Polycystic ovary syndrome (PCOS) is now recognized to be the most common endocrinopathy in women of reproductive age with a prevalence of 6.6-6.8%. PCOS, a syndrome of unknown etiology, was initially regarded as a reproductive disorder. However, in the last 15 years the role of insulin resistance (IR) has been identified as a significant contributor to the pathogenesis of PCOS, and the metabolic and cardiovascular sequelae of the syndrome have been increasingly appreciated. The coexistence and interaction of reproductive and cardiometabolic abnormalities in the context of PCOS have created a need for a modified therapeutic management of affected women. Insulin sensitizers, particularly metformin, have been introduced as a pharmaceutical option targeting not only IR, but several other aspects of the syndrome, including reproductive abnormalities. The landscape of the multifaceted actions of metformin evolves to broaden the therapeutic implications of this old drug in a new fashion for patients with PCOS. Most recently, the spectrum of metformin's targets has been expanded, and molecular studies have explored the tissue-specific mechanisms of metformin in the liver, the muscle, the endothelium, and the ovary. The use of metformin in pregnant women with PCOS comprises another scarcely explored, but promising area of research. This review attempts to cover the spectrum of metformin's cellular actions in different tissues and to summarize the current literature regarding the potential medical value of this medication in PCOS. Even if many of these actions are individually modest, they seem to be collectively sufficient to confer therapeutic benefits not only in cardiometabolic aspects but also in reproductive aspects of PCOS.

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Polycystic ovary syndrome (PCOS) affects 6.6-6.8% of women in reproductive age. Insulin resistance and hyperinsulinemia play a critical role in the pathogenesis of PCOS and are associated with a high risk for type 2 diabetes mellitus and cardiometabolic abnormalities. Metformin has been introduced as a therapeutic option in PCOS, targeting of cardiometabolic and reproductive abnormalities on the basis of its action on the reduction of glucose levels and the attenuation of insulin resistance. The tissue-specific actions of metformin as well as the molecular mechanisms involved in the liver, the muscle, the endothelium, and the ovary are elucidated in this review. The use of metformin in pregnant women with PCOS is another of its positive features. Overall, available data supports the therapeutic usefulness of metformin on cardiometabolic risk and reproduction assistance in PCOS women.

In women with PCOS, the degree of anxiety, state and trait (STAI-S, STAI-T) appears to vary in a pattern similar to that of hyperandrogenemia and insulin resistance, independently of age and BMI. The pathophysiological mechanisms underlying the association of psychological morbidities with androgen excess and insulin resistance in PCOS remain to be elucidated.

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

OBJECTIVE: To investigate liver enzymes in a cohort of women with Polycystic Ovary Syndrome (PCOS) and controls divided according to body mass index (BMI) and their association with features of the syndrome. DESIGN: Eighty-three PCOS women and 64 healthy women were studied. Patients and controls were subdivided into two groups, a lean subgroup (BMI <25kg/ m 2 ) and an overweight/obese subgroup (BMI >25kg/m 2 ). Clinical history, height and weight were obtained and metabolic and hormonal parameters were determined. RESULTS: Serum fasting insulin, fasting glucose, HOMA-IR, triglycerides and total cholesterol were significantly higher (p<0.05) in women with PCOS compared to controls. No significant difference in serum liver enzymes levels between PCOS women and controls was detected. However, serum levels of alanine aminotransferase (ALT) (17.7 vs. 14.1 U/L, p<0.05) and γ-glutamyl transpeptidase (γGT) (17.9 vs. 13.4 U/L, p<0.05) were significantly higher in overweight/obese PCOS women compared with overweight/obese controls. In overweight/obese PCOS patients and controls, ALT levels were positively correlated with free androgen index (FAI) (r=0.25 p<0.05) and total testosterone levels (r=0.33 p<0.01). CONCLUSIONS: The finding of elevated liver enzymes in overweight/obese PCOS women raises the question of screening for non-alcoholic fatty liver disease in this group.Key words: Body Mass Index, Insulin resistance, Liver enzymes, Non-alcoholic fatty liver disease, Polycystic Ovary Syndrome Research paper HORMONES 2009, 8(3):199-206 22,24 A significant elevation of aminotransferase levels (ALT and/or AST above 60 U/L) is highly likely to concur with the imaging finding of fatty infiltration in obese women with PCOS.22 Ultrasonographic evidence is more prevalent than the biochemical evidence of NAFLD in lean, overweight and obese PCOS women, 25 but the use of a lower cutoff for ALT may significantly increase the sensitivity of this marker in identifying mild NAFLD. 26Overall, existing evidence of NAFLD in PCOS women is still scarce and presents certain limitations. Of the available studies, only one included a control group. 24 Moreover, only one study included both lean and obese patients, 25 while the others either included only overweight/obese patients or did not subdivide patients according to BMI. 21,22 Additionally, serum levels of γGT were determined only in one of the available four studies. 25The aim of the present study was to investigate liver enzymes in a cohort of women with PCOS and controls divided according to BMI in order to explore a possible independent effect of PCOS and obesity on liver function and to uncover potential associations of serum liver enzymes with hormonal parameters and indices of insulin resistance.

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome that is characterized from oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. Clinical expression is determined by genetic as well as environmental factors. Women with PCOS are a specific group of women which have several aspects of metabolic syndrome (MBS). Concomitantly MBS could be part of metabolic abnormalities present in PCOS. Stress has been linked to aggravate the metabolic abnormalities present in MBS. An interaction seems to exist between stress, environmental, as well as genetic factors, starting from the prenatal age and continuing to the adult life. This results in specific endocrinological and metabolic disorders which are shared by women with PCOS and women with MBS.

The data from the current study suggest that higher levels of AGEs are positively associated with higher androgen levels. This association, identified for the first time, may provide an additional insight into the pathophysiological mechanisms linking the described higher prevalence of cardiovascular events with higher androgen levels in postmenopausal women.