This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jasuja, R. Articles by Bhasin, S. Search for Related Content PubMed PubMed Citation Articles by Jasuja, R. Articles by Bhasin, S.

Tetrahydrogestrinone Is an Androgenic Steroid that Stimulates Androgen Receptor-Mediated, Myogenic Differentiation in C3H10T1/2 Multipotent Mesenchymal Cells and Promotes Muscle Accretion in Orchidectomized Male Rats

Division of Endocrinology (R.J., A.M., K.L.H., J.N.A., R.S., G.D., A.S., S.B.), Charles R. Drew University of Medicine, Los Angeles, California 90059; Department of Molecular and Medical Pharmacology (D.H.C., Y.-C.C., B.S.), University of California, Los Angeles, Los Angeles, California 90095; Section of Endocrinology (R.J., S.B.), Boston University, Boston, Massachusetts 02118; and Department of Medicine (C.C., M.B.), University of California, San Diego, La Jolla, California 92093

Address all correspondence and requests for reprints to: Ravi Jasuja, Ph.D., Division of Endocrinology, Charles R. Drew University of Medicine, Los Angeles, California 90059. E-mail: jasuja{at}ucla.edu.

The discovery of tetrahydrogestrinone (THG) abuse by several elite athletes led the U.S. Congress to declare it a controlled substance, although conclusive evidence of its anabolic/androgenic activity is lacking. We determined whether THG affects myogenic differentiation and androgen receptor (AR)-mediated signaling, whether it binds to AR, and whether it has androgenic and anabolic effects in vivo. Accordingly, we measured the dissociation constant for THG with a fluorescence anisotropy assay using recombinant AR-ligand binding domain. The AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, multipotent C3H10T1/2 cells. We performed molecular modeling of the THG:AR interaction. The androgenic/anabolic activity was evaluated in orchidectomized rats. THG bound to AR with an affinity similar to that of dihydrotestosterone. In multipotent C3H10T1/2 cells, THG upregulated AR expression, induced AR nuclear translocation, dose dependently increased the area of myosin heavy chain type II-positive myotubes, and up-regulated myogenic determination and myosin heavy chain type II protein expression. The interaction between AR and the A ring of THG was similar to that between AR and the A ring of dihydrotestosterone, but the C17 and C18 substituents in THG had a unique stabilizing interaction with AR. THG administration prevented the castration-induced atrophy of levator ani, prostate gland, and seminal vesicles and loss of fat-free mass in orchidectomized rats. We conclude that THG is an anabolic steroid that binds to AR, activates AR-mediated signaling, promotes myogenesis in mesenchymal multipotent cells, and has anabolic and androgenic activity in vivo. This mechanism-based approach should be useful for rapid screening of anabolic/androgenic agents.