbonetti, A., et al. Testicular Cancer in Infertile Men With and Without Testicular Microlithiasis: A
Systematic Review and Meta-Analysis of Case-Control Studies. Front Endocrinol (Lausanne), 2019.
10: 164.
https://www.ncbi.nlm.nih.gov/pubmed/30949131
1654. Ager, M., et al. Radiological features characterising indeterminate testes masses: a systematic
review and meta-analysis. BJU Int, 2023. 131: 288.
https://www.ncbi.nlm.nih.gov/pubmed/35980855
1655. Eifler, J.B., Jr., et al. Incidental testicular lesions found during infertility evaluation are usually benign
and may be managed conservatively. J Urol, 2008. 180: 261.
https://www.ncbi.nlm.nih.gov/pubmed/18499177
1656. Kirkham, A.P., et al. Targeted testicular excision biopsy: when and how should we try to avoid radical
orchidectomy? Clin Radiol, 2009. 64: 1158.
https://www.ncbi.nlm.nih.gov/pubmed/19913124
1657. Dell'Atti, L., et al. Are ultrasonographic measurements a reliable parameter to choose non-palpable
testicular masses amenable to treatment with sparing surgery? J BUON, 2018. 23: 439.
https://www.ncbi.nlm.nih.gov/pubmed/29745090
1658. Esen, B., et al. Should we rely on Doppler ultrasound for evaluation of testicular solid lesions? World J
Urol, 2018. 36: 1263.
https://www.ncbi.nlm.nih.gov/pubmed/29572727
1659. Shtricker, A., et al. The value of testicular ultrasound in the prediction of the type and size of testicular
tumors. Int Braz J Urol, 2015. 41: 655.
https://www.ncbi.nlm.nih.gov/pubmed/26401856
1660. Sriprasad S, et al. High frequency colour doppler ultrasound of focal testicular lesion: Crossing
vessels (criss-cross) pattern identifies primary malignant tumour. Eur Urol Suppl, 2003. 2: 155.

246 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1661. Elert, A., et al. Accuracy of frozen section examination of testicular tumors of uncertain origin. Eur
Urol, 2002. 41: 290.
https://www.ncbi.nlm.nih.gov/pubmed/12180230
1662. Gokhale, S., et al. Epididymal Appearance in Congenital Absence of Vas Deferens. J Ultrasound Med,
2021. 40: 1085.
https://www.ncbi.nlm.nih.gov/pubmed/32955739
1663. Du, J., et al. Differential diagnosis of azoospermia and etiologic classification of obstructive
azoospermia: role of scrotal and transrectal US. Radiology, 2010. 256: 493.
https://www.ncbi.nlm.nih.gov/pubmed/20515977
1664. McQuaid, J.W., et al. Ejaculatory duct obstruction: current diagnosis and treatment. Curr Urol Rep,
2013. 14: 291.
https://www.ncbi.nlm.nih.gov/pubmed/23733548
1665. Berkowitz, G.S., et al. Prevalence and natural history of cryptorchidism. Pediatrics, 1993. 92: 44.
https://www.ncbi.nlm.nih.gov/pubmed/8100060
1666. van Brakel, J., et al. Scrotal ultrasound findings in previously congenital and acquired unilateral
undescended testes and their contralateral normally descended testis. Andrology, 2015. 3: 888.
https://www.ncbi.nlm.nih.gov/pubmed/26216342
1667. van Brakel, J., et al. Fertility potential in a cohort of 65 men with previously acquired undescended
testes. J Pediatr Surg, 2014. 49: 599.
https://www.ncbi.nlm.nih.gov/pubmed/24726121
1668. Varela-Cives, R., et al. A cross-sectional study of cryptorchidism in children: testicular volume and
hormonal function at 18 years of age. Int Braz J Urol, 2015. 41: 57.
https://www.ncbi.nlm.nih.gov/pubmed/25928530
1669. Skakkebaek, N.E., et al. Testicular dysgenesis syndrome: an increasingly common developmental
disorder with environmental aspects. Hum Reprod, 2001. 16: 972.
https://www.ncbi.nlm.nih.gov/pubmed/11331648
1670. Zhang, L., et al. Maternal gestational smoking, diabetes, alcohol drinking, pre-pregnancy obesity and
the risk of cryptorchidism: a systematic review and meta-analysis of observational studies. PLoS
One, 2015. 10: e0119006.
https://www.ncbi.nlm.nih.gov/pubmed/25798927
1671. Bergbrant, S., et al. Cryptorchidism in Sweden: A Nationwide Study of Prevalence, Operative
Management, and Complications. J Pediatr, 2018. 194: 197.
https://www.ncbi.nlm.nih.gov/pubmed/29331326
1672. Gracia, J., et al. Clinical and anatomopathological study of 2000 cryptorchid testes. Br J Urol, 1995.
75: 697.
https://www.ncbi.nlm.nih.gov/pubmed/7613821
1673. Hadziselimovic, F., et al. Infertility in cryptorchidism is linked to the stage of germ cell development at
orchidopexy. Horm Res, 2007. 68: 46.
https://www.ncbi.nlm.nih.gov/pubmed/17356291
1674. Bu, Q., et al. The Effectiveness of hCG and LHRH in Boys with Cryptorchidism: A Meta-Analysis of
Randomized Controlled Trials. Horm Metab Res, 2016. 48: 318.
https://www.ncbi.nlm.nih.gov/pubmed/27050251
1675. Wei, Y., et al. Efficacy and safety of human chorionic gonadotropin for treatment of cryptorchidism: A
meta-analysis of randomised controlled trials. J Paediatr Child Health, 2018. 54: 900.
https://www.ncbi.nlm.nih.gov/pubmed/29655188
1676. Cortes, D., et al. Hormonal treatment may harm the germ cells in 1 to 3-year-old boys with
cryptorchidism. J Urol, 2000. 163: 1290.
https://www.ncbi.nlm.nih.gov/pubmed/10737531
1677. Radmayr, C., et al. EAU Guidelines on Paediatric Urology. EAU Guidelines edn. presented at the 37th
EAU Annual Congress, Amsterdam 2022, 2022.
https://uroweb.org/guideline/paediatric-urology/
1678. Verkauskas, G., et al. Histopathology of Unilateral Cryptorchidism. Pediatr Dev Pathol, 2019. 22: 53.
https://www.ncbi.nlm.nih.gov/pubmed/30012073
1679. Yavetz, H., et al. Cryptorchidism: incidence and sperm quality in infertile men. Andrologia, 1992. 24:
293.
https://www.ncbi.nlm.nih.gov/pubmed/1356318
1680. Wilkerson, M.L., et al. Fertility potential: a comparison of intra-abdominal and intracanalicular testes
by age groups in children. Horm Res, 2001. 55: 18.
https://www.ncbi.nlm.nih.gov/pubmed/11423737

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 247

1681. Lee, P.A. Fertility after cryptorchidism: epidemiology and other outcome studies. Urology, 2005. 66:
427.
https://www.ncbi.nlm.nih.gov/pubmed/16098371
1682. Rohayem, J., et al. Delayed treatment of undescended testes may promote hypogonadism and
infertility. Endocrine, 2017. 55: 914.
https://www.ncbi.nlm.nih.gov/pubmed/28070708
1683. Giwercman, A., et al. Prevalence of carcinoma in situ and other histopathological abnormalities in
testes of men with a history of cryptorchidism. J Urol, 1989. 142: 998.
https://www.ncbi.nlm.nih.gov/pubmed/2571738
1684. Pettersson, A., et al. Age at surgery for undescended testis and risk of testicular cancer. N Engl J
Med, 2007. 356: 1835.
https://www.ncbi.nlm.nih.gov/pubmed/17476009
1685. Chan, E., et al. Ideal timing of orchiopexy: a systematic review. Pediatr Surg Int, 2014. 30: 87.
https://www.ncbi.nlm.nih.gov/pubmed/24232174
1686. Loebenstein, M., et al. Cryptorchidism, gonocyte development, and the risks of germ cell malignancy
and infertility: A systematic review. J Pediatr Surg, 2020. 55: 1201.
https://www.ncbi.nlm.nih.gov/pubmed/31327540
1687. Bloom, D.A. Two-step orchiopexy with pelviscopic clip ligation of the spermatic vessels. J Urol, 1991.
145: 1030.
https://www.ncbi.nlm.nih.gov/pubmed/1673160
1688. Koni, A., et al. Histopathological evaluation of orchiectomy specimens in 51 late postpubertal men
with unilateral cryptorchidism. J Urol, 2014. 192: 1183.
https://www.ncbi.nlm.nih.gov/pubmed/24840535
1689. Giwercman, A., et al. Initiation of sperm production after bilateral orchiopexy: clinical and biological
implications. J Urol, 2000. 163: 1255.
https://www.ncbi.nlm.nih.gov/pubmed/10737515
1690. Jones, P.F. Approaches to orchidopexy. Br J Urol, 1995. 75: 693.
https://www.ncbi.nlm.nih.gov/pubmed/7613820
1691. Heidenreich, A. Contralateral testicular biopsy in testis cancer: current concepts and controversies.
BJU Int, 2009. 104: 1346.
https://www.ncbi.nlm.nih.gov/pubmed/19840011
1692. Peng, X., et al. The association risk of male subfertility and testicular cancer: a systematic review.
PLoS One, 2009. 4: e5591.
https://www.ncbi.nlm.nih.gov/pubmed/19440348
1693. Skakkebaek, N.E. Carcinoma in situ of the testis: frequency and relationship to invasive germ cell
tumours in infertile men. Histopathology, 1978. 2: 157.
https://www.ncbi.nlm.nih.gov/pubmed/27442
1694. von der Maase, H., et al. Carcinoma in situ of contralateral testis in patients with testicular germ cell
cancer: study of 27 cases in 500 patients. Br Med J (Clin Res Ed), 1986. 293: 1398.
https://www.ncbi.nlm.nih.gov/pubmed/3026550
1695. Montironi, R. Intratubular germ cell neoplasia of the testis: testicular intraepithelial neoplasia. Eur
Urol, 2002. 41: 651.
https://www.ncbi.nlm.nih.gov/pubmed/12074783
1696. Jacobsen, R., et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort
study. BMJ, 2000. 321: 789.
https://www.ncbi.nlm.nih.gov/pubmed/11009515
1697. van Casteren, N.J., et al. Testicular microlithiasis and carcinoma in situ overview and proposed
clinical guideline. Int J Androl, 2009. 32: 279.
https://www.ncbi.nlm.nih.gov/pubmed/19207616
1698. Huyghe, E., et al. Increasing incidence of testicular cancer worldwide: a review. J Urol, 2003. 170: 5.
https://www.ncbi.nlm.nih.gov/pubmed/12796635
1699. Li, D.K., et al. Relationship between urine bisphenol-A level and declining male sexual function. J
Androl, 2010. 31: 500.
https://www.ncbi.nlm.nih.gov/pubmed/20467048
1700. Nassan, F.L., et al. A crossover-crossback prospective study of dibutyl-phthalate exposure from
mesalamine medications and semen quality in men with inflammatory bowel disease. Environ Int,
2016. 95: 120.
https://www.ncbi.nlm.nih.gov/pubmed/27575365

