Essay: Pathophysiology, diagnosis, and management of polycystic ovary syndrome

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Introduction
Polycystic ovary syndrome (PCOS) was first reported in 1935 by Stein and Leventhal who described seven women dealing with amenorrhea, hirsutism, and enlarged ovaries with multiple cysts (Stein and Leventhal, 1935). This syndrome was given the name Stein–Leventhal syndrome after these two physicians for sometime. In the 1960s, however, the term polycystic ovary syndrome (PCOS) was first introduced and gradually started to replace its former name. It is now recognized as a common complex heterogeneous endocrine disorder in reproductive-age women associated with reproductive, metabolic and psychological features. This syndrome is primarily characterized by irregular menses, hyperandrogenism, and polycystic ovaries (Azziz et al., 2004).
Given the fact that one out of five women of reproductive age is affected by this syndrome, and studies which suggest that 5% to 10% of females 18 to 44 years of age are affected by PCOS, it is deemed to be the most common endocrine abnormality among women of reproductive age in the US. In Saudi Arabia, the prevalence of PCOS is still unknown although it is believed to be similar to the other studies. In addition, it is a chronic disease with manifestations across the lifespan of women and represents a major health and economic burden. Therefore, the aim of this research is to review this subject in depth taking in consideration the pathogenesis, clinical features, diagnosis, complications and management.
Material and Methods
This study was performed by a literature search of English-language studies which was conducted on PubMed (from 1994 to 2016) and CENTRAL (Cochrane Central Register of Controlled Trials) using the terms, ‘PCOS’, ‘polycystic ovary syndrome’, and ‘polycystic ovary disease’.
Epidemiology
Polycystic ovary syndrome is the most common endocrine disease in women of child-bearing age. Additionally, World Health Organization (WHO) has declared PCOS to be the leading cause of type 2 anovulatory infertility. Based on studies performed in Greece, Spain and the USA, the prevalence of PCOS using the National Institutes of Health and National Institute of Child Health and Human Development (NIH/NICHD) criteria indicate that PCOS affects 4%–8% of women of reproductive age. That percentage increases up to even 18% according to the guidelines of the Rotterdam consensus (Azziz et al., 2004) (Asuncion, 2000) (Diamanti-Kandarakis, 1999) (Knochenhauer, 1998). Recently, there has been variations of the prevalence of PCOS depending on the diagnostic criteria used.
Pathophysiology
Normally, females of reproductive age experience cycles of hormonal activity that repeat at about one-month intervals. With every cycle, a woman\’s body prepares for a potential pregnancy, whether or not that is the woman\’s intention. The term menstruation refers to the periodic shedding of the uterine lining.
Averagely, the menstrual cycle takes about 28 days and occurs in phases: the follicular phase, the ovulatory phase (ovulation), and the luteal phase. There are four major hormones (chemicals that stimulate or regulate the activity of cells or organs) involved in the menstrual cycle: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and progesterone. During the follicular phase of the menstrual cycle, which starts on the first day of a woman’s period, two hormones; follicle stimulating hormone (FSH) and luteinizing hormone (LH), are released from the brain, specifically the pituitary gland, and travel in the bloodstream to the ovaries. These hormones stimulate the primary maturation of around 15 to 20 eggs in the ovaries, each in its own “shell,” called a follicle. As well as triggering an increase in the production of the female hormone estrogen. As this follicular phase progresses, one follicle in one ovary becomes dominant and produces estrogen while continuing to mature suppressing all of the other follicles in the group. The second phase, or ovulation, begins on the 14th day after the follicular phase started. The rise in estrogen from the dominant follicle triggers a surge in the amount of luteinizing hormone that is produced, which causes the dominant follicle to release its egg from the ovary into the fallopian tube. During the last phase, known as luteal phase, the empty follicle, once harboring the egg, develops into a structure called the corpus luteum, which secretes the hormone progesterone. Progesterone prepares the uterus for the implantation of a fertilized egg. If the egg is not fertilized, it passes through the uterus, and the lining covering it breaks down and sheds, and the next menstrual period begins.
