MODELING THE MENOPAUSAL TRANSITION AND MENOPAUSE

描述(由申请人提供)： 美国绝经后人口正在增加，并将在未来十年占所有女性的三分之一。心血管疾病将是这一人群最大的单一死亡原因，而骨质疏松症和由此导致的骨折将影响多达一半的女性，许多其他人将遭受严重的认知能力下降。新出现的证据表明，这些疾病起源于绝经前，特别是在绝经前的几年期间(“围绝经期过渡”)，其特点是卵巢激素的分泌波动--并最终下降。非人灵长类动物在生殖特征和疾病易感性方面与女性非常相似。然而，尽管一些非人类灵长类物种经历了更年期，但这些个体往往年龄较大，无法大量获得。因此，研究人员在对围绝经期过渡和更年期的病理生物学建模，以及评估可能延缓或抑制这些疾病发展的干预措施方面的能力一直受到限制。这些疾病构成了女性绝经后健康负担的主要部分。目前的应用旨在解决上述更年期模型中的不足，通过将食蟹猴(Macaca Fascularis)暴露于4-乙烯基环己烯二环氧化物(VCD)，VCD选择性地破坏卵巢原始卵泡和初级卵泡。这种方法最初是在小鼠身上开发的，会导致逐渐的卵巢衰竭，并导致卵泡耗尽的动物保留剩余的卵巢组织，并显示出类似于更年期女性的激素谱。该项目的四个主要目标是：1)确定VCD暴露将充分减少初级和原始卵泡到导致逐渐卵巢衰竭的水平；2)确定卵巢完全衰竭(更年期)所需的时间长度，并确定这种围绝经期过渡和随后的更年期的激素特征；3)描述慢性病(动脉粥样硬化、骨质疏松症)风险标记物的变化；以及4)为卵巢完好、卵泡耗竭的猴子建立可用于更年期健康研究的外部资源。因此，该模型将促进对围绝经期和绝经后主要健康问题的研究，包括心血管疾病、骨质疏松症、糖尿病、认知功能减退、性功能障碍和生殖道癌。因此，拟议的计划与多个NIH研究所的任务直接相关，包括但不限于NIA、NICHD、NHLBI、NIDDK和NIMH。

DESCRIPTION (provided by applicant): The postmenopausal population of the U.S. is increasing and will comprise one-third of all women during the next decade. Cardiovascular disease will be the largest single cause of death in this population, while osteoporosis and resulting fractures will affect up to half of women and many others will suffer from significant cognitive decline. Emerging evidence suggests that these diseases originate premenopausally, especially during the several years ("the peri-menopausal transition") that precede menopause and that is characterized by fluctuating - and ultimately declining - ovarian hormone production. Nonhuman primates closely resemble women in reproductive characteristics and disease vulnerability. However, while some nonhuman primate species experience menopause, such individuals tend to be aged and are not available in large numbers. As a result, researchers have been limited in their ability to model the pathobiology of the peri-menopausal transition and menopause, and to evaluate interventions that might delay or inhibit the development of those diseases that comprise the majority of the postmenopausal health burden in women. The current application is designed to address the foregoing deficiency in menopausal models by exposing cynomolgus monkeys (Macaca fascicularis) to 4-vinylcyclohexene diepoxide (VCD), which selectively destroys ovarian primordial and primary follicles. This approach, developed initially in mice, induces a gradual ovarian failure and results in a follicle depleted animal that retains residual ovarian tissue and that displays a hormone profile similar to that of menopausal women. The four primary aims of the this project are to: 1) determine the VCD exposure that will sufficiently reduce primary and primordial follicles to a level that induces gradual ovarian failure; 2) determine the length of time required for complete ovarian failure (menopause) and define the hormone characteristics of this peri-menopausal transition and subsequent menopause; 3) characterize changes in risk markers for chronic disease (atherosclerosis, osteoporosis); and 4) establish a resource for extramural investigators of ovary-intact, follicle-depleted monkeys that can be used in studies focused on menopausal health. This model will thus facilitate research on the major peri- and postmenopausal health concerns, including cardiovascular disease, osteoporosis, diabetes, cognitive decline, sexual dysfunction, and reproductive tract cancers. Therefore the proposed program is directly relevant to the missions of multiple NIH Institutes, including - but not limited to - NIA, NICHD, NHLBI, NIDDK and NIMH.