Role of 5-alpha Reductase in Testosterone Actions

描述(申请人提供)：睾酮，男性主要的循环雄激素，也是一种前激素，在体内转化为两种活跃的代谢物，雌二醇17β和5-α二氢睾酮(DHT)。在一些靶组织中，睾酮作为活性激素；然而，在其他靶器官中，雄激素的作用需要将其转化为雌二醇或DHT。睾酮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，该项目的主要目标是确定睾酮5-α还原为DHT是否在调节其对男性脱脂质量、肌肉大小、肌肉力量和腿部力量的影响方面是必需的。第二个目标是确定5-α降低睾酮是否对于维持雄激素对性功能(性欲、总体性活动、夜间阴茎肿胀(NPT)、对视觉性爱刺激的反应和阴茎僵硬)的影响是必要的。为了测试这些关于5-α还原作用的假设，我们将在没有和存在一种新的、有效的5-α还原酶抑制剂(非那雄胺)同时抑制1型和2型类固醇5-α还原酶同工酶的情况下，比较每项结果指标的睾酮剂量反应曲线。21-40岁的健康青年男性将接受长效促性腺激素释放激素激动剂的治疗，以抑制内源性睾酮的产生，并同时随机分配到8组中的一组：1组，每周50毫克，加用安慰剂；2组，每周睾丸酮125毫克，每天加安慰剂；3组，每周睾丸酮300毫克，每天加安慰剂；4组，每周睾丸酮600毫克，加安慰剂；5组，每周50毫克，加用非那雄胺2.5 mg；6组，每周12 5毫克，加用非那雄胺；7组，每周3 00毫克，加用非那雄胺；第8组，600 mg TE加非那雄胺，每日1次。能量和蛋白质摄入量以及运动刺激将标准化。在基线和20周后，将测量以下结果：通过DEXA扫描测量身体成分、氧化氢和溴化钠稀释；通过核磁共振扫描测量大腿肌肉体积；通过测量1次重复最大力量和腿力来测量肌肉性能；通过国际勃起功能指数、性欲清单和每日性行为日志测量性功能；以及在脑电耦合、NPT记录和对视觉色情刺激的反应中阴茎勃起和僵硬；总和游离睾酮、DHT、雌二醇、SHBG和黄体生成素水平。为了安全起见，我们将观察血红蛋白/红细胞压积、睡眠呼吸暂停评分、AST和ALT、PSA、血脂、载脂蛋白和脂蛋白颗粒，以及前列腺检查。一个多学科的研究团队，使用先前验证的“间质细胞钳”模型，使用一种有效的5-α还原酶两种亚型的抑制剂，关注潜在的混杂变量，如能量摄入和运动刺激，以及功率和效果大小，应该有助于阐明5-α减少在调节雄激素作用中的作用。这项研究将加深我们对类固醇5-α-还原酶系统的生物学作用的理解，并在确定不经历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药物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.