Prevalence of acne vulgaris among women with polycystic ovary syndrome: a systemic review and meta-analysis.

OBJECTIVE: The aim of this meta-analysis was to evaluate the prevalence of acne among women with PCOS worldwide, and in subgroups of patients with different age, geographical-region, and PCOS definition-criteria, compared to healthy non-PCOS counterparts. METHODS: A comprehensive literature search was performed in PubMed (including Medline), Web of Science, and Scopus databases for retrieving articles in English investigating the prevalence of PCOS. 'Meta-prop' method was applied to estimate pooled prevalence of acne in both groups. Meta-regression was conducted to find the association between acne in women with and without PCOS. RESULTS: We used 60 studies, included data of 240,213 women with PCOS and 1,902,022 healthy-controls for the meta-analysis. The overall pooled prevalence of acne among women with and without PCOS, was 43% (95% CI: 41-45%) and 21% (95% CI: 19-22%), respectively, which was 1.6-fold significantly higher than among healthy-controls. The pooled prevalence of acne in adults, and in adolescents PCOS patients were 42 and 59%, respectively, which were significantly higher than non-PCOS counterparts. The pooled estimated prevalence of acne in adult PCOS women was 76% using the NIH definition and 36% by Rotterdam-criteria; both were significantly higher than non-PCOS counterparts, respectively. In subgroups of adults, who used Rotterdam-definition, the highest prevalence of acne in PCOS patients was reported in East Asia and was 3.5-fold higher than non-PCOS counterparts. CONCLUSIONS: Despite the presence of heterogeneity and publication bias among available literature, it may be concluded that acne is one of the common dermatological manifestations in PCOS. In addition, results highlight geographical differences among PCOS patients.

Risk of hypertension in women with polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression.

BACKGROUND: A limited number of publications have assessed the prevalence of hypertension (HTN) in polycystic ovary syndrome (PCOS) patients with inconclusive results. Since in general populations the occurrence of hypertension is related to age per se, we investigated the prevalence (P) / relative risk (RR) of HTN in pooled patients with PCOS, vs control population among reproductive age women with PCOS, compared to menopause/aging patients. METHODS: PubMed, Scopus, ScienceDirect, web of science, and Google scholar were systematically searched for retrieving observational studies published from inception to April 2019 investigating the HTN in patients with PCOS. The primary outcome of interest was pooled P and RR of HTN in reproductive and menopausal/aging women with PCOS compared to control population. RESULTS: The pooled prevalence of HTN in reproductive and menopausal/aging women with PCOS was higher than in the control population [(Pooled P: 0.15, 95% CI: 0.12-0.18 vs. Pooled P: 0.09, 95% CI: 0.08-0.10) and (Pooled P: 0.49, 95% CI: 0.28-0.70 vs. Pooled P: 0.40, 95% CI: 0.22-0.57), respectively]. Compared to the control population, pooled relative risk (RR) of HTN patients was increased only in reproductive age PCOS (1.70-fold, 95% CI: 1.43-2.07) but not in menopausal/aging patients who had PCOS during their reproductive years. The same results were obtained for subgroups of population-based studies. Meta-regression analysis of population-based studies showed that the RR of HTN in reproductive age PCOS patients was 1.76-fold than menopausal/aging PCOS patients (P = 0.262). CONCLUSION: This meta-analysis confirms a greater risk of HTN in PCOS patients but demonstrates that this risk is increased only in reproductive age women with PCOS, indicating that after menopause, having a history of PCOS may not be as an important predisposing factor for developing HTN.

Cardiovascular events among reproductive and menopausal age women with polycystic ovary syndrome: a systematic review and meta-analysis.

