Aromatase Inhibitors and Weight Loss in Severely Obese Men with Hypogonadism

摘要 肥胖男性丰富的脂肪组织中芳香化酶活性的增加导致了 雄激素转化为雌激素（雌二醇[E2]，雌酮），导致高雌激素水平。这反过来 向下丘脑-垂体-性腺单位发送负反馈，导致促性腺激素减少， 睾丸激素（T）的产生减少和一种称为低促性腺激素性腺功能减退症（HHG）的疾病。 因此，T疗法可能仅导致芳香酶活性的底物（T）增加和E2进一步增加。 虽然体重减轻（WL）会导致T水平升高，但仅通过改变生活方式的WL受到以下因素的限制： T和体重恢复的上升幅度较低，这是常见的。芳香化酶抑制剂（AIs）可以降低E2 生产和增加T，但很少或没有关于向WL中添加AI以生产 增强芳香化酶抑制，改善HHG肥胖男性的症状。这项工作的主要目的是 建议是评价AI作为WL的辅助治疗（AI+WL）与单独WL相比在严重 患有高血糖症的肥胖男性该建议的中心假设是，在WL（饮食+运动）中添加AI 将导致肥胖相关HHG的激素异常逆转，从而改善 性腺功能减退症状，对身体成分（和代谢风险因素）无显著不良影响， 骨头我们假设：1）AI+ WL将完全逆转肥胖相关的激素异常， HHG是因为AI在降低HHG中芳香酶活性方面的额外作用超过单独WL的作用。 2）AI+ WL将导致肌肉力量、肌肉收缩、 与单独WL相比，由于T的增加更大，3）AI+WL将导致更大的 与单独WL相比，由于T的增加更大，瘦体重增加，但可能会减弱脂肪的损失 由于E2的更大降低，WL的质量和代谢改善，以及4）尽管AI+WL将具有 降低骨矿物质密度（BMD）和损害骨质量的可能性，因为更大的减少 在E2中，与单独使用WL保存相比，由于基线时E2水平较高， 增加的肌肉质量。我们将随机抽取100名肥胖男性，BMI ≥35 kg/m2，总T <300 ng/dl，E2 > 40 pmol/L和促黄体生成素<9 mIU/L，分别给予AI、阿那曲唑（每日1 mg）、+WL或安慰剂每日+WL，持续12 个月此外，作为次要目标，我们将阐明我们的中心假设的机制， 综合的方式，使用简单/偏相关和多元回归分析，以确定 激素因素和介质可以解释观察到的肌肉力量和症状的变化，肌肉 体重、身体成分（和代谢危险因素）、BMD和骨质量。 本研究的结果将确定AI联合WL在重度男性中的实用性和安全性。 肥胖者中性腺功能减退症的病因与雌激素分泌过量有关，因此代表 这是一种针对越来越多的肥胖性腺功能减退男性的潜在策略。

ABSTRACT The increased aromatase activity in the abundant fat tissues of obese men results in enhanced conversion of androgens to estrogens, (estradiol [E2], estrone), leading to high estrogen levels. This in turn sends negative feedback to the hypothalamic-pituitary-gonadal unit resulting in reduced gonadotropins, and decreased testosterone (T) production and a condition called hypogonadotropic hypogonadism (HHG). Accordingly, T therapy may only lead to increased substrate (T) for aromatase activity and further E2 increase. Although weight loss (WL) results in increased T levels, WL by lifestyle change alone is limited by the lower magnitude of rise in T and weight regain which is common. Aromatase inhibitors (AIs) can reduce E2 production and increase T but little or no information is available on the efficacy of adding an AI to WL to produce enhanced aromatase inhibition in improving symptoms in obese men with HHG. The primary objective of this proposal is to evaluate the efficacy of an AI as an adjunct to WL (AI+WL) compared to WL alone in severely obese men with HHG. The central hypothesis of this proposal is that the addition of an AI to WL (diet+exercise) will lead to reversal of the hormonal abnormality in obesity-associated HHG resulting in improvement in hypogonadal symptoms without significant adverse effects on body composition (and metabolic risk factors) and bone. We hypothesize that: 1) AI+ WL will completely reverse the hormonal abnormality in obesity-associated HHG because of the additional effect of an AI over and above that of WL alone in reducing aromatase activity in the expanded adipose tissue volume, 2) AI+ WL will result in greater improvement in muscle strength, muscle mass and symptoms compared to WL alone because of the greater increase in T, 3) AI+WL will lead to a greater increase in lean mass due to a greater increase in T compared to WL alone but may attenuate the loss of fat mass and metabolic improvement from WL due to a greater reduction in E2, and 4) although AI+WL will have the potential of reducing bone mineral density (BMD) and impairing bone quality because of a greater reduction in E2 compared to preservation by WL alone, this will be minimized because of high levels of E2 at baseline and the increased muscle mass. We will randomize 100 obese men with BMI ≥35 kg/m2, total T <300 ng/dl, E2 > 40 pmol/L and luteinizing hormone <9 mIU/L to AI, anastrozole (1 mg daily), +WL, or placebo daily+WL for 12 months. Additionally as a secondary aim, we will elucidate the mechanism for our central hypothesis in an integrated manner by using simple/partial correlation and multiple regression analyses to determine which of the hormonal factors and mediators may explain the observed changes in muscle strength and symptoms, muscle mass, body composition (and metabolic risk factors), BMD and bone quality. Results from this study will establish the utility and safety of AIs in conjunction with WL in men with severe obesity among whom the etiology of hypogonadism is related to excess estrogen production, thus representing a potential strategy among the growing number of obese hypogonadal men.