Male hypogonadism: Symptoms and treatment

Peeyush Kumar, Nitish Kumar, [...], and Ajay Patidar

Additional article information

Abstract
Male hypogonadism is a condition in which the body does not produce enough of
the testosterone hormone; the hormone that plays a key role in masculine growth
and development during puberty. There is a clear need to increase the awareness of
hypogonadism throughout the medical profession, especially in primary care
physicians who are usually the first port of call for the patient. Hypogonadism can
significantly reduce the quality of life and has resulted in the loss of livelihood and
separation of couples, leading to divorce. It is also important for doctors to
recognize that testosterone is not just a sex hormone. There is an important
research being published to demonstrate that testosterone may have key actions on
metabolism, on the vasculature, and on brain function, in addition to its well-
known effects on bone and body composition. This article has been used as an
introduction for the need to develop sensitive and reliable assays for sex hormones
and for symptoms and treatment of hypogonadism.
Keywords: Male hypogonadism, pituitary, sex hormone, testosterone, testis

INTRODUCTION
Hypogonadism is a medical term for decreased functional activity of the gonads.
The gonads (ovaries or testes) produce hormones (testosterone, estradiol,
antimullerian hormone, progesterone, inhibin B, activin) and gametes (eggs or
sperm).[1] Male hypogonadism is characterized by a deficiency in testosterone – a
critical hormone for sexual, cognitive, and body function and development.
Clinically low testosterone levels can lead to the absence of secondary sex
characteristics, infertility, muscle wasting, and other abnormalities. Low
testosterone levels may be due to testicular, hypothalamic, or pituitary
abnormalities. In individuals who also present with clinical signs and symptoms,
clinical guidelines recommend treatment with testosterone replacement therapy.
CLASSIFICATION OF MALE HYPOGONADISM
There are two basic types of hypogonadism that exist:
Primary: This type of hypogonadism – also known as primary testicular failure –
originates from a problem in the testicles.
Secondary: This type of hypogonadism indicates a problem in the hypothalamus or
the pituitary gland – parts of the brain that signal the testicles to produce
testosterone. The hypothalamus produces the gonadotropin releasing hormone,
which signals the pituitary gland to make the follicle-stimulating hormone (FSH)
and luteinizing hormone. The luteinizing hormone then signals the testes to
produce testosterone. Either type of hypogonadism may be caused by an inherited
(congenital) trait or something that happens later in life (acquired), such as an
injury or an infection.

Primary Hypogonadism
Common causes of primary hypogonadism include:
Klinefelter's Syndrome: This condition results from a congenital abnormality of the
sex chromosomes, X and Y. A male normally has one X and one Y chromosome.
In Klinefelter's syndrome, two or more X chromosomes are present in addition to
one Y chromosome. The Y chromosome contains the genetic material that
determines the sex of a child and the related development. The extra X
chromosome that occurs in Klinefelter's syndrome causes abnormal development
of the testicles, which in turn results in the underproduction of testosterone.

Undescended testicles
Before birth, the testicles develop inside the abdomen and normally move down
into their permanent place in the scrotum. Sometimes, one or both of the testicles
may not descend at birth. This condition often corrects itself within the first few
years of life without treatment. If not corrected in early childhood, it may lead to
malfunction of the testicles and reduced production of testosterone.

Mumps orchitis
If a mumps infection involving the testicles in addition to the salivary glands
(mumps orchitis) occurs during adolescence or adulthood, long-term testicular
damage may occur. This may affect normal testicular function and testosterone
production.

Hemochromatosis
Too much iron in the blood can cause testicular failure or pituitary gland
dysfunction, affecting testosterone production.

Injury to the Testicles

Because of their location outside the abdomen, the testicles are prone to injury.
Damage to normally developed testicles can cause hypogonadism. Damage to one
testicle may not impair testosterone production.

Cancer treatment
Chemotherapy or radiation therapy for the treatment of cancer can interfere with
testosterone and sperm production. The effects of both treatments are often
temporary, but permanent infertility may occur. Although many men regain their
fertility within a few months after the treatment ends, preserving sperm before
starting cancer therapy is an option that many men consider. Howell et al. reported
that hypogonadism was seen in 30% of the men with cancer and 90% of these
gentlemen had germinal epithelial failure.[2]

Normal aging
Older men generally have lower testosterone levels than younger men do. As men
age, there's a slow and continuous decrease in testosterone production. The rate
that testosterone declines varies greatly among men. As many as 30% of men older
than 75 have a testosterone level that is below normal, according to the American
Association of Clinical Endocrinologists. Whether or not treatment is necessary
remains a matter of debate.[3]

Secondary Hypogonadism
In secondary hypogonadism, the testicles are normal, but function improperly due
to a problem with the pituitary or hypothalamus. A number of conditions can cause
secondary hypogonadism, including:
Kallmann syndrome
Abnormal development of the hypothalamus – the area of the brain that controls
the secretion of pituitary hormones – can cause hypogonadism. This abnormality is
also associated with the impaired development of the ability to smell (anosmia).