The pathophysiology of PCOS results from a primary defect in the pituitary function, as well as, defects in insulin secretion and action, and ovarian function. Increased luteinizing hormone (LH) and gonadotropin–releasing hormone (GnRH) levels relative to follicle-stimulating hormone (FSH) was the first laboratory abnormality identified in classic PCOS.
Raised LH levels will lead to an increase of androgen production and secretion by ovarian theca cells. The increase in LH seems to be the result of abnormal sex steroid feedback rather than the cause of androgen excess. Patients with PCOS are less susceptible to suppression of LH by luteal phase hormones, where the modest rise in androgen levels in patients with PCOS absurdly stimulates LH pulsatility.
Moreover, use of antiandrogen treatment lowers the elevated LH pulse frequency of PCOS to a normal level, suggesting that androgen excess interferes with the hypothalamic inhibitory feedback of female hormones, principally progesterone (Rosenfield and Bordini, 2010).
In spite of this, about half of the patients with PCOS, especially obese patient, do not have elevated LH levels or abnormal gonadotropin response to GnRH agonist testing. Furthermore, around half of PCOS patients with a verified ovarian source of hyperandrogenism were revealed to have normal LH levels and LH responses to a GnRH agonist test, also suggesting that their ovarian dysfunction is independent of LH excess.
Another major influence in the pathophysiology of PCOS is the association with insulin and its function; In the ovary, insulin helps to regulate ovarian function, and acts in conjunction with LH to enhance androgen production which can lead to anovulation (González, 2012).
Etiology and risk factors
A detailed pathogenesis of PCOS has not been clarified yet. Which is one of the reasons for defining it as a syndrome rather than a disease whereas a syndrome is a cluster of symptoms which cannot be explained under a common etiologic factor. However, the individual susceptibility probably depends on prenatal androgen exposure, genetic factors, ethnic origin and environmental risk factors (Zhang et al., 2012).
The interaction of a number of genetic and environmental factors determine the heterogeneous, clinical, and biochemical phenotype, which is why PCOS is described as an oligogenic disorder (Barber and Franks, 2010).
Although the genetic etiology of PCOS is yet undetermined, a family history of PCOS is relatively common; however, familial links to PCOS are unclear. Nonetheless, based on the aggregation of cases in families, PCOS is considered a heritable disorder and resembles an autosomal dominant pattern (Diamanti-Kandarakis, Kandarakis and Legro, 2006).
Hence, a family history of PCOS is considered a risk factor. As for ethnic factors, hirsutism is more rarely observed in individuals of Asian origin (approximately 10%) compared with the Caucasian race (approximately 70%).
Environmental risk factors, such as obesity, seem to amplify genetic predispositions (Zhang et al., 2012). Obesity is a prevalent characteristic of PCOS (Shannon and Wang, 2012), ranging from 12.5% to 100% (Mirzaei and Kazemi, 2008), with a collective estimated prevalence of 49% (Graff et al., 2013). These environmental factors implicated in PCOS (e.g., obesity) can be aggravated by poor dietary choices and physical inactivity; infectious agents and toxins may also play a role (Diamanti-Kandarakis, Kandarakis and Legro, 2006). The reproductive and metabolic features of PCOS are sometimes reversible with lifestyle modifications such as weight loss and exercise (Shannon and Wang, 2012).
Clinical features of PCOS
The clinical presentation of PCOS varies widely. These considerably distinctive features, displaying a varying degree of expression in each individual, emphasize the phenotypic variability of PCOS, and is in fact another reason why it is considered as a syndrome. Women with PCOS may present with an array of serious clinical implications including reproductive manifestations (hirsutism, infertility and pregnancy complications) (Boomsma et al., 2006), psychological problems (reduced quality of life, poor self-esteem, depression, anxiety) (Deeks, Gibson-Helm and Teede, 2010), and metabolic implications (insulin resistance, metabolic syndrome, impaired glucose tolerance (IGT), diabetes mellitus type 2 (DM2) and potentially cardiovascular disease (CVD)) (Sir-Petermann et al., 2013) (Meikle, 2006).
