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 雄激素转化为雌激素(雌二醇、雌酮)，导致高雌激素水平。这又反过来 向下丘脑-垂体-性腺单位发送负反馈，导致促性腺激素减少，以及 睾酮(T)分泌减少和一种称为低促性腺激素减退(HHG)的情况。 因此，T治疗可能只会导致芳香酶活性底物(T)的增加和E2的进一步增加。 虽然减重(WL)会导致T水平升高，但仅通过改变生活方式来改变WL受到 较低幅度的T升高和体重回升是常见的。芳香酶抑制剂(AIs)可降低雌二醇水平 产量和提高T，但很少或根本没有关于在WL中添加AI以生产的效果的信息 增强芳香酶抑制在改善HHG肥胖男性症状中的作用。这样做的主要目标是 建议评估人工智能作为WL(人工智能WL)的附属工具与单独使用WL在严重程度上的效果 患有高血压的肥胖男性。这一提议的中心假设是，在WL(节食运动)中添加人工智能 将逆转肥胖相关的高血压患者的激素异常，从而改善 性腺功能减退症状对身体成分(和代谢危险因素)无明显不良影响 骨头。我们假设：1)AI WL将完全逆转肥胖相关的激素异常 HHG，这是因为在WL单独作用的基础上，AI在降低芳香酶活性方面具有额外的效果 脂肪组织体积的扩大，2)AI WL将导致肌肉力量、肌肉 与WL相比，WL单独因为T增加更大，3)AI WL会导致更大的 与WL相比，由于T的增加而导致的瘦体重的增加，但可能会减弱脂肪的损失 由于E2的更大减少，WL的质量和代谢有所改善，以及4)尽管AI WL将拥有 降低骨密度(BMD)的可能性和由于骨密度降低更大而损害骨质量的可能性 在E2中，与单独使用WL保存相比，这将被最小化，因为基线和 增加的肌肉质量。我们将100名肥胖男性随机分为体重指数≥35 kg/m2，总T&lt；300 ng/dl，E2&gt；40 促黄体生成素和黄体生成素/L给AI，阿那曲唑(每天1毫克)，WL，或安慰剂，每天WL，共12次 月份。此外，作为次要目标，我们将在一个 通过使用简单/偏相关和多元回归分析来确定 荷尔蒙因素和介质可以解释观察到的肌肉力量和症状的变化。 体重、身体成分(和代谢危险因素)、骨密度和骨质量。 这项研究的结果将确定人工授精联合西医治疗重症男性的有效性和安全性。 肥胖，其中性腺功能减退症的病因与雌激素分泌过多有关，因此代表了 在越来越多的肥胖性腺功能减退男性中，这是一种潜在的策略。

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.