Contemporary approaches to the management of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a common disorder in women in their reproductive years and is characterized by androgen excess, ovulatory dysfunction, and polycystic ovarian morphology. It is also associated with several metabolic abnormalities, particularly insulin resistance and obesity, which play an important role in the pathophysiology of PCOS and, in particular, negatively influence ovarian function and fertility. This review article summarizes the available treatment for women with PCOS. Specifically, current and potentially new therapies are discussed.

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive age women. Its diagnosis is based on the presence of at least two of the following criteria: hyperandrogenism, determined by the presence of total (TT) or free (FT) testosterone excess or hirsutism; ovarian dysfunction (OD), characterized by oligo-amenorrhea and chronic anovulation; and the detection of a specific polycystic ovarian morphology (PCOm). Diagnosis also requires the exclusion of all other well known disorders characterized by androgen excess^1–3 and may, accordingly, apply to several different phenotypes, defined on the basis of the combination of some of these criteria, with all the criteria defined as the classic phenotype. On the other hand, there is both scientific and clinical evidence that PCOS may be characterized by a list of dysmetabolic features, chiefly insulin resistance and compensatory hyperinsulinemia, glucose intolerance states, lipid abnormalities and low-grade inflammation, particularly in patients with the classic phenotype.⁴ In addition, it has been shown that excess body weight and obesity are increasingly associated with PCOS and which may, in turn, worsen the hormonal and metabolic features of PCOS and may, possibly, reduce the responsiveness to the most common therapeutic strategies extensively used worldwide.

Over the years, the need to improve the evaluation of the diagnostic criteria of PCOS as well as the clinical and therapeutic management of each patient became increasingly evident. In 2012, a document from the Expert Panel at the NIH (United States)⁵ suggested a list of actions aimed at improving the understanding in the diagnosis and management of PCOS, including the need for specific biological and clinical markers using a phenotype-biological approach; the advisability of expanding the use of more precise and accurate techniques for measuring circulating androgens; the promotion of scientific efforts to better define the causes, predictors, and long-term metabolic consequences of PCOS; and finally, improvement of optimal prevention and treatment strategies based on individual needs and the specific phenotypes. In this short review article, I will summarize the most commonly used therapeutic strategies in relation to the major criteria defining PCOS.

Treatment of hyperandrogenism in PCOS

Treatment of hyperandrogenism is a key step in the management of women with PCOS. Before discussing how to improve or normalize androgen blood levels, I would like to summarize the most recent news related to a crucial aspect, that is, how to define hyperandrogenemia and its relationship with the severity of hirsutism.

Definition of hyperandrogenemia and sources of androgens in women with PCOS

According to the current guidelines,^1–3 the fundamental criterion for diagnosis is represented by biochemical (elevated TT blood levels) and clinical hyperandrogenism (represented by hirsutism). A major aspect is the finding that an androgen profile, rather than the evaluation of TT alone, may be a more appropriate way to define hyperandrogenemia in women with PCOS. In fact, in 2009 the document by the Androgen Excess & PCOS Society (AE-PCOS) clearly showed that, based on the data reported in a list of 18 published studies, approximately 50–60% of women with PCOS had higher than normal blood TT or FT levels and that hirsutism was present in less than three-quarters of these patients.³ Although it can be accepted that TT and FT are major components of the androgen pool in women, at present it should also be accepted that the restriction of TT measurement alone could represent a simplistic limitation, due to the fact that a large number of weak or more potent androgens are not considered and that, particularly in women, most of the available immunoassays for androgen measurement are decidedly unsatisfactory.⁴ More advanced technologies, such as liquid chromatography and tandem pass spectrometry (LC-MS/MS)^6,7 are capable of measuring a variety of steroids. As a result, this could in fact reveal that androgen excess in women with PCOS may not be restricted to the contribution of the ovaries, but also that of the adrenal glands, the adipose tissue and, possibly, the skin, in which there is a rich steroidogenesis, with specific mechanisms of regulation of both the synthesis and metabolism of these hormones. Very recent studies have clearly shown that the combination of TT, Δ4-androstenedione (Δ4-A), the free androgen index (FAI) and 5α-dihydrotestosterone (DHT) better predict any adverse metabolic risk, chiefly insulin resistance and glucose intolerance states.^8,9 In addition, one study confirmed that the androgen profile was unrelated to the degree of hirsutism.⁹ Intriguingly, recent findings also support a potentially important role of adrenals in determining the hyperandrogenemic state in these patients. This is related to the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans, a pool of hormones that for a long period of time was thought to possess only minimal activity. At variance, a recent study by O’Reilly and coworkers,¹⁰ performed in a large cohort of women with PCOS, provided very good evidence that, apart from elevated blood levels of TT, Δ4A and dehydroepiandrosterone (DHEA), serum levels of adrenal 11-oxygenated androgens were significantly higher than in control subjects. Overall, these new data strongly support the concept that 11-oxygenated androgens may play a potentially important role in defining the androgenic status in women with PCOS and that their activity can be supported by the close correlation to markers of metabolic risk. We thus have a new perspective in the definition of hyperandrogenemia in women with PCOS, which may disclose different hyperandrogenic patterns according to the different phenotype of PCOS and the potential role of adrenals in determining the hormonal profile in these women. Whether this profile may differ according to the various PCOS phenotypes can represent an exciting challenge for future research.

