Metabolic effects of steroid hormones in obese men

描述(由申请人提供)： 肥胖男性患有胰岛素抵抗、血脂异常和心血管疾病等共病。她们的睾丸素(T)水平也低于非肥胖男性。对于T水平低于正常水平的腹型肥胖男性，一组人服用T可提高胰岛素敏感性，降低内脏脂肪。然而，心脏保护性高密度脂蛋白胆固醇(HDL-C)降低，这表明如果T被认为是一种肥胖的治疗方法，那么开发对血脂具有中性或改善作用的选择性雄激素受体调节剂(SARM)是必要的。这是一项前瞻性、随机、双盲试验，旨在确定T及其代谢物雌二醇(E_2)和5-α-二氢睾酮(DHT)对T水平偏低或偏低的肥胖男性的胰岛素敏感性、身体成分和脂肪代谢的影响。除安慰剂组外，年龄在21至50岁之间、体重指数大于30公斤/平方米、腰围大于100厘米、腰臀比大于1.0的男性将使用促性腺激素释放激素(GnRH)拮抗剂和外源性T将T钳制在正常范围内。将60名受试者随机分为4组：1)安慰剂组；2)单纯T组-GnRH拮抗剂+外源性T+口服安慰剂；3)芳香酶抑制剂组-GnRH拮抗剂+T+阿那曲唑；4)5α-还原酶抑制剂组-GnRH拮抗剂+T+度他雄胺。第三组将检查在没有E2的情况下的结果，而第四组将检查在没有DHT的情况下的结果。治疗前后采用静脉葡萄糖耐量试验检测胰岛素敏感性，双能X线吸收法检测总脂肪，核磁共振成像检测局部脂肪包括皮下、内脏和肌间脂肪，核磁共振检测心肌细胞内脂肪。治疗前后将获得脂肪和肌肉活检，以检查组织特异性胰岛素敏感性，并开始分析与胰岛素敏感性有关的基因表达变化。治疗前后将详细检查脂代谢，包括高密度脂蛋白、低密度脂蛋白大小和肝脂酶、脂蛋白脂酶、胆固醇酯转移蛋白和磷脂转移蛋白的活性。这些结果应该开始描述类固醇激素对重要代谢结果的影响，这些代谢结果对SARM的发展至关重要。

DESCRIPTION (provided by applicant): Obese men have comorbid conditions including insulin resistance, dyslipidemia and cardiovascular disease. They also have lower testosterone (T) levels than non-obese men. Administration of T to abdominally obese men with low-normal T levels by one group increased insulin sensitivity and decreased visceral fat. Cardioprotective high-density lipoprotein cholesterol (HDL-C) however, decreased, suggesting that developing selective androgen receptor modulators (SARMs) that are neutral to, or improve the lipid profile are required if T is to be considered a treatment for obesity. This is a prospective, randomized, double-blind trial to determine the effects of T and its metabolites, estradiol (E2) and 5alpha-dihydrotestosterone (DHT) on insulin sensitivity, body composition and lipid metabolism in obese men with low or low-normal T levels. Men between the ages of 21 and 50 years with a body mass index greater than 30 kg/m2, waist measurement greater than 100cm and a waist-to-hip ratio greater than 1.0 will have T clamped within the normal range using a gonadotropin releasing-hormone (GnRH) antagonist and exogenous T except in the placebo group. Sixty subjects will be randomized into one of 4 groups: 1) Placebo group; 2) T alone group- GnRH antagonist + exogenous T + oral placebo; 3) Aromatase inhibitor group- GnRH antagonist + T + anastrazole; and 4) 5alpha-reductase inhibitor group - GnRH antagonist + T + dutasteride. Group 3 will examine outcomes in the absence of E2 while group 4 will examine outcomes in the absence of DHT. Insulin sensitivity by the frequently-sampled intravenous glucose tolerance test, total fat by dual-energy X-ray absorptiometry, regional fat including subcutaneous, visceral and intermuscular fat by magnetic resonance imaging, and intramyocellular fat by 1H-nuclear magnetic resonance spectroscopy will be examined before and after treatment. Fat and muscle biopsies will be obtained before and after treatment to examine tissue-specific insulin sensitivity and to begin an analysis of altered gene expression as it pertains to insulin sensitivity. Lipid metabolism will be examined in detail before and after treatment to include HDL-C, lowdensity lipoprotein size and activities of hepatic lipase, lipoprotein lipase, cholesteryl ester transfer protein and phospholipid transfer protein. These outcomes should begin to describe steroid hormone effects on important metabolic outcomes important for the development of SARMs.