Presentation of PCOS may vary across the life cycle of the patient due to the heterogeneous nature of PCOS and the wide spectrum of clinical features. Generally, PCOS is a chronic condition that usually begins in adolescence then transitions to include infertility and increase metabolic complications over time. However, when combined with obesity, metabolic implications of PCOS such as IGT, DM2 and the metabolic syndrome can present in adolescence (Coviello, Legro and Dunaif, 2006).
Reproductive features of PCOS
Hyperandrogenism
Clinical hyperandrogenism primarily includes hirsutism, acne and male pattern alopecia. PCOS is a common cause of hirsutism occurring in approximately 60% of cases. Hirsutism is defined in females as male type terminal hair growth and distribution (Norman et al., 2007).
Acne affects one third of cases and is not particularly specific for PCOS (Norman et al., 2007). Studies have shown that androgen levels are elevated in woman with acne, although the severity of acne has not been positively correlated with any particular hormone with the exception of the adrenal androgen, dehydroepianandrosterone sulfate (DHEA-S) (Karrer-Voegeli et al., 2009). Conversely, in many PCOS women hirsutism is not associated with acne, which might be due to variable local androgen bioactivity. An enzyme called 5-α-reductase controls the androgen activity in the hair follicle by converting free testosterone to the more potent dihydrotestosterone (DHT). This enzyme has two isoforms: type 1 is located in the sebaceous glands and pubic skin and type 2 is present primarily in the hair follicle, genital skin, and adult scalp. This explains the different clinical manifestations seen in hyperandrogenic women when the degree of hirsutism is not well-matched with the severity of the acne (Archer and Chang, 2004).
Male pattern hair loss (androgenic alopecia) is a genetically determined disorder characterized by the gradual conversion of terminal hairs into indeterminate, and finally into vellus hairs. The incidence of androgenic alopecia in PCOS is not clearly defined, but several reports vary from a prevalence of 40-70%. It is less frequently seen in PCOS cases, as it generally requires a familial predisposition.
Ovarian abnormalities and Infertility
Most of the women suffering from PCOS will seek gynecological counseling due to menstrual irregularity, with 70% to 80% of women presenting with oligomenorrhoea or amenorrhoea. Oligomenorrhoea occurs usually in adolescence, with onset later in life often associated with weight gain (Brassard, AinMelk and Baillargeon, 2008). Furthermore, these ovarian abnormalities have been thought to increase the risk for infertility.
Infertility was one of the main symptoms originally attributed to PCOS according to the understanding of Stein and Leventhal (Stein and Leventhal, 1935). The consequent epidemiologic studies implied that about 90% to 95% of women attending infertility clinics with anovulation, have been diagnosed with PCOS, which is the most common cause of anovulatory infertility. (Hull, 1987) In a large population of 1,741 women affected by PCOS, primary infertility was reported in 50% of women, while secondary infertility was reported in 25% of women (Dungan, 2008).
On the other hand, there is currently a debate on the legitimacy of the relationship between PCOS and infertility. Research has concluded that 60% of women with PCOS are fertile (defined as the ability to conceive within 12 months), although time to conceive is often increased.
Psychological features of PCOS
There are very few studies to date that have explored the psychological aspect of PCOS, since most research has focused primarily on the biological and physiological features of the syndrome. However, these psychological features do, in fact, compromise quality of life and adversely impact on mood and psychological well-being. (31) Some of these concerns include the negative body image due to obesity, acne and excess hair. Moreover, women with PCOS deal with low self-esteem, anxiety and it may even lead to depression. The other challenge for patients is dealing with psychosocial impact of mood disturbance and reduced psychological well-being on motivation and the ability to implement and sustain successful lifestyle changes that are critical in this condition. (32)
Metabolic features of PCOS
Obesity
Actually, obesity is considered a serious growing epidemic disorder in the world population, especially in the childhood and teenage years. Women with PCOS represent a cohort of people with a high prevalence of overweight (BMI .25 kg/m2) and obesity (BMI .30 kg/m2) compared to healthy women, up to 61% of prevalence,93 with a typical central distribution of adipose tissue, although there is a wide variability in the estimates of obesity in PCOS women across different countries and ethnicities.13 In the Western countries, such as Australia, USA, and UK, the PCOS women have the highest prevalence of overweight and obesity,94,95 compared to Chinese PCOS women (only 20% has a BMI of 25 kg/m2 or greater).96 The causal role in the association between obesity and PCOS has yet to be determined but cultural, lifestyle, and ethnic factors take part in these conditions.
