Polycystic Ovarian Syndrome Model: Androgen-Treated Pubertal Monkeys

多囊卵巢综合症模型：雄激素治疗的青春期猴

• 批准号: 7875392
• 负责人: JUDY L CAMERON
• 金额: $ 25.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-03 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875392
• 关键词: Androgens; Animals; Body fat; Calories; Central obesity; Characteristics; Cholesterol; Chronic; Clinical; Clinical Treatment; Control Animal; Data; Development; Diet; Disease; Etiology; Exposure to; Fatty acid glycerol esters; Feedback; Female; Female Adolescents; Fetal Development; Future; Grant; Hirsutism; Hormonal; Hyperandrogenism; Implant; Incidence; Individual; Infertility; Insulin; Irregular Menstruation; Lead; Link; Macaca mulatta; Measures; Metabolic; Modeling; Monkeys; Neurosecretory Systems; Obesity; Ovarian; Pathway interactions; Physiologic pulse; Pilot Projects; Pituitary Gland; Polycystic Ovary Syndrome; Premenopause; Primates; Progesterone; Puberty; Severities; Silastic; Study models; Symptoms; Syndrome; Testing; Testosterone; Weight; Woman; Women' s Group; disease characteristic; early adolescence; emerging adult; girls; improved; insulin sensitivity; mullerian-inhibiting hormone; novel; public health relevance; relating to nervous system; reproductive; reproductive axis; young adult

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.

描述（由申请人提供）：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升高（类似于在易患多囊卵巢综合征 (PCOS) 的青春期女孩中观察到的情况）是否会导致该疾病的病理特征灵长类动物模型。这项资助建立在对一组雌性恒河猴收集的初步数据的基础上，这些数据在过去 3 年中接受了睾酮 (T) 治疗，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内继续研究这些有价值的雌性猴子，以确定它们在进入青年期时是否会出现与多囊卵巢综合征相关的其他症状。这种新型 PCOS 灵长类动物模型的开发不仅有助于提高我们对 PCOS 病因学的理解，而且有助于未来测试 PCOS 新临床治疗方法的研究。 PCOS 是一种常见疾病，发生于 6-8% 的绝经前女性，是无排卵性不孕的最常见原因。临床症状包括多毛症、雄激素过多症、月经不调、多囊卵巢、LH/FSH 比率升高、脉动性 LH 分泌增加、垂体对 GnRH 的反应性增加以及对孕酮负反馈的敏感性降低。多囊卵巢综合症患者肥胖（尤其是腹部肥胖）和胰岛素不敏感的发病率有所增加，但并非所有多囊卵巢综合症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雄激素过多症是 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子，通过皮下 T 填充硅橡胶植入物，现在具有增加的脉动 LH 分泌和对 GnRH 的反应性。在拟议的项目中，我们将 (1) 确定青春期发育过程中循环雄激素轻微升高对 (a) 生殖轴中枢神经驱动的持续影响（通过测量脉动 LH 分泌、对 GnRH 的反应性以及对黄体酮的敏感性）负反馈），（b）卵泡发育和囊性卵泡的存在，（c）PCOS的激素伴随物（包括胰岛素敏感性降低，抗苗勒氏管激素增加）和（d）身体脂肪分布； (2) 确定是否可以通过降低成年早期的循环雄激素水平来逆转青春期雄激素暴露的影响，以及 (3) 确定典型的西方饮食（其中 30% 的热量来自脂肪）是否会加剧 PCOS 症状的发展/严重程度。 公共健康相关性：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。该项目将进一步检查雄激素暴露后神经内分泌、卵巢和代谢的变化，以验证该灵长类动物模型用于多囊卵巢综合征的病因学和治疗研究。