The OD-PCOm phenotype: a hyperandrogenemic entity or not?

Another issue is represented by some new findings in the definition of the so-called nonhyperandrogenic phenotype of PCOS, characterized by OD plus PCOm, but normal TT blood levels and no hirsutism. Whether women with the OD-PCOm phenotype may be defined as normo-androgenemic was first investigated by Dewailly and coworkers 10 years ago.¹¹ They reported that a subset of patients with the OD-PCOm phenotype had normal TT blood levels; however, both TT and Δ4A (measured by an enzyme linked immunosorbent assay) were significantly higher than control women without PCOS, even though their blood levels were in the normal reference range, which suggests that the absence of overt hyperandrogenemia might simply represent a false-negative finding in the subset of PCOS women with this phenotype. Accordingly, we recently demonstrated that more than 50% of patients with the OD-PCOm phenotype displayed a specific pattern of steroid abnormalities, characterized by elevated Δ4A or FAI but normal TT blood levels (measured by LC-MS/MS), which confirms that they are truly hyperandrogemic.⁹ Undoubtedly, this new aspect merits further consideration by additional studies.

Treatment of hyperandrogenemia and hirsutism

At present the treatment of hyperandrogenemia and hirsutism is based on therapeutic protocols aimed at reducing the endogenous production of androgens, and on the utilization of nonhormonal procedures. Increased androgen production rates and tissue availability represent the main pathophysiological mechanisms responsible for hirsutism. In fact, androgens may also be generated de novo in the hair follicles, therefore circulating androgen levels do not quantify the real exposure of the hair follicle to androgens, since a quota is generated locally. Hirsutism by itself may cause important psychological problems and dissatisfaction as suggested in several studies.^12,13 Physicians should therefore decide whether hirsutism is to be treated or not by evaluating its severity while also considering the patient’s subjective perception of the condition. It is important to emphasize that hirsutism may be exacerbated by the presence of obesity, particularly the abdominal phenotype,¹⁴ and that it may predict the metabolic sequelae¹⁵ or failure to conceive with infertility treatment.¹⁶ One major problem is that the evaluation of hirsutism is performed by visual scoring (the so-called modified Ferriman–Gallwey score), which has been shown to be potentially subject to interobserver variability.¹⁷ Unfortunately, although objective methods for assessing hair growth (such as photographic evaluation, weighing of shaved or plucked hairs and microscopic measurements) have been proposed,¹⁸ these are complex, inconvenient and costly, and their use is therefore extremely limited. In any case, the diagnosis and evaluation of hirsutism should always be associated with an androgen profile, as mentioned above.

