Reviews

The pathogenesis and treatment

of polycystic ovary syndrome: What’s new?
Sylwia BednarskaA–D, Agnieszka SiejkaB–F
Department of Clinical Endocrinology, Medical University of Lodz, Łódź, Poland

A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of article

Advances in Clinical and Experimental Medicine, ISSN 1899-5276 (print), ISSN 2451-2680 (online) Adv Clin Exp Med. 2017;26(2):359–367

Address for correspondence

Sylwia Bednarska
Abstract
E-mail: [email protected] Polycystic ovary syndrome (PCOS) is currently the leading cause of menstrual complications in women. It is
characterized by clinical and/or biochemical hyperandrogenism, ovulation abnormalities and the presence
Funding sources
none declared
of enlarged and/or polycystic ovaries in ultrasound images (12 or more small bubbles located circumfer-
entially and/or ovarian volume > 10 mL). It is often comorbid with hyperinsulinemia, dyslipidemia, over-
Conflict of interest weight or obesity, and is a risk factor for the development of diabetes and cardiovascular diseases (CVDs).
none declared The treatment of patients with PCOS depends on the prevailing symptoms. The aim of this paper is to pres-
ent the etiopathogenesis, clinical and biochemical implications, and non-pharmacological and pharmaco-
Received on June 11, 2015 logical treatment options – those approved by worldwide scientific organizations as well as new therapies
Revised on August 09, 2015 whose initial results are encouraging enough to prompt researchers to explore them further.
Accepted on September 10, 2015
Key words: treatment, statins, metformin, PCOS

DOI
10.17219/acem/59380

Copyright
Copyright by Author(s)
This is an article distributed under the terms of the
Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
360 S. Bednarska, A. Siejka. PCOS: What’s new?

