POLYCYSTIC OVARIAN SYNDROME MODEL: ANDROGEN-TREATED PUBERTAL MONKEYS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这是一项R21拨款，旨在确定青春期发育期间循环雄激素水平的轻微上升是否会导致灵长类动物模型中这种疾病的病理特征，这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。这项资助建立在一组雌性恒河猴身上收集的有希望的初步数据基础上，这些恒河猴在过去3年里接受了睾酮(T)治疗，并显示出多囊卵巢综合征特有的一些神经内分泌变化。这笔赠款将允许我们在接下来的两年里继续研究这些有价值的雌性猴子，以确定它们在进入年轻成年期后是否会出现与多囊卵巢综合征相关的其他症状。这种新的灵长类多囊卵巢综合征动物模型的建立不仅有助于提高我们对多囊卵巢综合征病因的理解，也将有助于未来测试多囊卵巢综合征新的临床治疗方法的研究。多囊卵巢综合征是一种常见的疾病，发生在6-8%的绝经前妇女中，是导致无排卵性不孕的最常见原因。临床症状包括多毛症、高雄激素血症、月经不调、多囊卵巢、黄体生成素/卵泡刺激素比值升高、黄体生成素分泌节律性增加、对促性腺激素释放激素的反应性增强、对孕酮负反馈的敏感性降低。PCOS的肥胖率增加，特别是腹型肥胖症，以及胰岛素不敏感，但并不是所有的PCOS患者都有这些代谢症状。多囊卵巢综合征的发病机制(S)尚不清楚，但越来越多的证据表明，高雄激素血症是多囊卵巢综合征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子，通过sc T填充硅胶植入物，现在有更多的脉动性黄体生成素分泌和对GnRH的反应性。在拟议的项目中，我们将(1)确定在青春期发育过程中循环雄激素略有升高对(A)中枢神经驱动生殖轴的持续影响(通过测量搏动性的促黄体生成素分泌、对促性腺激素释放激素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)多囊卵巢综合征的激素伴随(包括胰岛素敏感性降低，反髓激素增加)和(D)体脂分布；(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，以及(3)确定典型的西方饮食(30%的卡路里来自脂肪)是否会增加多囊卵巢综合征症状的发展/严重程度。公共卫生相关性：这个项目建立在从一组雌性恒河猴身上收集的有希望的初步数据基础上，这些数据表明，青春期血液中睾酮水平的轻微上升会导致多囊卵巢综合征的神经内分泌症状。该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，以验证这一灵长类动物模型是否适用于多囊卵巢综合征的病因和治疗研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.