Pituitary disorders
An abnormality in the pituitary gland can impair the release of hormones from the
pituitary gland to the testicles, affecting normal testosterone production. A
pituitary tumor or other type of brain tumor located near the pituitary gland may
cause testosterone or other hormone deficiencies. Also, the treatment for a brain
tumor such as surgery or radiation therapy may impair pituitary function and cause
hypogonadism.

Inflammatory disease
Certain inflammatory diseases such as sarcoidosis, Histiocytosis, and tuberculosis
involve the hypothalmus and pituitary gland and can affect testosterone production,
causing hypogonadism.

HIV/AIDS
This virus can cause low levels of testosterone by affecting the hypothalamus, the
pituitary, and the testes.

Medications
The use of certain drugs, such as, opiate pain medications and some hormones, can
affect testosterone production.[4]

Obesity
Being significantly overweight at any age may be linked to hypogonadism.
Stress-induced Hypogonadism
Stress, excessive physical activity, and weight loss have all been associated with
hypogonadism. Some have attributed this to stress-induced hypercortisolism,
which would suppress hypothalamic function.[5]

ROLE OF TESTOSTERONE
Throughout the male lifespan, testosterone plays a critical role in sexual, cognitive,
and body development. During fetal development, testosterone aids in the
determination of sex. The most visible effects of rising testosterone levels begin in
the prepubertal stage. During this time, body odor develops, oiliness of the skin
and hair increase, acne develops, accelerated growth spurts occur, and pubic, early
facial, and axillary hair grows. In men, the pubertal effects include enlargement of
the sebaceous glands, penis enlargement, increased libido, increased frequency of
erections, increased muscle mass, deepening of voice, increased height, bone
maturations, loss of scalp hair, and growth of facial, chest, leg, and axillary hair.
Even as adults, the effects of testosterone are visible as libido, penile erections,
aggression, and mental and physical energy.

Pathophysiology of Testosterone and Hypogonadism

The cerebral cortex – the layer of the brain often referred to as the gray matter – is
the most highly developed portion of the human brain. This portion of the brain,
encompassing about two-thirds of the brain mass, is responsible for the
information processing in the brain. It is within this portion of the brain that
testosterone production begins. The cerebral cortex signals the hypothalamus to
stimulate production of testosterone. To do this, the hypothalamus releases the
gonadotropin-releasing hormone in a pulsatile fashion, which stimulates the
pituitary gland – the portion of the brain responsible for hormones involved in the
regulation of growth, thyroid function, blood pressure, and other essential body
functions. Once stimulated by the gonadotropin-releasing hormone, the pituitary
gland produces the follicle-stimulating hormone and the luteinizing hormone. Once
released into the bloodstream, the luteinizing hormone triggers activity in the
Leydig cells in the testes. In the Leydig cells, cholesterol is converted to
testosterone. When the testosterone levels are sufficient, the pituitary gland slows
the release of the luteinizing hormone via a negative feedback mechanism, thereby,
slowing testosterone production. With such a complex process, many potential
problems can lead to low testosterone levels. Any changes in the testicles,
hypothalamus or pituitary gland can result in hypogonadism. Such changes can be
congenital or acquired, temporary, or permanent.
Recent studies have found that testosterone production slowly decreases as a result
of aging, although the rate of decline varies. Unlike women who experience a rapid
decline in hormone levels during menopause, men experience a slow, continuous
decline over time. The Baltimore Longitudinal Study of Aging reported that
approximately 20% of men in their 60s and 50% of men in their 80s are
hypogonadal.[6] The New Mexico Aging Process Study showed a decrease in
serum testosterone of 110 ng/dL every 10 years.[7] As hormone levels decline
slowly, this type of hypogonadism is sometimes referred to as the partial androgen
deficiency of the aging male (PADAM). With the growing elderly population, the
incidence of PADAM may increase over the next few decades.
Regardless of the age or comorbid conditions, obesity is associated with
hypogonadism. The Baltimore Longitudinal Study of Aging found that testosterone
decreased by 10 ng/dL per 1-kg/m2 increase in body mass index.[6] Another study
also showed reduced testosterone levels in men with increased total abdominal
adiposity.[8] The proposed causes for the effects of obesity on testosterone level
include increased clearance or aromatization of testosterone in the adipose tissue
and increased formation of inflammatory cytokines, which hinder the secretion of
the gonadotropin-releasing hormone.[9] Similar to the projections for an aging
population, the increasing incidence of obesity may lead to an increased incidence
of secondary hypogonadism. When the risk factors of obesity and age are removed,
diabetes mellitus still remains an independent risk factor for hypogonadism.
Although diabetes mellitus–related hypogonadism was previously thought to be
associated with testicular failure, study results show one-third of diabetic men had
low testosterone levels, but also had low pituitary hormone levels.[10] Population
projections expect the number of cases of diabetes mellitus to rise from 171 million
in 2000 to 366 million in 2030.[11] This drastic increase in cases will impact the
prevalence of hypogonadism as well. Certain medications are shown to reduce
testosterone production. Among the medications known to alter the hypothalamic-
pituitary-gonadal axis are spironolactone, corticosteroids, ketoconazole, ethanol,
anticonvulsants, immunosuppressants, opiates, psychotropic medications, and
hormones.