Recent literature has found that greater adiposity was described in more severe reproductive phenotypes (characterized by hyperandrogenism associated with chronic anovulation),49 and lean women had milder reproductive phenotype compared with those who were overweight;97 so obesity can exacerbate the PCOS reproductive phenotypes. It also appears that obesity could have a bidirectional relationship with PCOS, as women with PCOS are more inclined to weight gain and excessive weight gain increases PCOS prevalence, unmasking a latent PCOS condition, but this yet remains to be clarified.
Insulin resistance
Insulin is a hormone produced by the pancreas to control the amount of sugar in the blood. It helps to move glucose from blood into cells, where it\’s broken down to produce energy.
Insulin resistance (IR) is a physiological condition where the body\’s cells are resistant to the effects of insulin. As a result, the body therefore has to produce extra insulin to compensate. High levels of insulin stimulate the ovaries to produce too much testosterone, which interferes with the development of the follicles i.e. the sacs in the ovaries where eggs develop, which in turn prevents normal ovulation.
Insulin resistance have also been found in some cases to lead to weight gain, which may exacerbate many of PCOS symptoms, because having excess fat causes the body to produce even more insulin. Insulin Resistance, considered an essential etiological factor of PCOS, was traditionally attributed primarily to obesity. Although the demonstration of insulin resistance is not required to make the diagnosis of PCOS, it is clear that hyperinsulinemic insulin resistance plays a prominent role in PCOS. The prevalence of insulin resistance in PCOS ranges from 50%–70%57–60 and occurs independently of obesity.
Metabolic syndrome
Metabolic syndrome is not a disease, but rather a clustering or “constellation” of abnormal conditions. Although there are several definitions of what is required to be diagnosed with metabolic syndrome, most health care professionals use criteria from the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association. Consistent with the increased prevalence of insulin resistance, metabolic syndrome is also more common in women with PCOS. A meta-analysis (32) has shown that women with PCOS have higher levels of triglycerides (TG), LDL cholesterol and total cholesterol (TC), and lower HDL cholesterol
levels compared with control women, regardless of body mass index (BMI). Lean women with PCOS were also more likely to have metabolic syndrome than lean women without PCOS (OR 3.00, 95% CI 1.24–6.78).62 The components of metabolic syndrome are associated with insulin resistance and are summarized in Table 3.63
A specific abnormal pattern of insulin receptor phosphorylation, namely increased serine phosphorylation and reduced tyrosine phosphorylation, appears to be responsible for insulin resistance observed in PCOS.
Cardiovascular risk
As reported by the main scientific societies,13,15,49 women with PCOS present an increased prevalence of classic risk factors for cardiovascular disease (CVD) such as hypertension, dyslipidemia, diabetes, and obesity and nonclassic risk factors such as C-reactive protein (CRP), homocysteine, and tumor necrosis factor-α.50 PCOS at any age is characterized by greater odds for elevated CVD risk markers and these elevated makers can occur without obesity but are magnified with obesity.13
In 2004, a worldwide case-control study of patients from 52 countries was published, the INTERHEART study,51 that found nine potentially modifiable risk factors, accounted for over 94% of the population-attributable risk of a first myocardial infarction in women; the nine factors included smoking, hypertension, dyslipidemia, diabetes, visceral obesity, psychosocial factors, decreased consumption of fruits and vegetables, regular consumption of alcohol, and regular physical activity. The majority of these occur in the PCOS woman. It is estimated that the prevalence of each risk factor is approximately double for women with PCOS when compared with controls, while it is 1.5 times higher in BMI-matched studies beginning in adolescence and it is found in e
very decade.
