Update on Polycystic Ovary Syndrome

Abstract

We have witnessed an enormous expansion in clinical and basic data regarding polycystic ovary syndrome (PCOS) over the last 70 years, since Stein and Leventhal first described it. The current knowledge regarding PCOS appears to have broader health implications and has profoundly altered our view of the gravity of this condition.

Concomitantly, a tremendous growth of interest in the diagnosis and management of the syndrome has developed from different subspecialisms of the medical sciences.

The Athens PCOS International Congress intended to be the exclusive forum where the leading experts, from major disciplines such as endocrinology and obstetrics and gynecology, discussed state-of-the-art scientific advances of this multifaceted syndrome.

The congress goal was to present the many unresolved issues of hormonal, reproductive and metabolic aspects of the syndrome by pointing out the gaps where evidence is not sufficient and to consolidate our knowledge when it is justified by the provided data.

This report provides an overview of the lectures of the well-known investigators and clinicians who convened in this international Congress in an effort to synthesize recent knowledge regarding the msot common endocrinopathy of reproductive-aged women.

Definition, epidemiology & pathophysiology of PCOS

The definition of PCOS has been a matter of conflict and confusion for many years. Bart CJM Fauser emphasized the importance of understanding that PCOS has moved from a histology diagnosis of ovarian tissue, to a heterogeneous clinical syndrome, to a reproductive endocrine abnormality and finally to a metabolic disease characterized by hyperinsulinemia and dyslipidemia [1,2]. This shift of focus from ovarian abnormalities and ovulation induction for infertility, towards the prevention of long-term health consequences, has major implications for patients' health and may also be represented by the involvement of many medical specialists.

There is consistent clinical evidence that the clinical features of PCOS may change throughout the lifespan, from adolescence to postmenopausal age. Insulin resistance and hyperinsulinemia are key features of women with PCOS, particularly in the presence of obesity. Renato Pasquali stressed the important role of insulin resistance in PCOS. Insulin excess does in fact have a direct responsibility in favoring androgen excess and oligoanovulation in PCOS. Conversely, insulin resistance represents the main pathophysiological event leading to the development of the metabolic syndrome [4,5]. It appears that the prevalence of insulin resistance in PCOS exceeds that expected in the general population and is even higher in the presence of obesity, particularly the abdominal phenotype [4]. However, it can be found even in some normal-weight women with PCOS.

David A Ehrmann laid emphasis on the increased prevalence of impaired glucose tolerance, which is estimated to be 30–40%, while that of Type 2 diabetes mellitus (DM) is 5–10% [6]. Genetic and environmental factors influence the risk of DM in PCOS. Women with PCOS appear to have an increased risk of developing gestational DM, although this has not been firmly established. Once defects in insulin secretion develop in the setting of the characteristic insulin resistance of PCOS, glucose intolerance becomes evident and this may occur as early as the second decade of life. Studies by Arslanian and colleagues have demonstrated that metabolic precursors to Type 2 DM are evident among obese adolescents with PCOS [7].

PCOS is characterized by hyperandrogenemia and disordered gonadotropin secretion, often associated with insulin resistance. The extensive heterogeneity of PCOS has led to multiple mutually inconsistent theories of its etiology including:

A primary defect in insulin action and/or secretion leading to hyperinsulinemia

A primary neuroendocrine defect leading to an exaggerated luteinizing hormone (LH) pulse frequency and amplitude

A primary defect in ovarian/adrenal androgen biosynthesis resulting in hyperandrogenism [8]

However, no single mechanism appears to account for all forms of the syndrome, suggesting that PCOS is a group of diseases that have different pathophysiological mechanisms but lead to closely related clinical phenotypes.

Walter L Miller called attention to the importance of understanding the cell biology of androgen biosynthesis and insulin action, which will permit delineating the pathophysiologies of PCOS and may lead to more specific pharmacological therapy.

Andrea Dunaif pointed out the necessity of further study of the role already identified and other mechanisms impairing the insulin receptor or its downstream signaling proteins in women with PCOS. The plausible cause of this unique form of insulin resistance is a postbinding defect in insulin signaling, associated with constitutive serine phosphorylation of the insulin receptor or downstream signaling proteins secondary to an as yet unidentified serine kinase, selectively affecting the metabolic, but not mitogenic, actions of insulin in some tissues [10 –12]. Such a defect might lead to increased susceptibility to factors inducing insulin resistance that are present in vivo, such as free fatty acids and cytokines.

