The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and=or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.

Obesity, particularly the abdominal phenotype, is associated with several reproductive disturbances. Whereas mechanisms by which obesity affect fertility are complex and still not completely understood, an important role appears to be played by the presence of a condition of functional hyperandrogenism and hyperinsulinaemia, which accompanies the insulin-resistant state. In women with the polycystic ovary syndrome, abdominal obesity may be co-responsible for the development of hyperandrogenism and associated chronic anovulation, through mechanisms primarily involving the insulin-mediated overstimulation of ovarian steroidogenesis and decreased sex hormone-binding globulin blood concentrations. By these mechanisms, obesity may also favour resistance to clomiphene and gonadotrophin-induced ovulation and reduce outcomes of IVF/ICSI procedures. Due to the beneficial effects of weight loss, lifestyle intervention programmes should represent the first-line approach in the treatment of infertile obese women. Insulin-sensitizing agents may add further benefits, particularly if administered in combination with hypocaloric dieting. Therefore, individualized pharmacological support aimed at favouring weight loss and improving insulin resistance should be widely extended in clinical practice in obese infertile patients. This may be beneficial even during pregnancy, thereby permitting favourable physiological delivery and healthy babies.

We conclude that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment appears to have a more favourable outcome on body fat distribution, androgens, lipids, hirsutism and menses. However, our data emphasize the dominant role of hypocaloric dieting in improving insulin resistance and hyperinsulinaemia. Therefore, this study provides a rationale for specifically targeting different therapeutical options for PCOS according to the required outcomes.

Introduction Gender dysphoria is characterized by a strong discomfort with the gender assigned at birth and the urge to live as a member of the opposite gender. The acquisition of phenotypic features of the desired gender requires the use of cross-sex hormones. Female-to-male (FtM) transsexual persons are treated with testosterone to induce virilization. Aim The aim of the study was to assess the effects of three different testosterone formulations on body weight and composition and metabolic and bone parameters. Methods Forty-five FtM transsexuals were randomly assigned to receive testoviron depot (i.m.: 100 mg/10 days; n = 15), testosterone gel (50 mg/die; n = 15), and testosterone undecanoate (i.m.: 1,000 mg every 6 weeks for the first 6 weeks and then every 12 weeks, n = 15). FtM individuals were studied before, at week 30, and at week 54 of testosterone treatment. Main Outcome Measures Anthropometric, metabolic, bone, hematological, and biochemical parameters were evaluated at baseline and after 12 months of treatment. Results Lean body mass significantly increased and fat mass decreased in all groups. No modifications were reported in fasting insulin and insulin sensitivity index. High-density plasma lipoprotein levels declined significantly and low-density lipoprotein concentrations increased significantly in the three groups. The activated partial thromboplastin time and factor I did not change while prothrombin time significantly increased in all groups. At week 54, all subjects were amenorrheic and time to amenorrhea did not differ between the three groups. Current general life satisfaction was increased in all subjects after 1 year of treatment. Conclusions One-year testosterone administration in FtM transsexuals appears to be very safe with no differences among the testosterone formulations used. Our study is preliminary, and the detection of subtle or long-term differences in the effects of the three formulations may require further larger and longer term studies in this and other populations.