This study aimed to evaluate the prevalence (P)/hazard ratio (HR) of cardiovascular (CV) events among reproductive age and menopausal age women with polycystic ovary syndrome (PCOS) in comparison with healthy controls. PubMed, Scopus, ScienceDirect, Web of science, and Google scholar were searched for retrieving observational studies published up to April 2018 investigating CV events in patients with PCOS. The primary outcomes were a composite outcome of CV events [including coronary arterial disease (CAD), cardiovascular disease (CVD), myocardial infarction (MI), angina, heart failure, and ischemic heart disease] and mortality due to CV events; secondary outcomes were specific CVD events, including cerebrovascular disease, CAD, CVD, MI, angina, heart failure, ischemic heart disease, and stroke. In this meta-analysis, both fixed and random effect models were used. Potential sources of heterogeneity were explored by meta-regression and subgroup analyses. Sixteen studies including 12 population-based were analyzed for the meta-analysis. Results showed that the pooled HRs of CV events in PCOS patients of reproductive age and in menopausal/aging women were higher than healthy controls (pooled HR: 1.38, 95% CI: 1.12-1.71) and (pooled HR: 1.53, 95% CI: 1.15, 2.04), respectively. Compared to healthy controls, analysis of population-based studies revealed that the HR of CV events increased only in reproductive age PCOS patients (1.43-fold, 95% CI: 1.27, 1.61), whereas the difference was not statistically significant when comparing menopausal/aging PCOS patients to healthy controls (1.03-fold, 95% CI: 0.41, 2.59). Sufficient data were not available for comparing the HRs of mortality due to CV events between the two PCOS age groups. Mainly based on population-based study, we found a greater risk of CV events in reproductive aged but not in menopausal/aging PCOS women, suggesting that having a history of PCOS during reproductive ages may not be an important risk factor for developing events in later life. This is a preliminary assumption and needs to be reevaluated by further comprehensive cohort studies of longer duration, initiated in the reproductive period, considering all known CVD risk factors.

Characterization of metabolic changes in the phenotypes of women with polycystic ovary syndrome in a large Mediterranean population from Sicily.

OBJECTIVE: To better characterize the metabolic alterations in various phenotypes of polycystic ovary syndrome (PCOS) in a large homogeneous (Sicilian) Mediterranean population with a low prevalence of obesity. DESIGN: Retrospective study. PATIENTS: A total of 1215 consecutively evaluated women with PCOS divided into four Rotterdam phenotypes (A, B, C and D) and in 108 matched ovulatory, nonhyperandrogenic women. MEASUREMENTS: BMI, fasting glucose, total cholesterol, HDL cholesterol, triglycerides, LDL cholesterol and an oral glucose tolerance test. RESULTS: The overall prevalence of obesity was 31%, metabolic syndrome 6.6%, diabetes 2.1%, altered glucose metabolism 13.1%, and abnormal lipid profile 60%. Phenotype B had the highest prevalence of obesity, metabolic syndrome, altered glucose metabolism and lipid abnormalities compared to other PCOS phenotypes and controls. Phenotype A was more obese and more women had metabolic syndrome compared to phenotypes C and D but phenotype C had a similar prevalence of altered glucose metabolism and lipid abnormalities compared to phenotype A which had a higher BMI. These metabolic abnormalities in A and C were higher compared to phenotype D and controls. Multivariate analysis showed that BMI predicts only abnormalities in fasting glucose and triglycerides, while there was no association with androgens. CONCLUSIONS: In Mediterranean women with PCOS from Sicily with a lower prevalence of obesity, the prevalence of diabetes, altered glucose metabolism and metabolic syndrome were much lower than reported in US studies. Phenotype B was the most metabolically affected phenotype, followed by phenotype A. Phenotype C had an intermediate disorder but with a high prevalence of altered glucose metabolism and lipid alterations. Only the normoandrogenic phenotype D had no metabolic abnormalities.

Relationships Between Biochemical Markers of Hyperandrogenism and Metabolic Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

While several studies have documented an increased risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS), associations between androgenic and metabolic parameters in these patients are unclear. We aimed to investigate the relationships between biochemical markers of hyperandrogenism (HA) and metabolic parameters in women with PCOS. In this systematic review and meta-analysis, a literature search was performed in the PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science from 2000 to 2018 for assessing androgenic and metabolic parameters in PCOS patients. To assess the relationships between androgenic and metabolic parameters, meta-regression analysis was used. A total number of 33 studies involving 9905 patients with PCOS were included in this analysis. The associations of total testosterone (tT) with metabolic parameters were not significant; after adjustment for age and BMI, we detected associations of this androgen with low-density lipoproteins cholesterol (LDL-C) (ß=0.006; 95% CI: 0.002, 0.01), high-density lipoproteins cholesterol (HDL-C) (ß=-0.009; 95% CI: -0.02, -0.001), and systolic blood pressure (SBP) (ß=-0.01; 95% CI: -0.03, -0.00). We observed a positive significant association between free testosterone (fT) and fasting insulin (ß=0.49; 95% CI: 0.05, 0.91); this association remained significant after adjustment for confounders. We also detected a reverse association between fT and HDL-C (ß=-0.41; 95% CI: -0.70, -0.12). There was a positive significant association between A4 and TG (ß=0.02; 95% CI: 0.00, 0.04) after adjustment for PCOS diagnosis criteria. We also found significant negative associations between A4, TC, and LDL-C. Dehydroepiandrosterone sulfate (DHEAS) had a positive association with LDL-C (ß=0.02; 95% CI: 0.001, 0.03) and a reverse significant association with HDL-C (ß=-0.03; 95% CI: -0.06, -0.001). This meta-analysis confirmed the associations of some androgenic and metabolic parameters, indicating that measurement of these parameters may be useful for predicting metabolic risk in PCOS patients.

