Urinary Estrogen Metabolites in a 2-year Soy Trial Among Premenopausal Women

题目：在绝经前妇女中进行的一项为期2年的大豆试验中的尿液雌激素代谢物大豆食品及其生物活性成分异黄酮被认为与内源性雌激素相互作用，而内源性雌激素在乳腺癌的病因中起着不可或缺的作用。这项癌症流行病学的小额拨款建议使用现有的尿液样本进行额外的分析，这些样本是在220名绝经前妇女中进行的为期2年的随机大豆试验中收集的。我们将探讨大豆对乳腺癌的潜在保护作用的两种假设，这两种假设并不是最初研究的一部分，因为当时没有适当的分析技术来测量尿液中雌激素和异黄酮的代谢物，但现在已经有了。一种是大豆食品改变了雌激素代谢，这是通过尿液中的一系列甾体雌激素来评估的，使其成为一种遗传毒性较小的代谢物。其次，大豆的有益作用可能只有那些肠道细菌能够将大豆中的主要异黄酮之一——大豆苷元转化为马酚的人才能体会到。该研究的具体目的是探索每天两份大豆对雌激素代谢细胞色素改变的影响，雌激素代谢在尿液中2-、161-和4-羟基雌激素代谢物的形成中表达，并检查雌马酚排泄状态是否影响大豆对乳腺癌风险的生物标志物的评估，这是在最初的试验和目前的项目中测量的。在黄体期收集并保存在-80℃的冷冻尿液样本将使用液相色谱-质谱法分析9种雌激素和代谢物以及雌马酚。对于198名受试者（98名干预受试者和100名对照），在干预至少一年后，我们将分析基线和最终样本中的雌激素代谢物，而雌酚将仅在干预组中每个女性总异黄酮浓度最高的两个尿液样本中进行测量。由于对照组的受试者不食用大豆食品，因此无法评估他们产生雌马酚的状况。统计分析将采用混合模型来比较大豆处理后雌激素代谢物的水平和模式，同时考虑到重复测量。一般的线性模型将用于比较不同的生物标志物的equol状态，即类固醇激素，乳房x线摄影密度，和尿雌激素代谢物。此外，我们将检查马酚生产者状态与种族、体重、终生大豆摄入量和其他饮食因素的关系。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Title: Urinary Estrogen Metabolites in a 2-Year Soy Trial among Premenopausal Women Soy foods and their bioactive ingredients isoflavones are thought to interact with endogenous estrogens which play an integral role in the etiology of breast cancer. This small grant in cancer epidemiology proposes additional analyses using existing urine samples that were collected as a part of a 2-year randomized soy trial among 220 premenopausal women. We will explore two hypotheses for the potential protective effects of soy against breast cancer that were not part of the original study because the appropriate analytical techniques to measure urinary metabolites of estrogens and isoflavones were not developed at the time but are available now. One is that soy foods alter estrogen metabolism as assessed by an array of steroidal estrogens in urine to a pattern of less genotoxic metabolites. Second, beneficial effects from soy may only be experienced by subjects who have intestinal bacteria that are able to convert dadzein, one of the major isoflavones in soy beans, to equol. The specific aims of the proposed study are to explore the effect of two daily servings of soy on cytochrome alterations of estrogen metabolism as expressed in the formation of urinary 2-, 161-, and 4- hydroxy estrogen metabolites and to examine whether equol excretor status influences the response to soy as assessed by biomarkers for breast cancer risk measured in the original trial and in the current project. Frozen urine samples collected during the luteal phase and stored at -80:C will be analyzed for nine estrogens and metabolites and for equol using liquid chromatography-mass spectrometry. For each of the 198 subjects (98 intervention subjects and 100 controls) who have a urine sample after at least one year of intervention, we will analyze the baseline and the final sample for estrogen metabolites, whereas equol will be measured in the two urine samples with the highest total isoflavone concentration for each woman in the intervention group only. Because subjects in the control group were not consuming soy foods, their equol producing status cannot be assessed. The statistical analysis will apply mixed models to compare levels and patterns of estrogen metabolites by soy treatment, while taking into account the repeated measures. General linear models will be used to compare the different biomarkers by equol status, i.e., steroid hormones, mammographic density, and urinary estrogen metabolites. In addition, we will examine equol producer status in relation to ethnicity, body weight, lifetime soy intake, and other dietary factors. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Title: Urinary Estrogen Metabolites in a 2-year Soy Trial Among Premenopausal Women Public Health Significance: The hormonal effects of soy foods continue to be emphasized in scientific and popular publications and need to be understood better, in particular in light of emerging concerns about potential adverse effects of soy among breast cancer survivors and women at high risk for breast cancer. This project will explore two hypotheses of how soy and isoflavones may protect against breast cancer and will help to understand the role of soy foods in breast cancer development and prevention.