HYPERANDROGENISM AND INSULIN RESISTANCE IN WOMEN

卵巢高雄激素血症是最常见的 育龄妇女的内分泌疾病。 拟定病因 这种常见临床综合征的机制包括原发性 下丘脑-垂体单位、卵巢和 肾上腺 一个独特的机会，以确定一个特定的 卵巢高雄激素血症的分子原因是由 观察到高胰岛素血症通常与 雄激素过多症 本提案的目的是测试 胰岛素和胰岛素样生长因子（IGFs） 调节女性卵巢雄激素的产生和代谢。 初步证据表明，胰岛素、IGF-1和LH 刺激切碎人孵育中雄激素产生 卵巢基质和卵泡膜。 为了进一步探索这些影响， 计划进行以下实验：1）确定详细的 胰岛素、IGF-1和LH刺激的剂量反应曲线 卵泡膜和气孔雄激素的产生，2）测定 胰岛素、IGF-1和LH对卵泡膜雄激素产生的影响 从健康或闭锁卵泡中获得，3）分析 胰岛素和胰岛素样生长因子与胰岛素受体的结合特征， 卵巢卵泡膜和间质中IGF-1和IGF-1受体的分析， 胰岛素和胰岛素样生长因子对卵泡膜特异性酶的影响 雄激素生物合成（例如17 β-羟基类固醇脱氢酶）， 5)用斑点印迹法检测卵巢组织中mRNA的存在 胰岛素和胰岛素样生长因子1受体。 初步证据表明，口服100 高胰岛素血症-高雄激素血症妇女的葡萄糖gms 产生血清雄烯二酮，睾酮和 双氢睾酮 为了测试胰岛素和葡萄糖对 循环中的雄烯二酮和睾酮，以下 实验计划：1）检查50克，100克 克和200克或口服葡萄糖;和25克和50克的 静脉注射葡萄糖对循环胰岛素和雄激素的影响，2） 直接检测高胰岛素血症对循环胰岛素的影响 通过使用正葡萄糖钳夹;和3）直接测试 高血糖对循环雄激素的影响 止血钳 这些实验应该能提供重要的信息 关于代谢因素在调节 卵巢雄激素的产生和代谢。

Ovarian hyperandrogenism is one of the most common endocrinopathies of reproductive age women. Proposed etiologic mechanisms for this common clinical syndrome include primary abnormalities of the hypothalamic-pituitary unit, the ovary and the adrenal gland. A unique opportunity to identify a specific molecular cause of ovarian hyperandrogenism is provided by the observation that hyperinsulinemia is commonly associated with hyperandrogenism. The objective of this proposal is to test the hypothesis that insulin and insulin-like growth factors (IGFs) regulate ovarian androgen production and metabolism in women. Preliminary evidence indicates that insulin, IGF-1 and LH stimulate androgen production in incubations of minced human ovarian stroma and theca. To further explore these effects the following experiments are planned: 1) determination of detailed dose-response curves for insulin, IGF-1 and LH stimulation of thecal and stomal androgen production, 2) determination of the effects of insulin, IGF-1 and LH on androgen production in theca obtained from healthy or atretic follicles, 3) analysis of the binding characteristics of insulin and IGFs to insulin receptors, and IGF-1 receptors in ovarian theca and stroma, 4) analysis of the effects of insulin and IGFs on specific enzymes of thecal androgen biosynthesis (e.g. 17B - hydroxysteroid dehydrogenase), 5) use dot blots to probe ovarian tissue for the presence of mRNA for the insulin and IGF-1 receptors. Preliminary evidence indicated that the oral administration of 100 gms of glucose to hyperinsulinemic-hyperandrogenic women produces an acute rise in serum androstenedione, testosterone and dihydrotestosterone. To test the effects of insulin and glucose on circulating androstenedione and testosterone, the following experiments are planned: 1) examine the effects of 50 gm, 100 gm and 200 gm or oral glucose; and 25 gm and 50 gm of intravenous glucose on circulating insulin and androgens, 2) directly test the effects of hyperinsulinemia on circulating insulin by using a euglycemic clamp; and 3) directly test the effects of hyperglycemia on circulating androgens by using a hyperglycemic clamp. These experiments should yield important information concerning the role of metabolic factors in the regulation of ovarian androgen production and metabolism.