Features of polycystic ovary syndrome (PCOS) in women with functional hypothalamic amenorrhea (FHA) may be reversible with recovery of menstrual function.

OBJECTIVE: Since features of polycystic ovary syndrome (PCOS) have been found to be prevalent in women with functional hypothalamic amenorrhea (FHA), we wished to determine what happens to these features after recovery of menstrual function in FHA Design: Prospective cohort study. Twenty-eight women with FHA and 30 age-matched ovulatory controls were studied. METHODS: Twenty-eight women with FHA and 30 age-matched ovulatory controls were studied. We measured serum estradiol, LH, FSH, testosterone, DHEAS, anti-Mullerian hormone (AMH), body mass index, and ovarian morphology on transvaginal ultrasound. RESULTS: At baseline, 12 of the 28 women (43%) had increased AMH (>4.7 ng/mL), and higher testosterone and larger ovaries compared to the other 16 women with normal AMH. One year after recovery of menstrual function, in the 12 women with increased AMH, serum AMH, testosterone and ovarian size decreased, while LH and estradiol increased. At one year, only one of the 12 women in the high AMH group developed clinical features of PCOS. CONCLUSIONS: In the majority of women with FHA who have PCOS-like features, these features may be due to the hypothalamic state and appear to be reversible. Few women may develop clinical PCOS after recovery.

Androgens and Hypertension in Men and Women: a Unifying View.

PURPOSE OF REVIEW: This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. RECENT FINDINGS: Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be a major determinant of the increased prevalence of hypertension. The relationship between androgen signalling and NF-kB might explain the pathophysiological mechanism leading to the development of endothelium dysfunction and hypertension.

Increased anti-Mullerian hormone levels and ovarian size in a subgroup of women with functional hypothalamic amenorrhea: further identification of the link between polycystic ovary syndrome and functional hypothalamic amenorrhea.

BACKGROUND: Functional hypothalamic amenorrhea is a disorder characterized by cessation of menstrual cycles in the absence of organic disease. In most patients, it occurs in adult life after a stressful event and may be related to a condition of mild chronic energy deprivation. The endocrine pattern is characterized by low estrogen levels with an absent response to a progestogen challenge test and low-normal gonadotropin levels. A few studies have shown that some of these women may have some features of polycystic ovary syndrome; these features include an increased androgen response to gonadotropins, increased anti-Mullerian hormone levels, and altered ovarian morphology or increased ovarian size. These findings suggest a link between these 2 completely different disorders: functional hypothalamic amenorrhea and polycystic ovary syndrome. The importance of the possible coexistence of these disorders in some women is important for follow-up of these women and in their treatment if they desire to become pregnant. OBJECTIVE: To determine whether a subgroup of well-characterized women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. STUDY DESIGN: Retrospective analysis of women with functional hypothalamic amenorrhea. Forty consecutive patients and 28 normal age-matched control patients were studied. Blood was obtained for serum anti-Mullerian hormone, androgens, and other hormone levels and all women had ovarian ultrasonographic measurements. RESULTS: In the entire group of women with functional hypothalamic amenorrhea, anti-Mullerian hormone and ovarian volume were greater than in control patients. In 13 patients (32.5%), anti-Mullerian hormone was elevated (>4.7 ng/mL, levels consistent with polycystic ovary syndrome) and in this group, ovarian volume was significantly greater than in the remaining patients with functional hypothalamic amenorrhea. Four of the 13 women with functional hypothalamic amenorrhea who had elevated anti-Mullerian hormone levels (10%), also had ovarian volume ≥10 cc (consistent with polycystic ovarian syndrome). In these patients all studied androgens were in the upper normal range or slightly elevated despite low-normal gonadotropins; mean total testosterone was significantly greater than in the other patients with increased anti-Mullerian hormone values with normal ovarian size (P<.05.) Six other women with functional hypothalamic amenorrhea who had increased anti-Mullerian hormone also had isolated elevations of some androgen levels, but mean testosterone and ovarian size were normal. CONCLUSIONS: As many as 10% of women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. Because no signs or symptoms of this disorder were reported by these women before the appearance of the amenorrhea, it does not seem to be a coincidental relationship. The possibility that functional hypothalamic amenorrhea favors the appearance of polycystic ovary syndrome or more likely, that a mild (ovulatory) phenotype of polycystic ovary syndrome predisposes to the development of functional hypothalamic amenorrhea should be considered. Possible mechanisms are unclear and need to be investigated but may involve common vulnerabilities such as psychologic and mood disturbances.