Typical ways to treat hyperandrogenism include cosmetic procedures (specifically for hirsutism), estro-progestins, antiandrogens alone or combined with ethinylestradiol, and if necessary, insulin sensitizers, particularly metformin. Cosmetic measures may be effective as individual treatments in controlling mild and localized hirsutism and, in some cases, they can be associated with a pharmacological treatment in cases of clinically moderate to severe hirsutism. They include both depilatory and epilatory methods.¹⁹ Chemical depilatory methods often require multiple treatments and may have side effects, such as hair growth or pigmentation.¹⁹ Epilatory methods, which have been refined in the last few years, include various widely available options: electrolysis, thermolysis, and mostly, laser treatment. The latter may offer a clear clinical advantage in terms of outcome as defined by a permanent amelioration of hirsutism, although this is largely operator dependent.²⁰ A Cochrane review of hair removal by lasers showed good effectiveness of these techniques, although the performance of alexandrite and diode lasers proved to be higher, with relatively modest side effects.²¹

As mentioned above, the most commonly used therapy in the treatment of hyperandrogenemia is a systemic pharmacological approach. Even today, estrogen–progestin compounds (EPs) may lead to an acceptable improvement of the hyperandrogenic state, and in addition, they are safe and have a positive cost-effectiveness aspect. Their efficacy is mainly justified by the ability of progestin to suppress luteinizing hormone (LH) levels and thus ovarian androgen production, and by the ability of estrogen (specifically ethinylestradiol) to increase sex-hormone-binding globulin (SHBG), thereby reducing bioavailable free androgens.²² Moreover, EPs induce a moderate reduction of adrenal androgens, probably through a direct interaction with adrenal steroid synthesis. In addition, some progestins have antiandrogenic properties, due to their antagonizing effects on the androgen receptor and to the inhibition of 5α-reductase activity. This class of compounds includes cyproterone acetate, drospirenone, dienogest, clormadinone acetate, and ‘third-generation’ progestins (desogestrel, gestodene, norgestimate).²² A review article on the efficacy of this panel of drugs is available for further consideration.¹⁹ Unfortunately, almost all studies investigating the potential efficacy of drugs on hirsutism lasted for a maximum of 6–12 months, so it is unclear how long any systemic treatment should be continued. Older reports, mostly relative to high-dose EPs, showed the efficacy of these compounds in reducing hirsutism with a 60–100% response.²² In a systematic review of nine studies using cyproterone acetate to treat hirsutism in different regimens, either dosed at 2 mg associated with ethinylestradiol or given at 25–100 mg, an improvement of hirsutism was seen both in patients with PCOS and in those with idiopathic hirsutism when compared with placebo.²³ A comparative study of an EP containing 0.15 mg of desogestrel plus 30 µg of ethinylestradiol versus an EP containing 2 mg of cyproterone acetate plus 35 µg of ethinylestradiol demonstrated a similar efficacy in reducing hirsutism in a group of adolescents with PCOS.²⁴ Drospirenone/ethinylestradiol pills seem to be more efficacious in reducing hirsutism when compared with a formulation containing 2 mg of chlormadinone acetate and 30 µg Ehinylestradiol (EE);²⁵ although drospirenone per se has little antiandrogenic effect, its combination with contraceptive doses of estrogens confers an antiandrogen effect via inhibition of gonadotropin secretion. Since all EPs alone are efficacious in reducing hirsutism, probably more in normal weight than in obese patients, EPs containing a progestin with antiandrogen properties should be preferred for the treatment of hirsutism in the latter.

Antiandrogens may represent an alternative way to improve both hyperandrogenemia and hirsutism. The most commonly used antiandrogens are androgen receptor blockers (flutamide, spironolactone) and 5α-reductase inhibitors (finasteride). Their use varies considerably in different countries, which is partly due to the indications of regulatory agencies, although they have been proved to be very effective.²⁶ Flutamide has been considered with particular attention, in both adolescent²⁶ and adult^27,28 women with PCOS, due to its potentially negative effect on liver function. Importantly, it has been reported that side effects can be easily avoided if low doses (for example 62.5–125 mg/daily) are administered.^27,28 A recent review article reported that at these low doses hepatic dysfunction is extremely rare, whereas long-term efficacy on hirsutism is preserved.²⁹ Obviously, antiandrogens should not be given to pregnant women due to the risk of feminization of male fetuses and should only be prescribed to women using secure contraception.