Polycystic ovary syndrome (PCOS), also known as description of the syndrome, Stein and Leventhal em-
the Stein-Leventhal syndrome, is one of the most com- phasized that a high ratio of luteinizing hormone (LH)
mon endocrinopathies among women of reproductive to follicle-stimulating hormone (FSH) is one of the basic
age. It is estimated that it affects 3–15% of all women. disorders. It has also been suggested that the underlying
An abnormality in the ovaries is the primary cause of causes of PCOS include increased frequency of gonado-
the disorder, but additional agents, such as obesity and tropin-releasing hormone (GnRH) pulses that stimulate
environmental factors, affect the development of indi- the theca cells to produce androgen; decreased levels of
vidual symptoms.1 The Rotterdam criteria (2003) are the FSH (and thus a defect in the late luteal and early follicu-
most widely used and relevant criteria for the diagnosis lar phases); insulin resistance via a post-receptor defect in
of PCOS. The disorder is diagnosed if 2 of the 3 specified the fat tissue and skeletal muscles (abnormal phosphoryl-
conditions are met: (1) hyperandrogenism (detected by ation of tyrosine kinase); pancreatic beta-cell dysfunction;
clinical and/or biochemical testing) (2) ovulation abnor- and obesity.1,3 It is often impossible to determine defini-
malities, and/or (3) 12 or more cysts on one ovary and/or tively what is a cause and what is an effect in the develop-
ovarian volume > 10 mL. There are also 2 other defini- ment of PCOS. In addition, it is generally recognized that
tions of the syndrome in addition to the Rotterdam cri- obesity increases menstrual disorders and hyperandrog-
teria. According to the criteria proposed by the National enism, while weight reduction reduces the clinical signs.
Institutes of Health (NIH, 2009), a diagnosis of PCOS in- Reduced insulin sensitivity is an important issue in both
volves detection of clinical or biochemical hyperandro- obese and underweight women with PCOS; it is estimat-
genism and chronic ovulation disorders. The Androgen ed that 50–70% of women with the condition show insulin
Excess Society (2006), on the other hand, treats hyper- resistance of varying intensities.3
androgenism as the basic PCOS disorder and the pre-
requisite for a diagnosis, in combination with one of the Genetic factors
2 remaining Rotterdam criteria.2 In all these cases, PCOS
can be diagnosed after Cushing’s syndrome, congenital The influence of genetic factors was highlighted by
adrenal hyperplasia and/or androgen-secreting tumors Davies et al., who proved that mothers of women with
have been ruled out. PCOS are more likely to have a cardiovascular disease and
Based on the Rotterdam criteria, 4 phenotypes of PCOS that their risk of hypertension is twice as high as mothers
can be distinguished: (1) classic: hyperandrogenism (H), of women without PCOS, while fathers of women with
ovulation disorders (O) and a polycystic ovary (P) detected PCOS are twice as likely to have heart disease and 4 times
by USG (HOP); (2) with hyperandrogenism and ovulation more likely to have experienced cerebral stroke.5 Tan et al.
disorders, but with a normal ovarian USG image (HO); emphasized the increased likelihood of insulin resistance
(3) with hyperandrogenism and a polycystic ovary USG (IR) associated with certain genes (such as INSIG2 and
image, but without ovulation disorders (HP); (4) with MC4R) and the particular impact of TCF7L2 SNP on the
ovulation disorders and a polycystic ovary USG image, but development of diabetes mellitus type 2 (DM2) and body
