Polycystic ovarian syndrome (PCOS) affects approximately 5-10% of reproductive aged women and is characterized by hyperandrogenic anovulation, early-onset type II diabetes mellitus, obesity, atherosclerosis and endrometrial cancer. Hyperinsulinemia plays a key role in the mechanism of hyperandrogenic anovulation. The etiology of PCOS in women, however, is unknown. Prenatal androgen excess in female rhesus monkeys results in ovarian, endocrinological and metabolic features in adulthood that closely resemble those found in women with PCOS. In Project #3 of this SCOR application, we propose to employ a unique non-human primate model of PCOS to define a fetal origin for the syndrome. We propose that hyprandrogenism, the core functional disorder in women with PCOS, reprograms multiple fetal organ systems in females resulting in the phenotypic expression of the syndrome. Recent findings of prevalent PCOS in women exposed to in utero androgen excess strongly support this hypothesis. Our preliminary results suggest that early exposure to androgen excess during gestation produces ovarian hyperandrogenism, LH hypersecretion and impaired pancreatic insulin secretion in adult animals. This project will [1] demonstrated increased fetal and neonatal LH hypersecretion in female rhesus monkeys following prenatal androgenization on Dys 40-80 of gestation (LH defect), [2] establish ovarian hyperandrogenism in fetal and neonatal PA female rhesus monkeys [ovarian defect], [3] characterize the neonatal ovaries removed from PA female rhesus monkeys for morphological abnormalities and changed mRNA expression indicative of hyperandrogenic phenotype [ovarian defect], [4] determine whether in utero testosterone (T) excess during Days 40-80 of gestation induces impaired fetal and neonatal pancreatic insulin secretion in female rhesus monkeys [beta0cell defect], [5] assess impairments in fetal and neonatal physical development induced by prenatal androgen excess. The project will also provide a complementary and experimental study to that in PCOS pregnancies in [Project #1] and will produce hypothalamic and pancreatic tissue to determine whether prenatal androgen excess in female rhesus monkeys results in profound suppression of KATP channel subunit expression [Project #4].
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