The efficacy of metformin on androgen and, indirectly, on hirsutism has been investigated.¹⁹ A systematic review and meta-analysis of randomized controlled studies on metformin or thiazolidinediones, alone or combined with EPs or antiandrogens, confirmed that insulin sensitizers only produce significant but modest effects on hyperandrogenemia and have only limited efficacy on hirsutism with respect to placebo.³⁰ The use of metformin alone in these patients is, therefore, questionable.

In general, the side effects of the compounds discussed above are relatively acceptable, mild and reversible, with some exceptions. EPs may be associated with an increased risk of thromboembolism.³¹ A recent systematic review and meta-analysis focused on the risk of venous thromboembolism and cardiovascular risk factors and events in women taking drospirenone added to ethinylestradiol, supporting the concept that long-term use of this drug may be associated with higher risks, compared with both no treatment or levonorgestrel combined with ethinylestradiol.³¹ This event should therefore be taken into account when planning a treatment including drospirenone. Unfortunately, the use of flutamide is not currently recommended in many countries, although it has been shown that the potential hepatotoxicity of this drug is extremely rare when low doses are administered.

Treatment of ovarian dysfunction (oligo-amenorrhea and oligo-anovulation) and infertility

OD and chronic anovulation are cardinal features of adult women with PCOS and can be easily defined. By contrast, these disorders may be relatively difficult to define in adolescents.

Treatment of menstrual dysfunction in adolescent girls with PCOS

Recently, the Pediatric Endocrine Society defined appropriate criteria for the diagnosis of PCOS in adolescence, which included an otherwise unexplained combination of abnormal uterine bleeding pattern, abnormal for age and persistent for 1–2 years, and evidence of hyperandrogenism, by increased TT levels or moderate–severe hirsutism or moderate–severe inflammatory acne vulgaris.³² As briefly discussed in the previous paragraph, it is not always easy to distinguish menstrual alterations, even in later Tanner stages, as it may be difficult to prove that anovulation is frankly pathologic. In many cases a proper evaluation over time is appropriate in order to avoid misdiagnosis. Nevertheless, specific attention should be paid in adolescent girls to the presence of excess weight or obesity that is often associated with insulin resistance and hyperinsulinemia which per se may be a causative factor responsible for androgen excess. In addition, both insulin resistance and obesity may impair both thecal and granulosa cell function, as well as follicle recruitment and growth.⁴ As a consequence, hyperandrogenemia, insulin excess and obesity are also associated with an increased susceptibility to ovarian dysfunction and chronic anovulation. Treatment of OD during adolescence therefore requires specific attention, if necessary including both the use of EPs as well as the correction of comorbidities such as excess weight or obesity and metabolic alterations, such as insulin resistance. The recent Endocrine Society guidelines suggested that EP compounds should be used only in late adolescence (Tanner stage 4–5).³³ Although the best EP for adolescents and the appropriate duration of therapy are uncertain,³⁴ a longer duration of treatment with EPs seems to favor a lower chance of developing signs of hyperandrogenism during adulthood.³⁵ Excess body weight in adolescent girls may be responsible for an increased prevalence of PCOS,³⁶ therefore long-term lifestyle intervention should always be planned. Nevertheless, the treatment of PCOS in adolescents is still controversial, since many clinical researchers support a symptom-driven approach, whereas others support an approach targeting the underlying reproductive or hormonal and metabolic abnormalities associated with PCOS.³⁷ At present there are no well powered, randomized, double-blind, placebo-controlled trials in adolescents with PCOS, therefore the goal of treating hyperandrogenism and providing contraception prompts the use of EPs as the mainstay of therapy for adolescents with PCOS.³⁸ Importantly, short-term studies demonstrated that metformin restored menstrual regularity, and improved hyperandrogenemia and metabolic dysregulations in obese as well as in nonobese adolescents with PCOS,^39–41 suggesting that metformin may be highly beneficial in adolescents with PCOS, probably much more than in adult women with PCOS.⁴²