without evidence of hyperandrogenism (OP).1–3 weight gain in patients with PCOS (a per-allele weight
Despite these seemingly clear criteria, the etiology of gain of 1.56 kg/m2).6 The etiology of IR was also discussed
PCOS remains unknown, and precise treatment proce- by Fica et al., who, while highlighting the complex mecha-
dures have not been established. PCOS therefore con- nisms of PCOS, identified insulin receptor autophospho-
tinues to be the object of research and scientific inquiry. rylation, reduced levels of phosphatidylinositol-3-kinase
In this paper, the postulated causes and possible effects in muscle tissue and visceral adiposity as probable mech-
of the clinical and biochemical syndrome are discussed, anisms.7
along with currently accepted and novel therapeutic
methods. Hyperinsulinemia/insulin resistance
Hyperinsulinemia in combination with pancreatic beta
Etiopathogenesis cell dysfunction results in an increased risk of many dis-
eases, including type 2 diabetes, hypertension, dyslipid-
A defect of the ovarian cells (most likely theca cells) is emia, endothelial dysfunction, atherosclerosis and cardio-
the underlying cause of PCOS, resulting in excessive an- vascular diseases. Insulin also stimulates the theca cells
drogen synthesis and the clinical and biochemical symp- of the ovary to produce excessive testosterone, which is
toms of the disease.1,2 In the literature, reference is made responsible for the clinical symptoms of hyperandrogen-
to the participation of genetic factors, including ethnic- ism (acne, hirsutism, alopecia).8 Cardiovascular risk is
ity; there is a higher frequency of PCOS in Spanish, na- also elevated in women who are chronic smokers, as dem-
tive American and Mexican women.41 In their original onstrated in a recent work by Marotti et al.4
Adv Clin Exp Med. 2017;26(2):359–367 361

Inflammation population, with type 2 diabetes occurring at the highest

frequency (3–7 times), especially in Indians.2,44 Other fre-
The role of inflammation in PCOS has been the subject quent disorders include hirsutism (85–90%) symptoms of
of a number of studies, and direct correlations have been metabolic syndrome (MS, approximately 40%), obesity/
found between increased levels of inflammation markers overweight (40–60%), lipid disorders, arterial hyperten-
(CRP, ferritin, leukocyte TNF-α, IL-6, IL-18) and the de- sion (approximately 20%) (Table 1). It is worth noting that
velopment of PCOS. Other contributors include elevated any excessive weight in these patients impairs the regu-
levels of PAI1 and free fatty acids, influencing excessive larity of menstrual bleeding and responses to metformin
phosphorylation of serine residues, leading to a rise in in- and insulin treatment, exacerbates the symptoms of hy-
sulin resistance.9 Newly emerging issues include a path- perandrogenism and also increases cardiovascular risk
ogenic correlation of the markers of iron overload with (Fig. 1).3,11,15
PCOS. Increased levels of ferritin and transferrin and Recent reports have revealed a close correlation be-
a higher frequency of the HP2/HP2 genotype of the hapto- tween mental disorders and clinical PCOS symptoms
globin α chain have been observed, causing a reduction of such as acne, hirsutism, infertility, obesity and a poorer
anti-inflammatory cytokines and antioxidant molecules, quality of life. A higher frequency of depression, drug-re-
leading to a state of chronic inflammatory response.10,11 lated and bipolar disorders, bulimia, anorexia or non-spe-