Oncogenic risk
Since PCOS is considered as a lifelong multisystemic and multifaceted disorder, the reproductive and metabolic alterations characterizing the syndrome may be also associated with an increased risk of the development of cancers, such as the endometrial, ovarian, and breast cancer, which recognize potential hormonal and/or metabolic pathogenetic mechanisms. The potential mechanisms which could promote the onset of neoplastic diseases in these women, particularly endometrial cancer, include the chronic anovulatory state, resulting in an unopposed estrogen action, associated with hyperandrogenism.117
At present, based on the most recent meta-analysis,118 women with PCOS of all ages seem to be at an increased risk of endometrial cancer. In particular, the risk of endometrial cancer may be even higher in the premenopausal subgroup of women with PCOS, while overall the risk of ovarian and breast cancer was not significantly increased.118 These current results are consistent with previous reviews published on cancer in PCOS116,119,120
Unfortunately, as with studies of cardiovascular risk, the assessment of cancer risk in PCOS women is complicated by the presence of various potential confounding factors such as obesity, T2DM, inflammation, and metabolic syndrome, which are highly represented in PCOS populations. Obesity is a recognized risk factor for endometrial cancer and the authors of the most recent meta-analysis118 acknowledge that the increased risk of this cancer could be attributed, at least in part, to increased prevalence of obesity in PCOS women. The same issue applies to T2DM, another possible confounding factor that is most representative in PCOS women and associated with an higher risk of endometrial cancer, possibly secondary to hyperinsulinemia, hyperglycemia, and inflammation.122 Therefore, there is uncertainty as to whether increased endometrial cancer risk is due to different metabolic risk factors or PCOS itself, which is characterized by many metabolic and reproductive complications that could be responsible for an increased oncology risk on endometrium. Nonetheless, it is generally accepted that PCOS women with amenorrhea are at greater risk for endometrial hyperplasia and cancer;13 therefore, ESHRE/ASRM Consensus Workshop Group has established a proper endometrial surveillance with ultrasound and/or biopsy to assess endometrial thickening in women which experience extended period of amenorrhea, based on clinical suspicion and presentation, and in these women periodic progestogen withdrawal is also recommended, at least four episodes per year.13 There is limited and contradictory evidence regarding the risk of ovarian131 and breast cancer121 in women with PCOS; so currently, the ESHRE/ASRM consensus statement13 does not recommend routine surveillance strategy and/or clinical care to detect ovarian and breast cancer in women with PCOS. There is also insufficient evidence to evaluate any association of PCOS with vaginal, vulvar, and cervical cancer.
Diagnosis
Diagnostic criteria outlined in Table 1 have been modified on four occasions since the National Institute of Health first defined the syndrome in 1990 (2), highlighting the complex nature of the disorder. In 2003, the Rotterdam criteria were published and further revised in 2004 (3), followed by the Androgen Excess Society criteria in 2006 (4), subsequently modified by the Androgen Excess and PCOS Society (AE-PCOS) in 2009 (5). Today, the Rotterdamcriteria are the most widely utilized guideline requiring any two of the following three features: androgen excess –identified clinically or biochemically; chronic anovulation; or polycystic ovarian morphology (3). Despite frequent amendments to diagnostic criteria, the features first described by Stein and Leventhal continue to be recognized in the various classification systems. In particular, ovarian dysfunction manifesting as either oligomenorrhoea amenorrhoea and hyperandrogenism can be considered the
hallmarks of the syndrome (6), having been consistently recognized throughout the literature. Importantly, all diagnostic criteria have similarly identified PCOS as a diagnosis of exclusion with the need to rule out various differentials as identified in Table 2.