Uberto Pagotto called attention to PCOS as a potential future target for cannabinoid 1 receptor-antagonist therapy [13]. Rimonabant seems to work not only as an anorectic drug but also as a positive modulator of crucial metabolic steps at the peripheral level, inducing an improvement of the lipid and glycemic profiles partially independent of weight loss. In the case of the PCOS associated with obesity, this class of drugs may offer the opportunity for relevant improvement of insulin resistance, while the improvement in the lipid profile and the increase in adiponectin may correct metabolic alterations. In addition, the deleterious effects of exogenous and endogenous cannabinoids on the hypothalamic–pituitary–ovarian axis at various levels may be corrected by the addition of a drug believed to normalize the overactivation of the system.

The concept that diseases such as the metabolic syndrome begin in adulthood no longer appears to be accurate. An uncertain proportion of children with premature adrenarche (PA) appear at risk of developing these adult diseases. Sharon E Oberfield underlined some of the risk factors and markers of children with PA associated with development of adulthood metabolic syndrome and PCOS, including obesity, Hispanic ethnicity and African–American versus Caucasian race, decreased insulin sensitivity in childhood, and the phenotype of excessive adrenal E5-steroid secretion [14].

The association of visceral adiposity and intramyocellular lipid (IMCL) with insulin resistance has been established in adults and obese children and adolescents. Women with PCOS also tend to have abdominal adiposity. Increased trunk fat by dual x-ray absorptiometry (DXA) in prepubertal girls with PA, and its correlation with hyperinsulinism without differences in body mass index (BMI) compared with controls, suggests that there may be an increase in visceral adipose tissue in girls with PA. Initial analysis of a small pilot study demonstrated a significant increase in IMCL deposition in girls with PA [15,16].

Genetics of PCOS

Héctor F Escobar-Morreale highlighted the genetic contribution to PCOS. The familial aggregation of PCOS suggests that genetic factors are involved in the pathogenesis of this common disorder [17]. Genomic variants that favor insulin resistance and hyperinsulinism would probably facilitate androgen synthesis, especially in women whose androgen synthesis is primarily exaggerated. The influence of insulin resistance and its related genomic variants on the development of PCOS is possibly a continuous ‘gray-scale’ variable: at one extreme, in some patients the primary defect in steroidogenesis is severe enough to result in PCOS without the need of the facilitating role of hyperinsulinism; whereas at the other extreme, a mild excess in androgen synthesis is triggered by the concurrent stimulatory effect of insulin resistance and hyperinsulinism in other patients. In morbidly obese women, PCOS may actually resolve after normalizing insulin sensitivity in response to weight loss achieved after bariatric surgery [18], in sharp contrast with the fact that PCOS may also occur in lean, insulin-sensitive women.

Clinical aspects & diagnosis of PCOS

Ann E Taylor described the clinical evaluation of PCOS, which begins with a complete medical history and physical examination. The clinician has a responsibility to evaluate all the health impacts of the condition on the patient. It is important to remember that individual patients who may not meet strict criteria may still benefit from some of the same interventions [19].

Bulent O Yildiz described laboratory investigations that are used in patients with PCOS, mainly for the determination of biochemical hyperandrogenemia and ovulatory dysfunction. There is considerable heterogeneity in laboratory measurements and the biochemical phenotype could change over time [20]. Hormonal and biochemical abnormalities in PCOS include high serum androgen levels, low sex hormone-binding globulin (SHBG), inappropriate gonadotropin secretion, acyclic estrogen production, hyperinsulinemia/insulin resistance and lipid/lipoprotein alterations [21]. At a minimum, the initial laboratory work-up of a PCOS patient may include measuring free testosterone, dehydroepiandrosterone sulfate (DHEAS), prolactin and 17(OH) progesterone levels. Measurement of serum free testosterone levels or calculation of the free androgen index and DHEAS levels are used for the determination of hyperandrogenism. δ 4 androstenedione (A4), LH levels or the LH:follicle-stimulating hormone (FSH) ratio are not recommended for the routine evaluation of PCOS, whereas luteal-phase progesterone might be helpful to confirm ovulatory function in hyperandrogenic patients with apparently regular menses. In order to exclude thyroid dysfunction, hyperprolactinemia and non-classical congenital adrenal hyperplasia, thyroid-stimulating hormone, prolactin, and basal or stimulated 17(OH) progesterone levels should be evaluated. If other rare disorders with similar clinical presentation are suspected, further hormonal and biochemical evaluation would be necessary.

