A Study of Estrogen and Body Mass Index in Fuchs’ Endothelial Corneal Dystrophy

摘要 终末期Fuchs角膜内皮营养不良（FECD），通常发生在70岁以后，是一种 角膜盲的主要原因。1 -3唯一确定的可改变的FECD风险因素是吸烟，4，5 关于FECD可改变的危险因素的流行病学数据极少。FECD导致的失明得到纠正 然而，对于角膜移植，移植是昂贵的，供体组织在全球范围内是有限的，并发症 可能会出现，老年人并不总是需要手术。6，7与年龄相仿的男性相比， 女性绝经后FECD患病率增加。8，9我们假设， 暴露与FECD风险降低有关，从而解释了观察到的性别差异。至今没有 已发表的研究检查了内源性或外源性雌激素测量之间的关联 暴露和FECD; BMI（循环雌激素水平的决定因素之一）之间相关性的研究，10-12 4，13研究结果表明，BMI和FECD之间没有关联13， 高BMI对FECD的保护作用。4利用25年以上妇女健康倡议的丰富资源 (WHI)研究中，我们建议检查FECD与内源性和外源性之间的关系 雌激素暴露WHI由观察性研究（OS）和临床试验组成，包括两项 激素治疗（HT）、单独雌激素或雌激素加孕酮的随机对照临床试验， 14 -17提示FECD的结局，包括角膜内皮营养不良和 角膜移植，可以从医疗保险索赔数据中确定。WHI有一个广泛的数据库， 参与者的人口统计学资料、生殖史、健康行为和健康结果。我们建议使用 在同一年或更早的WHI OS登记期间参加Medicare的WHI OS女性样本 基线（1993-1998）（n= 27，960），以检查医疗保险索赔与事件结果之间的关联 指示1993-2017年FECD和（目标1）估计终生内源性雌激素暴露， 绝经期激素治疗的使用和持续时间（外源性雌激素暴露），不同时间点的BMI 在参与者的整个成年生活中，测量了2,562名妇女的血清雌二醇浓度 (of 27,960）。我们还建议（目标2）使用参加医疗保险的WHI HT妇女样本， 随访期间的时间（1993-2017）（n= 20，236），以检查Medicare索赔与 1993-2017年FECD的结局指标，以及随机接受绝经期激素治疗作为 两个HT。这些数据将为我们了解FECD中的雌激素暴露和BMI提供信息。这些发现 可能导致算法的发展，以确定女性在FECD进展的风险较高，并指导 努力为未来的试验，可能会评估激素干预，旨在减少FECD的风险， 进展

ABSTRACT End-stage Fuchs' endothelial corneal dystrophy (FECD), typically occurring after the 7th decade of life, is a leading cause of corneal blindness.1-3 The only well-established modifiable risk factor for FECD is smoking,4,5 and minimal epidemiologic data exists on modifiable risk factors for FECD. Blindness from FECD is corrected with corneal transplantation, however, transplantation is costly, donor tissue is limited globally, complications can arise, and surgery is not always desired in the elderly.6,7 Compared to men of similar age, there is an increase in the prevalence of FECD after menopause in women.8,9 We hypothesize that higher estrogen exposure is associated with reduced risk of FECD, thus explaining this observed sex disparity. To date, no published studies have examined associations between endogenous or exogenous measures of estrogen exposure and FECD; studies on associations between BMI, one determinant of circulating estrogen levels,10-12 and FECD are very limited.4,13 Study results have shown both no association between BMI and FECD13 and a protective effect of high BMI on FECD.4 Using the rich resource of the 25+ year Women's Health Initiative (WHI) study, we propose to examine the association between FECD and endogenous and exogenous estrogen exposure. The WHI consists of an Observational Study (OS) and Clinical Trials, including two randomized, controlled clinical trials of hormone therapy (HT), estrogen-alone or estrogen plus progestin, each compared to placebo.14-17 Outcomes indicative of FECD, including endothelial corneal dystrophy and corneal transplant, can be identified from Medicare claims data. The WHI has an extensive database on participants' demographics, reproductive history, health behaviors and health outcomes. We propose to use a sample of WHI OS women enrolled in Medicare during the same year or earlier as their enrollment in WHI OS baseline (1993-1998) (n=27,960) to examine the association between Medicare claims for incident outcomes indicative of FECD from 1993-2017 and (Aim 1) estimated lifetime endogenous estrogen exposure, menopausal hormone therapy use and duration (exogenous estrogen exposure), BMI at different time points throughout a participants' adult life, and measured serum estradiol concentration in a subset of 2,562 women (of the 27,960). We also propose (Aim 2) to use a sample of the WHI HT women enrolled in Medicare some time during follow-up (1993-2017) (n=20,236), to examine the association between Medicare claims for outcomes indicative of FECD from 1993-2017 and randomization to menopausal hormone therapy as part of the two HTs. Such data will inform our understanding of estrogen exposure and BMI in FECD. These findings could lead to development of algorithms to identify women at higher risk for FECD progression, and guide endeavors for future trials that may evaluate hormonal interventions aimed at reducing FECD risk and progression.