AMH MEASUREMENT VERSUS OVARIAN ULTRASOUND IN THE DIAGNOSIS OF POLYCYSTIC OVARY SYNDROME IN DIFFERENT PHENOTYPES.

OBJECTIVE: This study was designed to assess the value of serum anti-Müllerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) in various phenotypes and to assess ovarian ultrasound parameters. METHODS: We performed a retrospective matched controlled study of 113 females with various PCOS phenotypes and 47 matched controls. The diagnostic utility of AMH measurement and ovarian ultrasound were compared. Using receiver operating characteristic (ROC) curve analyses, the threshold for AMH (>4.7 ng/mL) and ultrasound parameters (follicle number per ovary [FNPO] >22 and ovarian volume [OV] >8 cc) were established. RESULTS: In the entire cohort, AMH had a low sensitivity of 79%; while FNPO and OV were 93% and 68%, respectively. Specificities ranged from 85 to 96%. In classic anovulatory PCOS, AMH exhibited a sensitivity of 91%, and for FNPO and OV the corresponding sensitivities were 92% and 72%. In the ovulatory phenotype, AMH sensitivity was only 50%, while FNPO and OV were 95% and 50%, respectively. In the nonhyperandrogenic phenotype, the sensitivity of AMH was 53% while those for FNPO and OV were 93% and 67%. CONCLUSION: AMH does not appear to be helpful for all subjects with PCOS but may be of some value in those who are anovulatory. However, FNPO was highly sensitive in all phenotypes, and was the single best criterion assessed for all subjects, suggesting the important role of ultrasound.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME - PART 2.

Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists and the Androgen Excess Society aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2014. Insulin resistance is believed to play an intrinsic role in the pathogenesis of PCOS. The mechanism by which insulin resistance or insulin give rise to oligomenorrhea and hyperandrogenemia, however, is unclear. Hyperinsulinemic-euglycemic clamp studies have shown that both obese and lean women with PCOS have some degree of insulin resistance. Insulin resistance is implicated in the ovulatory dysfunction of PCOS by disrupting the hypothalamic-pituitary-ovarian axis. Given the association with insulin resistance, all women with PCOS require evaluation for the risk of metabolic syndrome (MetS) and its components, including type 2 diabetes, hypertension, hyperlipidemia, and the possible risk of clinical events, including acute myocardial infarction and stroke. Obese women with PCOS are at increased risk for MetS with impaired glucose tolerance (IGT; 31 to 35%) and type 2 diabetes mellitus (T2DM; 7.5 to 10%). Rates of progression from normal glucose tolerance to IGT, and in turn to T2DM, may be as high as 5 to 15% within 3 years. Data suggest the need for baseline oral glucose tolerance test every 1 to 2 years based on family history of T2DM as well as body mass index (BMI) and yearly in women with IGT. Compared with BMI- and age-matched controls, young, lean PCOS women have lower high-density lipoprotein (HDL) size, higher very-low-density lipoprotein particle number, higher low-density lipoprotein (LDL) particle number, and borderline lower LDL size. Statins have been shown to lower testosterone levels either alone or in combination with oral contraceptives (OCPs) but have not shown improvement in menses, spontaneous ovulation, hirsutism, or acne. Statins reduce total and LDL cholesterol but have no effect on HDL, C-reactive protein, fasting insulin, or homeostasis model assessment of insulin resistance in PCOS women, in contrast to the general population. There have been no long-term studies of statins on clinical cardiac outcomes in women with PCOS. Coronary calcification is more prevalent and more severe in PCOS than in controls. In women under 60 years of age undergoing coronary angiography, the presence of polycystic ovaries on sonography has been associated with more arterial segments with >50% stenosis, but the relationship between PCOS and actual cardiovascular events remains unclear. Therapies for PCOS are varied in their effects and targets and include both nonpharmacologic as well as pharmacologic approaches. Weight loss is the primary therapy in PCOS--reduction in weight of as little as 5% can restore regular menses and improve response to ovulation- inducing and fertility medications. Metformin in premenopausal PCOS women has been associated with a reduction in features of MetS. Clamp studies using ethinyl estradiol/drosperinone combination failed to reveal evidence of an increase in either peripheral or hepatic insulin resistance. Subjects with PCOS have a 1.5-times higher baseline risk of venous thromboembolic disease and a 3.7-fold greater effect with OCP use compared with non-PCOS subjects. There is currently no genetic test to screen for or diagnose PCOS, and there is no test to assist in the choice of treatment strategies. Persistent bleeding should always be investigated for pregnancy and/or uterine pathology--including transvaginal ultrasound exam and endometrial biopsy--in women with PCOS. PCOS women can have difficulty conceiving. Those who become pregnant are at risk for gestational diabetes (which should be evaluated and managed appropriately) and the microvascular complications of diabetes. Assessment of a woman with PCOS for infertility involves evaluating for preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes and evaluating the couple for other common infertility issues that may affect the choice of therapy, such as a semen analysis. Women with PCOS have multiple factors that may lead to an elevated risk of pregnancy, including a high prevalence of IGT--a clear risk factor for gestational diabetes--and MetS with hypertension, which increases the risk for pre-eclampsia and placental abruption. Women should be screened and treated for hypertension and diabetes prior to attempting conception. Women should be counseled about weight loss prior to attempting conception, although there are limited clinical trial data demonstrating a benefit to this recommendation. Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or letrozole, an aromatase inhibitor.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1.

