Polycystic Ovarian Syndrome Model: Androgen-Treated Pubertal Monkeys

描述（由申请人提供）：这是一项R21资助，旨在确定青春期发育期间循环雄激素水平的轻微升高（让人想起在易患多囊卵巢综合征（PCOS）的青春期女孩中观察到的情况）是否会导致灵长类动物模型中该疾病的病理特征。这项研究建立在一组在过去3年中接受睾酮（T）治疗的雌性恒河猴中收集的有希望的初步数据的基础上，并显示出PCOS的一些神经内分泌变化特征。这笔赠款将使我们能够在未来两年继续研究这些有价值的雌性猴子，以确定它们在进入成年期时是否会发展出与PCOS相关的其他生殖学。开发这种新的PCOS灵长类动物模型不仅有助于提高我们对PCOS病因的理解，而且有助于未来的研究，以测试PCOS的新临床治疗方法。多囊卵巢综合征是一种常见的疾病，发生在6-8%的绝经前妇女，是无排卵性不孕症的最常见原因。临床症状包括多毛症、高雄激素血症、月经不调、多囊卵巢、LH/FSH比值升高、LH脉冲性分泌增加、垂体对GnRH的反应性增加和对孕酮负反馈的敏感性降低。肥胖症的发病率增加，特别是腹部肥胖，以及PCOS中的胰岛素不敏感性，但并非所有PCOS患者都有这些代谢症状。引发PCOS的因果机制尚不清楚，但越来越多的证据表明高雄激素血症是PCOS发展的最终共同途径。我们发现，与接受胆固醇填充植入物的对照动物相比，在青春期发育期间暴露于轻度高雄激素血症的雌性猴，通过SC T填充的硅橡胶植入物，现在具有增加的脉冲式LH分泌和增加的对GnRH的反应性。在这个计划中，我们将（1）确定在青春期发育过程中循环雄激素的轻微升高对（a）生殖轴的中枢神经驱动的持续影响（通过测量脉冲LH分泌、对GnRH的反应性和对孕酮负反馈的敏感性），（B）卵巢卵泡发育和囊性卵泡的存在，（c）PCOS的激素伴随物（包括降低的胰岛素敏感性、增加的抗米勒管激素）和（d）身体脂肪分布;（2）确定青春期雄激素暴露的影响是否可以通过降低成年早期的循环雄激素水平来逆转，和（3）确定典型的西方饮食（30%的热量来自脂肪）是否会增加PCOS症状的发展/严重程度。 公共卫生相关性：该项目建立在一组雌性恒河猴中收集的有希望的初步数据的基础上，这些数据表明，青春期循环睾酮水平的轻微升高会导致多囊卵巢综合征的神经内分泌症状。本项目将进一步研究雄激素暴露后的神经内分泌、卵巢和代谢变化，以验证该灵长类动物模型用于PCOS病因学和治疗研究。

DESCRIPTION (provided by applicant): This is a R21 grant to determine if a slight elevation in circulating androgen levels during pubertal development, reminiscent of that observed in adolescent girls predisposed to polycystic ovarian syndrome (PCOS), leads to pathological characteristics of this disease in a primate model. The grant builds on promising preliminary data collected in a group of female rhesus monkeys who were treated with testosterone (T) for the past 3 years and are showing some neuroendocrine changes characteristic of PCOS. This grant would allow us to continue to study these valuable female monkeys for the next two years to determine if they develop additional symptomology associated with PCOS as they enter young adulthood. Development of this novel primate model of PCOS would be useful not only in improving our understanding of the etiology of PCOS but also in future studies to test new clinical treatments for PCOS. PCOS is a common disorder, occurring in 6-8% of premenopausal women and representing the most common cause of anovulatory infertility. Clinical symptoms include hirsutism, hyperandrogenism, menstrual irregularity, polycystic ovaries, an increased ratio of LH/FSH, increased pulsatile LH secretion, increased pituitary responsiveness to GnRH, and decreased sensitivity to progesterone negative feedback. There is an increased incidence of obesity, particularly abdominal obesity, as well as insulin insensitivity in PCOS, but not all individuals with PCOS have these metabolic symptoms. The causal mechanism(s) underlying the initiation of PCOS are not known, but there is growing evidence that hyperandrogenism represents a final common pathway for the development of PCOS. We have found that female monkeys exposed to mild hyperandrogenism during pubertal development, via sc T-filled silastic implants, now have increased pulsatile LH secretion and increased responsiveness to GnRH compared to control animals receiving cholesterol-filled implants. In the proposed project we will (1) determine the continued effect of a slight elevation in circulating androgen over pubertal development on (a) the central neural drive to the reproductive axis (by measuring pulsatile LH secretion, responsiveness to GnRH, and sensitivity to progesterone negative feedback), (b) ovarian follicular development and the presence of cystic follicles, (c) hormonal concomitants of PCOS (including decreased insulin sensitivity, increased antimullerian hormone) and (d) body fat distribution; (2) determine if the effects of pubertal androgen exposure can be reversed by decreasing circulating androgen levels in early adulthood, and (3) determine if a typical Western diet (with 30% of calories from fat) augments the development/severity of PCOS symptoms. PUBLIC HEALTH RELEVANCE: This project builds on promising preliminary data collected in a group of female rhesus monkeys showing that a slight elevation in circulating testosterone levels during puberty leads to neuroendocrine symptoms characteristic of polycystic ovarian syndrome. This project will examine further the neuroendocrine, ovarian and metabolic changes following androgen exposure to validate this primate model for studies on the etiology and treatment of PCOS.