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、LH分泌过多、高雄激素血症和胰岛素抵抗。作为女性最常见的内分泌疾病，影响4-7%的育龄妇女，并且作为不孕症的常见原因，占无排卵的75%，PCOS对女性生殖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化（PA）雌性恒河猴作为PCOS的模型。接受促卵泡激素（FSH）治疗的PA雌猴IVF表现出LH分泌过多，循环胰岛素过量，卵泡内类固醇生成从雌二醇（E2）和雄烯二酮（A4）到孕酮（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。由于胰岛素增强FSH诱导的颗粒细胞分化，导致LH诱导的P4产生，我们假设PA猴中a）过早卵泡黄素化和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逆转PA猴的此类异常，并将在特定目标1和2中检验我们的预测。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。我们预测，颗粒细胞LH受体、胰岛素受体（IR）和生长分化因子-9（GDF-9）转录的失调会导致PCOS女性卵丘细胞增殖不良（具体目标3）。我们进一步假设d）PCOS患者的有减数分裂能力和无减数分裂能力的卵母细胞在GDF-9和其他发育相关信使核糖核酸（mRNA）的表达方面受损（具体目的4）。该提案的长期目标是：1）定义卵母细胞发育能力的分子标志物，通过提高胚胎卵裂和胚泡形成率来提高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，以及2）为PCOS的跨代效应提供额外的，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.