The need for a calibrated imaging of polycystic ovaries is stronger since the recent consensus conference held in Rotterdam (The Netherlands) in 2003. Didier Dewailly emphasized the importance of ultrasonography to be viewed as a diagnostic tool that requires the same quality controls as a biological one. This supposes that its results are expressed as quantitative variables rather than purely descriptive data. Currently, 2D ultrasonography remains the standard for imaging polycystic ovaries and the current consensus definition of PCOS determined at the joint American Society for Reproductive Medicine (ASRM)/European Society for Human Reproduction & Embryology (ESHRE) consensus meeting on PCOS rests on this technique [2]. The transabdominal route should always be the first step of pelvic sonographic examination, followed by the transvaginal route (except in virgin or refusing patients), which offers a better spatial resolution. Other techniques such as Doppler, 3D and magnetic resonance imaging (MRI) can help the diagnosis but are only second-line techniques [22 –24].

Reproductive & gynecological abnormalities of PCOS

PCOS is the most common cause of anovulatory infertility, but the mechanism of anovulation remains uncertain. Recent data have emerged concerning this common feature of PCOS and were analyzed by S Franks. Anovulation in PCOS is characterized by the arrest of antral follicle growth in the final stages of maturation. There is evidence that the abnormal endocrine environment in PCOS (specifically elevation of LH and/or insulin) plays an important role in the arrest of antral follicles, but abnormalities in early follicle development have also been shown to be present [27]. The numbers of primary and secondary follicles in the polycystic ovary are approximately twice those observed in the normal ovary. Increased density of small preantral follicles in ovarian cortical biopsies from anovulatory women with PCOS, a reduced proportion of primordial (resting) follicles and a reciprocally increased proportion of early growing follicles in tissue from women with PCOS, regardless of their ovulatory status, have also been found [28]. Recent data indicate that primordial and transitional follicles in ovarian sections obtained from anovulatory women with PCOS lack anti-Mullerian hormone, a growth factor that appears to have an autocrine or paracrine role in the inhibition of initiation of follicle growth [29].

It has been demonstrated that women with PCOS present an increased risk for DM and hypertension during pregnancy. These complications might be attributed to the coexisting insulin resistance and β-cell dysfunction in a significant percentage of women with PCOS before conception [6,7]. D Panidis and Neoklis A Georgopoulos oulined the association of PCOS with late pregnancy complications. Although a cause and effect relationship between the insulin-resistance syndrome and gestational DM and new-onset hypertension in pregnancy has not been proven, the associations between these conditions raise the possibility that interventions that improve insulin sensitivity may reduce the likelihood of these pregnancy complications. Since obesity is both a major contributor to insulin resistance and a well-established risk factor for pre-eclampsia, interventions that are scheduled to reduce weight before pregnancy and/or to avoid excessive weight gain during pregnancy may prove effective. Moreover, increased exercise, which improves insulin sensitivity, may also reduce risk. Multiple studies have demonstrated associations between markers of insulin resistance and gestational DM and hypertensive pregnancy.

Adenocarcinoma of the endometrium is the most common malignancy of the female genital tract, accounting for 6% of all cancers among women. The incidence is rising as life expectancy increases and this rise has been associated with an epidemic of obesity and physical inactivity [30,31]. The average mean age of women developing endometrial cancer secondary to unopposed estrogens is 63 years, with 25% of all endometrial cancers occuring in premenopausal women. The main explanation for the development of endometrial cancer in young women is unopposed estrogen secondary to anovulation. PCOS is thought to explain the majority of those cases. E Diakomanolis discussed screening, cancer risk assessment and therapeutic interventions in patients with endometrial cancer. The risk of developing endometrial cancer has been shown to be adversely influenced by a number of factors including obesity, long-term use of unopposed estrogens, multiparity and infertility. However, the true risk of endometrial cancer in women with PCOS is difficult to ascertain.

PCOS may be regarded as a sex-specific form of the metabolic syndrome. Vincenzo Toscano emphasized the role of glucose intolerance in women with PCOS. A total of 30–40% of obese women with PCOS of reproductive age have impaired glucose tolerance, and 10% have Type 2 DM. These prevalence rates are the highest known among women of similar age. Insulin resistance alone cannot fully account for the predisposition to the development of impaired glucose tolerance and Type 2 DM in PCOS. In insulin-resistant patients with normal glucose tolerance, insulin secretion is sufficient for the degree of insulin action impairment; when the pancreatic β cell is no longer able to compensate for this defect, glucose tolerance begins to deteriorate [32].