Polycystic Ovary Syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists (AACE) and the Androgen Excess and PCOS Society (AES) aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2015. PCOS has been defined using various criteria, including menstrual irregularity, hyperandrogenism, and polycystic ovary morphology (PCOM). General agreement exists among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological) and polycystic ovaries. There is need for careful clinical assessment of women's history, physical examination, and laboratory evaluation, emphasizing the accuracy and validity of the methodology used for both biochemical measurements and ovarian imaging. Free testosterone (T) levels are more sensitive than the measurement of total T for establishing the existence of androgen excess and should be ideally determined through equilibrium dialysis techniques. Value of measuring levels of androgens other than T in patients with PCOS is relatively low. New ultrasound machines allow diagnosis of PCOM in patients having at least 25 small follicles (2 to 9 mm) in the whole ovary. Ovarian size at 10 mL remains the threshold between normal and increased ovary size. Serum 17-hydroxyprogesterone and anti-Müllerian hormone are useful for determining a diagnosis of PCOS. Correct diagnosis of PCOS impacts on the likelihood of associated metabolic and cardiovascular risks and leads to appropriate intervention, depending upon the woman's age, reproductive status, and her own concerns. The management of women with PCOS should include reproductive function, as well as the care of hirsutism, alopecia, and acne. Cycle length >35 days suggests chronic anovulation, but cycle length slightly longer than normal (32 to 35 days) or slightly irregular (32 to 35-36 days) needs assessment for ovulatory dysfunction. Ovulatory dysfunction is associated with increased prevalence of endometrial hyperplasia and endometrial cancer, in addition to infertility. In PCOS, hirsutism develops gradually and intensifies with weight gain. In the neoplastic virilizing states, hirsutism is of rapid onset, usually associated with clitoromegaly and oligomenorrhea. Girls with severe acne or acne resistant to oral and topical agents, including isotretinoin (Accutane), may have a 40% likelihood of developing PCOS. Hair loss patterns are variable in women with hyperandrogenemia, typically the vertex, crown or diffuse pattern, whereas women with more severe hyperandrogenemia may see bitemporal hair loss and loss of the frontal hairline. Oral contraceptives (OCPs) can effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. Physiologic doses of dexamethasone or prednisone can directly lower adrenal androgen output. Anti-androgens can be used to block the effects of androgen in the pilosebaceous unit or in the hair follicle. Anti-androgen therapy works through competitive antagonism of the androgen receptor (spironolactone, cyproterone acetate, flutamide) or inhibition of 5α-reductase (finasteride) to prevent the conversion of T to its more potent form, 5α-dihydrotestosterone. The choice of antiandrogen therapy is guided by symptoms. The diagnosis of PCOS in adolescents is particularly challenging given significant age and developmental issues in this group. Management of infertility in women with PCOS requires an understanding of the pathophysiology of anovulation as well as currently available treatments. Many features of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Menstrual irregularities with anovulatory cycles and varied cycle length are common due to the immaturity of the hypothalamic-pituitary-ovarian axis in the 2- to 3-year time period post-menarche. Persistent oligomenorrhea 2 to 3 years beyond menarche predicts ongoing menstrual irregularities and greater likelihood of underlying ovarian or adrenal dysfunction. In adolescent girls, large, multicystic ovaries are a common finding, so ultrasound is not a first-line investigation in women <17 years of age. Ovarian dysfunction in adolescents should be based on oligomenorrhea and/or biochemical evidence of oligo/anovulation, but there are major limitations to the sensitivity of T assays in ranges applicable to young girls. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with OCPs and anti-androgen medications. In lean adolescent girls, a dose as low as 850 mg daily may be effective at reducing PCOS symptoms; in overweight and obese adolescents, dose escalation to 1.5 to 2.5 g daily is likely required. Anti-androgen therapy in adolescents could affect bone mass, although available short-term data suggest no effect on bone loss.

