PHYSTOESTROGENS, STRESS AND ATHEROSCLEROSIS in Females

绝经前妇女通常被认为可以预防动脉粥样硬化和由此引起的冠心病（CHD）。然而，目前的数据支持这样的假设，即在绝经后妇女中观察到的动脉粥样硬化和临床事件起源于绝经前几年。相关数据进一步表明，临床或亚临床卵巢功能障碍史（后者可能相对常见）会增加患冠心病的风险。绝经前食蟹猴为研究动脉粥样硬化的育龄妇女提供了一个临床代用品。在这个模型中，与社会从属相关的压力导致卵巢功能障碍和雌激素缺乏，增强动脉粥样硬化，并损害冠状动脉血管舒张反应。用外源性雌激素治疗社会从属（即高风险）女性可抑制动脉粥样硬化并改善扩张剂反应。当前研究的总体目标是确定大豆植物雌激素（spe）是否可以作为组织特异性雌激素激动剂，对高危女性（推断为绝经前女性）具有类似的保护作用，而不会对其他组织产生不良影响。因此，96只猴子被安置在每6只动物的社会群体中，将被分为两种治疗条件；其中一半的动物将接受以大豆和酪蛋白为基础的饮食，其中含有大豆和酪蛋白，而其余的动物将食用以大豆和酪蛋白为基础的饮食，其中提取了大豆和酪蛋白。此外，社会住房将使一半的动物，即下属，处于卵巢损伤和动脉粥样硬化的高风险中。这项全面的围临床研究将确定SPEs治疗是否能抑制冠状动脉和颈动脉粥样硬化的进展，并改善高危、次要绝经前猴子的冠状动脉扩张剂反应。此外，该研究将确定SPEs是否抑制或增强绝经前猴子子宫内膜和乳腺组织中的增殖和雌激素反应，以及SPEs是否对这些雌性动物的骨骼发育和骨量峰值产生不利影响或改善。最后，该研究将确定spe是否会影响月经周期或生殖内分泌的任何方面。总之，该实验将为SPE治疗作为一种自然、安全、非药物干预手段用于女性动脉粥样硬化一级预防提供证据。

(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.