Sex Steroids & Mammographic Density in the Postmenopause

描述（由申请人提供）：较高的乳房x线摄影密度是乳腺癌的独立危险因素，与乳房x线摄影密度相关的风险程度大于几乎所有其他已知的乳腺癌危险因素。本申请拟继续开展“绝经后性类固醇和乳腺x线摄影密度”的研究，研究内源性和外源性性类固醇对乳腺x线摄影百分比密度的影响。这项研究是绝经后雌激素/黄体酮干预（PEPI）试验的结果，该试验将绝经后妇女随机分配到安慰剂、单雌激素或三种雌激素/黄体酮联合治疗中的一种。迄今为止，“性类固醇和乳房x线摄影密度研究”的主要发现是：1)仅外源性雌激素治疗不影响平均乳房x线摄影密度，但在3组雌激素/黄体酮治疗中乳房x线摄影密度显著增加；2)在三个雌激素/黄体酮组中，治疗时血清雌激素水平升高的程度预测了乳房x线密度的增加程度，但在单雌激素组中没有；3)内源性（治疗前）血清雌激素、雌二醇、黄体酮和性激素结合球蛋白水平与基线乳腺x线摄影密度呈正相关。基于这些发现，我们建议在本研究中继续开展工作，以进一步了解乳房x线摄影密度的变化，具体而言：1)还有哪些因素与基线（治疗前）乳房x线摄影密度相关？2)治疗期间还有哪些其他因素可以预测乳房x线摄影密度的增加？我们假设激素（除了那些已经研究的）、性类固醇生物合成/代谢途径的遗传多态性和性类固醇受体的遗传多态性将与基线乳房x线摄影密度和/或乳房x线摄影密度对激素治疗的反应有关。拟议的延续项目将持续4年，将在加州大学洛杉矶分校和南加州大学进行。使用储存的样本，我们将测量基线和12个月的催乳素和孕激素水平。我们还将从储存的样本中提取DNA，以评估选定的遗传多态性。在我们之前的工作中已经测量了乳房x线摄影密度结果数据和所有相关协变量。我们将量化该项目中测量的激素和基因暴露与乳房x线摄影密度（基线以及基线和12个月之间密度的变化）之间的关系。

DESCRIPTION (provided by applicant): Higher mammographic density is an independent risk factor for breast cancer and the magnitude of risk associated with mammographic density is greater than that associated with almost all other known risk factors for breast cancer. This application proposes to continue work in "Sex Steroids and Mammographic Density in the Postmenopause", a study of the effects of endogenous and exogenous sex steroids on mammographic percent-density. This study is an outgrowth of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, which randomly assigned postmenopausal women to placebo, estrogen-only, or one of three combination estrogen/progestin treatments. To date, the principal findings of the "Sex Steroids and Mammographic Density Study" are: 1) Exogenous estrogen-only treatment did not affect mean mammographic density but significant increases in mammographic density did occur in 3 groups assigned to estrogen/progestin treatments; 2) In the three estrogen/progestin groups, but not in the estrogen-only group, the degree of increase in serum estrone level on-treatment predicted the amount of increase in mammographic density; and 3) Endogenous (pre-treatment) serum levels of estrone, estradiol, progesterone, and sex hormone binding globulin were positively associated with baseline mammographic density. Based on these findings, we propose to continue work in this study to gain a further understanding of variation in mammographic density, specifically: 1) What other factors are associated with baseline (pre-treatment) mammographic density? and 2) What additional factors predict increases in mammographic density during treatment? We hypothesize that hormones (in addition to those already studied), genetic polymorphisms in sex steroid biosynthetic/metabolic pathways, and genetic polymorphisms in sex steroid receptors will be related to baseline mammographic density and/or mammographic density response to treatment with hormone therapy. The proposed continuation project will last 4 years and will take place at UCLA and USC. Using stored samples, we will measure baseline and 12-month levels of prolactin and progestins. We will also extract DNA from stored samples to assess selected genetic polymorphisms. The mammographic density outcome data and all relevant covariates have already been measured during our prior work. We will quantify the relations between the hormone and genetic exposures measured in this project and mammographic density (at baseline as well as change in density between baseline and 12 months).