Aromatase Inhibitors and Weight Loss in Severely Obese Men with Hypogonadism

芳香酶抑制剂与患有性腺功能减退症的严重肥胖男性的减肥

• 批准号: 9942488
• 负责人: REINA C VILLAREAL
• 金额: $ 37.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-07 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9942488
• 关键词: Adipose tissue; Adverse effects; Aging; Alternative Therapies; Androgens; Androstenedione; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Attenuated; Body Composition; Body Weight decreased; Body mass index; Bone Density; Clinical; Data; Dose; Elderly man; Estradiol; Estrogens; Estrone; Etiology; Fatty acid glycerol esters; Feedback; Follicle Stimulating Hormone; Follistatin; Functional disorder; GDF8 gene; Gonadotropins; Hematocrit procedure; Hormonal; Hypogonadism; Hypothalamic structure; Impairment; Insulin-Like Growth Factor I; Intervention; Klinefelter' s Syndrome; Lead; Letrozole; Life Style; Luteinizing Hormone; Mediator of activation protein; Medical; Metabolic; Morbid Obesity; Non obese; Obesity; Older Population; Outcome; Patients; Pharmaceutical Preparations; Pituitary Gland; Placebos; Production; Prostate; Prostate-Specific Antigen; Psychometrics; Quality of life; Randomized; Recommendation; Regression Analysis; Reporting; Research Design; Risk Factors; Safety; Serum; Sex Functioning; Symptoms; Syndrome; Testosterone; Thinness; Tissues; Vertebral column; Weight; alternative treatment; anastrozole; bone; bone metabolism; bone quality; bone turnover; cardiovascular risk factor; diet and exercise; efficacy evaluation; hypothalamic pituitary gonadal axis; improved; men; muscle form; muscle strength; obese patients; obesity treatment; older men; preservation; standard of care; substantia spongiosa; symptomatic improvement; treatment strategy

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.

抽象的 肥胖男性丰富的脂肪组织中芳香化酶活性的增加导致增强 conversion of androgens to estrogens, (estradiol [E2], estrone), leading to high estrogen levels.反过来 向下丘脑 - 垂体 - 基达单元发送负反馈，导致促性腺激素减少，并且 开发了睾丸激素（T）生产和一种称为性腺功能低下的疾病（HHG）。 根据每种疗法，芳香化酶活性并进一步增加E2可能会导致底物增加（t）。 尽管体重减轻（WL）导致t水平升高，但仅通过改变生活方式的WL就受到了限制 较低的T和重量恢复的幅度很常见。芳香酶抑制剂（AIS）可以减少E2 生产和增加T，但几乎没有或根本没有有关将AI添加到WL的效率的信息 增强HHG肥胖男性症状的芳香酶抑制作用。 The primary objective of this 建议是评估AI作为WL（AI+WL）的效率与仅在严重的WL中相比 肥胖的男人患有HHG。该提议的核心假设是在WL中添加AI（饮食+运动） will lead to reversal of the horseal abnormality in obesity-associated HHG resulting in improvement in 性交症状对身体成分（和代谢风险因素）和 骨。我们假设：1）AI+ WL将完全逆转与肥胖相关的激素异常 HHG是因为AI在降低芳香化酶活性中的AI额外影响 扩展的脂肪组织体积2）AI+ WL将导致肌肉强度更大，肌肉 与单独使用WL相比，质量和症状的增加，因为t的增加，3）AI+WL将导致更大的 与仅WL相比，由于T的增加而增加的瘦质量增加，但可能会减轻脂肪的损失 由于E2的减少较大，WL的质量和代谢改善，而AI+WL将具有4） 降低骨矿物质密度（BMD）并损害骨质质量的潜力 在E2中，与仅WL保存相比，这将被最小化，因为基线时的E2含量高 The increased muscle mass.我们将随机将100名BMI≥35kg/m2，总T <300 ng/dl，E2> 40随机分配 pmol/l和黄体效果<9 miu/l至AI，Anastrozole（每天1毫克）， +WL或每天的安慰剂 +WL 12 月份。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/部分相关和多元回归分析来确定哪个 骑马因素和调解人可能会解释观察到的肌肉力量和症状的变化，肌肉 质量，身体成分（和代谢风险因素），BMD和骨质质量。 这项研究的结果将在严重的男性中确定AIS与WL结合使用的实用性和安全性 肥胖症中的肥胖症患者的病因与过量的雌激素产生有关，从而代表 肥胖的性下个性男性越来越多的潜在策略。