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 女人。多囊卵巢综合征是不孕不育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。多囊卵巢综合征的根本原因 目前尚不清楚，但青春期是多囊卵巢综合征的关键发育窗口，在此期间，多囊卵巢综合征的病理生理学 展开。青春期高雄激素血症(HA)可代表完全发育期PCOS的前驱症状，且HA非常 在青春期肥胖的女孩中很常见(约60%)。因此，对青春期肥胖女孩的研究 提供一个机会来评估青春期HA的原因和后果，除了提供 对无症状HA如何进展为完全的多囊卵巢综合征的关键见解。这项提议旨在澄清 多囊卵巢综合征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- 释放激素(GnRH)、黄体生成素(LH)和卵泡刺激素(FSH)的分泌。更多 具体地说，这项提议将涉及以下关于神经内分泌出现的工作模式 多囊卵巢综合征的异常：(1)青春期周围透明质酸(来自任何来源)导致黄体生成素异常睡眠-觉醒模式 (GnRH)脉搏频率--即没有正常睡眠的高24小时频率--觉醒变化-- 导致黄体生成素过多、卵巢透明质酸、卵泡刺激素缺乏和无排卵；(2)青春期周围透明质酸也有拮抗作用 雌激素(和黄体酮)诱导的促性腺激素峰生成-另一个阻碍 周期排卵功能的建立。拟议项目的目标1涉及临床研究研究 旨在评估以下指标：如果急性黄体酮抑制觉醒的黄体生成素脉冲频率在 患有HA的女孩(目标1a)；如果雄激素受体阻滞剂(螺内酯)改善孕酮抑制 患有HA的女孩的唤醒黄体生成素脉冲频率(目标1b)；如果单用螺内酯使睡眠唤醒黄体生成素/卵泡刺激素正常化 患有HA的女孩的分泌物(Aim 1c)；如果每天(早上)小剂量黄体酮给药正常 患有HA的女孩的睡眠觉醒促黄体生成素/卵泡刺激素分泌(治疗可行性的试点试验；目标1D)。目标2 拟议的项目涉及临床研究，旨在：评估孕酮对 青春期晚期透明质酸女孩促性腺激素的分泌(目标2a)；评估雄激素受体的能力 阻断多囊卵巢综合征患者孕酮增加促性腺激素分泌的正常化(目标2b)； 雌激素促进多囊卵巢综合征促性腺激素释放的潜在损害(目标2c)。这些人类 研究将深入了解促性腺激素异常分泌的潜在机制。 新生的多囊卵巢综合征。这些研究将与项目II和III的基础研究相配合，以帮助阐明 多囊卵巢综合征的青春期个体发育，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.