MODELING THE MENOPAUSAL TRANSITION AND MENOPAUSE

美国的绝经后人口正在增加，在下一个世纪将占所有妇女的1/3。 十年心血管疾病将是这一人群最大的单一死因， 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 认知能力明显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（“围绝经期过渡期”）， 以卵巢激素分泌的波动和最终下降为特征。非人灵长 在生殖特征和疾病易感性方面与女性非常相似。然而，虽然一些 非人类灵长类物种经历更年期，这样的个体往往是老年人， 大量的。因此，研究人员在模拟肿瘤的病理生物学方面的能力有限。 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。 本申请被设计为通过暴露以下物质来解决绝经期模型中的上述缺陷： 食蟹猴（Macaca fascicularis）对4-乙烯基环己烯二环氧化物（VCD）的反应， 破坏卵巢原始卵泡和初级卵泡。这种方法最初是在小鼠中开发的， 逐渐的卵巢衰竭，导致卵泡耗竭的动物保留残留的卵巢组织， 显示出与绝经期妇女相似的激素分布。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的水平， 导致卵巢逐渐衰竭; 2）确定卵巢完全衰竭所需的时间长度 （更年期），并定义这种围绝经期过渡和随后的激素特征 3）表征慢性疾病（动脉粥样硬化、骨质疏松症）的风险标志物的变化; 和4）建立一个资源的卵巢完整，卵泡耗尽的猴子， 用于更年期健康的研究。因此，这一模式将有助于对主要问题的研究- 和绝经后的健康问题，包括心血管疾病，骨质疏松症，糖尿病，认知障碍， 性功能减退和生殖道癌症。因此，该计划直接 与多个NIH研究所的任务相关，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.