Clinical implications Table 1. Frequency of typical disorders in PCOS

Abnormality Frequency
In addition to hyperandrogenism and its related compli- Infertility 73–75%
cations, the most common abnormalities associated with
Hirsutism 85–90%
PCOS include menstrual disorders (amenorrhea or oligo-
Metabolic syndrome: 40%
menorrhea), often leading to infertility (in 73–74% of the abdominal obesity 30–70%
cases), abdominal obesity (30–70%) and type 2 diabetes diabetes type 2 10%
(approximately 10%).1,7 The prevalence of metabolic dis- arterial hypertension 20%
disturbed lipid metabolism unavailable
orders in women with PCOS is higher than in the healthy

Fig. 1. A chart of correlated symptoms in obese PCOS patients and possible targets for treatment (*)
362 S. Bednarska, A. Siejka. PCOS: What’s new?

cific dietary disorders was noted among PCOS patients.12 stage of the disease, with the possibility of many adverse
Chronic hyperandrogenemia, which leads to increased long-term sequelae. This indicates that it is necessary to
aromatization of androgens to estrogens in adipose tis- implement prevention strategies and interventions that
sue, may contribute further to the development of hor- must sometimes be started at an early stage in the devel-
mone-dependent tumors, such as endometrial, mammary opment of the symptoms.
or ovary neoplasms.13
Taking into account the considerations presented above,
it is advisable for routine oral glucose tolerance testing Currently applied treatment
(OGTT) to be performed in obese women with PCOS
(but routine OGTT is not necessary for women with The procedures used in PCOS treatment depend pri-
normal body weight). Patients diagnosed with PCOS are marily on the desired clinical effect: infertility treatment,
included in the groups at risk of developing diabetes, in regulation of menstrual disturbances, alleviation of the
accordance with the standards of the Polish Diabetes As- symptoms of hyperandrogenism or obesity treatment.
sociation.14 For women wishing to conceive, clomifene still remains
first-line therapy. It is an estrogen receptor modulator
that directly affects the hypothalamic-pituitary axis, act-
Biochemical disorders ing rapidly and effectively; 75% of the pregnancies in pa-
tients using clomifene are conceived in the first 3 months
In polycystic ovaries, abnormal steroidogenesis is man- of treatment.1
ifested primarily by increased production of androgens Another drug used with PCOS patients wishing to re-
and estradiol, and the malfunctioning hypothalamic-pi- store fertility is metformin; its effectiveness can be ob-
tuitary-ovarian axis is manifested by increased secretion served after 6 months of treatment.1,2 The role of metfor-
of LH, anti-mullerian hormone (AMH), a higher fre- min in inducing ovulation is still controversial. It is known
quency of GnRH pulses and a reduction in FSH concen- for certain that metformin contributes to reducing insulin
tration.1,2 These correlations (most importantly the par- levels and androgens, thus restoring the regularity of the
ticipation of androgens) are associated with a disturbed ovulatory cycle and periods. Metformin is a biguanide de-
lipid profile: an increase in very-low-density lipoprotein rivative, well-known for many years; it not only reduces
(VLDL), low-density lipoprotein (LDL) and triglycer- insulin resistance and blood pressure, improves the lipid
ides (TG), and a decrease in HDL- and LDL-cholester- profile and antioxidant characteristics and increases the
ol, regardless of body weight. Dyslipidemia, coagulation levels of sex hormone binding globulin (SHBG), but also
disorders, increased plasminogen activator inhibitor 1 (through its pleiotropic effect on the vascular endotheli-
(PAI1) and other metabolic consequences, increases in um) acts to protect the cardiovascular system.21,22 In ad-
the coronary artery calcium score and resultant increases dition, its dose-dependent protective effect against the
in carotid intima-media thickness (CIMT) lead to an in- risk of developing endometrial, mammary, intestinal and
crease in the risk of cardiovascular disorders.15 Obesity/ hepatic cancer has been reported by several authors.19,20
overweight coexisting with PCOS can lead to iron defi- Although many researchers claim that metformin plays
ciency (through increased production of proinflammato- a role in reducing body weight, a recent study has con-
ry cytokines, oxidative stress and a resultant increase in tradicted that view, pointing to the absence of any such
the levels of hepcidin, inhibiting the absorption of iron correlation; the only possible relationship involves redis-
from enterocytes), and thus the signs of anemia in those tribution of active visceral fat to inactive subcutaneous
women. There are many reports on the role of iron defi- fat.21 The starting dose of 500 mg once a day at lunch
ciency in the development of diabetes and its complica- time, increased to 3 tablets/24 h when tolerance is good,
tions. The opposite situation also occurs, and iron over- does not influence insulin resistance if it is not applied too
load in obese women with PCOS as measured by levels long.1 Tang et al. have shown a negative correlation in the
of ferritin, soluble transferrin receptor (sTfR), hepcidin reduction of insulin resistance after 6 months of therapy,
and heme iron, is also a risk factor for insulin resistance, as opposed to a study by Oppelt et al. that found increased
type 2 diabetes and cardiac disease. Reducing the con- insulin resistance after a 2-year period of intervention.22,23
sumption of red meat and the use of iron-zinc chelators Although older reports did not confirm the effect of met-
may be beneficial.10 Bu et al. have shown a relationship formin on clinical symptoms related to hyperandrogen-
between elevated serum levels of preptin (34-amino acid ism, recent data indicate effects of that kind, especially in
protein secreted from the beta cells of the pancreas along reducing skin problems (hirsutism, acne, acanthosis nig-
with insulin) with impaired glucose tolerance (IGT) in ricans).1,12
both PCOS patients and healthy controls, but found no Other therapeutic options for women with the problem
correlation with PCOS status.16 of infertility in PCOS are gonadotropins, used to induce
The results of the available studies suggest that PCOS ovulation, or laparoscopic surgery for patients resistant to
entails subclinical damage at the cellular level at an early pharmacological therapies. Laparoscopic techniques that
Adv Clin Exp Med. 2017;26(2):359–367 363

