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Objective: Research into cardiovascular disease (CV) prevention has demonstrated a variety of ultrasound (US) markers predicting risk in the general population but which have been scarcely used for polycystic ovary syndrome (PCOS). Obesity is a major factor contributing to CV disease in the general population, and it is highly prevalent in PCOS. However, it is still unclear how much risk is attributable to hyperandrogenism. This study evaluates the most promising US CV risk markers in PCOS and compares them between different PCOS phenotypes and BMI values., Design: Women fulfilling the Rotterdam criteria for PCOS were recruited from our outpatient clinic for this cross-sectional study., Methods: Participants (n = 102) aged 38.9 ± 7.4 years were stratified into the four PCOS phenotypes and the three BMI classes (normal-weight, overweight, obese). They were assessed for clinical and biochemical parameters together with the following US markers: coronary intima-media thickness (cIMT), flow-mediated vascular dilation (FMD), nitroglycerine-induced dilation (NTG), and epicardial fat thickness (EFT)., Results: There was no statistical difference among the four phenotypes in terms of cIMT, FMD, NTG or EFT, however all the US parameters except NTG showed significant differences among the three BMI classes. Adjusting for confounding factors in multiple regression analyses, EFT retained the greatest direct correlation with BMI and cIMT remained directly correlated but to a lesser degree., Conclusions: This study showed that obesity rather than the hyperandrogenic phenotype negatively impacts precocious US CV risk markers in PCOS. In addition, EFT showed the strongest association with BMI, highlighting its potential for estimating CV risk in PCOS.

Polycystic ovary syndrome (PCOS) recently has been identified as a risk factor associated with type 2 diabetes. However, the evidence derives from cross-sectional observational studies, retrospective studies, or short-term prospective studies. This long-term prospective study of a large cohort of women with PCOS, followed from youth to middle age, aimed at estimating, for the first time, the incidence and potential predictors of type 2 diabetes in this population. A total of 255 women with PCOS were followed for at least 10 years (mean follow-up 16.9 years). Six women were patients with diabetes at baseline, and another 42 women developed type 2 diabetes during the follow-up. The incidence rate of type 2 diabetes in the study population was 1.05 per 100 person-years. The age-standardized prevalence of diabetes at the end of follow-up was 39.3%, which is significantly higher with respect to that of the general Italian female population of a similar age (5.8%). The likelihood of developing type 2 diabetes significantly increased as BMI, fasting glucose, and glucose area under the curve at baseline increased and significantly decreased as sex hormone-binding globulin (SHBG) levels at follow-up increased. This study demonstrates that the risk of type 2 diabetes is markedly elevated in middle-aged women with PCOS and suggests including BMI, glucose, and SHBG-circulating levels in the risk stratification.

Aim: The aims of the study were to understand the association between insulin-like factor 3 (INSL3) and functional ovarian hyperandrogenism (FOH) in PCOS and the regulatory role played by LH., Subjects and Methods: Fifteen PCOS women were classified as FOH (FOH-PCOS, no.=8) and non-FOH (NFOH-PCOS, no.=7) according to the response of 17OH-progesterone to buserelin (a GnRH analogue) with respect to 15 controls. FOH-PCOS and NFOH-PCOS were compared for basal INSL3 levels. In addition, the effect of buserelin on INSL3 concentrations and the relationship between basal and buserelin-stimulated LH and 17OH-progesterone and INSL3 were evaluated., Results: Basal INSL3 levels were higher in FOH-PCOS than NFOH-PCOS (p=0.001) and controls (p=0.001), whereas they did not differ between NFOHPCOS and controls. In addition, FOH-PCOS had a higher response of LH to buserelin with respect to NFOH-PCOS. Within all PCOS women the levels of INSL3 positively correlated with free testosterone (p=0.022) and negatively with SHBG (r= p=0.031). Moreover, positive correlations with the absolute increase of 17OH-progesterone (p<0.001) and with the LH area under the curve (p=0.001) after buserelin administration were found. In the multiple regression analysis INSL3 persisted significantly correlated only with 17OH-progesterone response to buserelin. Finally, INSL3 was not significantly modified after buserelin administration either in FOHPCOS or in NFOH-PCOS., Conclusions: These data suggest that INSL3 is related to FOH in PCOS women, but this association seems not to be mediated by LH, further reinforcing the concept that a pathophysiological heterogeneity for ovarian hyperandrogenism in PCOS exists.

