Estrogen replacement therapy (ERT) reduces progression of coronary artery atherosclerosis (CAA) and osteopenia in menopausal women and in ovariectomized monkeys; however, androstenedione and testosterone levels are substantially greater in spontaneously menopausal than in ovariectomized females. Since all endogenous estrogens are derived from androgen precursors but the risk of cardiovascular disease appears to be increased by mild androgen excess, adequate studies of coronary artery atherosclerosis (CAA) in the menopause and perimenopausal interval will have to include models that mimic physiological levels of androgen. Since it is unknown whether ERT's cardioprotective benefits will be influenced by endogenous androgens, we are convinced that a more precise model of the human menopause is needed. Based on our prior extensive experience with the nonhuman ovariectomy model of osteopenia and diet-induced CAA we propose 1) to establish an improved monkey model which mimics reproductive hormone levels of normal menopausal women, normal perimenopausal women and menopausal women taking ERT and 2) to compare this improved model to the established ovariectomy model of the menopause as regards plasma lipids, lipoproteins and lipoprotein subfractions; markers of bone metabolism; and markers of carbohydrate metabolism in animals consuming an atherogenic diet. In the first phase of this study, we will use reproductive hormone levels to monitor adequacy of replacement of androstenedione and estradiol achieved by hormonal implant treatment modification of our well-defined ovariectomized female cynomolgus macaque model. To demonstrate behavior of the new more physiological model, in the second phase of the study, we will compare the responses of plasma markers associated with risk of CAA (lipids and lipoproteins), osteopenia (bone biomarkers) and diabetes mellitus (glucose, insulin and fructosamine) in the new and established (ovariectomy) models. In turn, use of the new model will lead to a clearer understanding of the role of endogenous androgens and residual endogenous estrogens in chronic diseases of aging women.
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