248 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1701. Giwercman, A., et al. Carcinoma in situ of the undescended testis. Semin Urol, 1988. 6: 110.
https://www.ncbi.nlm.nih.gov/pubmed/2903524
1702. Hoei-Hansen, C.E., et al. Current approaches for detection of carcinoma in situ testis. Int J Androl,
2007. 30: 398.
https://www.ncbi.nlm.nih.gov/pubmed/17705812
1703. Tan, I.B., et al. Testicular microlithiasis predicts concurrent testicular germ cell tumors and
intratubular germ cell neoplasia of unclassified type in adults: a meta-analysis and systematic review.
Cancer, 2010. 116: 4520.
https://www.ncbi.nlm.nih.gov/pubmed/20578177
1704. Oktay, K., et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline
Update. J Clin Oncol, 2018. 36: 1994.
https://www.ncbi.nlm.nih.gov/pubmed/29620997
1705. Lambertini, M., et al. Cancer and fertility preservation: international recommendations from an expert
meeting. BMC Med, 2016. 14: 1.
https://www.ncbi.nlm.nih.gov/pubmed/26728489
1706. Petersen, P.M., et al. Semen quality and reproductive hormones before orchiectomy in men with
testicular cancer. J Clin Oncol, 1999. 17: 941.
https://www.ncbi.nlm.nih.gov/pubmed/10071288
1707. Moody, J.A., et al. Fertility managment in testicular cancer: the need to establish a standardized and
evidence-based patient-centric pathway. BJU Int, 2019. 123: 160.
https://www.ncbi.nlm.nih.gov/pubmed/29920910
1708. Kenney, L.B., et al. Improving Male Reproductive Health After Childhood, Adolescent, and Young Adult
Cancer: Progress and Future Directions for Survivorship Research. J Clin Oncol, 2018. 36: 2160.
https://www.ncbi.nlm.nih.gov/pubmed/29874140
1709. Furuhashi, K., et al. Onco-testicular sperm extraction: testicular sperm extraction in azoospermic and
very severely oligozoospermic cancer patients. Andrologia, 2013. 45: 107.
https://www.ncbi.nlm.nih.gov/pubmed/22690948
1710. Tsutsumi, S., et al. Onco-testicular sperm extraction (onco-TESE) for bilateral testicular tumors: two
case reports. J Med Case Rep, 2017. 11: 139.
https://www.ncbi.nlm.nih.gov/pubmed/28511670
1711. Arnon, J., et al. Genetic and teratogenic effects of cancer treatments on gametes and embryos. Hum
Reprod Update, 2001. 7: 394.
https://www.ncbi.nlm.nih.gov/pubmed/11476352
1712. Eberhard, J., et al. Impact of therapy and androgen receptor polymorphism on sperm concentration in
men treated for testicular germ cell cancer: a longitudinal study. Hum Reprod, 2004. 19: 1418.
https://www.ncbi.nlm.nih.gov/pubmed/15105386
1713. Chatziparasidou, A., et al. Sperm aneuploidy in infertile male patients: a systematic review of the
literature. Andrologia, 2015. 47: 847.
https://www.ncbi.nlm.nih.gov/pubmed/25352353
1714. Paoli, D., et al. Fatherhood and Sperm DNA Damage in Testicular Cancer Patients. Front Endocrinol
(Lausanne), 2018. 9: 506.
https://www.ncbi.nlm.nih.gov/pubmed/30271379
1715. Kryukov, G.V., et al. Genetic Effect of Chemotherapy Exposure in Children of Testicular Cancer
Survivors. Clin Cancer Res, 2016. 22: 2183.
https://www.ncbi.nlm.nih.gov/pubmed/26631610
1716. Willemse, P.H., et al. Altered Leydig cell function in patients with testicular cancer: evidence for
bilateral testicular defect. Acta Endocrinol (Copenh), 1983. 102: 616.
https://www.ncbi.nlm.nih.gov/pubmed/6133401
1717. La Vignera, S., et al. Hypogonadism and Sexual Dysfunction in Testicular Tumor Survivors: A
Systematic Review. Front Endocrinol (Lausanne), 2019. 10: 264.
https://www.ncbi.nlm.nih.gov/pubmed/31133982
1718. Skinner, R., et al. Recommendations for gonadotoxicity surveillance in male childhood, adolescent,
and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer
Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Lancet Oncol,
2017. 18: e75.
https://www.ncbi.nlm.nih.gov/pubmed/28214419
1719. Richenberg, J., et al. Testicular microlithiasis imaging and follow-up: guidelines of the ESUR scrotal
imaging subcommittee. Eur Radiol, 2015. 25: 323.
https://www.ncbi.nlm.nih.gov/pubmed/25316054

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 249

1720. Pedersen, M.R., et al. Testicular microlithiasis and testicular cancer: review of the literature. Int Urol
Nephrol, 2016. 48: 1079.
https://www.ncbi.nlm.nih.gov/pubmed/27007613
1721. Pierik, F.H., et al. Is routine scrotal ultrasound advantageous in infertile men? J Urol, 1999. 162: 1618.
https://www.ncbi.nlm.nih.gov/pubmed/10524881
1722. Derogee, M., et al. Testicular microlithiasis, a premalignant condition: prevalence, histopathologic
findings, and relation to testicular tumor. Urology, 2001. 57: 1133.
https://www.ncbi.nlm.nih.gov/pubmed/11377326
1723. Miller, F.N., et al. Does testicular microlithiasis matter? A review. Clin Radiol, 2002. 57: 883.
https://www.ncbi.nlm.nih.gov/pubmed/12413911
1724. Giwercman, A., et al. Prevalence of carcinoma in situ and other histopathological abnormalities in
testes from 399 men who died suddenly and unexpectedly. J Urol, 1991. 145: 77.
https://www.ncbi.nlm.nih.gov/pubmed/1984105
1725. de Gouveia Brazao, C.A., et al. Bilateral testicular microlithiasis predicts the presence of the
precursor of testicular germ cell tumors in subfertile men. J Urol, 2004. 171: 158.
https://www.ncbi.nlm.nih.gov/pubmed/14665866
1726. Leblanc, L., et al. Testicular microlithiasis and testicular tumor: a review of the literature. Basic Clin
Androl, 2018. 28: 8.
https://www.ncbi.nlm.nih.gov/pubmed/30002831
1727. DeCastro, B.J., et al. A 5-year followup study of asymptomatic men with testicular microlithiasis. J
Urol, 2008. 179: 1420.
https://www.ncbi.nlm.nih.gov/pubmed/18289592
1728. Practice Committee of the American Society for Reproductive, M., et al. Report on varicocele and
infertility: a committee opinion. Fertil Steril, 2014. 102: 1556.
https://www.ncbi.nlm.nih.gov/pubmed/25458620
1729. Freeman, S., et al. Ultrasound evaluation of varicoceles: guidelines and recommendations of the
European Society of Urogenital Radiology Scrotal and Penile Imaging Working Group (ESUR-SPIWG)
for detection, classification, and grading. Eur Radiol, 2020. 30: 11.
https://www.ncbi.nlm.nih.gov/pubmed/31332561
1730. Bertolotto, M., et al. Ultrasound evaluation of varicoceles: systematic literature review and rationale
of the ESUR-SPIWG Guidelines and Recommendations. J Ultrasound, 2020. 23: 487.
https://www.ncbi.nlm.nih.gov/pubmed/32720266
1731. Sakamoto, H., et al. Testicular volume measurement: comparison of ultrasonography, orchidometry,
and water displacement. Urology, 2007. 69: 152.
https://www.ncbi.nlm.nih.gov/pubmed/17270639
1732. Baazeem, A., et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of
the role of varicocele repair. Eur Urol, 2011. 60: 796.
https://www.ncbi.nlm.nih.gov/pubmed/21733620
1733. Damsgaard, J., et al. Varicocele Is Associated with Impaired Semen Quality and Reproductive
Hormone Levels: A Study of 7035 Healthy Young Men from Six European Countries. Eur Urol, 2016.
70: 1019.
https://www.ncbi.nlm.nih.gov/pubmed/27423503
1734. Jensen, C.F.S., et al. Varicocele and male infertility. Nat Rev Urol, 2017. 14: 523.
https://www.ncbi.nlm.nih.gov/pubmed/28675168
1735. Pallotti, F., et al. Varicocele and semen quality: a retrospective case-control study of 4230 patients
from a single centre. J Endocrinol Invest, 2018. 41: 185.
https://www.ncbi.nlm.nih.gov/pubmed/28647897
1736. Elzanaty, S. Varicocele repair in non-obstructive azoospermic men: diagnostic value of testicular
biopsy - a meta-analysis. Scand J Urol, 2014. 48: 494.
https://www.ncbi.nlm.nih.gov/pubmed/25001949
1737. Esteves, S.C., et al. Outcome of varicocele repair in men with nonobstructive azoospermia:
systematic review and meta-analysis. Asian J Androl, 2016. 18: 246.
https://www.ncbi.nlm.nih.gov/pubmed/26680033
1738. Kim, H.J., et al. Clinical significance of subclinical varicocelectomy in male infertility: systematic
review and meta-analysis. Andrologia, 2016. 48: 654.
https://www.ncbi.nlm.nih.gov/pubmed/26589369
1739. Kim, K.H., et al. Impact of surgical varicocele repair on pregnancy rate in subfertile men with clinical
varicocele and impaired semen quality: a meta-analysis of randomized clinical trials. Korean J Urol,
2013. 54: 703.
https://www.ncbi.nlm.nih.gov/pubmed/24175046

