Polycystic Ovarian Syndrome Model: Androgen-Treated Pubertal Monkeys

描述（由申请人提供）：这是一项R21拨款，旨在确定在灵长类动物模型中，青春期发育期间循环雄激素水平的轻微升高是否导致多囊卵巢综合征（PCOS）易感的青春期女孩的病理特征。这项资助建立在一组雌性恒河猴的初步数据基础上，这些雌性恒河猴在过去3年里接受了睾酮(T)治疗，显示出多囊卵巢综合征的一些神经内分泌变化特征。这笔拨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。这种新型多囊卵巢综合征灵长类动物模型的建立不仅有助于我们进一步了解多囊卵巢综合征的病因，而且有助于进一步研究多囊卵巢综合征的新的临床治疗方法。多囊卵巢综合征是一种常见的疾病，发生在6-8%的绝经前妇女中，是无排卵性不孕的最常见原因。临床症状包括多毛、雄激素过多、月经不规律、多囊卵巢、LH/FSH比值升高、脉动性LH分泌增多、垂体对GnRH反应性增高、对孕激素负反馈敏感性降低。多囊卵巢综合征患者的肥胖发生率增加，尤其是腹部肥胖，以及胰岛素不敏感，但并非所有多囊卵巢综合征患者都有这些代谢症状。多囊卵巢综合征的发病机制尚不清楚，但越来越多的证据表明，雄激素过多是多囊卵巢综合征发展的最终共同途径。我们发现，雌性猴子在青春期发育期间暴露于轻度高雄激素，通过sc - t填充的硅胶植入物，现在与接受胆固醇填充植入物的对照动物相比，它们的脉动性LH分泌增加，对GnRH的反应性增加。在拟议的项目中，我们将(1)确定青春期循环雄激素轻微升高对以下方面的持续影响：(a)生殖轴的中枢神经驱动（通过测量脉动性LH分泌、对GnRH的反应和对黄体酮负反馈的敏感性），(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）。增加抗苗勒管激素)和(d)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；(3)确定典型的西方饮食（30%的热量来自脂肪）是否会增加多囊症的发展/严重程度。

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.