can successfully trigger ovulation include ovarian biopsy which may lead to the use of isotretinoin as a first line
and electrocautery, laparoscopic ovarian drilling, trans- treatment for PCOS patients with acne, second only to
vaginal hydrolaparoscopy, ultrasound guided transvaginal oral contraceptive therapy. Isotretinoin may improve the
ovarian needle drilling or laparoscopic ovarian multi-nee- patients’ reduced AMH levels, which correlate with ele-
dle intervention.1,43 vated androgen levels.26 However, the results of a recently
PCOS patients whose goal is not pregnancy are usually published study by Cetinözman et al. indicate that severe
advised to use oral contraceptives (OCP), which effectively acne does not correlate with the level of androgens or
restore the rhythm of bleeding, reduce hyperandrogenism sensitivity to insulin. Isotretinoin therapy not only fails to
and also contribute to reducing the risk of endometrial produce the desired clinical effect but contributes to an
hyperplasia.1 The effects of excessive androgen synthe- increase in body weight and triglyceride levels in the pa-
sis on a patient’s appearance – hirsutism, acne, alopecia, tients.27 Due to the high costs, the multitude of potential
acanthosis nigricans – are among the most frequent prob- adverse effects and its problematic effectiveness, isotreti-
lems causing patients with PCOS to seek medical care. noin treatment is not yet widely recommended in PCOS,
They are also among the main causes of deterioration in although the prospects are promising.
their quality of life, chronic stress and mental disorders, Androgenetic alopecia (AGA) is another problem as-
including depression.12 The pharmacological therapies sociated with PCOS. Antiandrogenic drugs (cyproterone
for these problems primarily make use of antiandrogen acetate) and inhibitors of 5-alpha reductase (finasteride)
drugs, such as cyproterone acetate in combination with are particularly effective in hyperandrogenism accompa-
ethinyl estradiol (OCP), spironolactone or metformin. nied by increased body mass, but a good response has also
Drugs that are not normally used in the treatment of been observed with a 2% solution of a drug called minox-
hyperandrogenism, but which can be taken into consider- idil used twice a day for at least 6 months. This chemical,
ation, include long-acting GnRH analogs, ketoconazole, after it is converted to its active form (minoxidil sulfate),
glucocorticoids, flutamide and finasteride. opens the ATP-dependent potassium channels in cells,
Local procedures intended to reduce excessive hair causing a vasodilatation effect by increasing the produc-
growth include beauty treatments, such as hair removal, tion of vascular endothelial growth factor (VEGF) in der-
electrolysis, laser destruction of the follicles and/or appli- mal papillae, stimulating hepatocyte growth factor (HGF)
cation of a cream containing 13.9% ornithine decarboxy- production and activating the synthesis of prostaglandins,
lase inhibitor and 13.9% eflornithine. Studies have shown which are mechanisms that ultimately lead to stimulation
that the substances contained in the cream, applied twice of hair growth.28
a day for 6 months reduce hair growth. The cream is well Other therapeutic options include combination ther-
tolerated and, in combination with laser epilation, is more apy. An interesting alternative was proposed recently
effective than hair removal methods used alone.25 by Vinaixa et al., who subjected non-obese women with
Another goal of therapy in PCOS is to reduce obesity, PCOS to 3-month flutamide-metformin-pioglitazone
where in addition to lifestyle modification, diet and phar- polytherapy combined with ester-progestogen treatment,
macological therapy with metformin, surgical methods pointing to the benefit of such treatment with respect to
have been applied. It has been demonstrated that bariatric the lipid profile (reduced LDL, increased HDL) higher an-
procedures for the treatment of obesity greatly improve drogen levels as well as increased carotid intima media
the profile of patients with PCOS by preventing metabolic (CIM) thickness, which in turn prevents the occurrence
syndrome; reducing body weight, blood pressure and the of atherosclerosis and related complications.29
risk of cardiovascular diseases; restoring normal function Another alternative is the use of thiazolidinedione de-
of the hypothalamic-pituitary axis; improving reproduc- rivatives, which stimulate peroxisome proliferator-acti-
tive function; and also, as demonstrated by Eid et al., nor- vated receptor type γ (PPAR-γ), enhance insulin sensi-
malizing blood pressure in approximately 78% of treated tivity, reduce the level of glucose. However, these drugs
patients with previous hypertension.24 do not reduce androgen levels and can contribute to pa-
tients’ weight gain; in addition, they are contraindicated
for women wishing to become pregnant.30
New therapeutic options Encouraging results suggest that metformin combina-
tion therapy with new drugs acting on the incretin sys-
Among the new therapeutic options for PCOS patients, tem (glucagon-like peptide receptor agonists 1-GLP-1, for
isotretinoin – a popular drug used to treat acne – de- example liraglutide or exenatide) leads to more effective
serves to be mentioned. In a study by Cakir et al., women weight reduction, lowers insulin resistance and improves
with acne (46 without PCOS and 50 with PCOS) received reproductive function. However, they are still not regis-
intramuscular injections of 0.5–1 mg/kg/dL isotretinoin, tered as drugs with a high safety profile in women of re-
and the effects of the treatment were observed after one productive age.31
and 2 years. In both groups, the therapy was highly ef- Several studies have recently been published on the ef-
fective (91.6% achieved complete remission of their acne), fectiveness of vitamin D supplementation, especially in
364 S. Bednarska, A. Siejka. PCOS: What’s new?

