Population-Based Reference Ranges for Estradiol and Estrone in Men

描述（由申请人提供）：雌二醇17 （E2）和雌酮(E1) -人类中最丰富的两种雌激素-在男性健康和疾病中的作用仍然知之甚少。虽然低和高E2水平与男性不良健康结果相关，但对E1和E2直接放射免疫测定的准确性的担忧使现有数据的解释变得模糊。尽管E1在血液循环中与E2一样丰富，但人们对E1与男性预后的关系知之甚少。总E1和游离E2水平的参考限值对临床决策至关重要。在缺乏以人群为基础的参考范围的情况下，将总E1和游离E2水平划分为正常、低或高的值充满了很大的误分类风险。来自波士顿大学、弗雷明汉心脏研究（FHS）、欧洲男性衰老研究（EMAS）、康科德健康与男性衰老项目（CHAMP）、梅奥诊所和疾病控制中心的研究人员合作的目的是在FHS第三代（Gen 3）队列的健康年轻男性参考样本中产生总和游离E1和E2水平的参考限值。总E1和E2水平将使用液相色谱串联质谱法（LC- MS/MS）测量，游离E1和E2将使用质量作用方程从总E1和E2和SHBG计算。FHS第3代中产生的参考限制将适用于3个地理位置不同的验证队列中的男性- FHS第3代加FHS后代队列（第2代）（FHS广泛样本），EMAS和CHAMP队列。我们将总E1和游离E2水平与糖尿病、心血管疾病、骨密度、身体功能和性症状联系起来，并根据年龄、体重指数、腰围、血压、吸烟、血脂、血糖、饮食和身体活动进行调整。我们将评估E1和E2水平的遗传力，以评估遗传效应对E1和E2水平个体间变异性的贡献。在纵向随访期间，总E1和游离E2将与不良结局（主要：死亡率、糖尿病、心血管疾病事件；次要：功能限制和残疾进展、骨质疏松症）的发生率相关。建议将男性分为E1和E2水平正常、低和高的人群时，将考虑到他们的统计分布以及与参考限度不同程度偏差的结果之间的关系。该建议将促进我们对E1和E2水平在男性中的作用的理解，并为执业医生解释E1和E2水平提供一个标准化框架。由于结果数据是通过FHS、EMAS和CHAMP合同提供的支持收集的，因此该项目具有很高的成本效益。使用最先进的LC-MS/MS分析和标准校准器，基于人群的参考样本，三个具有良好特征结果的地理上不同的验证队列，以及在内容领域具有丰富专业知识的跨学科研究团队，应该最大限度地提高成功的机会。

DESCRIPTION (provided by applicant): The role of estradiol 17 (E2) and estrone (E1) - the two most abundant estrogens in humans - in men's health and disease remains poorly understood. Although both low and high E2 levels have been associated with adverse health outcomes in men, concerns about the accuracy of direct radioimmunoassays for E1 and E2 has clouded interpretation of available data. Even though E1 is as abundant in circulation as E2, very little is known about the association of E1 with outcomes in men. Reference limits for total and free E1 and E2 levels are essential for clinical decision making. In the absence of population-based reference ranges, the partitioning of total and free E1 and E2 levels into normal, low, or high values has been fraught with substantial risk of misclassification. The objective of this collaboration among investigators from Boston University, the Framingham Heart Study (FHS), the European Male Aging Study (EMAS), the Concord Health and Ageing in Men Project (CHAMP), the Mayo Clinic, and the Centers for Disease Control is to generate reference limits for total and free E1 and E2 levels in a healthy reference sample of young men in the FHS third generation (Gen 3) cohort. Total E1 and E2 levels will be measured using liquid chromatography tandem mass spectrometry (LC- MS/MS) and free E1 and E2 will be calculated from total E1 and E2 and SHBG using law of mass action equations. Reference limits generated in FHS Gen 3 will be applied to men in 3 geographically distinct validation cohorts - FHS Gen 3 plus FHS Offspring cohort (Gen 2) (FHS broad sample), EMAS, and CHAMP cohorts. We will relate total and free E1 and E2 levels to diabetes, cardiovascular disease, bone mineral density, physical function, and sexual symptoms, adjusting for age, body mass index, waist circumference, blood pressure, smoking, lipids, glucose, diet and physical activity. We will assess the heritability of E1 and E2 levels to evaluate the contribution of genetic effects on interindividual variability in E1 and E2 levels. Total and free E1 and E2 will be related to the incidence of adverse outcomes (primary: mortality, diabetes mellitus, cardiovascular disease events; secondary: progression of functional limitations and disability, osteoporosis) during longitudinal follow-up. The recommendations for partitioning of men into those with normal, low and high E1 and E2 levels will be guided by considerations of their statistical distribution and the association of outcomes with varying degree of deviations from the reference limits. The proposal will advance our understanding of the role of E1 and E2 levels in men and provide a standardized framework for the interpretation of E1 and E2 levels by practicing physicians. The project is highly cost effective because the outcomes data have been collected through the support provided by the FHS, EMAS and CHAMP contracts. The use of state-of-the-art, LC-MS/MS assay and a standard calibrator, a population-based reference sample, three geographically distinct validation cohorts with well characterized outcomes, and an inter-disciplinary team of investigators with substantial expertise in the content areas should maximize the chances of success.