ROLE OF ANDROGENS IN THE NEUROENDOCRINE DYSFUNCTION OF NASCENT PCOS

高雄激素性多囊卵巢综合征（PCOS）影响大约8-10%的育龄妇女， 妇女多囊卵巢综合征是不孕症和妇科健康状况不佳的主要原因，它与肥胖有关， 胰岛素抵抗/高胰岛素血症、2型糖尿病和子宫内膜癌。PCOS的病因 目前尚不清楚，但青春期是一个关键的发育窗口，在此期间，PCOS的病理生理学 展开围青春期高雄激素血症（HA）可以代表全面发展的PCOS的前兆，HA是非常危险的。 在青春期前肥胖女孩中很常见（总体约60%）。因此，对青春期肥胖女孩的研究 提供了一个机会，以评估原因和后果的青春期周围HA，除了提供 无症状HA如何发展为全面PCOS的关键见解。本提案旨在阐明 PCOS如何在青春期开始和发展，主要关注异常促性腺激素的作用- 促性腺激素释放激素（GnRH）、促黄体生成激素（LH）和促卵泡激素（FSH）分泌。更 具体而言，本提案将针对以下有关神经内分泌的出现的工作模型 PCOS异常：（1）青春期周围HA（任何来源）导致LH睡眠-觉醒模式异常 （GnRH）脉冲频率-即24小时高频率，没有正常的睡眠-觉醒变化- 导致LH过剩、卵巢HA、FSH缺乏和不排卵;（2）青春期前后HA也拮抗 雌激素（和孕激素）诱导的促性腺激素激增产生-另一个障碍， 建立周期性排卵功能。拟议项目的目的1涉及临床研究 旨在评估以下内容：如果急性孕酮抑制唤醒LH脉冲频率受损， 患有HA的女孩（目的1a）;如果雄激素受体阻滞剂（螺内酯）改善了 HA女孩的觉醒LH脉冲频率（目的1b）;如果单独使用螺内酯使睡眠-觉醒LH/FSH正常化 HA女孩的分泌（目标1c）;如果每日（早晨）低剂量孕酮给药正常化 HA女孩的睡眠-觉醒LH/FSH分泌（一项治疗可行性的初步试验;目的1d）。目标2 拟议的项目涉及临床研究，旨在：评估孕激素增加 青春期晚期HA女孩的促性腺激素分泌（目的2a）;评估雄激素受体的能力 阻断以使PCOS中孕酮增加促性腺激素分泌正常化（目的2b）;并评估 PCOS中雌二醇增加促性腺激素释放的潜在损害（目的2c）。这些人类 研究将提供深入了解促性腺激素分泌异常的发展机制， 新生PCOS这些研究将与项目II和III的基础研究协同作用，以帮助阐明 PCOS的青春期个体发育，所有这些都是为了制定合理的预防和/或治疗策略。

Hyperandrogenic polycystic ovary syndrome (PCOS) affects approximately 8-10% of reproductive-aged women. PCOS is a major cause of infertility and poor gynecological health, and it is associated with obesity, insulin resistance/hyperinsulinemia, type 2 diabetes, and endometrial cancer. The underlying causes of PCOS remain unclear, but puberty is a critical developmental window during which the pathophysiology of PCOS unfolds. Peripubertal hyperandrogenemia (HA) can represent a precursor to full-blown PCOS, and HA is very common (~ 60% overall) in peripubertal girls with obesity. Thus, the study of peripubertal girls with obesity provides an opportunity to evaluate the causes and consequences of peripubertal HA, in addition to providing key insights into how asymptomatic HA progresses to full-blown PCOS. This proposal is designed to elucidate how PCOS begins and develops across puberty, primarily focusing on the role of abnormal gonadotropin- releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) secretion. More specifically, this proposal will address the following working model regarding the emergence of neuroendocrine abnormalities in PCOS: (1) peripubertal HA (from any source) leads to abnormal sleep-wake patterns of LH (GnRH) pulse frequency—namely, high 24-hour frequency without normal sleep-wake changes—which contributes to LH excess, ovarian HA, FSH deficiency, and anovulation; (2) peripubertal HA also antagonizes estrogen- (and progesterone-) induced gonadotropin surge generation—another impediment to the establishment of cyclic ovulatory function. Aim 1 of the proposed project involves clinical research studies designed to assess the following: if acute progesterone suppression of wake LH pulse frequency is impaired in girls with HA (Aim 1a); if androgen-receptor blockade (spironolactone) improves progesterone-suppression of wake LH pulse frequency in girls with HA (Aim 1b); if spironolactone alone normalizes sleep-wake LH/FSH secretion in girls with HA (Aim 1c); and if daily (morning) low-dose progesterone administration normalizes sleep-wake LH/FSH secretion in girls with HA (a pilot trial of therapeutic plausibility; Aim 1d). Aim 2 of the proposed project involves clinical research studies designed to: assess progesterone augmentation of gonadotropin secretion in late pubertal girls with HA (Aim 2a); evaluate the ability of androgen-receptor blockade to normalize progesterone augmentation of gonadotropin secretion in PCOS (Aim 2b); and assess potential impairments in estradiol augmentation of gonadotropin release in PCOS (Aim 2c). These human studies will provide insight into mechanisms underlying the development of abnormal gonadotropin secretion in nascent PCOS. These studies will synergize with the basic studies of Projects II and III to help elucidate the pubertal ontogeny of PCOS, all with a view to developing rational preventive and/or treatment strategies.