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The aim of this study was to investigate the phenotypic parameters and associated factors characterizing the development of glucose intolerance in polycystic ovary syndrome (PCOS). Among the 121 PCOS female subjects from the Mediterranean region, 15.7 and 2.5% displayed impaired glucose tolerance and type 2 diabetes, respectively. These subjects were included in a single group of overweight or obese subjects presenting with glucose intolerance (GI) states. PCOS women with normal glucose tolerance (81.8%) were subdivided into two groups: those who were overweight or obese and those of normal weight. Metabolic and hormonal characteristics of the GI group included significantly higher fasting and glucose-stimulated insulin levels, more severe insulin resistance, hyperandrogenemia, and significantly higher cortisol and androstenedione responses to 1-24 ACTH stimulation. One important finding was that lower birth weight and earlier age of menarche were associated with GI in PCOS women. Frequency of hirsutism, oligomenorrhea, acne, and acanthosis nigricans did not characterize women with GI. Our findings indicate that PCOS patients with GI represent a subgroup with specific clinical and hormonal characteristics. Our observations may have an important impact in preventative and therapeutic strategies. Diabetes 53: 2353-2358, 2004 P olycystic ovary syndrome (PCOS) affects 5-10% of women during their reproductive age (1,2) and is one of the most common causes of female infertility (1). The major clinical manifestations of the syndrome in adults are chronic anovulation, menstrual abnormalities, and hyperandrogenism (1). Most PCOS women present with insulin resistance and hyperinsulinemia (1), which play an important role in the pathogenesis of PCOS by modulating both ovarian and adrenal androgen production and decreasing sex hormoneϪbinding globulin (SHBG) liver synthesis and blood levels (3).Studies in American and Asian subjects have shown that, compared with the general population, women with PCOS have an increased risk for impaired glucose tolerance (IGT) and type 2 diabetes (4 -6), with a tendency toward early development of glucose intolerance (GI) states (7). However, to our knowledge, no studies have been performed on subjects from the Mediterranean region. The strong connection between PCOS and GI states is further emphasized by the high prevalence of polycystic ovarian morphology found on ultrasound scans in premenopausal women with type 2 diabetes (8) and those with previous gestational diabetes (9).As has been seen in the general population (10), there is evidence that insulin resistance may play a major pathophysiological role in the development of GI in PCOS women (11,12). The decreased insulin sensitivity in PCOS women appears in fact quite similar to that found in type 2 diabetic patients and to be relatively independent of obesity, fat distribution, and lean body mass (13). On the other hand, there is strong evidence that obesity per se, particularly the abdominal phenotype, represents an important indepe...

To investigate the impact of obstructive sleep apnea syndrome (OSAS) on testosterone levels and on the main parameters of the metabolic syndrome in abdominally obese men, 15 male subjects with abdominal obesity phenotype and polysomnographic diagnosis of OSAS (OB-OSAS) and 15 controls matched for age and anthropometric parameters (OB) were investigated. Anthropometry, SHBG, sex hormones and several parameters of the metabolic syndrome were measured. Only subjects with an Epworth Sleepiness Score greater than 10 underwent a polysomnographic study with calculation of the number of desaturation rates per sleeping hour (ODI), the minimal oxygen saturation during each desaturation episode (minSaO2) and the mean minimal arterial oxygen saturation for the whole night period (MminSaO2). Both total and free testosterone levels were lower in OB-OSAS than in OB patients. A negative correlation between polysomnographic parameters (ODI, minSaO2 and MminSaO2) and testosterone levels was found. The relationship between total and free testosterone and ODI persisted after adjusting for body mass index (BMI) and waist (W) values. Triglyceride and uric acid levels were significantly higher in OB-OSAS than in OB patients. A negative correlation between testosterone and acid uric level and a positive correlation between testosterone and HDL-cholesterol level was found, regardless of BMI and W circumference, particularly in the OB-OSAS group. Our study suggests that, in patients with obesity and OSAS, the severity of hypoxia during sleeping hours may be an additional factor in reducing testosterone levels, regardless of BMI and abdominal fatness. This may contribute in worsening metabolic abnormalities which, in men with OSAS, exceed those expected on the basis of degree of obesity and pattern of fat distribution.

We recently described a connection between androgens and ghrelin in women affected by the polycystic ovary syndrome. To further investigate the interaction between sex steroids and ghrelin, we investigated circulating ghrelin levels in a group of hypogonadal men before and after therapeutic intervention aiming at normalization low testosterone (T) concentrations. Seven hypogonadal men were compared with nine overweight/moderately obese men matched for body mass index and body fat distribution parameters, as well as with 10 normal weight controls. Total and free T and plasma ghrelin levels were significantly lower in the hypogonadal men than in the control groups. Hypogonadal men also had a significantly higher insulin resistance state. Ghrelin levels were positively correlated with both total and free T concentrations. A significant correlation was also found between ghrelin and the anthropometric parameters and the insulin resistance indexes. However, in a multiple regression analysis in which a correction for all covariants was performed, only the relationship with total and free T persisted. After the 6-month replacement T therapy, ghrelin levels of hypogonadal patients increased and did not differ significantly in comparison with both control groups. The positive correlation between ghrelin and androgens still persisted after T replacement therapy, after adjusting for confounding variables. These data further indicate that sex hormones modulate circulating ghrelin concentrations in humans. This may be consistent with the concept that ghrelin may exert a relevant role in the endocrine network connecting the control of the reproductive system with the regulation of energy balance.