Paracrine dysregulation of oocyte competence in PCOS

PCOS 患者卵母细胞能力的旁分泌失调

基本信息

批准号：
6948542
负责人：
Daniel A Dumesic
金额：
$ 39.95万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2007-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：女性的多囊卵巢综合征（PCOS）的特征在于缺乏，LH超催化，超雄激素和胰岛素抵抗。作为女性中最常见的内分泌病，影响了4-7％的生殖妇女，并且经常导致不育的原因，占发作的75％的占75％的妇女，对妇女的繁殖产生了惊人的不良生理，心理和财务后果。在促性腺激素刺激体外受精（IVF）期间，PCOS妇女的经历降低了繁殖力和妊娠丧失。由于人类对卵母细胞和胚胎发育的实验研究受到道德约束的限制，因此我们开发了产前雄激素化（PA）雌性恒河猴作为PCOS的模型。 PA雌性猴子接受卵泡刺激激素（FSH）治疗用于IVF，表现出LH的过度分泌，循环胰岛素过量，从雌二醇（E2）和雄激素（A4）转移到孕酮（P4）和孕激素（P4）的胚胎（a4）和富含胚胎的启动中，源自雌二醇（E2）和雄激素（A4）的夸张转移。由于胰岛素可以增强FSH诱导的颗粒糖细胞分化，从而导致LH诱导的P4产生，因此我们假设a）PA猴子中的卵泡过早的果胶化和b）PA猴子的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反应引起的。我们预测，pa猴中的这种异常是通过从减肥到饮食限制的提高胰岛素敏感性而反转的，并将在特定目标1和2中测试我们的预测。基于我们公认的非人类灵长类动物模型的数据，我们还假设c）过早的卵泡脂肪成分是对PCOS的较差的卵泡效果较差的PCOS妇女的较差的型号。我们预测，从过早的卵泡脂肪化中，LH受体，胰岛素受体（IR）和生长分化因子-9（GDF-9）转录的颗粒细胞失调会导致PCOS女性的不良Cumulus细胞增殖（特定目标3）。我们进一步假设d）PCOS患者的减数分裂和减数分裂和减少功能的卵母细胞在GDF-9和其他与发育相关的允许核糖核酸（MRNA）（特定目标4）中受到损害。该提案的长期目标是：1）定义卵母细胞发育能力的分子标记，从而通过提高胚胎裂解和胚泡形成的速率来增强IVF妊娠结局；虽然最大程度地减少了PCOS和其他胰岛素抵抗状态（例如肥胖和II型糖尿病）的妊娠丧失，以及2）对PCOS的转世代作用提供了额外的独特，独特的见解。