Background and Aims: The main objective was to evaluate the prevalence of the metabolic syndrome in Caucasian women with PCOS, using either of the currently proposed definitions (NCEP/ATPIII, IDF and AHA/NHLBI) and, therefore, to estimate the concordance between these three classifications. Secondary objectives were to evaluate: i) which individual criterion of the metabolic syndrome is most strongly associated with PCOS; and ii) whether the severity of hyperandrogenemia, hyperinsulinemia and insulin resistance may influence the presence of the metabolic syndrome in PCOS women., Methods and Results: The metabolic syndrome was assessed in 200 Caucasian women with PCOS and in 200 Caucasian controls, matched for age and BMI, considering the NCEP/ATPIII, IDF and AHA/NHLBI definitions. PCOS women had an increased prevalence of the metabolic syndrome compared with controls: 32 versus 23% with the NCEP/ATPIII, 39 versus 25% with the IDF and 37 versus 24% with the AHA/NHLBI, respectively (Cohen's Kappa index between the three classifications, P < 0.001). Multivariate logistic regressions revealed that among the individual criteria of the metabolic syndrome, only low HDL-cholesterol levels were significantly associated with PCOS (P < 0.001) which, in turn, are related to insulin(AUC) (P = 0.029) but not to androgens., Conclusion: This case-control study indicates a high prevalence of the metabolic syndrome in Caucasian PCOS women that is independent of the diagnostic classification used. Furthermore, it shows that low HDL-cholesterol is the criterion which best explains the high prevalence of the metabolic syndrome in PCOS subjects which, in turn, is influenced by hyperinsulinemia, rather than by hyperandrogenemia.

Objective: To evaluate serum total inhibin (the sum of precursors, subunits, and mature molecules of inhibin) along with inhibin A and inhibin B in a large sample of women with polycystic ovary syndrome (PCOS) and to investigate whether these parameters differ between lean and overweight PCOS patients., Design: Cross-sectional, controlled study., Setting: Academic health centers in Siena and Bologna, Italy., Patient(s): A group of women with PCOS (n = 145) was divided according to body mass index (BMI) into "lean PCOS" (BMI 19-25 kg/m(2), n = 52) and "overweight PCOS" (BMI 26-51 kg/m(2), n = 93). A group of healthy women (n = 90) with BMI 19-24 kg/m(2) and a history of regular menstrual cycles and normal results on physical examination served as controls., Intervention(s): Blood samples were drawn between cycle days 3 and 5 in PCOS patients and controls., Main Outcome Measure(s): Serum concentrations of total inhibin, inhibin A, inhibin B, FSH, and LH were measured using commercially available immunoassays., Result(s): Women with PCOS had serum total inhibin levels twice as high as in the control group (median = 115 vs. 47 pg/mL). Dimeric inhibin A concentration was lower in the PCOS group compared with controls (10 vs. 25 pg/mL), whereas inhibin B concentration did not differ significantly between PCOS and control groups. There was no difference of either total inhibin or inhibin A levels between lean and overweight women with PCOS, whereas the inhibin B level was higher in the lean PCOS subgroup compared with the overweight PCOS subgroup. Total inhibin did not show any linear correlation with inhibin B, inhibin A, or serum gonadotropins., Conclusion(s): Women with PCOS have high serum concentration of total inhibin but not of inhibin A or inhibin B, thus suggesting that PCOS women have an impaired processing of alpha-inhibin precursor proteins.