Symptoms
Hypogonadism is characterized by serum testosterone levels < 300 ng/dL in
combination with at least one clinical sign or symptom. Signs of hypogonadism
include absence or regression of secondary sex characteristics, anemia, muscle
wasting, reduced bone mass or bone mineral density, oligospermia, and abdominal
adiposity. Symptoms of post pubescent hypogonadism include sexual dysfunction
(erectile dysfunction, reduced libido, diminished penile sensation, difficulty
attaining orgasm, and reduced ejaculate), reduced energy and stamina, depressed
mood, increased irritability, difficulty concentrating, changes in cholesterol levels,
anemia, osteoporosis, and hot flushes. In the prepubertal male, if treatment is not
initiated, signs and symptoms include sparse body hair and delayed epiphyseal
closure.

Testing
Early diagnosis and treatment can reduce risks associated with hypogonadism.
Early detection in young boys can help to prevent problems due to delayed
puberty. Early diagnosis in men helps protect against the development of
osteoporosis and other conditions. The diagnosis of hypogonadism is based on
symptoms and blood work, particularly on testosterone levels. Often the first step
toward diagnosis is the Androgen Deficiency in Aging Male (ADAM) test – a 10
item questionnaire intended to identify men who exhibit signs of low testosterone.
Testosterone levels vary throughout the day and are generally highest in the
morning, so blood levels are typically drawn early in the morning. If low
testosterone levels are confirmed, further testing is done, to identify if the cause is
testicular, hypothalamic, or pituitary. These tests may include hormone testing,
semen analysis, pituitary imaging, testicular biopsy, and genetic studies. Once the
treatment starts, the patient may continue to have testosterone levels drawn to
determine if the medication is helping to produce adequate testosterone levels.

TREATMENT OPTIONS
Testosterone replacement therapy is the primary treatment option for
hypogonadism. Ideally, the therapy should provide physiological testosterone
levels, typically in the range of 300 to 800 ng/dL. According to the guidelines from
the American Association of Clinical Endocrinologists,[12] updated in 2002, the
goals of therapy are to:

 (1)

Restore sexual function, libido, well-being, and behavior

 (2)
Produce and maintain virilization

 (3)

Optimize bone density and prevent osteoporosis

 (4)

In elderly men, possibly normalize growth hormone levels

 (5)

Potentially affect the risk of cardiovascular disease

 (6)

In cases of hypogonadotropic hypogonadism, restore fertility[13]

To achieve these goals, several testosterone delivery systems are currently
available in the market. Clinical guidelines published in 2006, by the Endocrine
Society, recommend reserving treatment for those patients with clinical symptoms,
rather than for those with just low testosterone levels.

Transdermal Patch
Transdermal testosterone patches are available in India under the brand name
Androderm. Transdermal patches deliver continuous levels of testosterone over a
24-hour period. Application site reactions account for the majority of adverse
effects associated with transdermal patches, with elderly men proving particularly
prone to skin irritation. Local reactions include pruritus, blistering under the patch,
erythema, vesicle formation, indurations, and allergic contact dermatitis.
Approximately 10% of the patients discontinue patch therapy due to skin
reactions.[14] In one study, 60% of the subjects discontinued the patch between
weeks four and eight due to skin irritation.[15] A small percentage of patients may
also experience headache, depression, and gastrointestinal (GI) bleeding. Some
patients report that the patch easily falls off and is difficult to remove from the
package without good dexterity. Transdermal patches are more expensive than
injections, but the convenience of use and maintenance of normal diurnal
testosterone levels are advantageous. Some patients report that the patch is noisy
and therefore they feel stigmatized by its presence.
Topical Gel
Currently, two topical testosterone gels – Androgel and Testim, are available in
India. Application in the morning allows for testosterone concentrations that follow
the normal circadian pattern. Topical testosterone gels also provide longer-lasting
elevations in serum testosterone, compared to transdermal patches.[16] Similar to
patches, testosterone delivered via gels does not undergo first-pass metabolism.
Adverse effects associated with therapy include headache, hot flushes, insomnia,
increased blood pressure, acne, emotional labiality, and nervousness. Although
application site reactions occur, skin irritation is approximately 10 times less
frequent with gels than with transdermal patches.[17] Advantages associated with
topical gel include maintenance of normal diurnal testosterone levels and
documented increases in bone density.[18] Potential problems associated with the
gel are the potential for transfer of the gel from person to person and the cost.

