REGULATION OF GNRH DRIVE IN PCOS

多囊卵巢综合征（PCOS）是一种由卵巢引起的高雄激素血症引起的慢性无排卵症。最近，PCOS与胰岛素抵抗和高胰岛素血症有关。由于高雄激素血症和胰岛素抵抗，各自在无排卵发生中的独立作用尚不清楚。由于开发安全方便的恢复排卵的治疗方法取决于确定原因，本项目的目的是澄清高雄激素血症和胰岛素抵抗在多大程度上独立地导致PCOS的无排卵。PCOS无排卵的直接原因是促性腺激素分泌异常，其特征是循环LH升高和FSH不足，以维持卵泡发生。LH/FSH比值改变的一个可能原因是GnRH脉冲频率加快（反映为LH脉冲频率增加）。为了确定PCOS妇女无排卵的原因，我们将研究高雄激素血症和高胰岛素血症在维持快速LH脉冲频率和LH分泌减少中的作用：[1]用雄激素受体阻断剂氟替卡松减少雄激素作用; [2]用胰岛素增敏剂曲格列酮改善胰岛素抵抗; [3]用胰岛素敏感剂曲格列酮改善胰岛素抵抗。和[3]通过比较药物干预与安慰剂的效果。将对非肥胖PCOS女性进行研究，因为这些药物更可能降低雄激素作用或恢复相对瘦女性的胰岛素敏感性。非肥胖人群的使用将提供一个更清晰的概念测试有关PCOS无排卵的发病机制，这项研究的结果将直接相关的PCOS妇女不孕症的治疗。

Polycystic ovary syndrome (PCOS) is classically defined as chronic anovulation in the presence of hyperandrogenism of ovarian origin. More recently, PCOS has been associated with insulin resistance and hyperinsulinemia. Because hyperandrogenism and insulin resistance the independent role of each in the genesis of anovulation remains unclear. Since the development of safe and convenient therapies to restore ovulation depends on identifying the cause(s), the aim of this project is to clarify to what extent hyperandrogenism and insulin resistance independently contribute to anovulation in PCOS. The proximate cause of anovulation in PCOS is aberrant gonadotropin secretion characterized by elevated circulating LH and insufficient FSH to sustain folliculogenesis. A likely cause of the altered LH/FSH ratio is a rapid GnRH pulse frequency (as reflected by increased LH pulse frequency). To determine the cause of anovulation in women with PCOS, we will investigate the roles of hyperandrogenism and hyperinsulinemia in the maintenance of rapid LH pulse frequency and reduced LH secretion by: [1] reducing androgen action with the androgen receptor blocker, flutamide; [2] by improving insulin resistance insulin resistance with the insulin sensitizer, troglitazone; and [3] by comparing the effects of pharmacologic intervention to placebo. Non-obese women with PCOS will be studied because these pharmacological agents are more likely to reduce androgen action or restore insulin sensitivity in relatively lean women. The use of a non-obese population will afford a clearer test of concept regarding the pathogenesis of anovulation in PCOS and the results of this study will be directly relevant to the treatment of infertility in women with PCOS.