PARACRINE DYSREGULATION OF OOCYTE COMPETENCE IN POLYCYSTIC OVARY SYNDROME

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：进一步建立雄性化雌恒河猴作为多囊卵巢综合征的模型。女性多囊卵巢综合征（PCOS）以无排卵、黄体生成素分泌过多、雄激素分泌过多和胰岛素抵抗为特征。多囊卵巢综合征是最常见的女性内分泌病理，影响4-7%的育龄妇女，也是不孕不育的常见原因，占排卵的75%，对妇女的生殖健康产生了惊人的不良生理、心理和经济后果。在促性腺激素刺激体外受精（IVF）期间，多囊卵巢综合征妇女的生育能力下降，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）雌性恒河猴作为多囊卵巢综合征的模型。接受促卵泡激素（FSH）治疗的雌性猴表现出LH分泌亢进、循环胰岛素过量、卵巢卵泡含量从相对较低的雌二醇（E2）和雄烯二酮（A4）向相对较高的黄体酮（P4）的过度转变，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，导致黄体生成素诱导卵泡黄体生成，我们假设a)卵泡黄体生成过早和b)卵泡发育能力受损是由高胰岛素血症对卵泡成熟的不利影响引起的。我们预测，通过限制饮食减轻体重，改善胰岛素敏感性，可以逆转PA猴的这种异常。基于我们公认的多囊卵巢综合征非人灵长类动物模型的数据，我们还假设c)卵泡黄体生成素过早是接受促卵泡刺激素治疗的多囊卵巢综合征妇女卵母细胞发育能力差的原因。本提案的长期目标是确定卵子发育能力的分子标记，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）妇女的妊娠损失。这项研究使用了WNPRC动物服务和化验服务。

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.