Semaglutide Treatment of Excessive Body Weight in Obese PCOS Patients Unresponsive to Lifestyle Programs.

In spite of the widespread use of lifestyle modifications programs, many patients with PCOS are obese and prevalence of obesity in PCOS remains high. In this study, we present the data on the use of semaglutide, an incretin mimetic drug, in obese PCOS patients who were unresponsive to a lifestyle modification program. Twenty-seven obese patients with a diagnosis of PCOS, who did not reduce their body weight by a lifestyle modification program, were included in this study and treated by semaglutide, 0.5 mg subcutaneously once a week. After three months of treatment, an improvement in body weight with a mean decrease in body weight of 7.6 kg and a mean BMI loss of 3.1 was observed, while very few side effects were reported. Almost 80% of the studied obese PCOS patients obtained at least a 5% decrease in their body weight. Only a few patients (22%) obtained a decrease in body weight lower than 5% and were considered non-responsive to semaglutide, at least at the used doses. These patients presented a more severe obesity than responsive patients. Independently of results on body weight, and in patients who did not obtain a 5% decrease in their body weight, insulin basal values decreased, and HOMA-IR improved. Fasting blood glucose normalized in 80% of semaglutide-treated IFG PCOS women. In patients who were responsive to semaglutide (weight loss > 5%), the treatment was continued for additional three months. Weight loss slowed but continued and, at the end of the six months of therapy, the mean body weight loss was 11.5 kg and mean BMI reduced from 34.4 to 29.4. A total of 80% of responsive patients normalized menstrual cycles. In conclusion, treatment with semaglutide, at low doses, significantly reduces body weight in almost 80% of obese PCOS patients who were unresponsive to a previous lifestyle plan. It is often associated with the normalization of menstrual cycles, and these important results are obtained with very few side effects.

Need to Introduce the Finding of Obesity or Normal Body Weight in the Current Diagnostic Criteria and in the Classification of PCOS.

The diagnosis of PCOS is based on the Rotterdam guidelines: chronic anovulation, hyperandrogenism (biologic or clinical) and polycystic ovaries on ultrasound. Two of these three criteria are sufficient for making diagnosis of PCOS. However, one characteristic that is often associated to PCOS (obesity with severe insulin resistance and metabolic alteration regarding glucose metabolism and lipid pattern) has remained out of the current classification of PCOS. Because of this, patients with different metabolic and cardiovascular risk may be included in the same phenotype, and it makes more difficult to establish clear strategies of follow-up and treatment of the patients with increased risks, and also may hide genetic or environmental differences between PCOS patients. Our recent study has shown that metabolic alterations are linked to the weight and not to the Rotterdam phenotypes. Because of this, we suggest a new classification of PCOS phenotypes that divides each Rotterdam phenotype in obese (ob) or lean (l) sub-phenotype. An improved classification of PCOS may be essential for permitting new progress in our understanding of pathogenesis and treatment of PCOS (or of the different disorders that are part of PCOS).

Comparing Lean and Obese PCOS in Different PCOS Phenotypes: Evidence That the Body Weight Is More Important than the Rotterdam Phenotype in Influencing the Metabolic Status.

Polycystic Ovary Syndrome (PCOS) represents a heterogeneous disorder and, using Rotterdam diagnostic criteria, four main phenotypes (A, B, C, and D) have been distinguished. However, it remains unclear whether lean versus obesity status influences findings in the various phenotypes of women with PCOS. 274 women with PCOS were consecutively assessed. Among these women, there were 149 with phenotype A, 24 with phenotype B, 94 with phenotype C, and 7 with phenotype D. We found normal body weight to be very common (65%) in phenotype C patients, common (43%) in phenotype A and D patients, and less represented (but still 25%) in phenotype B patients. Obesity was common in phenotype B (54%) and phenotype A (33%) patients and uncommon in phenotype C (only 11%) and phenotype D (14%) patients. Obese and lean patients of each phenotype were compared. Compared to the phenotype C PCOS patients, both phenotype A and B patients had higher total testosterone circulating values and higher luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (p < 0.01) while anti-Mullerian hormone (AMH) levels were higher only in phenotype A PCOS patients. Instead, in the three obese PCOS phenotypes no differences in serum insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) calculation, and lipid blood values were observed. Analysis of data of lean patients gave similar results. Compared to the phenotype C PCOS patients, both phenotype A and B patients had higher total testosterone circulating values and higher LH/FSH ratio (p < 0.01) while AMH levels were higher only in phenotype A PCOS patients. However, no differences were observed in the circulating insulin levels, HOMA-IR calculation, or blood lipids between the three groups of lean PCOS patients. We conclude that Rotterdam phenotypes express the differences between PCOS patients in terms of ovulatory pattern and androgen secretion but fail to differentiate between obese patients with altered metabolic patterns and lean patients with normal metabolic patterns. A new classification of PCOS patients is needed and it should consider the influence of body weight on the metabolic patterns of PCOS patients.

