ROLE OF ANDROGENS IN THE NEUROENDOCRINE DYSFUNCTION OF NASCENT PCOS

雄激素在初生 PCOS 神经内分泌功能障碍中的作用

• 批准号: 10025179
• 负责人: Christopher Rolland McCartney
• 金额: $ 34.16万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025179
• 关键词: Acute; Address; Adult; Affect; Androgen Receptor; Androgenization; Androgens; Animal Model; Anovulation; Clinical Research; Data; Development; Diagnosis; Dose; Endometrial Carcinoma; Epigenetic Process; Estradiol; Estrogens; Exhibits; Feedback; Follicle Stimulating Hormone; Frequencies; Functional disorder; Generations; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth; Health; Hormone secretion; Hour; Human; Hyperinsulinism; Hypothalamic structure; Impairment; Infertility; Insulin Resistance; Luteinizing Hormone; Modeling; Mus; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovarian; Pattern; Periodicity; Physiologic pulse; Polycystic Ovary Syndrome; Prevention strategy; Primates; Progesterone; Puberty; Regulation; Research Design; Role; Sleep; Source; Spironolactone; Steroid biosynthesis; Testing; Therapeutic Trials; Woman; aged; design; girls; hormone deficiency; improved; insight; neurobiological mechanism; pilot trial; prenatal; prevent; reproductive; sleep abnormalities; subfertility; treatment strategy

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.

多雌激素多囊卵巢综合征（PCOS）影响约8-10％的复制年龄 女性。 PCOS是不育和妇科健康不良的主要原因，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的基本原因 尚不清楚，但青春期是一个关键的发育窗口，在此窗口中，PCOS的病理生理学 展开。腹膜多雄激素血症（HA）可以代表成熟PCOS的前体，HA非常 肥胖的周围女孩常见（总体约60％）。那，研究肥胖症周围女孩 除了提供了评估杂期HA的原因和后果外，还提供了评估周围HA的原因和后果的机会 关键的见解是如何发展到成熟的PCOS的如何发展。该建议旨在阐明 PCOS如何开始和跨青春期发展，主要关注促性腺激素异常的作用 释放马龙（GNRH），黄体化的马龙（LH）和刺激福利的马龙（FSH）分泌。更多的 具体而言，该提案将解决有关神经内分泌的出现的以下工作模型 PCOS的异常：（1）Peripubertal HA（来自任何来源）导致LH的异常睡眠效果模式 （gnRH）脉冲频率 - 即，高24小时的频率没有正常的睡眠效果变化 - 有助于LH超过LH，卵巢HA，FSH缺乏和创新； （2）周围HA也对抗 雌激素（和孕激素）诱导促性腺激素激增的产生 - 另一个障碍 建立环状排卵功能。拟议项目的目标1涉及临床研究 旨在评估以下内容：如果在 HA的女孩（AIM 1A）；如果雄激素受体阻断（螺内酯）改善了孕酮的抑制 HA的女孩的唤醒LH脉冲频率（AIM 1B）；如果仅螺内乳杆菌将睡眠效果LH/FSH归一化 HA患者的分泌物（AIM 1C）；如果每天（早上）低剂量孕酮给药 患有HA的女孩的睡眠效果LH/FSH分泌（热合理的试点试验； AIM 1D）。目标2 拟议的项目涉及旨在：评估孕激素促进的临床研究 HA（AIM 2A）的晚期青春期女孩的促性腺激素分泌；评估雄激素受体的能力 在PCOS中促性腺激素分泌的孕酮膨胀的g鼠（AIM 2B）；和评估 PCOS中促性腺激素释放的雌二醇增强的潜在损害（AIM 2C）。这些人 研究将提供有关促性腺激素分泌异常分泌的机制的洞察力 新生的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理性的预防和/或治疗策略。