250 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1740. Agarwal, A., et al. Efficacy of varicocelectomy in improving semen parameters: new meta-analytical
approach. Urology, 2007. 70: 532.
https://www.ncbi.nlm.nih.gov/pubmed/17905111
1741. Birowo, P., et al. The benefits of varicocele repair for achieving pregnancy in male infertility: A
systematic review and meta-analysis. Heliyon, 2020. 6: e05439.
https://www.ncbi.nlm.nih.gov/pubmed/33204888
1742. Cannarella, R., et al. Does Varicocele Repair Improve Conventional Semen Parameters? A Meta-
Analytic Study of Before-After Data. World J Mens Health, 2024. 42: 92.
https://www.ncbi.nlm.nih.gov/pubmed/37382284
1743. Baek, S.R., et al. Comparison of the clinical characteristics of patients with varicocele according to
the presence or absence of scrotal pain. Andrologia, 2019. 51: e13187.
https://www.ncbi.nlm.nih.gov/pubmed/30357879
1744. Asafu-Adjei, D., et al. Systematic Review of the Impact of Varicocele Grade on Response to Surgical
Management. J Urol, 2020. 203: 48.
https://www.ncbi.nlm.nih.gov/pubmed/31042452
1745. Yamamoto, M., et al. Effect of varicocelectomy on sperm parameters and pregnancy rate in patients
with subclinical varicocele: a randomized prospective controlled study. J Urol, 1996. 155: 1636.
https://www.ncbi.nlm.nih.gov/pubmed/8627841
1746. Fallara, G., et al. The Effect of Varicocele Treatment on Fertility in Adults: A Systematic Review and
Meta-analysis of Published Prospective Trials. Eur Urol Focus, 2023. 9: 154.
https://www.ncbi.nlm.nih.gov/pubmed/36151030
1747. Agarwal, A., et al. Impact of Varicocele Repair on Semen Parameters in Infertile Men: A Systematic
Review and Meta-Analysis. World J Mens Health, 2023. 41: 289.
https://www.ncbi.nlm.nih.gov/pubmed/36326166
1748. Kroese, A.C., et al. Surgery or embolization for varicoceles in subfertile men. Cochrane Database Syst
Rev, 2012. 10: CD000479.
https://www.ncbi.nlm.nih.gov/pubmed/23076888
1749. Persad, E., et al. Surgical or radiological treatment for varicoceles in subfertile men. Cochrane
Database Syst Rev, 2021. 4: CD000479.
https://www.ncbi.nlm.nih.gov/pubmed/33890288
1750. Machen, G.L., et al. Time to improvement of semen parameters after microscopic varicocelectomy:
When it occurs and its effects on fertility. Andrologia, 2020. 52: e13500.
https://www.ncbi.nlm.nih.gov/pubmed/31840291
1751. Pazir, Y., et al. Determination of the time for improvement in semen parameters after
varicocelectomy. Andrologia, 2021. 53: e13895.
https://www.ncbi.nlm.nih.gov/pubmed/33141946
1752. Cayan, S., et al. Can varicocelectomy significantly change the way couples use assisted reproductive
technologies? J Urol, 2002. 167: 1749.
https://www.ncbi.nlm.nih.gov/pubmed/11912402
1753. Peng, J., et al. Spontaneous pregnancy rates in Chinese men undergoing microsurgical subinguinal
varicocelectomy and possible preoperative factors affecting the outcomes. Fertil Steril, 2015. 103:
635.
https://www.ncbi.nlm.nih.gov/pubmed/25624191
1754. Kirby, E.W., et al. Undergoing varicocele repair before assisted reproduction improves pregnancy rate
and live birth rate in azoospermic and oligospermic men with a varicocele: a systematic review and
meta-analysis. Fertil Steril, 2016. 106: 1338.
https://www.ncbi.nlm.nih.gov/pubmed/27526630
1755. Ding, H., et al. Open non-microsurgical, laparoscopic or open microsurgical varicocelectomy for male
infertility: a meta-analysis of randomized controlled trials. BJU Int, 2012. 110: 1536.
https://www.ncbi.nlm.nih.gov/pubmed/22642226
1756. Locke, J.A., et al. Treatment of varicocele in children and adolescents: A systematic review and meta-
analysis of randomized controlled trials. J Pediatr Urol, 2017. 13: 437.
https://www.ncbi.nlm.nih.gov/pubmed/28851509
1757. Silay, M.S., et al. Treatment of Varicocele in Children and Adolescents: A Systematic Review and
Meta-analysis from the European Association of Urology/European Society for Paediatric Urology
Guidelines Panel. Eur Urol, 2019. 75: 448.
https://www.ncbi.nlm.nih.gov/pubmed/30316583
1758. Sajadi, H., et al. Varicocelectomy May Improve Results for Sperm Retrieval and Pregnancy Rate in
Non-Obstructive Azoospermic Men. Int J Fertil Steril, 2019. 12: 303.
https://www.ncbi.nlm.nih.gov/pubmed/30291690

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 251

1759. Jensen, S., et al. Varicocele treatment in non-obstructive azoospermia: a systematic review. Arab J
Urol, 2021. 19: 221.
https://www.ncbi.nlm.nih.gov/pubmed/34552773
1760. Chen, X., et al. Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with
clinical varicocele: A meta-analysis. Andrologia, 2017. 49.
https://www.ncbi.nlm.nih.gov/pubmed/28378913
1761. Soetandar, A., et al. Microsurgical varicocelectomy effects on sperm DNA fragmentation and
sperm parameters in infertile male patients: A systematic review and meta-analysis of more recent
evidence. Arch Ital Urol Androl, 2022. 94: 360.
https://www.ncbi.nlm.nih.gov/pubmed/36165486
1762. Zhang, Y., et al. Effect of varicocele on sperm DNA damage: A systematic review and meta-analysis.
Andrologia, 2022. 54: e14275.
https://www.ncbi.nlm.nih.gov/pubmed/34658054
1763. Cannarella, R., et al. Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal
Malondialdehyde Levels in Infertile Men with Clinical Varicocele: A Systematic Review and Meta-
Analysis. World J Mens Health, 2024. 42: 321.
https://www.ncbi.nlm.nih.gov/pubmed/38164034
1764. Lira Neto, F.T., et al. Effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in
infertile men with clinical varicocele: a systematic review and meta-analysis. Fertil Steril, 2021. 116:
696.
https://www.ncbi.nlm.nih.gov/pubmed/33985792
1765. Yan, S., et al. Should the current guidelines for the treatment of varicoceles in infertile men be
re-evaluated? Hum Fertil (Camb), 2021. 24: 78.
https://www.ncbi.nlm.nih.gov/pubmed/30905210
1766. Machen, G.L., et al. Extended indications for varicocelectomy. F1000Res, 2019. 8.
https://www.ncbi.nlm.nih.gov/pubmed/31543949
1767. Cayan, S., et al. Treatment of palpable varicocele in infertile men: a meta-analysis to define the best
technique. J Androl, 2009. 30: 33.
https://www.ncbi.nlm.nih.gov/pubmed/18772487
1768. Wang, H., et al. Microsurgery Versus Laparoscopic Surgery for Varicocele: A Meta-Analysis and
Systematic Review of Randomized Controlled Trials. J Invest Surg, 2020. 33: 40.
https://www.ncbi.nlm.nih.gov/pubmed/30339469
1769. Bryniarski, P., et al. The comparison of laparoscopic and microsurgical varicocoelectomy in infertile
men with varicocoele on paternity rate 12 months after surgery: a prospective randomized controlled
trial. Andrology, 2017. 5: 445.
https://www.ncbi.nlm.nih.gov/pubmed/28346969
1770. Fabiani, A., et al. Do sclero-embolization procedures have advantages over surgical ligature in
treating varicocele in children, adolescents and adults? Results from a systematic review and meta-
analysis. Andrologia, 2022. 54: e14510.
https://www.ncbi.nlm.nih.gov/pubmed/35750057
1771. McCullough, A., et al. A retrospective review of single-institution outcomes with robotic-assisted
microsurgical varicocelectomy. Asian J Androl, 2018. 20: 189.
https://www.ncbi.nlm.nih.gov/pubmed/29086759
1772. Chan, P., et al. Pros and cons of robotic microsurgery as an appropriate approach to male
reproductive surgery for vasectomy reversal and varicocele repair. Fertil Steril, 2018. 110: 816.
https://www.ncbi.nlm.nih.gov/pubmed/30316417
1773. Crestani, A., et al. Antegrade scrotal sclerotherapy of internal spermatic veins for varicocele
treatment: technique, complications, and results. Asian J Androl, 2016. 18: 292.
https://www.ncbi.nlm.nih.gov/pubmed/26763550
1774. Tauber, R., et al. Antegrade scrotal sclerotherapy for the treatment of varicocele: technique and late
results. J Urol, 1994. 151: 386.
https://www.ncbi.nlm.nih.gov/pubmed/8283530
1775. Makris, G.C., et al. Safety and effectiveness of the different types of embolic materials for the
treatment of testicular varicoceles: a systematic review. Br J Radiol, 2018. 91: 20170445.
https://www.ncbi.nlm.nih.gov/pubmed/29493263
1776. Sigmund, G., et al. Idiopathic varicoceles: feasibility of percutaneous sclerotherapy. Radiology, 1987.
164: 161.
https://www.ncbi.nlm.nih.gov/pubmed/3588899
1777. Seyferth, W., et al. Percutaneous sclerotherapy of varicocele. Radiology, 1981. 139: 335.
https://www.ncbi.nlm.nih.gov/pubmed/7220877

