PHARMACOLOGIC STUDIES OF SOY PHYTOESTROGENS

(摘自申请者摘要)在最后一个项目期间，研究人员获得了实验证据，支持大豆植物雌激素(异黄酮类)可能是女性传统激素替代疗法的有用替代方案，既能预防动脉粥样硬化，又不会对乳房和子宫内膜产生有害影响。研究人员还发现，在对青春期前和青春期前后的食蟹雄性进行的一项研究中，大豆异黄酮对心脏有保护作用，不会影响生殖系统。这些研究提高了研究人员对预防冠心病和激素依赖型癌症的潜在保护作用的公共卫生重要性的认识。在项目1中，研究人员建议加强他们对大豆植物雌激素的药理学研究，使用手术绝经的雌性和成熟的雄性猴子，采用一系列短期拉丁方设计，以评估不同剂量、形式和比例的植物雌激素对中间结果的影响(目标1、2、3)。目标4将是“最佳”处理(最佳蛋白质、异黄酮比率和剂量)和对照处理的长期比较。该项目将评估治疗对女性心血管疾病危险因素和生殖系统的影响，包括性别和骨骼终点。要解决的问题是：1.大豆蛋白中的高分子量部分或7S多肽成分在改善脂代谢方面比大豆分离蛋白更有效，并且是异黄酮类成分发挥作用所必需的这些部分之一？2.以染料木素或大豆苷元为主的大豆植物雌激素制剂对疾病标记物的影响是否不同？3.大豆植物雌激素剂量与疾病标记物之间的关系？4.最佳大豆处理对疾病标记物的长期影响？该项目与该项目的中心主题直接相关，特别是为了更好地了解大豆植物雌激素对心脏的保护作用。本项目将获得的数据应有助于理解项目2和项目3中获得的数据，而项目2和项目3将提供病理结果，以支持项目中使用的中间终点。

(Adapted from Applicant's Abstract) During the last program project period, the investigators obtained experimental evidence to support the conclusion that soy phytoestrogens (isoflavones) may be a useful alternative to traditional hormone replacement therapy for females, protecting against atherosclerosis without deleterious effects on the breast and endometrium. The investigators also found in a study with pre- and peripubertal cynomolgus males that the soy isoflavones were cardioprotective and did not affect the reproductive system. These studies increased the investigators' awareness of the public health importance of the simultaneous potential protective effects against coronary heart disease and hormone dependent cancers. In Project 1, the investigators propose to intensify their pharmacologic studies of the soy phytoestrogens using surgically menopausal female and mature male monkeys in a series of short-term Latin Square designs to assess the effects of varying doses, forms, and ratios of the phytoestrogens on intermediate outcomes (Aims 1, 2, 3). Aim 4 will be a longer-term comparison of "optimal" (best protein, isoflavone ratio, and dose) and control treatments. This project will assess treatment effects on cardiovascular disease risk factors and reproductive system of both genders and bone endpoints in females. The questions to be addressed are: 1. Is the high molecular weight fraction or the 7S peptide component in soy protein more effective than soy protein isolate on improving lipid metabolism and is one of these fractions required for the isoflavones to have their effect? 2. Are there different effects on disease markers with soy phytoestrogen preparations that are predominately genistein or predominately daidzein? 3. What is the relationship between dose of soy phytoestrogens and disease markers? 4. What are the longer-term effects of the optimal soy treatment on disease markers? This project relates directly to the central theme of the program project, specifically, to better understand the cardioprotective benefits of the soy phytoestrogens. The data to be obtained in this project should contribute to the understanding of data obtained in Projects 2 and 3 while Projects 2 and 3 will provide pathologic outcomes to support the intermediate endpoints used in this project.