Paracrine dysregulation of oocyte competence in PCOS

描述(申请人提供)：女性多囊卵巢综合征(PCOS)的特征是无排卵、促黄体生成素高分泌、高雄激素血症和胰岛素抵抗。PCOS是女性最常见的内分泌疾病，影响育龄妇女的4%-7%，是不孕不育的常见原因，占无排卵的75%，对女性生殖造成惊人的生理、心理和经济后果。在体外受精(IVF)的促性腺激素刺激过程中，PCOS妇女经历了生育力下降和妊娠丢失增加的情况。由于人类卵母细胞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(PA)雌性恒河猴作为多囊卵巢综合征的模型。接受卵泡刺激素(FSH)治疗进行体外受精的雌性猕猴表现为黄体生成素高分泌、循环胰岛素过剩、卵泡内类固醇合成从雌二醇(E2)和雄烯二酮(A4)过度转变为孕酮(P4)，以及从胚胎基因组激活开始的胚胎发育障碍。由于胰岛素促进了FSH诱导的颗粒细胞分化，导致了促黄体生成素诱导的P4的产生，我们假设a)卵泡黄素化过早和b)卵母细胞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，PA猴子的这种异常可以通过限制饮食减轻体重而改善胰岛素敏感性来逆转，并将在特定的目标1和2中测试我们的预测。基于我们公认的多囊卵巢综合征非人类灵长类动物模型的数据，我们还假设：c)过早的卵泡黄体化是接受FSH治疗的多囊卵巢综合征患者卵母细胞发育能力低下的原因之一。我们预测，卵泡黄素化早期，颗粒细胞对黄体生成素受体、胰岛素受体(IR)和生长分化因子-9(GDF-9)转录的调节失调会导致多囊卵巢综合征患者卵丘细胞增殖不良(目标3)。我们进一步假设：d)多囊卵巢综合征患者的减数分裂功能卵母细胞和减数分裂不功能卵母细胞的GDF-9和其他发育相关信使核糖核酸(MRNAs)的表达受损(特定目标4)。这项建议的长期目标是：1)定义卵母细胞发育能力的分子标志物，通过提高胚胎卵裂率和囊胚形成率来提高体外受精妊娠结局；同时将患有多囊卵巢综合征和其他胰岛素抵抗状态的妇女的妊娠损失降至最低，如肥胖和II型糖尿病；以及2)为多囊卵巢综合征的跨代影响提供额外的、独特的见解。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) in women is characterized by anovulation, LH hypersecretion, hyperandrogenism and insulin resistance. As the most common endocrinopathy in females, 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 consequence on reproduction in women. During gonadotropin stimulation for in vitro fertilization (IVF), PCOS women experience decreased fecundity and increased pregnancy loss. Since experimental investigation of oocyte 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 intrafollicular steroidogenesis from estradiol (E2) and androstenedione (A4) to progesterone (P4), and impaired embryo development beginning with embryonic genome activation. Because insulin enhances FSH-induced granulose cell differentiation, leading to LH-induced P4 production, we hypothesize that a) premature follicle luteinization and b) impaired oocyte 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 and will test our prediction in Specific Aims 1 and 2. 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. We predict that granulosa cell dysregulation of LH receptor, insulin receptor (IR) and growth differentiation factor-9 (GDF-9) transcription from premature follicle luteinization causes poor cumulus cell proliferation in PCOS women (Specific Aim 3). We further hypothesize that d) meiotically-competent and meiotically-incompetent oocytes of PCOS patients are impaired in expression of GDF-9 and other developmentally relevant messenger ribonucleic acids (mRNAs) (Specific Aim 4). The long-term objectives of this proposal are to: 1) define molecular markers of oocyte developmental competence that enhance IVF pregnancy outcome by improving rates of embryo cleavage and blastocyst formation; while minimizing pregnancy loss in women with PCOS and other insulin resistant states, such as obesity and Type II diabetes, and 2) to provide additional, unique, insight into the transgenerational effect of PCOS.