ANOVULATION IN PCOS--ETIOLOGY OF INCREASED LH SECRETION

PCOS 患者无排卵——LH 分泌增加的病因

• 批准号: 6744669
• 负责人: John C Marshall
• 金额: $ 12.24万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-23 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744669
• 关键词: adolescence (12-20); androgen inhibitor; androgens; clinical research; cooperative study; disease /disorder etiology; endogenous opioid; estradiol; female; follicle stimulating hormone; gonadotropin releasing factor; hormone regulation /control mechanism; human subject; hypothalamus; luteinizing hormone; menstrual cycle; neuroendocrine system; ovulation; polycystic ovary syndrome; progesterone; secretion; steroid hormone biosynthesis; young adult human (21-34)

Consistent features ofpolycystic ovarian syndrome (PCOS) include anovulation and hyperandrogenemia. In different individuals, these may be associated with hyperinsulinemia, obesity and associated disorders such as dyslipidemia. LH levels are elevated in up to 90% of patients when recent ovulation (and transient suppression of LH) has been excluded. The elevated LH reflects a persistently rapid frequency of GnRH secretion, enhancing LH synthesis, secretion and consequent androgen production by the ovary. An important aspect of normal ovulatory cycles is the differential synthesis and secretion of FSH and LH at different cycle stages. The ability to differentially secrete LH or FSH relates in part to changes in GnRH pulse frequency (slow frequency favors FSH) and slowing the GnRH pulse generator is effected by luteal progesterone (P). In PCOS, sensitivity to P is reduced by hyperandrogenemia and GnRH pulse frequency remains persistently rapid, leading to excess LH, normal or low FSH, excess androgen production and acyclicity. In SA1, we aim to pursue the primacy of P as the regulator of the GnRH pulse generator in normal women, in support of a thesis that elevation of P inhibits the rapid GnRH (1 pulse/h) secretion present after sexual maturation in adolescents. We also examine if excess androgens impair P induction of increased hypothalamic opioid activity, as a mechanism for reduced inhibition of GnRH pulse secretion. SA2 seeks to examine hypothalamic abnormalities in hyperandrogenemic adolescents, where hyperandrogenemia and abnormal LH secretion is documented and thought to be the forerunner of adult PCOS. We plan to determine ifhyperandrogenemia exerts similar inhibitory actions on P suppression of GnRH in adolescents prior to and after menarche. We will also study nocturnal LH, FSH and steroid secretion in eu- and hyperandrogenemic adolescent girls, to determine ifP effects the daytime suppression of GnRH pulse secretion during early pubertal maturation. If so, pubertal exposure to excess androgens may have similar actions to those seen in adults, leading to persistent 24 h GnRH secretion. In SA3, we aim to examine the efficacy of anti-androgens in enhancing the ability of P to inhibit GnRH pulse secretion, in efforts to enhance subsequent selective FSH secretion and follicular maturation upon steroid withdrawal. Our goal is to use physiologic principles to design protocols, which will inhibit the production of excess androgens and allow induction of cyclical follicular maturation and ovulation.

多囊卵巢综合征（PCOS）的特征包括无排卵和高雄激素血症。在不同的个体中，这些可能与高胰岛素血症、肥胖和相关疾病如血脂异常有关。当排除近期排卵（和LH短暂抑制）时，高达90%的患者LH水平升高。LH的升高反映了GnRH分泌的持续快速频率，从而增强了LH的合成、分泌和随后的卵巢雄激素产生。正常排卵周期的一个重要方面是FSH和LH在不同周期阶段的差异合成和分泌。差异分泌LH或FSH的能力部分与GnRH脉冲频率的变化有关（慢频率有利于FSH），并且减缓GnRH脉冲发生器受到黄体孕酮（P）的影响。在PCOS中，对P的敏感性因高雄激素血症而降低， GnRH脉冲频率持续快速，导致LH过多，FSH正常或低，雄激素过多和无周期性。 在SA 1中，我们的目标是追求P作为正常女性GnRH脉冲发生器的调节剂的首要地位，以支持P升高抑制青春期性成熟后GnRH快速分泌（1脉冲/小时）的论点。我们还研究了过量雄激素是否会损害P诱导下丘脑阿片活性增加，作为减少GnRH脉冲分泌抑制的机制。SA 2试图检查下丘脑异常， 高雄激素血症的青少年，其中高雄激素血症和LH分泌异常被记录并被认为是成人PCOS的先驱。我们计划确定高雄激素血症是否对月经初潮前后青少年的P抑制GnRH产生类似的抑制作用。我们还将研究正常和高雄激素血症的青春期女孩的夜间LH、FSH和类固醇分泌，以确定是否P影响青春期早期GnRH脉冲分泌的日间抑制。如果是这样的话，青春期暴露于过量的雄激素可能有类似的行动，在成人中看到的，导致持续24小时的GnRH分泌。在SA 3中，我们的目的是检查抗雄激素在增强P抑制GnRH脉冲分泌的能力方面的疗效，以增强随后的选择性FSH分泌和类固醇停药后的卵泡成熟。我们的目标是利用生理学原理来设计 方案，这将抑制过量雄激素的产生，并允许诱导周期性卵泡成熟和排卵。