HYPERANDROGENISM AND INSULIN RESISTANCE IN WOMEN

卵巢高雄激素血症是最常见的 育龄妇女的内分泌病。建议病因学 这种常见的临床综合征的发病机制包括 下丘脑-垂体单位、卵巢和 肾上腺。一个独特的机会来确定特定的 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 高雄激素血症。这项提案的目标是测试 假设胰岛素和胰岛素样生长因子(IGF) 调节女性卵巢雄激素的产生和代谢。 初步证据表明，胰岛素、胰岛素样生长因子-1和促黄体生成素 在人碎肉孵化中刺激雄激素的产生 卵巢间质和卵泡膜。为了进一步探讨这些影响， 计划进行以下实验：1)详细测定 胰岛素、胰岛素样生长因子-1和促黄体生成素刺激的剂量-反应曲线 鞘和吻合口雄激素的产生，2)测定 胰岛素、胰岛素样生长因子-1和黄体生成素对卵泡膜雄激素产生的影响 取自健康的或闭锁的卵泡，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性 和IGF-1受体在卵泡膜和间质中的表达，4)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(如17B-羟基类固醇脱氢酶)， 5)用斑点印迹法检测卵巢组织中是否存在mrna 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-高雄激素性妇女的葡萄糖摄入量 使血清中雄烯二酮、睾酮和 双氢睾丸素。为了测试胰岛素和葡萄糖对心脏功能的影响 循环中的雄烯二酮和睾酮，如下 实验计划：1)检验50克、100克的效果 转基因和200克或口服葡萄糖；以及25克和50克 静脉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 通过使用正常血糖钳；以及3)直接测试 使用高血糖药对循环雄激素的影响 夹子。这些实验应该会产生重要的信息 关于代谢因素在调节心脏功能中的作用 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.