Metabolic & cardiovascular abnormalities in PCOS

Djuro Macut outlined the disturbed lipid abnormality seen in PCOS. A frequent pattern of dyslipidemia in PCOS patients is decreased high-density lipoprotein (HDL)-cholesterol and increased triglyceride levels [33,34]. The predominant observation of most studies in women with PCOS was an elevation of low-density lipoprotein (LDL)-cholesterol in both lean and obese patients. Higher concentrations and proportions of the more atherogenic LDL-III subfraction was confirmed together with a smaller diameter of LDL particles. Among risk factors, dyslipidemia is certainly the most persistent, with a high prevalence in PCOS. The prevalence of the metabolic syndrome was 43–46% in women with PCOS, with lipid abnormalities as the most frequent component of the syndrome.

Nonalcoholic fatty liver disease (NAFLD) is probably the most common liver disease in the general population. Insulin resistance and hyperinsulinemia are frequently found in obese NAFLD subjects but are also noted in lean subjects having fatty liver disease with normal glucose tolerance [35 –37]. Walter Futterweit described the association of PCOS with NAFLD and nonalcoholic steatohepatitis through an estimation study, using the ultrasound method, of the prevalence and severity of NAFLD in both obese and nonobese women with PCOS.

Visceral obesity determines an excessive adipose production of hormones, cytokines and other products that are associated with an increased risk for cardiovascular disease (CVD). Patients with PCOS present excessive fat accumulation in visceral deposits. This altered fat distribution is present not only in obese, but also in overweight and normal-weight patients with PCOS. Enrico Carmina stressed that adipose tissue is an endocrine organ and that fat distribution is very important in modifying the hormonal activity of fat [38,39].

The great majority of women with hyperandrogenism and chronic anovulation have PCOS. George Chrousos underlined the importance of the fact that the clinical, endocrinological and ultrasonographic features of PCOS can also be found in a number of other disorders, particularly when associated with insulin resistance and hyperinsulinemia [40]. However, a number of women with PCOS have other underlying diagnoses, such as adrenal and ovarian androgen-secreting tumors, adrenal and/or ovarian steroidogenic deficiencies, other medical or endocrine disorders, and/or receive certain medications. These disorders may exhibit similar clinical, endocrinological and/or ultrasonographic features to PCOS, and their early identification may be based on the presence of distinct features and a high index of suspicion. The severity of hyperinsulinemia correlates with the degree of clinical expression of the syndrome, with the ovaries being appropriately responsive to the elevated levels of the hormone. It is therefore possible that insulin resistance may underlie the pathophysiology of several disorders with a PCOS phenotype.

Richard S Legro emphasized the fundamental priority of research in the 21st century, which should be the establishment of the long-term sequelae of PCOS and their relationship to the underlying insulin resistance [42]. Unfortunately, much of the hype surrounding the long-term sequelae of PCOS has focused on risk factors and risk-factor modeling. As an example of this, one of the most frequently cited (perhaps miscited is the proper term) publications notes a sevenfold increased risk of myocardial infarction in women with PCOS [41], although this conclusion was not based on events but risk-factor modeling.

Insulin resistance, hyperandrogenism and dyslipidemia are probably the major risk factors for the occurrence of CVD in PCOS. These cardiovascular risk (CVR) factors are often evident at an early age [43,44]. Francesco Orio discussed the increased CVR and putative CVD, characterized by an impairment of the heart structure and function, endothelial dysfunction, lipid abnormalities and low-grade chronic inflammation that are thought to be observed in PCOS. All these features are probably linked to insulin resistance. The risk of coronary artery disease and myocardial infarction has been reported to be increased in patients with PCOS compared with regularly cycling women [41], even if to date there is no evidence of increased cardiovascular mortality in PCOS. Several studies report alterations in intermediate end points for CVR in this population. In fact, endothelial and diastolic dysfunction have been shown to occur in PCOS and have been associated with both elevated androgen levels and insulin resistance. Recently, together with classical CVR factors such as total cholesterol levels and HDL-cholesterol levels, obesity, homocysteine levels and left-ventricular hypertrophy have been shown to be independently associated with an increased CVR.