Treatment of menstrual dysfunction in adult women with PCOS

Menstrual dysfunctions, particularly oligomenorrhea and amenorrhea, can be observed in the majority of adult patients with PCOS, ranging from 75% to 85%.^3,4 These patients are particularly interested in correcting both the excess of androgens as well as OD. If a patient wants a pregnancy, anovulatory infertility represents a major problem in fertile-age women with PCOS. From a clinical point of view, when an adult woman with PCOS is obese and insulin resistant, lifestyle intervention should always be adopted as the first therapeutic step. A number of uncontrolled intervention studies provided good evidence that, even in the short term, weight loss induced by lifestyle intervention may be followed by significant benefits on the whole spectrum of clinical, hormonal, and metabolic alterations of PCOS.⁴³ Fairly uniform improvements in many key features of PCOS have been repeatedly reported, even with only modest weight loss (5–10%).⁴⁴ The role of lifestyle in the preconception counselling of overweight women was particularly emphasized by an international workshop endorsed by European Society for Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM), a decade ago.⁴⁵ Unfortunately, very few centers worldwide apply this recommendation in their clinical practice, preferring pharmacological therapy in the first instance. Among pharmacological therapies, metformin and clomiphene citrate (CC) have been extensively used in the last few decades.

Pharmacological treatment of oligo-anovulation and infertility in adult PCOS

In the last two decades, major improvements have been achieved in ovulation induction protocols and techniques, including assisted reproductive technologies (ARTs), leading to a steady rise in pregnancy rates as demonstrated by national statistics worldwide. Anovulatory infertility, particularly the type due to PCOS, represents one of the major factors responsible for the increasing resort to ovulation induction worldwide. In this paragraph I will only discuss pharmacological therapies but not ARTs.

Metformin is a classic insulin-sensitizing drug and plays a major role in the treatment of type II diabetes. It is important to emphasize that many studies have provided evidence that treatment with metformin improved insulin resistance and compensatory hyperinsulinemia in most women with PCOS, thereby reducing circulating androgens and the free androgen fraction availability, due to an increase in SHBG synthesis.⁴⁴ The combination of these effects has been demonstrated to favor, in turn, ovarian thecal and granulosa cell function, thereby increasing fertility rates in otherwise hypofertile or infertile women with PCOS.⁴⁶ Metformin does, in fact, have pleiotropic actions on several tissues sensitive to the primary effect of insulin, such as the liver, the skeletal muscles, the adipose tissue, the endothelium, and the ovaries.⁴⁷ It also decreases hepatic glucose production mainly by inhibiting gluconeogenesis and increases insulin-mediated glucose uptake in the liver, visceral fat, and muscles.⁴⁸ As mentioned above, metformin also has a direct effect at the ovarian level. Consistent with its effects, most studies have shown that metformin significantly improves menstrual cycles and ovulation rates in most women with PCOS.⁴⁹ In addition, a decreased risk of abortion has been reported, mediated by the increase of some factors needed for implantation and pregnancy safekeeping, such as insulin growth factor binding protein 1 and glycodelin levels, or uterine artery blood flow. The highest level of evidence on the use of metformin versus placebo or no treatment comes from two meta-analyses published a decade ago. A meta-analysis, including 13 randomized controlled trials (RCTs) available at that time, clearly confirmed that metformin was effective in achieving ovulation in women with PCOS with an odds ratios (OR) of 3.88 when metformin was compared with placebo.⁵⁰ Another meta-analysis that evaluated a list of RCTs comparing metformin with placebo or no treatment confirmed that metformin significantly improved ovulation rate (OR = 2.12; 13 RCTs), and most importantly, clinical pregnancy rate (OR = 3.86; 6 RCTs) but not live birth rate (OR = 1.0; 2 RCTs) per woman.⁵¹ These data led to a widespread use of metformin to improve menses alteration and ovulatory performance. Unfortunately, therapeutic regimens of metformin administration in PCOS are still not well standardized in clinical practice, and various protocols have been used in the studies available in the literature, with an extremely variable target dose of 1500–2550 mg/day having been proposed.⁵² Although there are data supporting the effectiveness of metformin in improving metabolic issues, it should be remembered that its ability to reduce androgen and to improve menses is relatively independent of the doses.⁵²