252 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1778. Goldstein, M., et al. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and
lymphatic sparing technique. J Urol, 1992. 148: 1808.
https://www.ncbi.nlm.nih.gov/pubmed/1433614
1779. Ivanissevich, O. Left varicocele due to reflux; experience with 4,470 operative cases in forty-two
years. J Int Coll Surg, 1960. 34: 742.
https://www.ncbi.nlm.nih.gov/pubmed/13718224
1780. Palomo, A. Radical cure of varicocele by a new technique; preliminary report. J Urol, 1949. 61: 604.
https://www.ncbi.nlm.nih.gov/pubmed/18114752
1781. Jungwirth, A., et al. Clinical outcome of microsurgical subinguinal varicocelectomy in infertile men.
Andrologia, 2001. 33: 71.
https://www.ncbi.nlm.nih.gov/pubmed/11350369
1782. Rotker, K., et al. Recurrent varicocele. Asian J Androl, 2016. 18: 229.
https://www.ncbi.nlm.nih.gov/pubmed/26806078
1783. Miersch, W.D., et al. Laparoscopic varicocelectomy: indication, technique and surgical results. Br J
Urol, 1995. 76: 636.
https://www.ncbi.nlm.nih.gov/pubmed/8535687
1784. Tan, S.M., et al. Laparoscopic varicocelectomy: technique and results. Br J Urol, 1995. 75: 523.
https://www.ncbi.nlm.nih.gov/pubmed/7788264
1785. World Health Organization, WHO Manual for the Standardized Investigation, Diagnosis and
Management of the Infertile Male. 2000, Cambridge University Press: Cambridge.
1786. Purvis, K., et al. Infection in the male reproductive tract. Impact, diagnosis and treatment in relation to
male infertility. Int J Androl, 1993. 16: 1.
https://www.ncbi.nlm.nih.gov/pubmed/8468091
1787. Weidner, W., et al. Relevance of male accessory gland infection for subsequent fertility with special
focus on prostatitis. Hum Reprod Update, 1999. 5: 421.
https://www.ncbi.nlm.nih.gov/pubmed/10582781
1788. Gimenes, F., et al. Male infertility: a public health issue caused by sexually transmitted pathogens.
Nat Rev Urol, 2014. 11: 672.
https://www.ncbi.nlm.nih.gov/pubmed/25330794
1789. Fode, M., et al. Sexually Transmitted Disease and Male Infertility: A Systematic Review. Eur Urol
Focus, 2016. 2: 383.
https://www.ncbi.nlm.nih.gov/pubmed/28723470
1790. Rusz, A., et al. Influence of urogenital infections and inflammation on semen quality and male
fertility. World J Urol, 2012. 30: 23.
https://www.ncbi.nlm.nih.gov/pubmed/21748371
1791. Liversedge, N.H., et al. Antibiotic treatment based on seminal cultures from asymptomatic male
partners in in-vitro fertilization is unnecessary and may be detrimental. Hum Reprod, 1996. 11: 1227.
https://www.ncbi.nlm.nih.gov/pubmed/8671429
1792. Taylor-Robinson, D. Evaluation and comparison of tests to diagnose Chlamydia trachomatis genital
infections. Hum Reprod, 1997. 12: 113.
https://www.ncbi.nlm.nih.gov/pubmed/9433967
1793. Khoshakhlagh, A., et al. Comparison the diagnostic value of serological and molecular methods for
screening and detecting Chlamydia trachomatis in semen of infertile men: A cross-sectional study.
Int J Reprod Biomed, 2017. 15: 763.
https://www.ncbi.nlm.nih.gov/pubmed/29492473
1794. Paez-Canro, C., et al. Antibiotics for treating urogenital Chlamydia trachomatis infection in men and
non-pregnant women. Cochrane Database Syst Rev, 2019. 1: CD010871.
https://www.ncbi.nlm.nih.gov/pubmed/30682211
1795. Liang, Y., et al. Comparison of rRNA-based and DNA-based nucleic acid amplifications for detection
of Chlamydia trachomatis, Neisseria gonorrhoeae, and Ureaplasma urealyticum in urogenital swabs.
BMC Infect Dis, 2018. 18: 651.
https://www.ncbi.nlm.nih.gov/pubmed/30541468
1796. Weidner, W., et al. Ureaplasmal infections of the male urogenital tract, in particular prostatitis, and
semen quality. Urol Int, 1985. 40: 5.
https://www.ncbi.nlm.nih.gov/pubmed/3883615
1797. Taylor-Robinson, D. Infections due to species of Mycoplasma and Ureaplasma: an update. Clin Infect
Dis, 1996. 23: 671.
https://www.ncbi.nlm.nih.gov/pubmed/8909826

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 253

1798. Huang, C., et al. Mycoplasma and ureaplasma infection and male infertility: a systematic review and
meta-analysis. Andrology, 2015. 3: 809.
https://www.ncbi.nlm.nih.gov/pubmed/26311339
1799. Moreno-Sepulveda, J., et al. Seminal human papillomavirus infection and reproduction: a systematic
review and meta-analysis. Andrology, 2021. 9: 478.
https://www.ncbi.nlm.nih.gov/pubmed/33220146
1800. Lyu, Z., et al. Human papillomavirus in semen and the risk for male infertility: a systematic review and
meta-analysis. BMC Infect Dis, 2017. 17: 714.
https://www.ncbi.nlm.nih.gov/pubmed/29121862
1801. Xiong, Y.Q., et al. The risk of human papillomavirus infection for male fertility abnormality: a meta-
analysis. Asian J Androl, 2018. 20: 493.
https://www.ncbi.nlm.nih.gov/pubmed/29623908
1802. Depuydt, C.E., et al. Infectious human papillomavirus virions in semen reduce clinical pregnancy rates
in women undergoing intrauterine insemination. Fertil Steril, 2019. 111: 1135.
https://www.ncbi.nlm.nih.gov/pubmed/31005311
1803. Aitken, R.J., et al. Seminal leukocytes: passengers, terrorists or good samaritans? Hum Reprod, 1995.
10: 1736.
https://www.ncbi.nlm.nih.gov/pubmed/8582971
1804. Trum, J.W., et al. Value of detecting leukocytospermia in the diagnosis of genital tract infection in
subfertile men. Fertil Steril, 1998. 70: 315.
https://www.ncbi.nlm.nih.gov/pubmed/9696227
1805. Krieger, J.N., et al. Seminal fluid findings in men with nonbacterial prostatitis and prostatodynia. J
Androl, 1996. 17: 310.
https://www.ncbi.nlm.nih.gov/pubmed/8792222
1806. Weidner, W., et al. Semen parameters in men with and without proven chronic prostatitis. Arch Androl,
1991. 26: 173.
https://www.ncbi.nlm.nih.gov/pubmed/1872650
1807. Castellini, C., et al. Relationship between leukocytospermia, reproductive potential after assisted
reproductive technology, and sperm parameters: a systematic review and meta-analysis of case-
control studies. Andrology, 2020. 8: 125.
https://www.ncbi.nlm.nih.gov/pubmed/31250986
1808. Jung, J.H., et al. Treatment of Leukocytospermia in Male Infertility: A Systematic Review. World J
Mens Health, 2016. 34: 165.
https://www.ncbi.nlm.nih.gov/pubmed/28053945
1809. Condorelli, R.A., et al. Chronic prostatitis and its detrimental impact on sperm parameters: a
systematic review and meta-analysis. J Endocrinol Invest, 2017. 40: 1209.
https://www.ncbi.nlm.nih.gov/pubmed/28488229
1810. Boeri, L., et al. Semen infections in men with primary infertility in the real-life setting. Fertil Steril,
2020. 113: 1174.
https://www.ncbi.nlm.nih.gov/pubmed/32299615
1811. Foresta, C., et al. HPV-DNA sperm infection and infertility: from a systematic literature review to a
possible clinical management proposal. Andrology, 2015. 3: 163.
https://www.ncbi.nlm.nih.gov/pubmed/25270519
1812. Boeri, L., et al. High-risk human papillomavirus in semen is associated with poor sperm progressive
motility and a high sperm DNA fragmentation index in infertile men. Hum Reprod, 2019. 34: 209.
https://www.ncbi.nlm.nih.gov/pubmed/30517657
1813. Wolff, H. The biologic significance of white blood cells in semen. Fertil Steril, 1995. 63: 1143.
https://www.ncbi.nlm.nih.gov/pubmed/7750580
1814. Wolff, H., et al. Impact of clinically silent inflammation on male genital tract organs as reflected by
biochemical markers in semen. J Androl, 1991. 12: 331.
https://www.ncbi.nlm.nih.gov/pubmed/1765569
1815. Dousset, B., et al. Seminal cytokine concentrations (IL-1beta, IL-2, IL-6, sR IL-2, sR IL-6), semen
parameters and blood hormonal status in male infertility. Hum Reprod, 1997. 12: 1476.
https://www.ncbi.nlm.nih.gov/pubmed/9262280
1816. Huleihel, M., et al. Distinct expression levels of cytokines and soluble cytokine receptors in seminal
plasma of fertile and infertile men. Fertil Steril, 1996. 66: 135.
https://www.ncbi.nlm.nih.gov/pubmed/8752625
1817. Shimonovitz, S., et al. High concentration of soluble interleukin-2 receptors in ejaculate with low
sperm motility. Hum Reprod, 1994. 9: 653.

254 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

 https://www.ncbi.nlm.nih.gov/pubmed/8046017
1818. Zalata, A., et al. Evaluation of beta-endorphin and interleukin-6 in seminal plasma of patients with
certain andrological diseases. Hum Reprod, 1995. 10: 3161.
https://www.ncbi.nlm.nih.gov/pubmed/8822435
1819. Alexander, R.B., et al. Elevated levels of proinflammatory cytokines in the semen of patients with
chronic prostatitis/chronic pelvic pain syndrome. Urology, 1998. 52: 744.
https://www.ncbi.nlm.nih.gov/pubmed/9801092
1820. La Vignera, S., et al. Markers of semen inflammation: supplementary semen analysis? J Reprod
Immunol, 2013. 100: 2.
https://www.ncbi.nlm.nih.gov/pubmed/23850173
1821. Ahmadi, M.H., et al. Association of asymptomatic Chlamydia trachomatis infection with male
infertility and the effect of antibiotic therapy in improvement of semen quality in infected infertile
men. Andrologia, 2018.
https://www.ncbi.nlm.nih.gov/pubmed/29292525
1822. Depuydt, C.E., et al. The relation between reactive oxygen species and cytokines in andrological
patients with or without male accessory gland infection. J Androl, 1996. 17: 699.
https://www.ncbi.nlm.nih.gov/pubmed/9016401
1823. Weidner, W., et al. Therapy in male accessory gland infection--what is fact, what is fiction?
Andrologia, 1998. 30 Suppl 1: 87.
https://www.ncbi.nlm.nih.gov/pubmed/9629448
1824. Comhaire, F.H., et al. The effect of doxycycline in infertile couples with male accessory gland
infection: a double blind prospective study. Int J Androl, 1986. 9: 91.
https://www.ncbi.nlm.nih.gov/pubmed/3539821
1825. Berger, R. et al., Epididymitis. In: Sexually Transmitted Diseases 1984, McGraw-Hill: New York.
1826. Berger, R.E., et al. Etiology, manifestations and therapy of acute epididymitis: prospective study of 50
cases. J Urol, 1979. 121: 750.
https://www.ncbi.nlm.nih.gov/pubmed/379366
1827. Weidner, W., et al. Acute nongonococcal epididymitis. Aetiological and therapeutic aspects. Drugs,
1987. 34 Suppl 1: 111.
https://www.ncbi.nlm.nih.gov/pubmed/3481311
1828. National guideline for the management of epididymo-orchitis. Clinical Effectiveness Group
(Association of Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases).
Sex Transm Infect, 1999. 75 Suppl 1: S51.
https://www.ncbi.nlm.nih.gov/pubmed/10616385
1829. Weidner, W., et al., Orchitis. In: Encyclopedia of Reproduction, 1999, Academic Press: San Diego.
1830. Robinson, A.J., et al. Acute epididymitis: why patient and consort must be investigated. Br J Urol,
1990. 66: 642.
https://www.ncbi.nlm.nih.gov/pubmed/2265337
1831. Rastrelli, G., et al. Metabolically healthy and unhealthy obesity in erectile dysfunction and male
infertility. Expert Rev Endocrinol Metab, 2019. 14: 321.
https://www.ncbi.nlm.nih.gov/pubmed/31464531
1832. Hakonsen, L.B., et al. Does weight loss improve semen quality and reproductive hormones? Results
from a cohort of severely obese men. Reprod Health, 2011. 8: 24.
https://www.ncbi.nlm.nih.gov/pubmed/21849026
1833. Lee, Y., et al. Impact of Bariatric Surgery on Male Sex Hormones and Sperm Quality: a Systematic
Review and Meta-Analysis. Obes Surg, 2019. 29: 334.
https://www.ncbi.nlm.nih.gov/pubmed/30382463
1834. Ibanez-Perez, J., et al. An update on the implication of physical activity on semen quality: a
systematic review and meta-analysis. Arch Gynecol Obstet, 2019. 299: 901.
https://www.ncbi.nlm.nih.gov/pubmed/30671700
1835. Sharma, R., et al. Cigarette Smoking and Semen Quality: A New Meta-analysis Examining the Effect
of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen.
Eur Urol, 2016. 70: 635.
https://www.ncbi.nlm.nih.gov/pubmed/27113031
1836. Ricci, E., et al. Semen quality and alcohol intake: a systematic review and meta-analysis. Reprod
Biomed Online, 2017. 34: 38.
https://www.ncbi.nlm.nih.gov/pubmed/28029592
1837. Alcoholism, N.I.o.A.A.a., The Physicians’ guide to helping patients with alcohol problems. 1995.
http://kobiljak.msu.edu/CAI/OST517/PhysicianGuide.html

