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-4-Androstene-3,17-Dione Binds Androgen Receptor, Promotes Myogenesis in Vitro, and Increases Serum Testosterone Levels, Fat-Free Mass, and Muscle Strength in Hypogonadal Men

Division of Endocrinology, Metabolism, and Molecular Medicine (R.J., P.R., R.P.M., A.B.S., T.W.S., J.A., A.M., R.S., W.E.T., M.L.L., T.D., I.S.-H., N.G.-C., S.B.), Charles R. Drew University of Medicine and Science, Los Angeles, California 90059; and Laboratory for Exercise Science (T.W.S.), El Camino College, Torrance, California 90502

Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., Professor of Medicine, UCLA School of Medicine, Director, Drew-UCLA Reproductive Science Research Center, Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059. sbhasin{at}ucla.edu.

Previous studies of 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.

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