CC is a selective estrogen receptor modulator (SERM) with both estrogenic and antiestrogenic properties, used as the first-line medical ovulation induction agent for over 40 years.⁵³ Acting as an antiestrogen, CC competitively inhibits the binding of estradiol to its receptors in the hypothalamus and pituitary which, in turn, blocks the negative feedback effect of endogenous estrogens including estradiol. This results in an increased secretion of pulsatile gonadotropin-releasing hormone secretion, leading in turn to an increase in follicle stimulating hormone (FSH) and LH secretion. The increase in FSH secretion stimulates follicular growth and estradiol production with the final occurrence of a mid-cycle LH surge and ovulation.⁵⁴ CC is usually administered for 5 days beginning on menstrual cycle day 2–5, starting with 50 mg/day and increasing to 150 mg/day. If ovulation cannot be achieved with these high doses, then a resistance to CC is suggested. If pregnancy cannot be achieved after six ovulatory cycles with CC, CC failure is definitely assumed.⁵⁵ Studies with CC have shown a performance of ovulation rate of 60–85% and a pregnancy rate of 30–50% after at least six ovulatory cycles. A meta-analysis comparing CC with placebo showed that CC improved ovulation rate per patient (OR = 7.5; p < 0.0001) and pregnancy rate per patient (OR=5.8; p < 0.01).⁵¹ There are also data supporting the concept that pretreatment with metformin may sensitize for CC action in women with PCOS.²⁰ In addition, other studies supported the concept that metformin may be effective in so-called CC-resistant women with PCOS.^56,57 An important study performed about 20 years ago clearly showed that the pretreatment with metformin for 1 month was able to significantly improve the ovulatory response to CC.⁵⁸ After that study, combined metformin and CC treatment became very popular and many later studies confirmed the adequacy of the therapy as well as the evidence of significant positive results.⁵⁹ A more recent study tested the hypothesis that treatment of women with PCOS with extended-release metformin is more likely to result in a live birth than treatment with CC and that the combination of the two therapies will result in the highest live-birth rate. This large RCT, named the ‘PPCOS trial’, compared three different treatments: CC+placebo, metformin+placebo, and the combination of CC+metformin for up to 6 months.⁶⁰ The study found that the live birth rate was significantly higher in the CC group (22.5%) than in the metformin group (7.2%), and that the combination therapy achieved a goal of 28.8%, whereas the conception rate among women who ovulated was significantly lower in the metformin group (21.7%) than in either the CC (39.5; p = 0.002) or the combination therapy group (46.0%, p < 0.001). As a matter of fact, a specific limitation of the study was that the majority of women enrolled were obese (in fact, most had massive obesity), and that no lifestyle therapy was prescribed to these women. It should also be pointed out that metformin and CC have critical pharmacological differences, since CC has a rapid action, whereas metformin’s onset of action is slower and gradual and up to 6 months of treatment may be needed to clinically improve ovulation.⁶¹ The conclusions of the PPCOS trial were, therefore, not universally accepted, particularly by endocrinologists. In addition, the study did not consider that the type of infertile woman with PCOS is a critical component of the decision process, since some women desire pregnancy immediately, whereas for most of them the timeline for achieving pregnancy differs considerably. In fact, it is well documented that ovulation may improve in many women with PCOS when treated with metformin for at least 6 months.⁶¹ I therefore support the idea that the rationale for pretreatment with metformin before adding CC is still appropriate.⁶² This is indirectly confirmed by another RCT comparing the effect of CC and metformin, alone or in combination, and lifestyle modification in more than 300 overweight women with PCOS.⁶³ The authors reported that clinical pregnancy was 12.2% in the CC group, 14.4% in the metformin group, 14.8% in the combination group, and 20% in the lifestyle modification group. These findings therefore confirm that in otherwise infertile women with PCOS and excess body weight or obesity lifestyle modification should be used as a first line of ovulation induction.

