Telangiectasia as a presenting sign of Graves' disease.

Acquired nevoid telangiectasia (ANT) is observed in several conditions including primary cutaneous disorders, systemic autoimmune disease and hyperestrogenism occurring in puberty, pregnancy and chronic liver disease. We describe a patient in whom ANT was a presenting sign of autoimmune hyperthyroidism, which improved after thyroidectomy. A 43-year-old Caucasian woman experienced an asymptomatic development of multiple widespread red skin lesions, diagnosed to be ANT. Blood tests revealed increased serum levels of free tri-iodothyronine and thyroxine and suppressed thyroid-stimulating hormone. Other causes of ANT were excluded. ANT improved but did not disappear after thyroidectomy. The possible pathogenetic factors linking ANT and Graves' disease, such as an immune-mediated process, altered estrogen metabolism or vasodilatation associated with hyperdynamic circulation, are discussed.

The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome.

A hypothetical role of glucocorticoids in human obesity has been suggested since the abdominal obesity phenotype and syndromes of endogenous or exogenous hypercortisolism share several clinical, metabolic, and cardiovascular similarities. An emerging body of evidence indicates that both neuroendocrine dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as peripheral alterations of cortisol metabolism may play a role in the pathophysiology of abdominal obesity. Major alterations of the HPA axis in vivo may be identified in different ways. They include evaluation of hormone concentrations: (a) in basal conditions, in blood, urine, or saliva samples; (b) during dynamic studies following stimulation with different neuropeptides or psychological stress challenges, or suppression with inhibiting agents of the HPA axis at different levels; and (c) after mixed meals or meals containing different nutrient compositions. In addition, alteration of peripheral cortisol metabolism can be detected by direct measurement of cortisol metabolites in urine, although this is a matter of more complex investigation. Alterations of the HPA axis in abdominal obesity are associated with insulin resistance, which suggests a direct responsibility of these hormonal alterations in the susceptibility of affected patients to develop both metabolic and cardiovascular diseases. According to available data, no single marker probably has the power to detect subtle alterations of the HPA axis in conditions, such as the abdominal obesity and the metabolic syndrome. On the contrary, they indicate the need for multiple parameters. At present, evaluation of urinary free cortisol, particularly during the night-time, and salivary-free cortisol appear to be promising for these purposes, whereas dynamic tests should be reserved for specific clinical settings, involving well-characterized patients.

Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study.

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.

Glucose intolerance in a large cohort of mediterranean women with polycystic ovary syndrome: phenotype and associated factors.

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.

Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome.

BACKGROUND: Hyperandrogenism, hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome (PCOS), contributing in different ways to the clinical expression of the syndrome. Weight loss is beneficial, but the additional administration of insulin-lowering drugs, such as metformin, and antiandrogens may produce further benefits, due to their different spectrum of action. The effects of long-term metformin and flutamide, an antiandrogen drug, added alone or in combination with a low-calorie diet, on body weight and fat distribution, androgens, metabolic parameters and clinical status in obese women with PCOS were investigated. METHODS: Forty obese women with PCOS were enrolled in the study. After a 1-month diet, according to single-blind design, the patients were allocated to treatment with placebo, metformin (850 mg/orally, twice daily), flutamide (250 mg/orally, twice daily) or metformin (850 mg/orally, twice daily) + flutamide (250 mg/orally, twice daily) for the following 6 months, while continuing hypocaloric dieting. At baseline and at the end of the study, sex hormone, SHBG, lipid, insulin and insulin sensitivity determinations were evaluated. At the same time, clinical parameters such as anthropometry, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissue, hirsutism and menses were also measured. RESULTS: We found that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment had some specific additional favourable effects with respect to the low-calorie diet alone. In particular, flutamide treatment seemed to add a significant effect in decreasing visceral fat, androstenedione, DHEA-S, total and low density lipoprotein (LDL) cholesterol and in improving hirsutism. Conversely, metformin had significant benefits on the menstrual status. The two drugs showed an additive effect in reducing testosterone concentrations and a synergistic effect in increasing high density lipoprotein (HDL) cholesterol and SHBG levels. Improvement of insulin sensitivity and hyperinsulinaemia appeared to depend on hypocaloric diet, without any further significant effect of the pharmacological treatments, either alone or in combination. CONCLUSIONS: 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.

Testosterone replacement therapy restores normal ghrelin in hypogonadal men.

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.

Obesity and reproductive disorders in women.

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.