MODELING THE MENOPAUSAL TRANSITION AND MENOPAUSE

美国的绝经后人口正在增加，在接下来的一年中将占所有女性的三分之一 十年。心血管疾病将是这一人群中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妇女，许多其他人将遭受 认知能力显著下降。新出现的证据表明，这些疾病起源于绝经前， 尤其是在绝经前的几年(“围绝经期过渡”)，也就是 以卵巢激素分泌波动--并最终下降--为特征。非人灵长类 在生殖特征和疾病易感性方面与女性极为相似。然而，虽然有些人 非人灵长类物种会经历更年期，这样的个体往往会变老，无法获得 满坑满谷。因此，研究人员在对该病的病理生物学建模方面的能力一直受到限制。 围绝经期过渡和更年期，并评估可能延迟或抑制更年期的干预措施 这些疾病构成了妇女绝经后健康负担的主要部分。 当前的应用程序旨在通过暴露以下内容来解决更年期模型中的上述缺陷 食蟹猴(猕猴)对4-乙烯基环己烯二环氧化物(VCD)的选择性 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，它诱导了一种 逐渐的卵巢衰竭，导致卵泡枯竭的动物保留剩余的卵巢组织， 显示与更年期女性相似的荷尔蒙概况。这个项目的四个主要目标 目的是：1)确定足以将初级和原始卵泡减少到一定水平的VCD暴露 导致渐进性卵巢衰竭；2)确定完全卵巢衰竭所需的时间 (更年期)，并确定这一围绝经期过渡和随后的激素特征 更年期；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)为卵巢完整、卵泡耗尽的猴子建立一个外部调查资源，可以 可用于关注更年期健康的研究。这一模型将有助于对主要围岩的研究。 和绝经后的健康问题，包括心血管疾病、骨质疏松症、糖尿病、认知 衰退、性功能障碍和生殖道癌。因此，建议的方案直接 与多个研究所的任务有关，包括--但不限于--NIA、NICHD、NHLBI、 NIDDK和NIMH。

The postmenopausal population of the US is increasing and will comprise 1/3 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 perimenopausal transition") that precede menopause and that is characterized byfluctuating - andultimately 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 perimenopausal 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 perimenopausal 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 NIHInstitutes, including - butnot limited to - NIA, NICHD, NHLBI, NIDDKand NIMH.