PHYSTOESTROGENS, STRESS AND ATHEROSCLEROSIS in Females

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(Adapted from Applicant's Abstract) Premenopausal women are usually thought to be protected from atherosclerosis and the resulting coronary heart disease (CHD). However, current data support the hypothesis that the atherosclerosis and clinical events observed among postmenopausal women have their origins in the premenopausal years. Related data suggest, further, that a history of clinical or subclinical ovarian impairment (the latter which may be relatively common) increases the risk for CHD. Premenopausal cynomolgus monkeys provide a periclinical surrogate for reproductive-aged women for the study of atherogenesis. In this model, the stress associated with social subordination induces ovarian dysfunction and estrogen deficiency, potentiates atherogenesis, and impairs coronary artery vasodilator responses. Treatment of socially subordinate (i.e. high risk) females with exogenous estrogen inhibits atherogenesis and improves dilator responses. The overall objective of the current study is to determine whether soy phytoestrogens (SPEs) might act as tissue-specific estrogen agonists to be similarly protective in high risk females (and by extrapolation, premenopausal women) without adverse effects on other tissues. Accordingly, 96 monkeys housed in social groups of six animals each will be divided into two treatment conditions; half the animals will receive a soy- and casein-based diet that contains SPEs while the rest will consume a soy- and casein-based diet from which SPEs have been extracted. Additionally, the social housing will place half of the animals, the subordinates, at high risk for ovarian impairment and atherosclerosis. This comprehensive, periclinical study will determine whether treatment with SPEs inhibits the progression of coronary and carotid artery atherosclerosis and improves coronary artery dilator responses in high risk, subordinate premenopausal monkeys. Furthermore, the study will determine whether SPEs inhibit or potentiate proliferation and estrogenic responses in the endometrium and mammary tissue of premenopausal monkeys, and whether SPEs adversely affect or improve bone development and peak bone mass in these females. Finally, the study will determine whether SPEs influence menstrual cyclicity or any aspect of the reproductive endocrine profile. In summary, the experiment will provide evidence concerning the use of SPE treatment as a natural, safe, nonpharmacologic intervention directed toward primary prevention of atherosclerosis in women.