Context: The exaggerated 17-hydroxyprogesterone response to GnRH agonists, which reflects functional ovarian hyperandrogenism (FOH), is believed to be the prominent abnormality in women with polycystic ovary syndrome (PCOS)., Objective: Our objectives were to quantify the prevalence of PCOS with FOH and to evaluate whether the presence of FOH may distinguish different clinical and biochemical phenotypes., Design, Setting, and Participants: We conducted an observational study at an academic hospital that included 148 PCOS women and 22 healthy age-matched normal-weight control women., Main Outcome Measures: A hormone profile was taken at baseline and in response to (1-24)ACTH and to a GnRH agonist, buserelin, administered during dexamethasone suppression., Results: Based on the data obtained in the control subjects, the PCOS patients were divided into two groups, one with a normal (NR-PCOS, n = 78) and one with a high 17-hydroxyprogesterone response (HR-PCOS, n = 70) to buserelin. The two groups of PCOS subjects had similar anthropometric parameters and clinical signs of hyperandrogenism. Age and body weight at menarche were significantly lower and higher, respectively, in the HR-PCOS group than the NR-PCOS group. Moreover, the HR-PCOS group had higher basal testosterone (P < 0.001), free androgen index (P < 0.01), 17-hydroxyprogesterone (P < 0.05), estrogens (P < 0.05), area under the curve for insulin (insulin(AUC)) (P < 0.05), and C-peptide(AUC) (P < 0.01) and lower insulin sensitivity (as composite insulin sensitivity index) (P < 0.05) than the NR-PCOS group. The response of 17-hydroxyprogesterone to (1-24)ACTH (as percent variation) was lower in the HR-PCOS group with respect to the NR-PCOS group (P < 0.05), whereas the response of cortisol, androstenedione, and dehydroepiandrosterone was similar. Finally, the HR-PCOS group had lower percent suppression of androstenedione (P < 0.001) and 17-hydoxyprogesterone (P < 0.05) to dexamethasone. In a multiple regression model applied in all PCOS women, insulin(AUC) but not androgens or markers of insulin resistance predicted the 17-hydroxyprogesterone response to buserelin to a highly significant extent (t = 3.269; P < 0.01)., Conclusions: This study indicates that the paradigm that FOH is a specific feature of the PCOS status can no longer be sustained. We have shown that women with an exaggerated 17-hydroxyprogesterone response to a GnRH agonist, buserelin, are characterized by more severe hyperandrogenemia, glucose-stimulated beta-cell insulin secretion, and worse insulin resistance than those without evidence of FOH. Our data may be consistent with the hypothesis that excess insulin may represent a candidate factor responsible for FOH in these women, through the overactivation of the cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) enzyme pathway.

Context: Insulin-like factor 3 (INSL3), a member of the relaxin-insulin family, is produced in the Leydig cells and at reduced levels in ovarian theca interna cells of antra follicles as well as in the corpora lutea and ovarian stroma. Among the factors potentially involved in the stimulation of gonadal expression of INSL3, recent data obtained in rats show an important role of LH. Ovaries from most women affected by polycystic ovary syndrome (PCOS) are characterized by hyperplasia of the theca interna and of cortical stroma and by an increased number of small antral follicles, and the majority of women with PCOS, particularly normal-weight subjects, have LH levels that are above the normal range., Objective: The objective of this study was to investigate INSL3 circulating levels in both normal-weight and overweight-obese PCOS women and the association of INSL3 with gonadotropin and androgenic pattern and with ovarian morphology., Design: This was a controlled study., Setting: The study took place at an academic hospital., Participants: The participants included 44 PCOS patients (22 normal-weight and 22 overweight-obese) and 44 controls comparable for age and body weight., Main Outcome Measures: The main outcome measures included INSL3 serum concentrations, measured by RIA, in PCOS patients and controls and their correlation with clinical and biochemical phenotype and with ovarian morphology., Results: INSL3 serum concentrations were significantly higher in PCOS patients with respect to controls (P = 0.003), particularly in normal-weight (P = 0.001) but not in overweight-obese (P = 0.312) PCOS patients. INSL3 serum concentrations were positively correlated with total and free testosterone and with LH levels in all women (total testosterone, P < 0.001; free testosterone, P = 0.001; LH, P = 0.002) as well as in PCOS patients (total testosterone, P = 0.024; free testosterone, P = 0.045; LH, P = 0.049). Moreover, in the PCOS group, INSL3 levels were related to a greater 17OH-progesterone response to buserelin (P = 0.015), an index of ovarian hyperandrogenism. Finally, in PCOS women, INSL3 levels were positively correlated with ovarian follicle number (P = 0.028)., Conclusions: INSL3 could be considered a new circulating hormone related to LH-dependent ovarian hyperandrogenism, particularly in normal-weight PCOS women.