Buccal Tablets
Buccal testosterone tablets, marketed as Striant, release testosterone in a pulsatile
manner, are similar to endogenous secretion. With this route, the peak testosterone
levels are rapidly achieved and a steady state is reached by the second dose
following twice-daily dosing. Similar to gel and transdermal products, buccal
administration avoids first-pass metabolism. Food and beverage do not alter drug
absorption. Although well-tolerated, transient gum irritation and a bitter taste are
the chief adverse effects associated with this route. Gum irritation tends to resolve
within the first week. Other adverse effects include dry mouth, toothache, and
stomatitis. Some patients find the buccal tablet uncomfortable and report concern
about the tablet shifting in the mouth while talking.

Implantable Pellet
Testosterone has also been formulated into an implantable pellet, marketed as
Testopel. This surgically implanted pellet slowly releases testosterone via zero-
order kinetics over many months (up to six months), although peak testosterone
levels are achieved within 30 minutes. The chief complaints associated with this
formulation are pellet extrusion, minor bleeding, and fibrosis at the site.
 Intramuscular Injections
Intramuscular formulations are also available, sold as Depo-Testosterone
(testosterone cypionate) and Delatestryl (testosterone enanthate). The testosterone
is suspended in oil to prolong absorption. Peak levels occur within 72 hours of
administration, but intramuscular administration is associated with the most
variable pharmacokinetics of all the formulations. In the first few days after
administration, supraphysiological testosterone levels are achieved, followed by
subphysiological levels near the end of the dosing interval. Such fluctuations, are
often associated with wide variations in mood, energy, and sexual function, and
prove distressing to many patients. To reduce fluctuations, lower doses and shorter
dosing intervals (two weeks) are often used. Injection site reactions are also
common, but are rarely the reason for discontinuation of therapy. Despite the
fluctuations in testosterone levels, intramuscular injections provide a cost-effective
option and the convenience of two- to four-week dosing intervals. Disadvantages
associated with injections include visits to the doctor's office, visits for dose
administration, and lack of physiological testosterone patterns.

Oral Tablets
Although not currently available in the India, oral testosterone tablets, under the
brand name Andriol, are available in other countries. In India, Android and
Testroid – both methyl testosterone products are FDA approved oral formulations.
Although relatively inexpensive, oral products undergo extensive first-pass
metabolism and therefore require multiple daily doses. Oral products are associated
with elevated liver enzymes, GI intolerance, acne, and gynecomastia. Regardless
of the treatment option, patients should be aware of the risks associated with
testosterone therapy, including:
 Worsening of the prostatic hypertrophy
 Increased risk of prostate cancer
 Lower sperm count with large doses
 Swelling of ankles, feet, or body, with or without heart failure
 Gynecomastia
 Sleep apnea
 Blood clots
Patients should be educated on the signs and symptoms of these adverse effects
and instructed to notify their doctor if any of these occur.

CONCLUSION
Hypogonadism affects men of all ages, either through congenital or acquired
causes. For patients who have clinical symptoms associated with their low
testosterone levels, treatment is essential for the prevention of sexual, cognitive,
and bodily changes. A variety of treatment options are available, utilizing different
dosage formulations, and providing patients with choices that best meet their
needs. Therefore, there is a clear need to increase the awareness of hypogonadism
throughout the medical profession, especially in primary care physicians who are
usually the first port of call for the patient.
In summary, there is a need for doctors to have an awareness of hypogonadism as a
common clinical condition. Key triggers for the physician to consider investigating
for hypogonadism are reduced libido, fatigue, osteoporosis and fractures, and
erectile dysfunction.

Footnotes
Source of Support: Nil

Conflict of Interest: Nil.

Article information
J Adv Pharm Technol Res. 2010 Jul-Sep; 1(3): 297–301.
doi: 10.4103/0110-5558.72420
PMCID: PMC3255409
PMID: 22247861