MODELING THE MENOPAUSAL TRANSITION AND MENOPAUSE

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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.