Context: The few controlled trials performed so far indicate that the addition of metformin and/or flutamide to a hypocaloric diet in obese women with polycystic ovary syndrome (PCOS) effectively influences different phenotypic aspects of the syndrome. All these studies are, however, characterized by a short to medium period of treatment., Objective: Our objective was to investigate the long-term effects of these therapies., Design and Setting: We conducted a prospective, randomized, placebo-controlled trial at a medical center., Patients: Of 80 overweight-obese women with PCOS, 76 completed the study., Interventions: Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo, metformin (850 mg, orally, twice a day), flutamide (250 mg, orally, twice a day), or metformin plus flutamide for the subsequent 12 months (20 subjects in each group)., Main Outcome Measures: We assessed clinical features, computerized tomography measurement of fat distribution, androgens, lipids, and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment., Results: After 6 months, compared with placebo, flutamide further decreased visceral/sc fat mass (P = 0.044), androstenedione (P < 0.001), dehydroepiandrosterone sulfate (P < 0.001), and hirsutism score (P < 0.001), whereas metformin further increased frequency of menstruation (P = 0.039). After 12 months, flutamide maintained the effects observed after 6 months on visceral/sc fat mass (P = 0.033) and androstenedione (P < 0.001), whereas it produced an additional decrease in dehydroepiandrosterone sulfate (P = 0.020) and hirsutism score (P = 0.019); metformin further improved the menstrual pattern (P = 0.013). Moreover, after 12 months, flutamide improved more than placebo the menstrual pattern (P = 0.008), glucose-stimulated glucose levels (P = 0.041), insulin sensitivity (P < 0.001), and low-density lipoprotein cholesterol levels (P = 0.003), whereas metformin decreased glucose-stimulated insulin levels (P = 0.014). The combination of the two drugs maintained the specific effect of each of the compounds, without any additive or synergistic effect., Conclusions: These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term.

Context: Somatostatin reduces LH, GH, and insulin, and somatostatin receptors are present at the ovarian level; somatostatin analogs are thus potential candidates for treatment of the polycystic ovary syndrome (PCOS)., Objective: The purpose of this study was to evaluate the effect of octreotide-LAR, a long-acting somatostatin analog, in anovulatory abdominal obese women with PCOS., Design: A single-blind, placebo-controlled study was performed, lasting for 7 months., Setting: The patients were ambulatory throughout the study., Patients: Twenty PCOS subjects were enrolled. Eighteen completed the study., Interventions: A low-calorie diet was given during the first month, a low-calorie diet plus octreotide-LAR (10 mg; n = 10 subjects) or placebo (n = 10 subjects) was then given, with one im injection every 28 d (for 6 months)., Main Outcome Measures: The main outcome measures were clinical features, computerized tomography measurement of fat distribution, androgens, GH, IGF-I, IGF-binding proteins (IGFBPs), fasting and glucose-stimulated insulin, and ovulation., Results: Octreotide had no additional effect in reducing body fat or improving fat distribution than placebo. Conversely, octreotide produced an additional decrease in fasting (P = 0.018) and glucose-stimulated (P = 0.038) insulin levels, an increase in IGFBP-2 (P = 0.042) and IGFBP-3 (P = 0.047), and an improvement in hirsutism (P = 0.004). Moreover, a trend toward greater reductions in testosterone (P = 0.061) and androstenedione (P = 0.069) was observed in women treated with octreotide-LAR compared with those given placebo. All women treated with octreotide ovulated at the end of the study compared with only one of those receiving placebo (P < 0.001)., Conclusions: Octreotide-LAR may be usefully applied to hypocalorically dieting, abdominal obese PCOS women to improve hyperandrogenism and the insulin-IGF-I system. Restoration of ovulatory menstrual cycles appears to be another advantage of this treatment.

Available literature indicates that polycystic ovary syndrome (PCOS) represents a condition with a high prevalence of the metabolic syndrome, a greater and precocious appearance of glucose intolerance states, including type 2 diabetes mellitus, and a potentially greater risk for cardiovascular diseases. With respect to metabolic disorders, however, there is also emerging evidence that they are more prevalent in PCOS rather than in the general population, and that there are regional differences in the world, depending on lifestyle and other environmental factors. This evidence should be taken into consideration in future strategies focusing on prevention of metabolic and cardiovascular disorders in PCOS, not only on treatment of infertility and signs of androgen excess.