Population-Based Reference Ranges for Estradiol and Estrone in Men

描述(申请人提供)：雌激素17(E2)和雌酮(E1)--人类体内含量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。尽管低水平和高水平的E2水平都与男性的不良健康结局有关，但对E1和E2的直接放射免疫分析的准确性的担忧影响了对现有数据的解释。尽管E1在血液循环中的含量和E2一样丰富，但人们对E1与男性结局之间的联系知之甚少。总的和游离的E_1和E_2水平的参考限值对于临床决策是必不可少的。在缺乏以人群为基础的参考范围的情况下，将总的和自由的E1和E2水平划分为正常、低或高三个值都充满了误分类的巨大风险。来自波士顿大学、弗雷明翰心脏研究(FHS)、欧洲男性老龄化研究(EMAS)、协和健康和男性老龄化项目(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)队列中年轻男性的健康参考样本中产生总的和游离的E1和E2水平的参考限值。总的E_1和E_2水平将用LC-MS/MS测量，游离的E_1和E_2水平将由总的E_1和E_2和SHBG利用质量作用方程计算出来。FHS Gen 3生成的参考限值将应用于3个不同地理位置的验证队列中的男性-FHS Gen 3+FHS后代队列(Gen 2)(FHS广泛样本)、EMAS和CHAMP队列。我们将根据年龄、体重指数、腰围、血压、吸烟、血脂、血糖、饮食和体力活动进行调整，将总的和游离的E1和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。我们将评估E_1和E_2水平的遗传力，以评估遗传效应对E_1和E_2水平个体间变异的贡献。总的和游离的E1和E2将与纵向随访期间不良结果的发生率(主要：死亡率、糖尿病、心血管疾病事件；次级：功能受限和残疾的进展、骨质疏松症)相关。将男性划分为正常、低水平和高水平的男性的建议将以他们的统计分布和结果与不同程度偏离参考限值的关系为指导。这项建议将促进我们对男性中E1和E2水平的作用的理解，并为执业医生解释E1和E2水平提供一个标准化的框架。该项目具有很高的成本效益，因为成果数据是通过FHS、EMAS和CHAMP合同提供的支助收集的。使用最先进的LC-MS/MS分析和标准校准器、基于总体的参考样本、三个具有良好特征的结果的地理上不同的验证队列以及一支在内容领域拥有丰富专业知识的跨学科调查团队，应该会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.