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 255

1838. Sidorkiewicz, I., et al. Endocrine-disrupting chemicals-Mechanisms of action on male reproductive
system. Toxicol Ind Health, 2017. 33: 601.
https://www.ncbi.nlm.nih.gov/pubmed/28464759
1839. Agarwal, A., et al. Correlation of reactive oxygen species levels with the fertilization rate after in vitro
fertilization: a qualified meta-analysis. Fertil Steril, 2005. 84: 228.
https://www.ncbi.nlm.nih.gov/pubmed/16009190
1840. Showell, M.G., et al. Antioxidants for male subfertility. Cochrane Database Syst Rev, 2014: CD007411.
https://www.ncbi.nlm.nih.gov/pubmed/25504418
1841. Smits, R.M., et al. Antioxidants for male subfertility. Cochrane Database Syst Rev, 2019. 3: CD007411.
https://www.ncbi.nlm.nih.gov/pubmed/30866036
1842. Steiner, A.Z., et al. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and
Infertility (MOXI) randomized clinical trial. Fertil Steril, 2020. 113: 552.
https://www.ncbi.nlm.nih.gov/pubmed/32111479
1843. Abbasi, B., et al. Synbiotic (FamiLact) administration in idiopathic male infertility enhances sperm
quality, DNA integrity, and chromatin status: A triple-blinded randomized clinical trial. Int J Reprod
Biomed, 2021. 19: 235.
https://www.ncbi.nlm.nih.gov/pubmed/33842820
1844. Asadi, M., et al. Effects of probiotic supplementation on semen parameters after varicocelectomy: A
randomized controlled trial. J Res Med Sci, 2023. 28: 74.
https://www.ncbi.nlm.nih.gov/pubmed/38152072
1845. Cannarella, R., et al. Effects of the selective estrogen receptor modulators for the treatment of male
infertility: a systematic review and meta-analysis. Expert Opin Pharmacother, 2019. 20: 1517.
https://www.ncbi.nlm.nih.gov/pubmed/31120775
1846. Chua, M.E., et al. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric
therapy for idiopathic male infertility: a meta-analysis. Andrology, 2013. 1: 749.
https://www.ncbi.nlm.nih.gov/pubmed/23970453
1847. Kamischke, A., et al. Analysis of medical treatment of male infertility. Hum Reprod, 1999. 14 Suppl 1:
1.
https://www.ncbi.nlm.nih.gov/pubmed/10573021
1848. Cooke, P.S., et al. Estrogens in Male Physiology. Physiol Rev, 2017. 97: 995.
https://www.ncbi.nlm.nih.gov/pubmed/28539434
1849. Schulster, M., et al. The role of estradiol in male reproductive function. Asian J Androl, 2016. 18: 435.
https://www.ncbi.nlm.nih.gov/pubmed/26908066
1850. Ring, J.D., et al. Current medical management of endocrine-related male infertility. Asian J Androl,
2016. 18: 357.
https://www.ncbi.nlm.nih.gov/pubmed/27098657
1851. Xu, X., et al. The Effect of Aromatase on the Reproductive Function of Obese Males. Horm Metab
Res, 2017. 49: 572.
https://www.ncbi.nlm.nih.gov/pubmed/28679145
1852. Del Giudice, F., et al. A systematic review and meta-analysis of clinical trials implementing aromatase
inhibitors to treat male infertility. Asian J Androl, 2020. 22: 360.
https://www.ncbi.nlm.nih.gov/pubmed/31621654
1853. Liu, P.Y., et al. Induction of spermatogenesis and fertility during gonadotropin treatment of
gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab, 2009.
94: 801.
https://www.ncbi.nlm.nih.gov/pubmed/19066302
1854. Ribeiro, R.S., et al. Clomiphene fails to revert hypogonadism in most male patients with
conventionally treated nonfunctioning pituitary adenomas. Arq Bras Endocrinol Metabol, 2011. 55:
266.
https://www.ncbi.nlm.nih.gov/pubmed/21779629
1855. Simoni, M., et al. Prospects for FSH Treatment of Male Infertility. J Clin Endocrinol Metab, 2020. 105.
https://www.ncbi.nlm.nih.gov/pubmed/32374828
1856. Zhang, X., et al. FSH can improve semen parameters in patients with idiopathic
oligoasthenoteratozoospermia: A systematic review and meta-analysis. Andrologia, 2022. 54:
e14596.
https://www.ncbi.nlm.nih.gov/pubmed/36104938
1857. Colacurci, N., et al. Recombinant FSH Improves Sperm DNA Damage in Male Infertility: A Phase II
Clinical Trial. Front Endocrinol (Lausanne), 2018. 9: 383.
https://www.ncbi.nlm.nih.gov/pubmed/30042737

256 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1858. Ding, Y.M., et al. Treatment of idiopathic oligozoospermia with recombinant human follicle-
stimulating hormone: a prospective, randomized, double-blind, placebo-controlled clinical study in
Chinese population. Clin Endocrinol (Oxf), 2015. 83: 866.
https://www.ncbi.nlm.nih.gov/pubmed/25761129
1859. Shinjo, E., et al. The effect of human chorionic gonadotropin-based hormonal therapy on
intratesticular testosterone levels and spermatogonial DNA synthesis in men with non-obstructive
azoospermia. Andrology, 2013. 1: 929.
https://www.ncbi.nlm.nih.gov/pubmed/24123916
1860. Simoni, M., et al. Treatment with human, recombinant FSH improves sperm DNA fragmentation in
idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: a pharmacogenetic
study. Hum Reprod, 2016. 31: 1960.
https://www.ncbi.nlm.nih.gov/pubmed/27329968
1861. Cannarella, R., et al. FSH dosage effect on conventional sperm parameters: a meta-analysis of
randomized controlled studies. Asian J Androl, 2020. 22: 309.
https://www.ncbi.nlm.nih.gov/pubmed/31274479
1862. Attia, A.M., et al. Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev,
2013. 8: CD005071.
https://www.ncbi.nlm.nih.gov/pubmed/23970458
1863. Santi, D., et al. FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis.
Endocr Connect, 2015. 4: R46.
https://www.ncbi.nlm.nih.gov/pubmed/26113521
1864. Cocci, A., et al. Effectiveness of highly purified urofollitropin treatment in patients with idiopathic
azoospermia before testicular sperm extraction. Urologia, 2018. 85: 19.
https://www.ncbi.nlm.nih.gov/pubmed/28799634
1865. Hussein, A., et al. Optimization of spermatogenesis-regulating hormones in patients with non-
obstructive azoospermia and its impact on sperm retrieval: a multicentre study. BJU Int, 2013. 111:
E110.
https://www.ncbi.nlm.nih.gov/pubmed/22958644
1866. Gul, U., et al. The Effect of Human Chorionic Gonadotropin Treatment Before Testicular Sperm
Extraction in Non-Obstructive Azoospermia. Annals of Clinical and Analytical Medicine, 2016. 07: 55.
1867. El Osta, R., et al. Anabolic steroids abuse and male infertility. Basic Clin Androl, 2016. 26: 2.
https://www.ncbi.nlm.nih.gov/pubmed/26855782
1868. Wosnitzer, M.S., et al. Obstructive azoospermia. Urol Clin North Am, 2014. 41: 83.
https://www.ncbi.nlm.nih.gov/pubmed/24286769
1869. Practice Committee of the American Society for Reproductive Medicine in collaboration with the
Society for Male, R., et al. The management of obstructive azoospermia: a committee opinion. Fertil
Steril, 2019. 111: 873.
https://www.ncbi.nlm.nih.gov/pubmed/31029241
1870. Schoor, R.A., et al. The role of testicular biopsy in the modern management of male infertility. J Urol,
2002. 167: 197.
https://www.ncbi.nlm.nih.gov/pubmed/11743304
1871. Adamopoulos, D.A., et al. 'Value of FSH and inhibin-B measurements in the diagnosis of
azoospermia'--a clinician's overview. Int J Androl, 2010. 33: e109.
https://www.ncbi.nlm.nih.gov/pubmed/19703093
1872. Radpour, R., et al. Genetic investigations of CFTR mutations in congenital absence of vas deferens,
uterus, and vagina as a cause of infertility. J Androl, 2008. 29: 506.
https://www.ncbi.nlm.nih.gov/pubmed/18567645
1873. Kalsi, J., et al. In the era of micro-dissection sperm retrieval (m-TESE) is an isolated testicular biopsy
necessary in the management of men with non-obstructive azoospermia? BJU Int, 2012. 109: 418.
https://www.ncbi.nlm.nih.gov/pubmed/21883824
1874. Kalsi JS, et al. Salvage microdissection testicular sperm extraction; outcome in men with Non
obstructive azoospermia. BJU International, 2011.
https://pubmed.ncbi.nlm.nih.gov/25220441/
1875. Silber, S.J., et al. Pregnancy with sperm aspiration from the proximal head of the epididymis: a new
treatment for congenital absence of the vas deferens. Fertil Steril, 1988. 50: 525.
https://www.ncbi.nlm.nih.gov/pubmed/3410105
1876. Esteves, S.C., et al. Sperm retrieval techniques for assisted reproduction. Int Braz J Urol, 2011. 37:
570.
https://www.ncbi.nlm.nih.gov/pubmed/22099268