autumn and winter. The authors have pointed out that vi- in the pathogenesis, progression and treatment of PCOS.
tamin D deficiency has an impact on the pathogenesis of It has been shown that increased intraovarian produc-
insulin resistance in PCOS.32 tion of nerve growth factor (NGF) and elevated muscle
Studies on the use of statins for the treatment of PCOS sympathetic nerve activity (MSNA) stimulate the devel-
seem to be extremely encouraging, especially consider- opment of obesity, hyperinsulinemia, obstructive sleep
ing that approximately 70% of women with this syndrome apnea (OSA) and metabolic disorders in PCOS patients.
are affected by lipid disorders and obesity. As blockers of In these cases the use of non-pharmacological interven-
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tions (weight reduction, continuous positive airway pres-
reductase, statins have pleiotropic effects through their sure in OSA, electroacupuncture stimulation of barore-
anti-inflammatory, antioxidant, antiproliferative and li- ceptors), pharmacological treatment (drugs that increase
pid-lowering activity. By blocking the formation of the insulin sensitivity) and surgical procedures (renal dener-
malonic acid required for the synthesis of cholesterol, vation) can bring surprising results.38,39
they inhibit the proliferation of cells in the ovarian the- Studies on the role of fibroblast growth factors (FGFs)
ca cell layer, with a resultant reduction in the synthesis in the pathogenesis of PCOS, metabolic disorders, type 2
of steroid hormones.1 This was confirmed by the results diabetes and the cutaneous manifestations of hyperan-
of Celik and Acbay, who demonstrated that a 12-week drogenism represent an absolutely new approach. It has
combination therapy with metformin and rosuvastatin been shown that FGFs – particularly FGF-1, -10, -19 and
is more effective in reducing the testosterone, DHEA-S, -21 – are involved not only in the regulation of carbo-
body weight, CRP, TG and LDL cholesterol than the use hydrate and lipid metabolism and show cardioprotective
of either of those drugs alone.33 Other authors com- activity (FGF-21), but are also responsible for the cutane-
pared the effects of different types of statins on selected ous manifestations of excessive activity of the sebaceous
endpoints. They proved, for example, that atorvastatin glands.40 Decreased levels of FGF-19 have been observed
is more effective than simvastatin in improving insulin among PCOS patients. An analog of FGF-21 called LY
sensitivity, reducing the level of insulin in the fasting 2405319, currently being tested in clinical settings, re-
state, lowering blood pressure and reducing the con- duces insulin resistance and lowers blood glucose, cho-
centration of advanced glycation end products (AGEs, lesterol, triglycerides, LDL, and also helps in weight re-
which can affect the course of many diseases and degen- duction.41
erative processes). Atorvastatin also reduces the level of In recent years, there have been reports concerning im-
serum malondialdehyde (MDA) as a marker of oxidative provement in insulin sensitivity in women with PCOS due
stress. MDA is indirectly connected with the reduction to myo-inositol treatment. It has been shown in some clin-
of levels of CRP and total testosterone, and with increas- ical trials that myo-inositol not only decreases glycemia
ing levels of 25-hydroxyvitamin D (25OHD) in PCOS in OGTT, the homeostatic model assessment (HOMA)
patients.34,35 index, and reduces the secretion of LH, DHEA, testoster-
An interesting issue is the finding that supplementa- one and progesterone but also improves the serum lipid
tion with omega-3, α-lipoic acid and N-acetyl cysteine profile (cholesterol, triglycerides).42 A high concentration
results in an antioxidant, anti-inflammatory effect, of myo-inositol in the follicular microenvironment im-
improves insulin sensitivity and the lipid profile of proves the availability of oocytes. Therefore myo-inositol
women with PCOS.36 Salehpour et al. demonstrated restores menstrual regularity, ovulation and effectively
that N-acetyl cysteine lowers levels of testosterone, re- increases the chances of getting pregnant. However, fur-
duces androgen response to gonadotropin stimulation, ther studies are needed to be able to use myo-inositol for
improves ovulation rates and long-term health after fertility treatment.42
6 months of ­treatment.37 Table 2 presents a summary of current and new med-
In recent years, attention has also been paid to the role ications, with their contraindications and possible side
of increased activity of the sympathetic nervous system effects.