Ricardo Azziz analyzed the methods of evaluation of insulin resistance that could be used in large, epidemiological studies, such as HOmeostasis Model Assessment (HOMA) or QUantitative Insulin-sensitivity ChecK Index (QUICKI), and those involving a smaller number of subjects. These studies should use the clamp, the frequently sampled intravenous glucose tolerance test (FS-IVGTT), the insulin suppression test or the frequently sampled oral glucose tolerance test (FS–OGTT) techniques [45,46]. Clinically, in PCOS the standard 2-h OGTT, measuring both insulin and glucose, yields the highest amount of information for a reasonable cost and risk. Detection of the metabolic syndrome will include obtaining a thorough medical history, waist and hip circumferences, blood-pressure measures, BMI calculation, a lipid profile, and either a serum fasting glucose levels or, preferably, the glucose response to OGTT. Screening should be initiated at the time of the initial diagnosis, regardless of age, and repeated periodically thereafter.

Management & treatment of PCOS

As stressed previously, PCOS is thought to arise from a combination of familial and environmental factors that interact to cause the menstrual and metabolic disturbances characteristic of the condition. Conditions of overweight and obesity contribute to reproductive dysfunction [25,26]. R Norman underlined the fact that alteration of the environmental components of this condition are fundamental to the management of the syndrome and that pharmaceutical treatment should only be used after adequate counseling and action relating to lifestyle alterations. Attention to weight loss, altered diet and exercise are important aspects to discuss with the patient as well as smoking cessation and improving psychological attitudes.

Onno E Janssen highlighted that, through the pandemic of obesity and DM, both prevention and treatment studies have proven that a combination of dietary changes and physical activity can reduce weight, CVR and progression of insulin resistance to overt DM in high-risk subjects such as PCOS patients [39].

George Mastorakos called attention to the importance of early recognition and prompt treatment in adolescents for preventing long-term sequelae. Menstrual irregularities during the first postmenarchal years should not be considered as benign, unless endocrine–metabolic evaluation is normal. The reduction of insulin resistance should be one of the main therapeutic goals [52,53]. Weight reduction and lifestyle modification are essential, especially in the crucial life period of adolescence. Metformin is the most widely used insulin-reducing agent, with good results and few side effects. New insulin-sensitizing agents, such as D-chiro-inositol, are currently undergoing Phase III clinical trials and are a promising option for the treatment of PCOS.

Regarding the new medical approach with insulin sensitizers, an extensive review of the literature will take place, referring to the management of metabolic, cardiovascular and reproductive abnormalities characterizing the syndrome. Evanthia Diamanti-Kandarakis discussed the current therapeutic approaches with insulin-sensitizing agents.

The majority of controlled and uncontrolled studies in different ethnic groups agree that metformin has a beneficial effect on insulin resistance, and on several CVR factors in PCOS, regardless of the bodyweight changes [51 –54]. However, the effects of metformin are not universal in every woman with the syndrome and, furthermore, the predicting factors of their response are not yet known. In addition, the documentation of the presence of insulin resistance does not appear to be a prerequisite for treatment with metformin in PCOS, probably because the methods used are not adequately sensitive to detect it [45] and because it is very likely that metformin works on several pathways besides improvement of insulin sensitization.

The thiazolinediones are a new family of insulin sensitizers, category B, for which large, long-term trials are needed to confirm their beneficial effects on the metabolic abnormalities in PCOS. Management with insulin sensitizers appears to improve several aspects of the syndrome in a global way and targets most of the associated metabolic and reproductive consequences.

John E Nestler discussed the unfortunate feature of infertility in PCOS. PCOS is characterized by anovulation and early pregnancy loss. Insulin resistance and compensatory hyperinsulinemia have an important role in the pathogenesis of infertility. Multiple studies have demonstrated the effectiveness of metformin in improving ovulatory rates as a single agent and in combination with clomiphene citrate [53]. Pregnancy rates are also increased when metformin is added to clomiphene. In addition, metformin with FSH induction may minimize ovarian hyperstimulation, although studies are limited. Recent data suggest that metformin improves the endometrial environment during the peri-implantation period, thereby decreasing the rate of early miscarriage. Rosiglitazone and pioglitazone monotherapy, as well as the combination of clomiphene and rosiglitazone, increase ovulatory rates. Prelimary studies suggest the thiazolinediones may be more effective in obese women with PCOS compared with metformin in improving ovulation. However, since the thiazolinediones are class C pregnancy drugs, their use as fertility agents is less clear than metformin.

