Metabolic effects of steroid hormones in obese men

描述（由申请人提供）： 肥胖男性有合并症，包括胰岛素抵抗，血脂异常和心血管疾病。他们的睾酮（T）水平也低于非肥胖男性。一组给予T水平低于正常值的腹部肥胖男性T，增加了胰岛素敏感性，减少了内脏脂肪。然而，具有保护作用的高密度脂蛋白胆固醇（HDL-C）降低，这表明如果T被认为是肥胖症的治疗方法，则需要开发对脂质谱中性或改善脂质谱的选择性雄激素受体调节剂（SARM）。这是一项前瞻性、随机、双盲试验，旨在确定T及其代谢产物雌二醇（E2）和5 α-双氢睾酮（DHT）对低或正常T水平的肥胖男性胰岛素敏感性、身体成分和脂质代谢的影响。年龄在21 - 50岁之间，体重指数大于30 kg/m2，腰围大于100 cm，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钳夹在正常范围内，安慰剂组除外。将60例受试者随机分为4组：1）安慰剂组; 2）单独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）5 α-还原酶抑制剂组-GnRH拮抗剂+T+度他雄胺。第3组将检查不存在E2的结果，而第4组将检查不存在DHT的结果。治疗前后将通过频繁采样静脉葡萄糖耐量试验检查胰岛素敏感性，通过双能X线吸收测定法检查总脂肪，通过磁共振成像检查局部脂肪（包括皮下、内脏和肌间脂肪），通过1H-核磁共振光谱检查肌内脂肪。在治疗前后进行脂肪和肌肉活检，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相关的基因表达改变。治疗前后将详细检查脂质代谢，包括HDL-C、低密度脂蛋白大小和肝脂肪酶、脂蛋白脂肪酶、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SARM发展的重要代谢结果的影响。

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.