Three tools can be used to diagnose PCOS (Table 2). In 1990, the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) hosted a panel of experts who developed the first known criteria for PCOS.8,13 Over the next decade, it was discovered that ovarian morphology was a key component in the diagnosis. The European Society Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) sponsored a workshop in Rotterdam. During the workshop, polycystic ovarian morphology on pelvic ultrasound was added to the NICHD/NIH criteria. It was then decided that only two of the three criteria had to be met for a diagnosis of PCOS. 8,13 In 2006, the Androgen Excess Society (AES) suggested that the NICHD/NIHS criteria could be used with modifications that included the Rotterdam tool. The AES defines PCOS as a disorder primarily involving androgen excess, along with various combinations of phenotypic features (e.g., hyperandrogenemia, hirsutism, oligo-ovulation/anovulation, and/or polycystic ovaries) that may promote a more accurate diagnosis.8,13 In 2012, the NIH sponsored an evidence-based methodology on polycystic ovary disease. The expert panel concluded that each criterion has its own strengths and weaknesses; however, the use of multiple criteria was considered confusing, impeding progress in understanding PCOS.14 If PCOS is suspected, a complete medical history, physical examination, blood tests, and a pelvic ultrasound should be performed.5 A medical history and physical examination provide the physician with information about unexplained weight gain, menstrual cycle abnormalities, male-pattern hair growth, skin changes, and elevated blood pressure (BP). Blood is drawn to assess hormone, glucose, and lipid levels, and a pelvic ultrasound is performed to scan for ovarian cysts.5,13,15 During the assessment period, other potential causes associated with reproductive, endocrine, and metabolic dysfunction should
be excluded. Physicians should rule out adrenal hyperplasia, Cushing’s syndrome, and hyperprolactinemia before a PCOS diagnosis is confirmed.5,13 After PCOS is diagnosed, studies show that more than 50% of patients develop prediabetes or diabetes, and there is an increased risk of myocardial infarction (MI), dyslipidemia, hypertension, anxiety, depression, endometrial cancer, and sleep apnea.4 Moreover, pregnant women with PCOS should be informed of the increased rates of miscarriage, gestational diabetes, pre-eclampsia, and premature delivery.4
Treatment
The treatment of PCOS in adolescent girls should aim to achieve ovulation, normalize the menstrual cycle, reduce and if possible eliminate hirsutism and acne, achieve weight loss, as well as to treat hyperlipidemia and hyperglycaemia in order to lower the risk of cardiovascular disease. Most protocols in puberty also aim to reduce the androgen excess.
However, most importantly, a healthy diet combined with exercise should be proposed as the number one priority, especially in overweight adolescent women. Obesity was closely related to IR; for this reason, weight loss represented a fundamental preliminary approach in the treatment of obese/overweight PCOS women. In fact, weight loss resulted in the restoration of spontaneous ovulation and higher fertility rate.145 Losing weight not only contributes to the prevention of the clinical manifestations of the PCOS, but also improves the young girl’s self-esteem [33]. Similarly, the use of cosmetics as well as hair removal, used in conjunction with androgen suppression therapy, could be effective in the treatment of hirsutism. However, lifestyle modification programs are related to a low compliance and a high dropout rate. To overcome this problem, the feasibility and the efficacy of a structured exercise training program was evaluated in obese anovulatory PCOS patients.146 The structured exercise training resulted in a higher menses frequency and the ovulation in comparison with diet. Successively, lifestyle modifications resulted more efficacious than clomiphene cictrate (CC) and metformin in terms of pregnancy rate, resulting in 12.2%, 14.4%, 14.8% and 20% of pregnancies after CC, metformin, CC plus metformin, and lifestyle modification, respectively.147
Clomiphene citrate
Available guidelines recommended CC as the first-line treatment of anovulatory infertility in women with PCOS.16 CC is an estrogen modulator, efficacious, simple to administer and to manage, safe and cheap. Specifically, CC was effective in increasing pregnancy rate compared to placebo (OR 5.8, 95% CI 1.6–21.5).148
According to the standard protocol, CC is administered for 5 days from second or third day of the menstrual cycle, starting from 50 mg/day and increasing up to 250 mg/day. “Managed care” studies showed that the most effective dosage is 100–150 mg/day and over 75% of ovulations occur already within a dosage of 100 mg/day.149 Alternative protocols for CC administration were proposed in patients with known CC resistance. Extended CC regimen resulted in higher ovulation and pregnancy rates in comparison with gonadotropins ovulation induction, suggesting that in CC-resistant PCOS patients a further period of CC administration might be preferable.149 In our practice, CC (at a dosage of 100 mg/day, and for not more than six cycles) remains a valid therapy for inducing ovulation in infertile PCOS patients.