Hirsutism affects 5–8% of premenopausal women and may be associated with underlying endocrine and metabolic disturbances or, more importantly, may be the initial manifestation of an androgen-secreting tumor. Increased androgen production and/or increased sensitivity of follicles to androgens may lead to a male-pattern body hair appearance. PCOS, nonclassic congenital adrenal hyperplasia, Cushing's syndrome, acromegaly and some drugs may be the underlying causes of hirsutism, or it may be idiopathic [3]. Fahrettin Kelestimur discussed the management of hirsutism, which involves a range of diagnostic and therapeutic issues. It is essential to identify the underlying cause of hirsutism. Antiandrogen plus combined oral contraceptive (OC) is a good choice for both treating hirsutism and preventing pregnacy. Therefore, the antiandrogen plus combined OC should be administered to women who are sexually active [54,55]. If the patient desires pregnancy and discontinues the OC, antiandrogen therapy should be stopped in order to prevent feminization of the male fetus. Although there are some data, duration, prevention of recurrence, effectiveness of low-dose antiandrogens and different antiandrogen combinations, and also the long-term safety of antiandrogen drugs in the treatment of hirsutism, remains to be investigated. Most of the treatment strategies in hirsutism are symptomatic and the treatment should be directed at the cause of the problem. In this regard, clinical and experimental studies have been published for identifying the pathophysiological mechanisms of hirsutism, particularly in women with PCOS, and it has been shown that insulin resistance has a significant role. Conversely, treatment with insulin sensitizers has shown very limited effects or was ineffective on hirsutism.

Shahla Nader outlined the benefits and potential risks of OC use in PCOS [56 –58]. The more immediate benefits include improvement in acne, hirsutism and alopecia, as well as regulation of abnormal cycles with the potential for preventing endometrial hyperplasia and, subsequently, cancer. In addition, OCs provide protection against pregnancy, especially if other medications such as antiandrogens, biguanides or thiazolidinediones are also given. While epidemiological evidence of actual increased risk of coronary events in PCOS subjects is lacking, surrogate markers are certainly consistent with an increased risk of CVD in PCOS. The effects of OCs on carbohydrate and lipid metabolism in normal and PCOS women are critical. Estrogen may impair carbohydrate tolerance and insulin sensitivity and this may be dose dependent. This effect may also be dependent on the endogenous insulin sensitivity of the individual. In addition, progestins with intrinsic androgenic properties may also impair insulin sensitivity and glucose tolerance. The lowering of free androgen levels may improve insulin sensitivity and glucose tolerance in some subjects. The composite effect of OCs on glucose tolerance and insulin sensitivity may be determined by the interplay of the above with the endogenous insulin sensitivity of the individual, which itself is determined genetically, environmentally and by other factors. OCs should be used cautiously in at least some subgroups of PCOS (obese patients, those with strong family histories of DM and, perhaps, adolescents).

Moreover, the estrogen component of OCs enhances hepatic production of SHBG, thereby reducing free androgen availability. OCs also reduce LH concentrations, reducing the drive to ovarian androgen production. Even adrenal androgen secretion may be reduced by OCs. However, many of the progestins used as components of OCs are 19-nortestosterone derivatives and thus have androgenic effects, thereby potentially negating the beneficial androgen-lowering effects of OCs. Norgestimate and desogestrel are virtually nonandrogenic and drospirenone, which is an analog of spironolactone, has antiandrogenic properties. In addition, norgestimate is an inhibitor of skin 5 α-reductase in vitro. OCs containing the antiandrogen cyproterone acetate are also available. The estrogen in OCs is virtually always the synthetic estrogen ethinyl estradiol.

It has been estimated that 80% of women with PCOS exhibit irregular and infrequent menstrual bleeding as a result of anovulation. The precise mechanism responsible for anovulation in PCOS is unknown, although decreased FSH secretion and follicle arrest at the midantral stage of development have been well documented. Jeffery Chang discussed the various treatment options for ovulation induction in women with PCOS [59,60]. Primary treatment has been directed towards follicle stimulation and ovulation induction. The latter presents with varied ovarian responses that range from a lack of initial follicle stimulation to an increased risk for ovarian hyperstimulation syndrome. In addition, insulin resistance and obesity can adversely influence clinical responses to commonly used regimens for ovulation induction. No single treatment regimen has proven to be uniformly successful in achieving ovulation in PCOS.