Increased Prevalence of Elevated DHEAS in PCOS Women with Non-Classic (B or C) Phenotypes: A Retrospective Analysis in Patients Aged 20 to 29 Years.

It is well known that a subgroup of women with PCOS present an excessive adrenal androgen production, generally associated with ovarian hyperandrogenism. In the past, it has been impossible to correlate adrenal hyperandrogenism to any clinical or hormonal pattern of PCOS. However, adrenal androgens are strictly dependent on age and their blood values reduce by 40% in patients moving from their twenties to thirties. Due to this, serum DHEAS values are strongly influenced by the age distribution of studied populations. To avoid this bias, in this study we retrospectively analyzed the clinical and hormonal data of PCOS women in their twenties (age between 20 and 29 years). Data of 648 young hyperandrogenic women with PCOS were evaluated. Serum DHEAS was increased in a third (33%) of studied patients and was associated with higher values of testosterone (T) and androstenedione (A). In each phenotype, patients with high DHEAS had higher values of T and A than patients with normal DHEAS of the same phenotype. Therefore, a DHEAS increase is generally part of a generalized higher androgen production in a subgroup of PCOS patients, independently of the finding of anovulatory or ovulatory cycles or of polycystic or normal ovaries. However, our study showed some important differences between PCOS phenotypes. A lower prevalence of increased DHEAS in A phenotype PCOS patients who generally have the highest androgen levels, versus non-classic (B or C) PCOS phenotypes, was observed. It was also found that patients with A phenotype PCOS present significantly lower BMI and serum insulin than patients with normal DHEAS of the same phenotype while, in patients with the B or C phenotype, the opposite occurs. We conclude that adrenal hyperandrogenism is more common in patients with non-classic (B and C) phenotypes of PCOS and is generally part of a generalized higher production of androgens in a subgroup of PCOS patients. However, other factors may increase the adrenal androgen production and influence the clinical expression of the syndrome. More studies in large, selected for age, populations of PCOS women with different phenotypes are needed.

Female Adult Acne and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.

In endocrine and reproductive endocrine literature, adult female acne is considered as a possible clinical expression of hyperandrogenism, with most polycystic ovary syndrome (PCOS) guidelines considering acne as a condition of androgen excess. Adult female acne, however, in the dermatological literature is considered as an inflammatory skin disease and new guidelines on adult female acne have been produced by dermatological societies, with little perspective from any endocrine or reproductive endocrine points of view. An expert task force was appointed by the AE-PCOS society to determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female adult acne. The following are the recommendations (level of evidence A or B): (1) diagnosis of female adult acne is mainly clinical, but a grading tool is needed for optimizing the treatment; (2) measurement of serum androgen values (total testosterone, free testosterone, and dehydroepiandrosterone sulfate) by high-quality assays is recommended in all women with adult acne; (3) in women with adult acne and proven hyperandrogenism, oral combined estroprogestins should be added to the topical or systemic treatment of acne, independently of severity of acne; (4) all second- and third-generation estroprogestins may be used, independently of the estrogen dose and progestin component; (5) spironolactone may be added to estroprogestins in women with moderate or severe hyperandrogenic adult acne, not responding to usual treatments; (6) estroprogestins may be used in nonhyperandrogenic patients with adult acne as second-line therapy.

