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R21赠款，以确定在青春期发育过程中循环雄激素水平的略有升高，让人联想到易于多囊卵巢综合征（PCOS）的青少年女孩观察到的雄激素水平是否会导致这种疾病模型中这种疾病的病理特征。该赠款基于在过去三年中接受睾丸激素（T）治疗的一组雌性恒河猴中收集的有希望的初步数据，并显示了PCOS的一些神经内分泌变化。这笔赠款将使我们能够在接下来的两年中继续研究这些有价值的雌猴，以确定它们是否在进入年轻成年时是否会产生与PCOS相关的其他症状。这种新型PCOS的灵长类动物模型的开发不仅在提高我们对PCOS病因的理解，还可以在未来的研究中测试PCOS的新临床治疗方法。 PCOS是一种常见的疾病，发生在6-8％的绝经前妇女中，代表了最常见的无育性不育症。临床症状包括多肌，超雄激素，月经不规则性，多囊卵巢，LH/FSH的增加比率增加，脉冲LH分泌增加，对GNRH的垂体反应增加以及对孕酮负反馈的敏感性降低。肥胖症，尤其是腹部肥胖症以及PCOS的胰岛素不敏感的发生率增加，但并非所有患有PCOS的人都有这些代谢症状。 PCOS启动的基础的因果机制尚不清楚，但越来越多的证据表明，超雄激素代表了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，通过SC T填充的硅质植入物在青春期发育过程中暴露于轻度超雄激素的雌性猴子现在已经增加了LH分泌的搏动性LH分泌和对GNRH的反应性。 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 （包括胰岛素敏感性降低，抗肺激素增加）和（d）体内脂肪分布； （2）确定青春期雄激素暴露的影响是否可以通过降低成年后的循环雄激素水平来逆转，并且（3）确定典型的西方饮食（脂肪中的卡路里的30％）是否会增加PCOS症状的发育/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，表明青春期期间循环睾丸激素水平的略有升高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，以验证这种灵长类动物模型，以研究PCOS的病因和治疗。