Sex Steroids & Mammographic Density in the Postmenopause

描述（由申请人提供）：乳腺摄影密度较高是乳腺癌的独立风险因素，与乳腺摄影密度相关的风险程度大于与几乎所有其他已知乳腺癌风险因素相关的风险程度。本申请建议继续开展“绝经后性类固醇和乳腺X线摄影密度”的工作，这是一项研究内源性和外源性性类固醇对乳腺X线摄影密度的影响。这项研究是绝经后雌激素/孕激素干预（PEPI）试验的结果，该试验将绝经后妇女随机分配到安慰剂组、仅雌激素组或三种雌激素/孕激素联合治疗组。迄今为止，“性类固醇和乳腺摄影密度研究”的主要发现是：1）仅外源性雌激素治疗不影响平均乳腺摄影密度，但在分配给雌激素/孕酮治疗的3组中，乳腺摄影密度确实发生显著增加; 2）在三个雌激素/孕激素组中，而不是在仅雌激素组中，治疗中血清雌酮水平的增加程度预测乳房X线摄影密度的增加量;和3）内源性（治疗前）血清雌酮、雌二醇、孕酮和性激素结合球蛋白水平与基线乳房X线摄影密度呈正相关。基于这些发现，我们建议继续本研究的工作，以进一步了解乳腺摄影密度的变化，特别是：1）还有哪些因素与基线（治疗前）乳腺摄影密度相关？以及2）哪些其他因素可预测治疗期间乳腺摄影密度的增加？我们假设激素（除了那些已经研究过的），性类固醇生物合成/代谢途径的遗传多态性，性类固醇受体的遗传多态性将与基线乳腺摄影密度和/或乳腺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，我们将测量催乳素和孕激素的基线和12个月水平。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。乳腺摄影密度结果数据和所有相关协变量已经在我们之前的工作中测量。我们将量化本项目中测量的激素和遗传暴露与乳腺X线摄影密度之间的关系（基线以及基线和12个月之间的密度变化）。

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).