PARACRINE DYSREGULATION OF OOCYTE COMPETENCE IN POLYCYSTIC OVARY SYNDROME

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。进一步发展产前雄激素化（PA）雌性恒河猴作为PCOS模型。 多囊卵巢综合征（PCOS）是一种以无排卵、LH分泌过多、高雄激素血症和胰岛素抵抗为特征的疾病。作为最常见的女性内分泌疾病，影响4-7%的育龄妇女，并作为不孕症的常见原因，占不排卵的75%，PCOS对妇女的生殖健康具有惊人的不良生理，心理和经济后果。在促性腺激素刺激体外受精（IVF）期间，PCOS妇女的生育力下降，妊娠丢失增加。由于人类卵子和胚胎发育的实验研究受到伦理约束的限制，我们开发了产前雄激素化（PA）雌性恒河猴作为PCOS的模型。接受卵泡刺激素（FSH）治疗的PA雌性猴IVF表现出LH分泌过多，循环胰岛素过量，卵泡含量从相对较低的雌二醇（E2）和雄烯二酮（A4）值到相对较高的孕酮（P4）值的过度变化，以及从胚胎基因组激活开始的胚胎发育受损。由于胰岛素促进卵泡成熟，导致LH诱导的卵泡黄素化，我们假设PA猴中a）卵泡过早黄素化和B）卵子发育能力受损是由高胰岛素血症对卵泡成熟的不良影响引起的。我们预测，通过饮食限制减轻体重，改善胰岛素敏感性，可以逆转PA猴的这种异常。基于我们公认的非人灵长类PCOS模型的数据，我们还假设c）卵泡过早黄素化是接受FSH治疗IVF的PCOS妇女卵母细胞发育能力差的原因。该提案的长期目标是定义卵子发育能力的分子标志物，通过改善胚胎发育来提高IVF妊娠结局，同时最大限度地减少PCOS和其他胰岛素抵抗状态（如肥胖和II型糖尿病）女性的妊娠损失。本研究使用WNPRC Animal Services和Assay Services。

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.