The use of aromatase inhibitors in correcting infertility in women with PCOS may represent a new challenge. It has been known for some time that this drug is able to favor fertility in infertile women with PCOS via a functional block of the hypothalamic–pituitary–ovarian function. A recent large, double-blind, multicenter, randomized trial tested the hypothesis that letrozole, a well known aromatase inhibitor, is superior to CC as an infertility treatment and could result in better pregnancy outcomes.⁶⁴ The main results in favor of letrozole were significantly increased cumulative ovulation rates and significantly higher live births, but there were no significant between-group differences in pregnancy loss or more twin pregnancies. Based on these findings, the authors suggested that letrozole is headed toward replacing CC as the first-choice option.⁶⁵ There is, however, still some concern about several aspects involving letrozole use in infertile women with PCOS, which mainly relate to the following: whether the efficacy is similar in obese versus normal weight women; the appropriateness of adding a lifestyle intervention plan in obese women with PCOS; its likely inefficacy on androgens; the lack of definition of so called (s.c.) letrozole resistance, and finally, the potential fetal risk. In fact, some potential teratogenic and embryotoxic or fetotoxic activity has been reported in animal models.⁶⁶ Further research is thus undoubtedly warranted in this area.

The impact of obesity on the development of PCOS and its treatment

Obesity has become a major contributor to the global burden of disease and its worldwide incidence is continually increasing, with a large variability among countries and continents.^67–69 This trend is also evident in young individuals, from childhood to adolescence. For example, in the United States, the prevalence of BMI by selected cutoff for young people aged 2–19 years is very high in both boys and girls, with peaks that can exceed well over 30%.⁷⁰ Again, in the same country, a retrospective study with a large cohort of individuals, the Longitudinal Assessment of Bariatric Surgery 2, reported that the risk of developing PCOS during late adolescence increased by approximately 75%.³⁶ These findings were in some way expected, since many previous studies had shown that the development of excess body weight or obesity during adolescence may favor menstrual and ovulatory disorders.⁷¹ As reported above, there is evidence that excess weight or obesity, particularly the abdominal-visceral phenotype, may per se be associated with elevated androgen production rates in adolescent girls.⁷² Intriguingly, longitudinal studies have shown that adolescent serum androgen levels may be preserved into adulthood and are associated with menstrual dysfunction, which suggests a potential risk of developing PCOS, particularly in the presence of high body mass index (BMI).⁷³ In addition, it has been shown that the neuroendocrine disruption (at the hypothalamic–pituitary level) can be associated with alterations in the sex hormone balance, including ample substrate aromatization in the fat tissue, which obviously contribute to early estrogenization in girls and increased adrenal androgen production. Insulin excess, due to the development of insulin resistance in the adipose tissue, may be responsible for these abnormalities, since insulin is able to stimulate adrenal steroidogenesis.^74,75 Additional mechanistic alterations responsible for androgen excess in adolescent obese girls have been widely summarized in previous review articles, to which the reader can refer for further details.^71,76,77 Overall, these findings suggest that the development of excess body weight during adolescence could be responsible for the development of the PCOS phenotype later in life. In adult women with PCOS it has been reported that obesity per se may significantly worsen the PCOS phenotype.⁷¹ This implies that a treatment of obesity with lifestyle intervention with or without antiobesity drugs and metformin, or with bariatric surgery, may be the first therapeutic choice in these patients. On the other hand, it should be mentioned that the recent Australian guidelines support the use of multidisciplinary lifestyle intervention (which may require behavioral change), also including an assessment of emotional wellbeing and, if necessary, treatment of associated psychological disorders.⁷⁸ In fact, these disorders are frequently associated with PCOS.⁴