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 257

1877. Esteves, S.C., et al. Reproductive potential of men with obstructive azoospermia undergoing
percutaneous sperm retrieval and intracytoplasmic sperm injection according to the cause of
obstruction. J Urol, 2013. 189: 232.
https://www.ncbi.nlm.nih.gov/pubmed/23174251
1878. Shih, K.W., et al. Testicular versus percutaneous epididymal sperm aspiration for patients with
obstructive azoospermia: a systematic review and meta-analysis. Transl Androl Urol, 2019. 8: 631.
https://www.ncbi.nlm.nih.gov/pubmed/32038959
1879. Schroeder-Printzen, I., et al. Microsurgical epididymal sperm aspiration: aspirate analysis and straws
available after cryopreservation in patients with non-reconstructable obstructive azoospermia.
MESA/TESE Group Giessen. Hum Reprod, 2000. 15: 2531.
https://www.ncbi.nlm.nih.gov/pubmed/11098022
1880. Van Peperstraten, A., et al. Techniques for surgical retrieval of sperm prior to ICSI for azoospermia.
Cochrane Database Syst Rev, 2006: CD002807.
https://www.ncbi.nlm.nih.gov/pubmed/16855991
1881. Van Peperstraten, A., et al. Techniques for surgical retrieval of sperm prior to intra-cytoplasmic sperm
injection (ICSI) for azoospermia. Cochrane Database Syst Rev, 2008. 2008: CD002807.
https://www.ncbi.nlm.nih.gov/pubmed/18425884
1882. Yoon, Y.E., et al. The role of vasoepididymostomy for treatment of obstructive azoospermia in the era
of in vitro fertilization: a systematic review and meta-analysis. Asian J Androl, 2018. 21: 67.
https://www.ncbi.nlm.nih.gov/pubmed/30106012
1883. Peng, J., et al. Pregnancy and live birth rates after microsurgical vasoepididymostomy for
azoospermic patients with epididymal obstruction. Hum Reprod, 2017. 32: 284.
https://www.ncbi.nlm.nih.gov/pubmed/28057874
1884. Farber, N.J., et al. The Kinetics of Sperm Return and Late Failure Following Vasovasostomy or
Vasoepididymostomy: A Systematic Review. J Urol, 2019. 201: 241.
https://www.ncbi.nlm.nih.gov/pubmed/30130545
1885. Schroeder-Printzen, I., et al. Surgical therapy in infertile men with ejaculatory duct obstruction:
technique and outcome of a standardized surgical approach. Hum Reprod, 2000. 15: 1364.
https://www.ncbi.nlm.nih.gov/pubmed/10831570
1886. Kolettis, P.N., et al. Vasoepididymostomy for vasectomy reversal: a critical assessment in the era of
intracytoplasmic sperm injection. J Urol, 1997. 158: 467.
https://www.ncbi.nlm.nih.gov/pubmed/9224325
1887. Matthews, G.J., et al. Patency following microsurgical vasoepididymostomy and vasovasostomy:
temporal considerations. J Urol, 1995. 154: 2070.
https://www.ncbi.nlm.nih.gov/pubmed/7500460
1888. Wan, B., et al. Current progress on the curative effects of vasoepididymostomy for patients with
obstructive azoospermia: An updated systematic review and meta-analysis of human studies.
Andrology, 2023. 11: 103.
https://www.ncbi.nlm.nih.gov/pubmed/36116029
1889. Wang, S.Y., et al. Outcomes of microsurgical vasoepididymostomy using intussusception technique:
a systematic review and meta‑analysis. Sci Rep, 2023. 13: 3340.
https://www.ncbi.nlm.nih.gov/pubmed/36849574
1890. Etafy, M., et al. Review of the role of robotic surgery in male infertility. Arab J Urol, 2018. 16: 148.
https://www.ncbi.nlm.nih.gov/pubmed/29713546
1891. Ramasamy, R., et al. Microscopic visualization of intravasal spermatozoa is positively associated
with patency after bilateral microsurgical vasovasostomy. Andrology, 2015. 3: 532.
https://www.ncbi.nlm.nih.gov/pubmed/25914288
1892. Ostrowski, K.A., et al. Impact on Pregnancy of Gross and Microscopic Vasal Fluid during Vasectomy
Reversal. J Urol, 2015. 194: 156.
https://www.ncbi.nlm.nih.gov/pubmed/25595861
1893. Scovell, J.M., et al. Association between the presence of sperm in the vasal fluid during vasectomy
reversal and postoperative patency: a systematic review and meta-analysis. Urology, 2015. 85: 809.
https://www.ncbi.nlm.nih.gov/pubmed/25697786
1894. Ruiz-Romero, J., et al. A new device for microsurgical sperm aspiration. Andrologia, 1994. 26: 119.
https://www.ncbi.nlm.nih.gov/pubmed/8042769
1895. Avellino, G.J., et al. Transurethral resection of the ejaculatory ducts: etiology of obstruction and
surgical treatment options. Fertil Steril, 2019. 111: 427.
https://www.ncbi.nlm.nih.gov/pubmed/30827517

258 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1896. R Hayden, et al. Detection and Management of Obstructive Azoospermia. Urology Practice, 2015. 2:
33.
http://dx.doi.org/10.1016/j.urpr.2014.08.002
1897. Jiang, H.T., et al. Multiple advanced surgical techniques to treat acquired seminal duct obstruction.
Asian J Androl, 2014. 16: 912.
https://www.ncbi.nlm.nih.gov/pubmed/25337841
1898. Ozturk, H., et al. Asymptomatic Sertoli cell tumour diagnosed during azoospermia work-up. Asian J
Androl, 2013. 15: 845.
https://www.ncbi.nlm.nih.gov/pubmed/24121977
1899. Fallick, M.L., et al. Leydig cell tumors presenting as azoospermia. J Urol, 1999. 161: 1571.
https://www.ncbi.nlm.nih.gov/pubmed/10210406
1900. Dieckmann, K.P., et al. Clinical epidemiology of testicular germ cell tumors. World J Urol, 2004. 22: 2.
https://www.ncbi.nlm.nih.gov/pubmed/15034740
1901. Eisenberg, M.L., et al. Increased risk of cancer among azoospermic men. Fertil Steril, 2013. 100: 681.
https://www.ncbi.nlm.nih.gov/pubmed/23790640
1902. Salonia, A., et al. Are infertile men less healthy than fertile men? Results of a prospective case-
control survey. Eur Urol, 2009. 56: 1025.
https://www.ncbi.nlm.nih.gov/pubmed/19297076
1903. Ventimiglia, E., et al. Infertility as a proxy of general male health: results of a cross-sectional survey.
Fertil Steril, 2015. 104: 48.
https://www.ncbi.nlm.nih.gov/pubmed/26006735
1904. Guo, D., et al. Hypertension and Male Fertility. World J Mens Health, 2017. 35: 59.
https://www.ncbi.nlm.nih.gov/pubmed/28868816
1905. Del Giudice, F., et al. Increased Mortality Among Men Diagnosed With Impaired Fertility: Analysis of
US Claims Data. Urology, 2021. 147: 143.
https://www.ncbi.nlm.nih.gov/pubmed/33017614
1906. Glazer, C.H., et al. Male factor infertility and risk of death: a nationwide record-linkage study. Hum
Reprod, 2019. 34: 2266.
https://www.ncbi.nlm.nih.gov/pubmed/31725880
1907. Choy, J.T., et al. Male infertility as a window to health. Fertil Steril, 2018. 110: 810.
https://www.ncbi.nlm.nih.gov/pubmed/30316415
1908. Bobjer, J., et al. High prevalence of androgen deficiency and abnormal lipid profile in infertile men
with non-obstructive azoospermia. Int J Androl, 2012. 35: 688.
https://www.ncbi.nlm.nih.gov/pubmed/22519695
1909. Patel, D.P., et al. Sperm concentration is poorly associated with hypoandrogenism in infertile men.
Urology, 2015. 85: 1062.
https://www.ncbi.nlm.nih.gov/pubmed/25735445
1910. Ventimiglia, E., et al. Primary, secondary and compensated hypogonadism: a novel risk stratification
for infertile men. Andrology, 2017. 5: 505.
https://www.ncbi.nlm.nih.gov/pubmed/28409903
1911. Nowroozi, M.R., et al. Assessment of testicular perfusion prior to sperm extraction predicts success
rate and decreases the number of required biopsies in patients with non-obstructive azoospermia. Int
Urol Nephrol, 2015. 47: 53.
https://www.ncbi.nlm.nih.gov/pubmed/25331197
1912. Jensen, C.F.S., et al. A Refined View on the Association Between Y-chromosome Microdeletions and
Sperm Concentration. Eur Urol, 2019. 76: 637.
https://www.ncbi.nlm.nih.gov/pubmed/31447078
1913. Donoso, P., et al. Which is the best sperm retrieval technique for non-obstructive azoospermia? A
systematic review. Hum Reprod Update, 2007. 13: 539.
https://www.ncbi.nlm.nih.gov/pubmed/17895238
1914. Bernie, A.M., et al. Comparison of microdissection testicular sperm extraction, conventional
testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a
systematic review and meta-analysis. Fertil Steril, 2015. 104: 1099.
https://www.ncbi.nlm.nih.gov/pubmed/26263080
1915. Abdel Raheem, A., et al. Testicular histopathology as a predictor of a positive sperm retrieval in men
with non-obstructive azoospermia. BJU Int, 2013. 111: 492.
https://www.ncbi.nlm.nih.gov/pubmed/22583840

