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酶活性增加，导致 雄激素转化为雌激素（雌二醇[E2]、雌酮），导致雌激素水平升高。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，并且 睾酮 (T) 产生减少，出现一种称为低促性腺激素性性腺功能减退症 (HHG) 的病症。 因此，T 疗法可能只会导致芳香酶活性底物 (T) 增加，并进一步增加 E2。 尽管体重减轻 (WL) 会导致 T 水平升高，但仅通过改变生活方式来实现的 WL 受到以下因素的限制： T 和体重回升的上升幅度较小，这是常见的。芳香酶抑制剂 (AI) 可以降低 E2 生产并增加 T，但很少或没有关于将 AI 添加到 WL 来生产的功效的信息 增强芳香酶抑制可改善患有 HHG 的肥胖男性的症状。此举的首要目标 提案的目的是评估人工智能作为 WL 的辅助手段（AI WL）与单独使用 WL 相比在严重疾病中的功效。 患有 HHG 的肥胖男性。该提案的中心假设是在WL（饮食锻炼）中添加AI 将导致肥胖相关 HHG 中荷尔蒙异常的逆转，从而改善 性腺功能减退症状，对身体成分（和代谢危险因素）没有显着不利影响，并且 骨头。我们假设：1）AI WL 将完全逆转肥胖相关的荷尔蒙异常 HHG 是因为 AI 在降低芳香酶活性方面比单独使用 WL 具有额外的效果 扩大的脂肪组织体积，2) AI WL 将导致肌肉力量、肌肉的更大改善 与单独的 WL 相比，由于 T 增加更大，因此质量和症状有所改善，3) AI WL 将导致更大的 与单独的体重相比，由于 T 的增加更大，导致瘦体重增加，但可能会减少脂肪的损失 由于 E2 的更大减少，WL 的质量和代谢得到改善，4) 尽管 AI WL 会有 由于骨矿物质密度（BMD）减少幅度更大，因此有可能降低骨矿物质密度（BMD）并损害骨质量 与单独使用 WL 进行保存相比，E2 中的情况将被最小化，因为基线时 E2 水平较高，并且 增加的肌肉质量。我们将随机抽取 100 名 BMI ≥35 kg/m2、总 T <300 ng/dl、E2 > 40 的肥胖男性 pmol/L 和黄体生成素 <9 mIU/L 至 AI、阿那曲唑（每日 1 mg）、WL 或安慰剂每日 WL，持续 12 次 几个月。此外，作为次要目标，我们将阐明我们的中心假设的机制 通过使用简单/偏相关和多元回归分析的综合方式来确定哪些 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。 这项研究的结果将确定 AI 与 WL 联合治疗患有严重疾病的男性的实用性和安全性 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 对于越来越多的肥胖性腺功能减退男性来说，这是一个潜在的策略。

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.