Role of 5-alpha Reductase in Testosterone Actions

描述（由申请人提供）：睾酮是男性主要的循环雄激素，也可作为激素原，在体内转化为两种活性代谢物，雌二醇17 β和5- α二氢睾酮（DHT）。睾酮在某些靶组织中起活性激素作用；然而，雄激素在其他靶器官中的作用需要将其转化为雌二醇或DHT。睾酮的5- α减少在调节其对肌肉和性功能的影响中的作用尚不清楚。因此，本项目的主要目的是确定5- α将睾酮还原为二氢睾酮对于调节其对男性无脂质量、肌肉大小、肌肉力量和腿部力量的影响是否必要。第二个目的是确定5- α睾丸激素的减少对于维持男性性功能（性欲、总体性活动、夜间阴茎肿胀（NPT）、对视觉性刺激的反应和阴茎刚性）的雄激素作用是否必要。为了验证这些关于5- α还原酶作用的假设，我们将比较在缺乏和存在一种新型的、有效的5- α还原酶抑制剂（duasteride）的情况下，每种结果测量的睾酮剂量反应曲线，这种抑制剂可以抑制1型和2型类固醇5- α还原酶同工酶。21-40岁的健康年轻男性将接受长效GnRH激动剂治疗，以抑制内源性睾酮的产生，并同时随机分配到8组之一：1组，睾酮酸（TE）每周50毫克，每日加安慰剂片；第2组，TE 125 mg /周加安慰剂/天；第3组，TE每周300毫克，每日加安慰剂；第4组，TE 600 mg TE每周加安慰剂；第5组，每周50毫克，加多司他胺2.5毫克/天；第6组，TE 125 mg /周，加杜司他胺/天；第7组，TE 300 mg /周，加杜司他胺每日；8组，每天服用600毫克TE加杜司他胺。规范能量、蛋白质摄入和运动刺激。将在基线和20周后测量以下结果：通过DEXA扫描、氧化氘和溴化钠稀释测量身体成分；大腿肌肉体积MRI扫描；通过测量1次重复最大力量和腿部力量的肌肉表现；通过国际勃起功能指数、性欲量表和性活动日记本进行性功能检查；和阴茎勃起和刚性期间脑电图耦合，NPT重新编码和响应视觉性刺激；总和游离睾酮、DHT、雌二醇、SHBG和LH水平。为了安全起见，我们将跟踪血红蛋白/红细胞压积、睡眠呼吸暂停评分、AST和ALT、PSA、血浆脂质、载脂蛋白和脂蛋白颗粒以及前列腺检查。一个多学科的研究小组，使用先前验证的“间质细胞钳”模型，使用5- α还原酶两种亚型的有效抑制剂，注意潜在的混淆变量，如能量摄入和运动刺激，以及功率和效应大小，应该有助于阐明5- α还原在介导雄激素作用中的作用。这项研究将增强我们对类固醇5- α还原酶系统的生物学作用的理解，并在确定不进行5- α还原的选择性雄激素受体调节剂是否可用作合成代谢剂方面具有直接的临床意义。

DESCRIPTION (provided by applicant): Testosterone, the predominant circulating androgen in men, also serves as a prohormone that is converted in the body to two active metabolites, estradiol 17beta and 5-alpha dihydrotestosterone (DHT). Testosterone serves as the active hormone in some target tissues; however, androgen effects in other target organs require its conversion to estradiol or DHT. The role of 5-alpha reduction of testosterone in mediating its effects on the muscle and sexual function remains unclear. Therefore, the primary objective of this project is to determine whether 5-alpha reduction of testosterone to DHT is obligatory for mediating its effects on fat-free mass, muscle size, muscle strength, and leg power in men. The secondary objective is to determine whether 5-alpha reduction of testosterone is necessary for maintenance of androgen effects on sexual function (sexual desire, overall sexual activity, nocturnal penile tumescence (NPT), response to visual erotic stimulus, and penile rigidity) in men. In order to test these hypotheses about the role of 5-alpha reduction, we will compare testosterone dose response curves for each outcome measure in the absence and presence of a novel, potent 5-alpha reductase inhibitor (duasteride) that inhibits both type 1 and type 2 steroid 5-alpha -reductase isoenzymes. Healthy young men, 21-40 years of age, will be treated with a long acting GnRH agonist to suppress endogenous testosterone production, and concomitantly, randomly assigned to one of 8 groups: group 1, testosterone enanthate (TE) 50-mg weekly, plus placebo tablets daily; group 2, TE 125-mg weekly plus placebo daily; group 3, TE 300-mg weekly plus placebo daily; group 4, TE 600 mg TE weekly plus placebo; group 5, 50-mg weekly, plus duasteride 2.5-mg daily; group 6, TE 125-mg weekly, plus duasteride daily; group 7, TE 300 mg weekly, plus duasteride daily; group 8, 600-mg TE plus duasteride daily. Energy and protein intake, and exercise stimulus will be standardized. The following outcomes will be measured at baseline and after 20 weeks: body composition by DEXA scan, deuterium oxide and sodium bromide dilution; thigh muscle volume by MRI scan; muscle performance by measurements of 1-repetition maximum strength and leg power; sexual function by International Index of Erectile Function, Sexual Desire Inventory, and daily logs of sexual activity; and penile erections and rigidity during EEG-coupled, NPT recoding and in response to a visual erotic stimulus; total and free testosterone, DHT, estradiol, SHBG, and LH levels. For safety, we will follow hemoglobin/hematocrit, sleep apnea scores, AST and ALT, PSA, plasma lipids, apolipoproteins, and lipoprotein particles, and prostate examinations. A multi-disciplinary team of investigators, the use of a previously validated "Leydig Cell Clamp" model, the use of a potent inhibitor of both subtypes of 5-alpha reductase enzyme, attention to potential confounding variables such as energy intake and exercise stimulus, and power and effect size should help elucidate the role of 5-alpha reduction in mediating androgen action. This study will enhance our understanding of the biologic role of the steroid 5-alpha-reductase system, and has immediate clinical relevance in establishing whether selective androgen receptor modulators that do not undergo 5-alpha reduction would be useful as anabolic agents.