Table 2. Drug treatments for PCOS

Drug Effects Contraindications Side effects

Metformin – restores regular bleeding and – hypersensitivity – gastrointestinal disorders
ovulation – renal insufficiency – lactic acidosis
– reduces insulin resistance – a cute or chronic diseases that may cause – dyspepsia, diarrhea, nausea, flatulence
– improves arterial tension values tissue hypoxia, such as cardiac or respira- – metallic aftertaste in the mouth
– improves lipid profile tory insufficiency
– shows antioxidant activity – lactation
– increases sex hormone binding – hepatic damage
globulin (SHBG) level
– may help reduce body weight
Adv Clin Exp Med. 2017;26(2):359–367 365

Table 2. Drug treatments for PCOS – cont.

Drug Effects Contraindications Side effects

Oral – restore regular periods – past or current thromboembolic complica- – arterial hypertension
Contraceptives – reduce symptoms of hyperan- tions, cerebro- or cardiovascular disorders – nausea, vomiting
drogenism – obesity (BMI over 30 kg/m2) – headache
– reduce risk of endometrial hyper- –p  regnancy or suspected pregnancy – dermal lesions (acne, hirsutism)
plasia – v alvular heart disease – body weight gain
– a ctive hepatic disease – turgid breasts
–m  ammary or uterine cancer – leg cramps
– r eproductive tract bleeding of unknown – vaginal staining or bleeding
etiology
– estrogen-dependent tumors
Clomifene – infertility treatment (ovulation – a llergy to clomifene – headache, vertigo
induction) – pregnancy – tiredness
– hepatic disease – disturbed vision
– primary hypopituitarism – nausea, vomiting
–d  isturbed thyroid or adrenal function – vasomotor symptoms
–u  terine bleeding of unknown etiology – facial flush
– hormone-dependent tumors – mastalgia
– abdominal pain
– paramenia
Eflornithine – controls facial hirsutism –h
 ypersensitivity to eflornithine or any – acne
adjuvant – chronic folliculitis barbae
– alopecia
– skin burning sensation
– xerodermia
– itching
– erythema
– skin formication
GnRH analogs – inhibit androgens –h
 ypersensitivity to any component of the – menopausal symptoms
product or other GnRH analogues – loss of bone mass
–p
 regnancy or lactation – vaginal dryness
–m
 etabolic disorders of the skeletal system – insomnia, mood swings, depression
– reduced libido
Ketoconazole – inhibits androgens – a cute or chronic hepatic disease – nausea
–p  regnancy or lactation – alopecia
– dry skin
– uterine bleeding
– headache
Steroids – inhibit androgens – c ontraindicated in patients affected by – adrenal suppression
symptoms or diseases which may be a side – infections
effect of their use, e.g. diabetes, hyperten- – neuro-psychiatric abnormalities
sion, infections – carbohydrate metabolism disorders, diabetes
– electrolyte imbalance
– osteoporosis
– changes in lipid and protein metabolism
– Cushing’s syndrome
– gastric ulcer
– muscle weakness
– growth disorders in children
– glaucoma
– menstrual disorders
Spironolactone – inhibits androgens – hyperkalemia – hypersensitivity
– touch-sensitive nipples – hyponatremia, hyperkalemia
– mastalgia – primary adrenal insufficiency
– menstrual disorders – severe renal and hepatic failure
– hirsutism – acute renal failure
– agranulocytosis
– headaches
– sleepiness
– ataxia
Flutamide – inhibits androgens –h
 ypersensitivity to any component of the – gynecomastia, mastalgia, galactorrhea
product – diarrhea, nausea, vomiting, increased appetite
– insomnia, fatigue
– abnormal liver function
366 S. Bednarska, A. Siejka. PCOS: What’s new?

Table 2. Drug treatments for PCOS – cont.

Drug Effects Contraindications Side effects

Finasteride – reduces alopecia –h
 ypersensitivity to any component of the – decreased libido
product – rash
–p
 regnancy, planned pregnancy or breast- – enlarged and tender breasts
feeding – hypersensitivity reactions
Isotretinoin – severe acne (due to reduced AMH –h  ypersensitivity to isotretinoin, peanuts, – dry skin and eyes with conjunctivitis
levels) soybeans or other ingredients – dry mucous membranes, cheilitis
–p  regnancy or lactation – contact lens intolerance
– liver failure – anemia, accelerated ESR, increase in
– hypervitaminosis A transaminase activity
– increased blood lipid levels – itching, skin inflammation, rash, skin
–u  se of tetracycline antibiotics hypersensitivity
– muscle and joint pain
– abnormal lipid profile
Statins – pleiotropic effects (anti- – a ctive liver disease (ALT, AST exceeding – muscle damage (myopathy)
inflammatory, antioxidant, 3 times the upper limit of normal values) – increase in liver enzymes in the serum
antiproliferative and lowers the –p  regnancy or lactation – headache
level of lipids) – hypersensitivity – blurred vision
– inhibition of cell proliferation in – insomnia
the theca layer of the ovaries and – ailments of the digestive tract
reduction of steroid hormone – rash
synthesis – joint pain
Fibroblast – regulation of carbohydrate and – unknown – unknown
growth factors lipid metabolism
(FGFs) – cardioprotection
– reduction of insulin resistance
Vitamin D3 – improves insulin sensitivity –p
 oisoning with or allergy to vitamin D – myocardial injury
– gastrointestinal symptoms: nausea, vomiting,
diarrhea
– hypercalciuria, polyuria, renal damage
– pain in the muscles or joints

Summary 4. Morotti E, Battaglia B, Fabbri R, Paradisi R, Venturoli S, Battaglia C.

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