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 259

1916. Caroppo, E., et al. Testicular histology may predict the successful sperm retrieval in patients with
non-obstructive azoospermia undergoing conventional TESE: a diagnostic accuracy study. J Assist
Reprod Genet, 2017. 34: 149.
https://www.ncbi.nlm.nih.gov/pubmed/27655389
1917. Cetinkaya, M., et al. Evaluation of Microdissection Testicular Sperm Extraction Results in Patients
with Non-Obstructive Azoospermia: Independent Predictive Factors and Best Cutoff Values for
Sperm Retrieval. Urol J, 2015. 12: 2436.
https://www.ncbi.nlm.nih.gov/pubmed/26706742
1918. Cissen, M., et al. Prediction model for obtaining spermatozoa with testicular sperm extraction in men
with non-obstructive azoospermia. Hum Reprod, 2016. 31: 1934.
https://www.ncbi.nlm.nih.gov/pubmed/27406950
1919. Guler, I., et al. Impact of testicular histopathology as a predictor of sperm retrieval and pregnancy
outcome in patients with nonobstructive azoospermia: correlation with clinical and hormonal factors.
Andrologia, 2016. 48: 765.
https://www.ncbi.nlm.nih.gov/pubmed/26688565
1920. Yildirim, M.E., et al. The association between serum follicle-stimulating hormone levels and the
success of microdissection testicular sperm extraction in patients with azoospermia. Urol J, 2014.
11: 1825.
https://www.ncbi.nlm.nih.gov/pubmed/25194084
1921. Ramasamy, R., et al. A comparison of models for predicting sperm retrieval before microdissection
testicular sperm extraction in men with nonobstructive azoospermia. J Urol, 2013. 189: 638.
https://www.ncbi.nlm.nih.gov/pubmed/23260551
1922. Yang, Q., et al. Follicle-stimulating hormone as a predictor for sperm retrieval rate in patients with
nonobstructive azoospermia: a systematic review and meta-analysis. Asian J Androl, 2015. 17: 281.
https://www.ncbi.nlm.nih.gov/pubmed/25337843
1923. Corona, G., et al. Sperm recovery and ICSI outcomes in men with non-obstructive azoospermia: a
systematic review and meta-analysis. Hum Reprod Update, 2019. 25: 733.
https://www.ncbi.nlm.nih.gov/pubmed/31665451
1924. Kim, S.W., et al. Azoospermic Men with a History of Cryptorchidism Treated by Orchiopexy Have
Favorable Outcomes after Testicular Sperm Extraction: A Systematic Review and Meta-Analysis.
World J Mens Health, 2023. 41: 81.
https://www.ncbi.nlm.nih.gov/pubmed/35274507
1925. Bachelot, G., et al. A Machine Learning Approach for the Prediction of Testicular Sperm Extraction
in Nonobstructive Azoospermia: Algorithm Development and Validation Study. J Med Internet Res,
2023. 25: e44047.
https://www.ncbi.nlm.nih.gov/pubmed/37342078
1926. Beliveau, M.E., et al. The value of testicular 'mapping' in men with non-obstructive azoospermia.
Asian J Androl, 2011. 13: 225.
https://www.ncbi.nlm.nih.gov/pubmed/21258355
1927. Ezeh, U.I., et al. A prospective study of multiple needle biopsies versus a single open biopsy for
testicular sperm extraction in men with non-obstructive azoospermia. Hum Reprod, 1998. 13: 3075.
https://www.ncbi.nlm.nih.gov/pubmed/9853859
1928. Rosenlund, B., et al. A comparison between open and percutaneous needle biopsies in men with
azoospermia. Hum Reprod, 1998. 13: 1266.
https://www.ncbi.nlm.nih.gov/pubmed/9647558
1929. Hauser, R., et al. Comparison of efficacy of two techniques for testicular sperm retrieval in
nonobstructive azoospermia: multifocal testicular sperm extraction versus multifocal testicular
sperm aspiration. J Androl, 2006. 27: 28.
https://www.ncbi.nlm.nih.gov/pubmed/16400074
1930. Jensen, C.F., et al. Multiple needle-pass percutaneous testicular sperm aspiration as first-line
treatment in azoospermic men. Andrology, 2016. 4: 257.
https://www.ncbi.nlm.nih.gov/pubmed/26789006
1931. Schlegel, P.N. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue
excision. Hum Reprod, 1999. 14: 131.
https://www.ncbi.nlm.nih.gov/pubmed/10374109
1932. Sacca, A., et al. Conventional testicular sperm extraction (TESE) and non-obstructive azoospermia:
is there still a chance in the era of microdissection TESE? Results from a single non-academic
community hospital. Andrology, 2016. 4: 425.
https://www.ncbi.nlm.nih.gov/pubmed/26872565

260 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1933. Amer, M., et al. Prospective comparative study between microsurgical and conventional testicular
sperm extraction in non-obstructive azoospermia: follow-up by serial ultrasound examinations. Hum
Reprod, 2000. 15: 653.
https://www.ncbi.nlm.nih.gov/pubmed/10686214
1934. Deruyver, Y., et al. Outcome of microdissection TESE compared with conventional TESE in non-
obstructive azoospermia: a systematic review. Andrology, 2014. 2: 20.
https://www.ncbi.nlm.nih.gov/pubmed/24193894
1935. Billa, E., et al. Endocrine Follow-Up of Men with Non-Obstructive Azoospermia Following Testicular
Sperm Extraction. J Clin Med, 2021. 10.
https://www.ncbi.nlm.nih.gov/pubmed/34362107
1936. Ramasamy, R., et al. Structural and functional changes to the testis after conventional versus
microdissection testicular sperm extraction. Urology, 2005. 65: 1190.
https://www.ncbi.nlm.nih.gov/pubmed/15922422
1937. Kalsi, J.S., et al. Salvage micro-dissection testicular sperm extraction; outcome in men with non-
obstructive azoospermia with previous failed sperm retrievals. BJU Int, 2015. 116: 460.
https://www.ncbi.nlm.nih.gov/pubmed/25220441
1938. Achermann, A.P.P., et al. Microdissection testicular sperm extraction (micro-TESE) in men with
infertility due to nonobstructive azoospermia: summary of current literature. Int Urol Nephrol, 2021.
53: 2193.
https://www.ncbi.nlm.nih.gov/pubmed/34410586
1939. Caroppo, E., et al. Intrasurgical parameters associated with successful sperm retrieval in patients
with non-obstructive azoospermia undergoing salvage microdissection testicular sperm extraction.
Andrology, 2021. 9: 1864.
https://www.ncbi.nlm.nih.gov/pubmed/34289247
1940. Zhang, F., et al. Predictors of successful salvage microdissection testicular sperm extraction
(mTESE) after failed initial TESE in patients with non-obstructive azoospermia: A systematic review
and meta-analysis. Andrology, 2024. 12: 30.
https://www.ncbi.nlm.nih.gov/pubmed/37172416
1941. Ozman, O., et al. Efficacy of the second micro-testicular sperm extraction after failed first micro-
testicular sperm extraction in men with nonobstructive azoospermia. Fertil Steril, 2021. 115: 915.
https://www.ncbi.nlm.nih.gov/pubmed/33358250
1942. Yucel, C., et al. Predictive factors of successful salvage microdissection testicular sperm extraction
(mTESE) after failed mTESE in patients with non-obstructive azoospermia: Long-term experience at a
single institute. Arch Ital Urol Androl, 2018. 90: 136.
https://www.ncbi.nlm.nih.gov/pubmed/29974724
1943. Eliveld, J., et al. The risk of TESE-induced hypogonadism: a systematic review and meta-analysis.
Hum Reprod Update, 2018. 24: 442.
https://www.ncbi.nlm.nih.gov/pubmed/29726895
1944. Jensen, C.F.S., et al. Microdissection Testicular Sperm Extraction Versus Multiple Needle-pass
Percutaneous Testicular Sperm Aspiration in Men with Nonobstructive Azoospermia: A Randomized
Clinical Trial. Eur Urol, 2022. 82: 377.
https://www.ncbi.nlm.nih.gov/pubmed/35599183
1945. Ernandez, J., et al. Evaluating the quality of reported outcomes for microsurgical TESE in men with
non-obstructive azoospermia: A methodological analysis. Andrology, 2021. 9: 1108.
https://www.ncbi.nlm.nih.gov/pubmed/33675583
1946. Foresta, C., et al. Suppression of the high endogenous levels of plasma FSH in infertile men are
associated with improved Sertoli cell function as reflected by elevated levels of plasma inhibin B.
Hum Reprod, 2004. 19: 1431.
https://www.ncbi.nlm.nih.gov/pubmed/15117900
1947. Oka, S., et al. Effects of human chorionic gonadotropin on testicular interstitial tissues in men with
non-obstructive azoospermia. Andrology, 2017. 5: 232.
https://www.ncbi.nlm.nih.gov/pubmed/27860441
1948. Hussein, A., et al. Clomiphene administration for cases of nonobstructive azoospermia: a multicenter
study. J Androl, 2005. 26: 787.
https://www.ncbi.nlm.nih.gov/pubmed/16291975
1949. Tharakan, T., et al. The Role of Hormone Stimulation in Men With Nonobstructive Azoospermia
Undergoing Surgical Sperm Retrieval. J Clin Endocrinol Metab, 2020. 105.
https://www.ncbi.nlm.nih.gov/pubmed/32810280

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 261

1950. Tharakan, T., et al. Does hormonal therapy improve sperm retrieval rates in men with non-obstructive
azoospermia: a systematic review and meta-analysis. Hum Reprod Update, 2022. 28: 609.
https://www.ncbi.nlm.nih.gov/pubmed/35526153
1951. Shiraishi, K., et al. Salvage hormonal therapy after failed microdissection testicular sperm extraction:
A multi-institutional prospective study. Int J Urol, 2016. 23: 496.
https://www.ncbi.nlm.nih.gov/pubmed/26989893
1952. Shiraishi, K., et al. Human chorionic gonadotrophin treatment prior to microdissection testicular
sperm extraction in non-obstructive azoospermia. Hum Reprod, 2012. 27: 331.
https://www.ncbi.nlm.nih.gov/pubmed/22128297
1953. Reifsnyder, J.E., et al. Role of optimizing testosterone before microdissection testicular sperm
extraction in men with nonobstructive azoospermia. J Urol, 2012. 188: 532.
https://www.ncbi.nlm.nih.gov/pubmed/22704105
1954. Gameiro, S., et al. Long-term adjustment to unmet parenthood goals following ART: a systematic
review and meta-analysis. Hum Reprod Update, 2017. 23: 322.
https://www.ncbi.nlm.nih.gov/pubmed/28164236
1955. Patel, A., et al. Role of Mental Health Practitioner in Infertility Clinics: A Review on Past, Present and
Future Directions. J Hum Reprod Sci, 2018. 11: 219.
https://www.ncbi.nlm.nih.gov/pubmed/30568350
1956. Sylvest, R., et al. Attitudes towards family formation among men attending fertility counselling.
Reprod Biomed Soc Online, 2018. 6: 1.
https://www.ncbi.nlm.nih.gov/pubmed/30182067
1957. Hammarberg, K., et al. Men's knowledge, attitudes and behaviours relating to fertility. Hum Reprod
Update, 2017. 23: 458.
https://www.ncbi.nlm.nih.gov/pubmed/28333354
1958. Tharakan, T., et al. Male Sexual and Reproductive Health-Does the Urologist Have a Role in
Addressing Gender Inequality in Life Expectancy? Eur Urol Focus, 2020. 6: 791.
https://www.ncbi.nlm.nih.gov/pubmed/31711931
1959. WHO. The health and well-being of men in the WHO European Region: better health through a gender
approach. 2018.
http://www.euro.who.int/en/publications/abstracts/the-health-and-well-being-of-men-in-the-who-
european-region-better-health-through-a-gender-approach-2018
1960. Salonia, A., et al. SARS-CoV-2, testosterone and frailty in males (PROTEGGIMI): A multidimensional
research project. Andrology, 2021. 9: 19.
https://www.ncbi.nlm.nih.gov/pubmed/32369678
1961. Kasman, A.M., et al. Male Infertility and Future Cardiometabolic Health: Does the Association Vary by
Sociodemographic Factors? Urology, 2019. 133: 121.
https://www.ncbi.nlm.nih.gov/pubmed/31377255
1962. Hanson, B.M., et al. Male infertility: a biomarker of individual and familial cancer risk. Fertil Steril,
2018. 109: 6.
https://www.ncbi.nlm.nih.gov/pubmed/29307404
1963. Brubaker, W.D., et al. Increased risk of autoimmune disorders in infertile men: analysis of US claims
data. Andrology, 2018. 6: 94.
https://www.ncbi.nlm.nih.gov/pubmed/29179258
1964. Glazer, C.H., et al. Male factor infertility and risk of multiple sclerosis: A register-based cohort study.
Mult Scler, 2018. 24: 1835.
https://www.ncbi.nlm.nih.gov/pubmed/29027840
1965. Wang, N.N., et al. The association between varicocoeles and vascular disease: an analysis of U.S.
claims data. Andrology, 2018. 6: 99.
https://www.ncbi.nlm.nih.gov/pubmed/29195012
1966. Warchol-Biedermann, K. The Risk of Psychiatric Morbidity and Course of Distress in Males
Undergoing Infertility Evaluation Is Affected by Their Factor of Infertility. Am J Mens Health, 2019. 13:
1557988318823904.
https://www.ncbi.nlm.nih.gov/pubmed/30819064
1967. Mottet, N., et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and
Local Treatment with Curative Intent. Eur Urol, 2017. 71: 618.
https://www.ncbi.nlm.nih.gov/pubmed/27568654
1968. Cornford, P., et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing,
Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol, 2017. 71: 630.
https://www.ncbi.nlm.nih.gov/pubmed/27591931