Metabolic profile of women with PCOS in Brazil: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disease affecting women of reproductive age and associated with reproductive and metabolic dysfunction. Few studies are available regarding metabolic traits in Brazilian women with PCOS. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding metabolic traits and comorbidities in Brazilian women with polycystic ovary syndrome (PCOS). METHODS: We systematically searched PubMed, Cochrane Central Register of Controlled Trials, and Embase for cross-sectional, case-control, or cohort studies focusing on populations of different regions from Brazil, published until July 31, 2019. Studies were selected if they reported PCOS diagnostic criteria. Studies without a control group were included if they presented relevant metabolic data. RESULTS: Of 4856 studies initially identified, 27 were included in the systematic review and 12 were included in the meta-analysis, for a total of 995 women with PCOS defined by Rotterdam criteria and 2275 controls from different regions of Brazil. Obesity, metabolic syndrome and IGT were prevalent, and standard mean differences for BMI (SMD 0.67, 95% CI, 0.29, 1.05), waist circumference (SMD 0.22, 95% CI 0.02, 0.41), systolic (SMD 0.66, 95% CI 0.30, 1.01) and diastolic blood pressure (SMD 0.55, 95% CI 0.24, 0.87), glucose (SMD 0.21, 95% CI 0.04, 0.38) and HOMA (SMD 0.78, 95% CI 0.52, 1.04) were significantly higher in Brazilian women with PCOS compared to controls. Lipid profile was more adverse in PCOS vs. non-PCOS women. Between-study heterogeneities were low/moderate for glucose and HOMA and moderate/high for the other variables. CONCLUSIONS: The data of this systematic review and meta-analysis indicate that Brazilian women with PCOS have a worse metabolic profile than women without PCOS with no important regional differences. The prevalence of metabolic changes is intermediate in Brazil vs. other countries.

The diagnosis of polycystic ovary syndrome in adolescents.

In women, the definition of polycystic ovary syndrome (PCOS) has become broad and includes several possible phenotypes. Because several features of PCOS may be in evolution in adolescents, we suggest that only firm criteria should be used to make a diagnosis of PCOS during adolescence. Hyperandrogenism, oligomenorrhea, and ovarian morphology change during adolescence and are discussed individually. Adolescents with incomplete criteria for a firm diagnosis of PCOS should be followed up carefully and may be diagnosed at a later time.

Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype.

BACKGROUND: Dyslipidemia is common in women with polycystic ovary syndrome (PCOS) but its prevalence in different PCOS phenotypes is still largely unknown. METHODS: We measured plasma lipids and lipoproteins in 35 anovulatory PCOS (age: 25 +/- 6 years, BMI: 28 +/- 6 kg/m(2)), 15 ovulatory PCOS (age: 30 +/- 6 years, BMI: 25 +/- 3 kg/m(2)) and 27 healthy women (controls) age- and BMI-matched with ovulatory PCOS. PCOS was diagnosed by the presence of clinical or biologic hyperandrogenism associated with chronic anovulation and/or polycystic ovaries at ultrasound. In women with normal menses chronic anovulation was indicated by low serum progesterone levels (<9.54 nmol/l) during midluteal phase (days 21-24) in two consecutive menstrual cycles. RESULTS: Total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol levels increased and high-density lipoprotein (HDL)-cholesterol decreased from controls to ovulatory and then to anovulatory PCOS (all P < 0.05). Levels of lipoprotein(a) (Lp(a)) and small, dense LDL increased (P < 0.0001 for both) and LDL size reduced (P < 0.005) between groups. Insulin resistance (by HOMA) showed a positive correlation with triglycerides and small, dense LDL and an inverse correlation with HDL-cholesterol and LDL size (P < 0.05 for all) in both PCOS phenotypes. No significant correlations were found with testosterone levels. At multivariate analysis, insulin resistance was independently associated with HDL-cholesterol and small, dense LDL in both PCOS phenotypes and with triglyceride concentrations in ovulatory PCOS only. CONCLUSIONS: Women with ovulatory PCOS showed milder forms of atherogenic dyslipidemia than anovulatory PCOS and this seemed to be related to the extent of insulin resistance. Future prospective studies are needed to assess the relative contribution of such alterations on cardiovascular risk.

Increasing adiposity in normal ovulatory women affects adipocytokine expression in subcutaneous and visceral abdominal fat.

OBJECTIVE: To determine which adipocytokines are differentially expressed as a function of body mass index (BMI), to compare expression of adipocytokines in abdominal subcutaneous and omental fat, and to correlate these findings with serum levels, BMI, and parameters of insulin resistance. METHODS: Serum and subcutaneous (sc) and omental (om) tissue were obtained from lean and obese ovulatory women undergoing gynecologic surgery. We determined adipocytokine expression in sc versus om abdominal fat and related this to increasing BMI. RESULTS: Serum leptin was higher and adiponectin lower in overweight subjects. Adipocytokines had higher expression in sc abdominal versus om adipose tissue with the most significant difference observed for leptin (P=0.01). As BMI increased, sc leptin expression increased and adiponectin expression decreased. The leptin/adiponectin ratio correlated significantly with BMI (R=0.84, P=0.0001). CONCLUSION: Increased adipocytokine expression correlates with BMI. Abdominal sc tissue has greater adipocytokine expression overall. The serum leptin/adiponectin ratio is highly correlated with BMI. These data may help in our understanding of how obesity affects women in a variety of ways.