Jasuja Ravi, Ramaraj Pandurangan, Mac Ricky Phong, Singh Atam B, Storer Thomas W, Artaza Jorge, Miller Aria, Singh Rajan, Taylor Wayne E, Lee Martin L, Davidson Tina, Sinha-Hikim Indrani, Gonzalez-Cadavid Nestor, Bhasin Shalender
Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
J Clin Endocrinol Metab. 2005 Feb;90(2):855-63. doi: 10.1210/jc.2004-1577. Epub 2004 Nov 2.
Previous studies of Delta 4-androstene-3,17-dione (4-androstenedione) administration in men have not demonstrated sustained increments in testosterone levels, fat-free mass (FFM), and muscle strength, and failure to demonstrate androstenedione's androgenic/anabolic effects has stifled efforts to regulate its sales. To determine whether 4-androstenedione has androgenic/anabolic properties, we evaluated its association with androgen receptor (AR) and its effects on myogenesis in vitro. Additionally, we studied the effects of a high dose of 4-androstenedione on testosterone levels, FFM, and muscle strength in hypogonadal men. We determined the dissociation constant (K(d)) for 4-androstenedione using fluorescence anisotropy measurement of competitive displacement of fluorescent androgen from AR ligand-binding domain. AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, pluripotent C3H10T1/2 cells, in which androgens stimulate myogenesis through an AR pathway. We determined effects of a high dose of androstenedione (500 mg thrice daily) given for 12 wk on FFM, muscle strength, and hormone levels in nine healthy, hypogonadal men. 4-Androstenedione competitively displaced fluorescent androgen from AR ligand-binding domain with a lower affinity than dihydrotestosterone (K(d), 648 +/- 21 and 10 +/- 0.4 nm, respectively). In C3H10T1/2 cells, 4-androstenedione caused nuclear translocation of AR and stimulated myogenesis, as indicated by a dose-dependent increase in myosin heavy chain II+ myotube area and up-regulation of MyoD protein. Stimulatory effects of 4-androstenedione on myosin heavy chain II+ myotubes and myogenic determination factor expression were attenuated by bicalutamide, an AR antagonist. Administration of 1500 mg 4-androstenedione daily to hypogonadal men significantly increased serum androstenedione, total and free testosterone, estradiol, and estrone levels and suppressed SHBG and high-density lipoprotein cholesterol levels. 4-androstenedione administration was associated with significant gains in FFM (+1.7 +/- 0.5 kg; P = 0.012) and muscle strength in bench press (+4.3 +/- 3.1 kg; P = 0.006) and leg press exercises (+18.8 +/- 17.3 kg; P = 0.045). 4-androstenedione is an androgen that binds AR, induces AR nuclear translocation, and promotes myogenesis in vitro, with substantially lower potency than dihydrotestosterone. 4-androstenedione administration in high doses to hypogonadal men increases testosterone levels, FFM, and muscle strength, although at the dose tested, the anabolic effects in hypogonadal men are likely because of its conversion to testosterone.
以往对男性使用Δ4-雄烯二酮（4-雄烯二酮）的研究未显示睾酮水平、去脂体重（FFM）和肌肉力量持续增加，且未能证明雄烯二酮的雄激素/合成代谢作用，这抑制了对其销售进行监管的努力。为了确定4-雄烯二酮是否具有雄激素/合成代谢特性，我们评估了其与雄激素受体（AR）的关联及其对体外肌生成的影响。此外，我们研究了高剂量4-雄烯二酮对性腺功能减退男性的睾酮水平、FFM和肌肉力量的影响。我们使用荧光各向异性测量法测定荧光雄激素从AR配体结合域的竞争性置换，从而确定4-雄烯二酮的解离常数（K(d)）。在间充质多能C3H10T1/2细胞中评估雄烯二酮的AR核转位和生肌活性，在这些细胞中雄激素通过AR途径刺激肌生成。我们确定了给予9名健康的性腺功能减退男性高剂量雄烯二酮（每日三次，每次500 mg），持续12周对FFM、肌肉力量和激素水平的影响。4-雄烯二酮从AR配体结合域竞争性置换荧光雄激素，其亲和力低于二氢睾酮（K(d)分别为648±21和10±0.4 nm）。在C3H10T1/2细胞中，4-雄烯二酮导致AR核转位并刺激肌生成，这表现为肌球蛋白重链II+肌管面积呈剂量依赖性增加以及MyoD蛋白上调。AR拮抗剂比卡鲁胺减弱了4-雄烯二酮对肌球蛋白重链II+肌管和生肌决定因子表达的刺激作用。对性腺功能减退男性每日给予1500 mg 4-雄烯二酮可显著提高血清雄烯二酮、总睾酮和游离睾酮、雌二醇和雌酮水平，并降低性激素结合球蛋白和高密度脂蛋白胆固醇水平。给予4-雄烯二酮与FFM显著增加（+1.7±0.5 kg；P = 0.012）以及卧推（+4.3±3.1 kg；P = 0.006）和腿举运动（+18.8±17.3 kg；P = 0.045）时肌肉力量增加有关。4-雄烯二酮是一种雄激素，可与AR结合，诱导AR核转位，并在体外促进肌生成，其效力远低于二氢睾酮。对性腺功能减退男性高剂量给予4-雄烯二酮可提高睾酮水平、FFM和肌肉力量，尽管在所测试的剂量下，性腺功能减退男性的合成代谢作用可能是由于其转化为睾酮。