There are very convincing data on the potential benefits of weight loss achieved by lifestyle intervention with or without insulin metformin or antiobesity drugs.^79,80 Unfortunately, most of these studies are relatively short, rarely exceeding 6 months.^79,80 These interventions even more rarely included psychological and behavioral support. Notably, a great interindividual variability in the response to weight loss has been reported and potential predictive factors are still largely underevaluated.^79–81 Nevertheless, there is some evidence that metformin doses (higher than 2000 mg/day) may favor the achievement of a more significant weight loss.^79,81 Here I would like to emphasize the data coming from studies using long-term lifestyle intervention and including patient empowerment and those coming from severely obese patients with PCOS treated with bariatric surgery. A long-term clinical study (follow-up period of 20.4 ± 12.5 months), using systematic lifestyle intervention⁸² and cyclic patient empowerment in 65 obese women with PCOS, reported very new data, based on clinical, biochemical (steroid blood levels), and morphological findings (ovarian morphology by ultrasound). In fact, at the end of the study, it was found that 15% of these women had a persistence of the full PCOS phenotype, 48% had a partial improvement (still hirsute, minor recovery in androgen blood levels and ovarian dysfunction), and finally, 37% completely recovered from all features of PCOS (normal androgen blood levels, hirsutism score below 8 and normal menses and ovarian morphology). Importantly, the extent of weight lost was similar among the three subgroups (BMI change values: −4.8 ± 2.9, −5.8 ± 3.1, and −5.4 ± 2.5, respectively).⁸³ These findings have obviously to be replicated, but they nonetheless confirm the importance of weight loss in improving or even completely correcting all PCOS clinical and endocrine disorders. Studies on the effects of bariatric surgery in women with PCOS and severe obesity reported much more convincing data on the benefits of sustained weight loss. In fact, a recent meta-analysis,⁸⁴ including 13 primary studies and involving more than 2000 patients with PCOS, has provided important confirmation of the effectiveness of weight loss in severely obese women with PCOS. The most astounding findings were that after 1 year and sustained weight loss (BMI decreased from 46.3 to 34.2), the prevalence of women with PCOS decreased from 45.6% preoperatively to 6.8% (p < 0.001) at the 12-month follow up. Interestingly, among the criteria used for the definition of PCOS at baseline, the study found that menstrual irregularities decreased from 56.2% to 7.7% (p < 0.0001), the incidence of hirsutism declined from 67.0% to 38.6% (p = 0.03), and infertility declined from 18.2% to 4.3% (p = 0.0009). It was therefore demonstrated that an important weight loss in relation to initial weight can effectively counteract the phenotypic characteristics of PCOS, including infertility. The results of these studies should therefore encourage the increasing use of the most appropriate strategies to correct obesity in patients with PCOS. In addition, as we suggested in a recent article, these data may also support the hypothesis that there may be a specific phenotype of PCOS secondary to obesity, which is ultimately consistent with the fact that PCOS is a syndrome and, therefore, there may be relatively different phenotypes with specific pathophysiological mechanisms.¹⁹

Conclusion

Although there are obvious differences in the clinical presentation of PCOS in adolescent girls and in adult women with PCOS, nonetheless many therapeutic possibilities exist to correct the major clinical and biochemical manifestations of PCOS. Every physician should be able to choose the most appropriate therapeutic protocol in relation to the severity of clinical manifestations and the possible prospect of a pregnancy. The presence of excess weight or obesity should in any case indicate the need for a specific therapy for significant weight loss. In such cases, pharmacological therapy can undoubtedly lead to more satisfactory clinical results. It should also be borne in mind that hirsutism therapy can include not only pharmacological approaches, but also epilatory therapies, such as laser therapy. This article does not consider the techniques of ovarian stimulation with gonadotropins or those of assisted fertilization, including ARTs, given their complexity which requires the intervention of dedicated professionals, and which goes beyond the objectives of the article itself.