Aromatase inhibitors
Aromatase inhibitors (AIs), such as estrogen modulators, were approved by the Food and Drug Administration as first-line adjuvant therapies for estrogen-receptor–positive breast cancer.150 Several data150 evaluated the efficacy of AIs, and in particular of letrozole, as first-line therapy for inducing ovulation in infertile patients affected by PCOS. Letrozole was usually administered at a dose of 2.5 mg/day, for 5 days from the third to the seventh day of the menstrual cycle.
More recently, a meta-analysis of RCTs showed that letrozole is related to significantly higher live-birth rates than CC (OR 1.64, 95% CI 1.32–2.04).151 Furthermore, the quality of the evidence was considered low due to the poor study transparency in reporting methods and in consideration of the more favorable results in the trials reporting live birth as primary end point. Excellent results of AIs in terms of cumulative live-birth rate and singleton pregnancy was reported in the largest multicenter randomized double-blind parallel controlled trial (Pregnancy in PCOS trial II, PPCOS II) comparing letrozole to CC.152
To date, letrozole remains an off-label drug.153 Studies are needed to validate the efficacy/safety of AIs over CC in further settings and to clarify its role in well-codified strategies and algorithms for ovulation induction in PCOS.150 Thus, the use of AIs in clinical and nonexperimental settings should be probably avoided.
Metformin
Metformin belongs to insulin-sensitizing drugs commonly used in treating T2DM. Because IR is a common condition in PCOS women, metformin was introduced in clinical practice in the treatment of these patients.154
Metformin is available in two formulations: immediate- and extended-release, which are administered orally. Even if no dose-finding study is available, metformin administration at incremental doses from 500 to 2,500 mg/day was proposed to treat women with PCOS.154 Several systemic and local effects were demonstrated to explain the reproductive benefits due to metformin administration.154
In practice, metformin seemed to restore the ovulatory function after almost 3 months of treatment; thus it could be recommended in PCOS patients who absolutely wish to avoid multiple gestations and/or in patients who do not tolerate CC and/or in those who do not have an imminent reproductive need.154 On the basis of literature data and on our experience, metformin (at a dosage of 1,700–2,000 mg/day, and for at least three cycles) should be used in selected cases of oligoanovulatory PCOS patients who wish to avoid multiple gestation and/or in patients who do not tolerate CC, are CC-resistant and/or in those who do not have an imminent reproductive need and/or in those undergoing IVF.
Oral contraceptives are the basis of hormone therapy, as they contribute to the reduction of hyperandrogenemia, hirsutism and acne [34-36]. A combination of 35mg ethinyl estradiol and 2 mg cyproterone acetate is usually administered. The latter is an antiandrogen, particularly effective in the reduction of testosterone and D4-androstendione and the normalization of the LH/ FSH ratio. However, it seems to have a negative effect on the lipid profile, causing a significant increase of triglyceride levels [37]. Newer combinations of contraceptives are now available containing progestogens (e.g. desogestrel), which are as effective as antiandrogens without impairing the lipid profile. Finally, a combination of 30mg ethinyl estradiol and drospirenone is also advisable. Its main advantage is that it does not cause weight gain due to its mild diuretic effects.
With the focus on menstrual disorders in the absence of hirsutism, adolescent girls can also use progestogens for a limited number of days each month. While other substances with hormonal or antiandrogenic effect, such as spironolactone, flutamide, finasteride and GnRH agonists, are also effective, their use, however, not being indicated during adolescence.
