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Role of the Follicle-Depleted Ovary in the Pathogenesis of Chronic Diseases

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The worldwide population of postmenopausal women is increasing (expected to be 1.1 billion by 2025) and these women are surviving longer than their predecessors. Coronary heart disease (CHD), osteoporosis, and the metabolic syndrome comprise a substantial part of the health burden affecting this population. However, despite considerable epidemiological and clinical research, the initiation and trajectory of these chronic and degenerative conditions remain unclear. Two specific gaps in knowledge are: 1) whether or to what extent the perimenopause is a time of accelerated disease progression; and 2) whether the pathobiological changes that have accumulated by the time of menopause establish the trajectory of postmenopausal disease outcomes. Accordingly, this application seeks support to continue a study of peri- and post-menopausal monkeys. The study in progress takes advantage of a nonhuman primate model of the menopausal transition developed recently at our institution. This model was adapted from a mouse model of perimenopause which uses a chemical (4-vinylcyclohexene diepoxide -VCD) to destroy primordial follicles via apoptosis and atresia. The model recapitulates the physiological changes experienced by women during the perimenopausal transition, including decreased numbers and ultimate depletion of primordial follicles and subsequent decreases in antimullerian hormone (AMH). Further, the stroma of the resulting follicle-depleted ovary has similar biologic activity (e.g. androgen production) to that of naturally postmenopausal women. As summarized, this model has several advantages over ovariectomized animals, a research platform that does not yield hormonal characteristics or risk factors (e.g., serum lipids) comparable to those observed in naturally postmenopausal women. The existing gaps in knowledge surrounding the perimenopausal transition and postmenopause prompted us to propose the following four Specific Aims: 1) Determine the extent to which diet induced atherosclerosis progression, as measured directly through biopsy, differs among ovariectomized (OVX), perimenopausal (VCD treated) and premenopausal monkeys, whether perimenopausal atherosclerosis extent determines the extent of postmenopausal atherosclerosis development, and finally, whether the trajectories of atherosclerosis progression differ between the peri and postmenopausal phases; 2) Determine whether bone loss occurs during the perimenopausal transition and to compare the magnitude of any bone loss that does occur with that observed during the postmenopausal phase; 3) Determine if and to what extent, elements of the metabolic syndrome appear during the perimenopausal transition, and whether the increases are greater in peri or postmenopausal phase; and 4) To compare and contrast the hormonal characteristics of VCD-treated monkeys both peri- and postmenopausally, with those observed in their OVX and premenopausal counterparts, and to determine whether changes in ovarian hormones in these reproductive phases are associated with changes in atherosclerosis extent and cardiovascular, skeletal, and metabolic risk biomarkers. PUBLIC HEALTH RELEVANCE: The information gained through this investigation will provide women and their physicians with urgently required evidence on which to base decisions concerning peri- and postmenopausal treatment options. In addition, the outcomes observed in this study might well extend beyond the vascular and musculoskeletal systems to include other tissues that are sensitive to the effects of ovarian hormones, such as the brain.
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