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直接免疫分析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。在没有严格推导的参考范围的情况下，将总的和游离的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)、男性骨质疏松性骨折研究(MROS)、协和健康与男性老龄化项目(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。我们还将生成年龄调整的参考限值(Z-Score法)。使用LC-MS/MS(LC-MS/MS)测量总的E_1和E_2水平，计算游离E_1和E_2。FHS Gen 3生成的参考限值将适用于4个不同地理位置的队列中的男性-FHS Gen 3+FHS后代队列(Gen 2)(FHS大样本)、EMAS、MRO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E1和E2水平的遗传度，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，基线总的和游离的E1和E2以及E2和E1的纵向变化将与不良结果的发生率(主要：死亡率、糖尿病、心血管疾病事件~继发性：功能受限和残疾的进展、骨质疏松、非椎体骨折)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，因为它利用了来自四个特征良好的队列的现有结果数据。使用LC-MS/MS分析、标准校准器和以社区为基础的参考样品、4个不同地理位置的验证队列的可用性以及跨学科的调查团队将最大限度地增加成功的机会。

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 immunoassays for E1 and E2 has clouded interpretation of available data. Even though E1 is as abundant in circulation as E2, 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 rigorously-derived 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 Osteoporotic Fractures in Men Study (MrOS), 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. We also will generate age-adjusted reference limits (Z-score approach). 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. Reference limits generated in FHS Gen 3 will be applied to men in 4 geographically distinct cohorts - FHS Gen 3 plus FHS Offspring cohort (Gen 2) (FHS broad sample), EMAS, MrOS, 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 inter-individual variability in E1 and E2 levels. Baseline total and free E1 and E2 as well as longitudinal changes in E2 and E1 will be related to the incidence of adverse outcomes (primary: mortality, diabetes mellitus, cardiovascular disease events~ secondary: progression of functional limitations and disability, osteoporosis, nonvertebral fractures) 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 it leverages existing outcomes data from four well characterized cohorts. The use of LC-MS/MS assay, a standard calibrator, and a community-based reference sample, the availability of 4 geographically distinct validation cohorts, and an inter-disciplinary team of investigators would maximize the chances of success.