Metformin, aimed to manage insulin resistance, is widely used in the treatment of PCOS, in daily doses ranging from 500 mg to 2000 mg. It has been shown to reduce hyperandrogenemia by increasing the levels of SHBG. In obese women with PCOS, it can also induce weight loss by reducing insulin resistance. Lastly, metformin is beneficial in adolescent girls with PCOS with regard to ovulation, the normalization of the menstrual cycle and even loss of weight [38,39].
Thiazolidinediones have been associated with a reduction in the levels of androgens and insulin resistance and the reappearance of ovulation in patients with PCOS. In a number of studies, rosiglitazone and pioglitazone are reported to be effective in restoring normal menstrual cycles and reducing insulin levels in women with PCOS [40,41].
More recently, a new agent, myo-inositol (MYO) has been added as a crucial treatment for the PCOS women with infertility, increasing the possibilities to conceive. Myo-inositol is a vitamin B-like substance that can function as the basis of a number of signalling and secondary messenger molecules in insulin signalling pathways. Myo-inositol seems to correct the mal-functioning insulin pathways and reduce the signs and symptoms of insulin resistance [42].
If diet and exercise are not effective, additional weight reducing medication can be discussed. Orlistat inhibits the intestinal absorption of fat and sibutramine acts directly on the appetite center of the brain. Both cause additional weight loss of 3% and 8.5%, respectively [43,44]. However, there is not yet sufficient evidence regarding the safety of these drugs in adolescence [43].
Management of the long-term complications
The long-term risks observed in women with PCOS are not the same in all PCOS patients but they vary according to different phenotypes and results were negatively affected by obesity and lifestyle factors. When Rotterdam criteria are applied, almost uniformly accepted by the main scientific societies,13,15,16 the prevalence of PCOS in the population increases to over 20%,160 with a large majority, approximately 75%, of referred PCOS women having “classic” PCOS (according to NIH criteria) and the remaining 25% equally divided between ovulatory and non-hyperandrogenic PCOS phenotypes.161 Several studies13,162 suggest that women with PCOS, based on the classic-NIH criteria, exhibit a more detrimental metabolic and cardiovascular profile compared to milder phenotypes. In line with these considerations, the main scientific societies dealing with PCOS,13,15,16,49 have recently proposed guidelines and consensus statements, suggesting a correct diagnostic approach to PCOS patients and an effort to properly identify the phenotype of each patient, with the aim to target specific treatments and to prevent these severe long-term risks.
In consideration of the increasing prevalence of obesity, particularly abdominal, and the important bearing on the phenotype of PCOS, it is recommended that BMI and waist circumference be determined at every visit,167 considering the presence of abdominal obesity in European women with a waist circumference of at least 80 cm.167
Regarding the cardiovascular risk in PCOS women, AE-PCOS Society49 proposed, according to CVD risk classification provided by American Heart Association,168 to categorize the PCOS-related CVD risk as: “at risk” for PCOS women with any following risk factors: obesity, cigarette smoking, hypertension, dyslipidemia, subclinical vascular disease, IGT, and/or family history of premature CVD (,55 years of age in male relative, ,65 years of age in female relative); and “at high risk” for PCOS women with metabolic syndrome and/or T2DM and/or overt vascular or renal disease.
There is an overall consensus about the increased cardiovascular risk in the PCOS patients, due to relevant metabolic dysfunctions. Therefore, all societes13,15,16,49 agree to recommend a CVD risk assessment at any age, for blood pressure, complete lipid profile (including total, LDL, HDL, non-HDL cholesterol, and triglycerides), waist circumference, BMI, glucose profile, cigarette smoking, and a family history of early CVD. Moreover, depression and anxiety disorders are recognized as risk factors for CVD and they are common in PCOS women; so it is suggested that PCOS patients be assessed also for depression, anxiety, and QoL.15,16,49 Because cardiovascular risk increases with age and it can be exacerbated by obesity and worsened by environmental insults, periodic reassessment for CVD risk is suggested but there is no agreement how often the CVD risk assessment should be repeated.

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