This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To further develop the prenatally androgenized (PA) female rhesus monkey as a model for PCOS. Polycystic ovary syndrome (PCOS) in women is characterized by anovulation, LH hypersecretion, hyperandrogenism and insulin resistance. As the most common female endocrine pathology, affecting 4-7% of reproductive-aged women, and as a frequent cause of infertility, accounting for 75% of anovulation, PCOS has staggering adverse physiological, psychological and financial consequences for women s reproductive health. During gonadotropin stimulation for in vitro fertilization (IVF), PCOS women experience decreased fecundity and increased pregnancy loss. Since experimental investigation of egg and embryo development in humans is limited by ethical constraints, we have developed the prenatally androgenized (PA) female rhesus monkey as a model for PCOS. PA female monkeys undergoing follicle stimulating hormone (FSH) therapy for IVF exhibit LH hypersecretion, circulating insulin excess, an exaggerated shift in ovarian follicle content from relatively low values of estradiol (E2) and androstenedione (A4) to relatively high values of progesterone (P4), and impaired embryo development beginning with embryonic genome activation. Because insulin enhances ovarian follicle maturation, leading to LH- induced follicle luteinization, we hypothesize that a) premature follicle luteinization and b) impaired egg developmental competence in PA monkeys are caused by adverse effects of hyperinsulinemia on follicle maturation. We predict that such abnormalities in PA monkeys are reversed by improved insulin sensitivity from weight loss through dietary restriction. Based upon data from our recognized nonhuman primate model of PCOS, we also hypothesize that c) premature follicle luteinization is a cause of poor oocyte developmental competence in PCOS women undergoing FSH therapy for IVF. The long-term objectives of this proposal are to define molecular markers of egg developmental competence that enhance IVF pregnancy outcome by improving embryo development, while minimizing pregnancy loss in women with PCOS and other insulin resistant states, such as obesity and Type II diabetes. This research used WNPRC Animal Services and Assay Services.
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