262 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

1969. Punnen, S., et al. Long-term health-related quality of life after primary treatment for localized prostate
cancer: results from the CaPSURE registry. Eur Urol, 2015. 68: 600.
https://www.ncbi.nlm.nih.gov/pubmed/25242555
1970. Walker, L.M., et al. On the Relationship Between Erectile Function and Sexual Distress in Men with
Prostate Cancer. Arch Sex Behav, 2020. 49: 1575.
https://www.ncbi.nlm.nih.gov/pubmed/32072396
1971. Rosser, B.R.S., et al. The Sexual Functioning of Gay and Bisexual Men Following Prostate Cancer
Treatment: Results from the Restore Study. Arch Sex Behav, 2020. 49: 1589.
https://www.ncbi.nlm.nih.gov/pubmed/31016492
1972. Walsh, T.J., et al. Increased risk of high-grade prostate cancer among infertile men. Cancer, 2010.
116: 2140.
https://www.ncbi.nlm.nih.gov/pubmed/20309846
1973. Al-Jebari, Y., et al. Risk of prostate cancer for men fathering through assisted reproduction:
nationwide population based register study. BMJ, 2019. 366: l5214.
https://www.ncbi.nlm.nih.gov/pubmed/31554611
1974. Salonia, A., et al. Sperm banking is of key importance in patients with prostate cancer. Fertil Steril,
2013. 100: 367.
https://www.ncbi.nlm.nih.gov/pubmed/23651627
1975. Le Bihan-Benjamin, C., et al. Fertility preservation and cancer: How many persons are concerned? Eur
J Obstet Gynecol Reprod Biol, 2018. 225: 232.
https://www.ncbi.nlm.nih.gov/pubmed/29754073
1976. Falk, A.T., et al. Brachytherapy and fertility. Hum Fertil (Camb), 2016. 19: 85.
https://www.ncbi.nlm.nih.gov/pubmed/27308857
1977. Terrier, J.E., et al. Decrease in Intercourse Satisfaction in Men Who Recover Erections After Radical
Prostatectomy. J Sex Med, 2018. 15: 1133.
https://www.ncbi.nlm.nih.gov/pubmed/30033192
1978. McInnis, M.K., et al. Sex After Prostate Cancer in Gay and Bisexual Men: A Review of the Literature.
Sex Med Rev, 2020. 8: 466.
https://www.ncbi.nlm.nih.gov/pubmed/32169431
1979. Vlachopoulos, C.V., et al. Prediction of cardiovascular events and all-cause mortality with erectile
dysfunction: a systematic review and meta-analysis of cohort studies. Circ Cardiovasc Qual
Outcomes, 2013. 6: 99.
https://www.ncbi.nlm.nih.gov/pubmed/23300267
1980. Dong, J.Y., et al. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective
cohort studies. J Am Coll Cardiol, 2011. 58: 1378.
https://www.ncbi.nlm.nih.gov/pubmed/21920268
1981. Zhao, B., et al. Erectile Dysfunction Predicts Cardiovascular Events as an Independent Risk Factor: A
Systematic Review and Meta-Analysis. J Sex Med, 2019. 16: 1005.
https://www.ncbi.nlm.nih.gov/pubmed/31104857
1982. Guo, W., et al. Erectile dysfunction and risk of clinical cardiovascular events: a meta-analysis of seven
cohort studies. J Sex Med, 2010. 7: 2805.
https://www.ncbi.nlm.nih.gov/pubmed/20367771
1983. Yamada, T., et al. Erectile dysfunction and cardiovascular events in diabetic men: a meta-analysis of
observational studies. PLoS One, 2012. 7: e43673.
https://www.ncbi.nlm.nih.gov/pubmed/22962586
1984. Osondu, C.U., et al. The relationship of erectile dysfunction and subclinical cardiovascular disease: A
systematic review and meta-analysis. Vasc Med, 2018. 23: 9.
https://www.ncbi.nlm.nih.gov/pubmed/29243995
1985. Fan, Y., et al. Erectile dysfunction and risk of cardiovascular and all-cause mortality in the general
population: a meta-analysis of cohort studies. World J Urol, 2018. 36: 1681.
https://www.ncbi.nlm.nih.gov/pubmed/29725807
1986. Wilkins, E., et al., European Heart Network - Cardiovascular Disease Statistics 2017, Brussels.
http://www.ehnheart.org/images/CVD-statistics-report-August-2017.pdf
1987. van Bussel, E.F., et al. Predictive value of traditional risk factors for cardiovascular disease in older
people: A systematic review. Prev Med, 2020. 132: 105986.
https://www.ncbi.nlm.nih.gov/pubmed/31958478
1988. Gerdts, E., et al. Sex differences in cardiometabolic disorders. Nat Med, 2019. 25: 1657.
https://www.ncbi.nlm.nih.gov/pubmed/31700185

SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025 263

1989. World Health Organization. World Health Statistics 2019: Monitoring Health for the SDGs, sustainable
development goals. 2019.
https://www.who.int/publications/i/item/9789241565707
1990. Sandberg, K., et al. Sex differences in primary hypertension. Biol Sex Differ, 2012. 3: 7.
https://www.ncbi.nlm.nih.gov/pubmed/22417477
1991. Everett, B., et al. Gender differences in hypertension and hypertension awareness among young
adults. Biodemography Soc Biol, 2015. 61: 1.
https://www.ncbi.nlm.nih.gov/pubmed/25879259
1992. World Health Organization. Gender, Women And the Tobacco Epidemic. 2010.
https://www.who.int/publications/i/item/9789240004849
1993. Navar-Boggan, A.M., et al. Hyperlipidemia in early adulthood increases long-term risk of coronary
heart disease. Circulation, 2015. 131: 451.
https://www.ncbi.nlm.nih.gov/pubmed/25623155
1994. Stamler, J., et al. The Multiple Risk Factor Intervention Trial (MRFIT)--importance then and now.
JAMA, 2008. 300: 1343.
https://www.ncbi.nlm.nih.gov/pubmed/18799447
1995. Seidell, J.C., et al. Fat distribution and gender differences in serum lipids in men and women from
four European communities. Atherosclerosis, 1991. 87: 203.
https://www.ncbi.nlm.nih.gov/pubmed/1854366
1996. Hazzard, W.R. Atherogenesis: why women live longer than men. Geriatrics, 1985. 40: 42.
https://www.ncbi.nlm.nih.gov/pubmed/3965355
1997. Burnett, A.L., et al. Erectile Dysfunction: AUA Guideline. J Urol, 2018. 200: 633.
https://www.ncbi.nlm.nih.gov/pubmed/29746858
1998. Mulhall, J.P., et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol,
2018. 200: 423.
https://www.ncbi.nlm.nih.gov/pubmed/29601923
1999. Fode, M., et al. Late-onset Hypogonadism and Testosterone Therapy - A Summary of Guidelines from
the American Urological Association and the European Association of Urology. Eur Urol Focus, 2019.
5: 539.
https://www.ncbi.nlm.nih.gov/pubmed/30858073
2000. Ibarra, F. P., et al. Study UNICO: Perception of Urologists and Andrologists, in Spain, about the Use of
Sildenafil Oral Suspension in Patients with Erectile Dysfunction.. Arch Esp Urol. 2023. 76: 139.
https://pubmed.ncbi.nlm.nih.gov/37139619/
2001. Boeri, L., et al. A. Sildenafil oral suspension formulation for erectile dysfunction: is it love at first
sight? Int J Impot Res, 2025.
https://pubmed.ncbi.nlm.nih.gov/39856253/

14. CONFLICT OF INTEREST

All members of the EAU Sexual and Reproductive Health Guidelines Panel have provided disclosure statements
on all relationships that they have that might be perceived to be a potential source of conflict of interest. This
information is publicly accessible through the European Association of Urology website http://www.uroweb.
org/guidelines/. This document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.

264 SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE MARCH 2025

15. CITATION INFORMATION
The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the
citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location,
or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:

EAU Guidelines. Edn. presented at the EAU Annual Congress, Madrid 2025. ISBN 978-94-92671-29-5.

If a publisher and/or location is required, include:

EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/

References to individual guidelines should be structured in the following way:

Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

16. COPYRIGHT AND TERMS OF USE

The content of the EAU Guidelines and all products derived from them is made available for personal and
educational use only. No commercial usage is authorised. No part of the EAU Guidelines or any related products
may be translated or reproduced in any form without written permission from the EAU. Furthermore, the EAU
prohibits the usage or upload of its Guidelines, and any material derived from these texts (whether in full or
in part) on external websites, bots, pages, portals, servers, software, or external applications, including those
employing artificial intelligence technologies and infrastructure, such as large language models and generative
AI, deep learning and machine learning, unless written permission has been granted for such by the EAU.

The EAU accepts no responsibility for the content, quality, or performance of materials, applications and
products derived from the EAU Guidelines and does not endorse or warrant their use. In the event of any
discrepancies the original language version shall be considered authoritative.

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