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Androgen Excess-Induced Endocrine-Metabolic Dysfunctions: Novel Strategy for Treatment in the Polycystic Ovary Syndrome Overweight/Obese Phenotype

Eduardo Spinedi*1 and Daniel P Cardinali2

Transient, early in life, hyperandrogenemia predisposes the organism to develop Polycystic Ovary Syndrome (PCOS is a hormonal disorder common among women of reproductive age. Women with PCOS may have infrequent or prolonged menstrual periods or excess male hormone (androgen) levels. The ovaries may develop numerous small collections of fluid (follicles) and fail to regularly release eggs). Genetic and environmental (epigenetic) factors also play relevant roles in PCOS development. PCOS and Metabolic Syndrome (MS) female phenotypes share common characteristics. Indeed, hyperadiposity and sleep disturbances have been reported to increase in PCOS women and obstructive sleep apnea is a common feature in both phenotypes. Maturation of the LH-RH secretion pattern in pubertal girls is closely related to changes in the sleep-wake cycle, and could have relevance in the pathogenesis of PCOS. When analyzed the impact of neonatal? and rogenization (testosterone propionate, TP; sc 1.25 mg/rat-pup) on endocrine-metabolic biomarkers and ovarian function in female rats over development (juvenile and adult ages), TP individuals displayed accelerated growth, hypertrophic adiposity (expressing high and low mRNA levels of leptin and adiponectin, respectively), enhanced peripheral concentrations of non-esterified fatty acid (NEFA), plasminogen activator inhibitor-1 (PAI-1), leptin and insulin. These features were accompanied by early vaginal opening, permanent estrous cycle and dysfunctional ovarian steroidogenesis, with conserved glomerulosa cell endocrine function. Indeed, studies of juvenile TP ovaries rats indicated that primary and antral follicle frequencies were 3- and 15-fold higher and lower, respectively; whereas secondary and atretic follicle frequencies were 3- and 5-fold lower and higher, respectively, large cystic images without corpus luteum were found in adult TP rats. These data strongly suggest that neonatal hyperandrogenemia induced metabolic-endocrine and ovarian misprogramming, suggesting that this phenotype is highly susceptible to develop an enhanced risk of MS, overweight/obesity, type 2 Diabetes Mellitus and cardiovascular disease (CVD). It has also been found that melatonin-treated diet-induced obese (DIO) rodents are protected against several obesity co-morbidities.