This Article Full Text Full Text (PDF) All Versions of this Article: 147/6/3016    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Attardi, B. J. Articles by Reel, J. R. Search for Related Content PubMed PubMed Citation Articles by Attardi, B. J. Articles by Reel, J. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB RU-486

Dimethandrolone Undecanoate: A New Potent Orally Active Androgen with Progestational Activity

BIOQUAL, Inc., Rockville, Maryland 20850

Address all correspondence and requests for reprints to: Dr. Barbara J. Attardi, Molecular Endocrinology Laboratory, BIOQUAL, Inc., 9600 Medical Center Drive, Rockville, Maryland 20850. E-mail: bjattardi{at}bioqual.com.

Dimethandrolone (DMA), the 17ß-undecanoic acid ester of dimethandrolone (DMAU; 7,11ß-dimethyl-19-nortestosterone) is a potent androgen currently in development for therapeutic uses in men. Cleavage of the 17ß-ester bond liberates the biologically active DMA. In this study we investigated the activity of DMAU and DMA both in vivo and in vitro. DMAU was active orally in castrate rat bioassays, and when administered sc, a single dose produced prolonged androgenic activity and suppression of LH with sustained circulating levels of DMA. DMA, other 19-norandrogens, and C-19 androgens bound to recombinant rat androgen receptor with high affinity and were equipotent in stimulating luciferase activity (EC₅₀, 10^–10–10^–9 M) in CV-1 cells cotransfected with a human androgen receptor expression vector and a luciferase reporter plasmid with three hormone response elements. Because various 19-norandrogens are also known to bind to progestin receptors (PR) and to possess progestational activity in vivo, we evaluated the binding affinity of DMA for rabbit PR and recombinant human PR-A and PR-B and its ability to induce PR-mediated transcription and endogenous alkaline phosphatase activity in T47DCO human breast cancer cells. DMA and related 19-norandrogens bound with high affinity to both rabbit and human PR, whereas the less active 11-methyl stereoisomer of DMA and C-19 androgens showed low or negligible binding to PR. In T47DCO cells, 10^–8 M DMA and other 19-norandrogens stimulated transcription of a progestin/glucocorticoid/androgen response element-thymidine kinase-luciferase reporter plasmid to the same extent as R5020, the potent progestin promegestone (EC₅₀, 10^–9 M), but C-19 androgens had no effect. Antiprogestins were potent inhibitors of transactivation and alkaline phosphatase activity induced by DMA and other 19-norandrogens in T47DCO cells, whereas antiandrogens were weak inhibitors. DMA and DMAU also exhibited dose-dependent progestational activity in the estrogen-primed immature female rabbit, as assessed by induction of endometrial gland arborization. The dual androgenic and progestational activities of DMA make it a potential candidate for a single-agent male contraceptive as well as for androgen therapy in men, pending a successful outcome of pharmacokinetic and toxicity studies currently in progress.