Stefano Palomba gave a surgical approach to ovulation induction in PCOS patients. To date, the new surgical technique of ovulation induction using the laparoscopic access is considered the first-choice treatment for clomiphene-resistant women with PCOS [61,62]. These are day-surgery procedures and are characterized not only by effectiveness in ovulation induction and reproductive outcomes, but also by few side effects and no further need for ongoing monitoring. In addition, ovarian drilling corrects the main endocrine abnormalities associated with PCOS [63] and the benefits achieved seem to be maintained for several years after the procedure. Despite these favorable aspects, ovarian drilling is an invasive procedure that can be associated with postoperative pelvic adhesion formation and with other (theoretical) rare complications including premature ovarian failure.

Antoni J Duleba discussed the role of oxidative stress in PCOS and the novel use of statins in PCOS treatment [64,65]. Growing evidence points to statins as agents capable of correcting dyslipidemia and improving systemic inflammation, endothelial function and oxidative stress. It is likely that statins may block the excessive growth of θ-interstitial cells and may limit excessive steroidogenesis. In addition, by reducing oxidative stress, statins may also indirectly reduce steroidogenesis and cellular proliferation. The inhibition of N-glycosylation of insulin and insulin-like growth factor (IGF)-1 receptors, along with the inhibition of the mevalonate pathway by statins, can abrogate the actions of insulin, which would otherwise contribute to the thecal hyperplasia and hyperandrogenemia that occur with PCOS. Given the involvement of the mevalonate pathway in the post-translational modification of small GTPases involved in many signaling pathways, care must be taken to avoid the use of statins in women who are trying to conceive.

Future perspective

PCOS patients present a high risk of developing Type 2 DM and possibly CVD and, therefore, the role and prevalence of insulin resistance, hyperinsulinemia and the metabolic syndrome require epidemiological and clinical longitudinal studies.

Future multicenter studies in women with PCOS should focus on markers involved in the low-grade chronic inflammation of PCOS, since one of the clinical end points may include the prevention of CVD.

The normative ranges and biological importance of circulating androgens, clinical relevance of gonadotropin abnormalities, other associated biochemical abnormalities, value of routinely performing standard OGTT, and the normal ranges of insulin during the test need to be clarified.

The ultrasonography study of PCOS must be viewed as a diagnostic tool that requires the same quality controls as a biological one and its results must be expressed as quantitative variables rather than purely descriptive data, since its use has widened the clinical spectrum of PCOS.

Molecular mechanisms responsible for insulin resistance in PCOS and the potential impact of obesity and multiple environmental and genetic factors require more intensive investigation.

The role of insulin resistance and hyperandrogenemia as a primary cause of PCOS and the genes responsible for the different clinical aspects of PCOS should be investigated, allowing us to distinguish different subsets of patients within the heterogeneous group of women with PCOS, leading to more etiologically oriented treatment and pharmaceutical interventions targeted to different phenotypes.

In order to find the actual genomic variants with a causative role in PCOS, future genetic studies should compare women who, for a similar degree of insulin resistance, do or do not present with PCOS. Furthermore, the modifying role of the genomic variants related to insulin resistance on the metabolic abnormalities associated with PCOS require carefully designed studies in which PCOS patients and nonhyper-androgenic women are studied separately and environmental factors are eliminated.

The identification of genetic markers may enable characterization of PCOS patients who are at high risk for the development of Type 2 DM at a time when glucose tolerance is normal, minimizing the risk of conversion from normal to abnormal glucose tolerance.

Data on the safety and efficacy of both metformin and thiazolinediones are needed to define their use not only for the induction of ovulation but for prevention of miscarriage. Metformin appears to have a moderate effect on elevated glycotoxins in insulin-resistant normoglycemic women with PCOS.

Rimonabant and related upcoming cannabinoid 1 receptor antagonist drugs may be proposed not only for tackling visceral obesity but also for dealing with the variety of alterations related to the pathological fat increase in abdominal depots. Furthermore, the disturbance of the gonadotropin-releasing hormone pulse, usually present in PCOS patients, may be normalized by adding cannabinoid 1 receptor antagonists to dietary counseling and change of lifestyle.

Finally, new data are needed concerning phenotype and prognosis of PCOS based on the Rotterdam consensus before a possible revision of this consensus can be discussed in a meaningful way.

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