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

Abstract

Dimethandrolone (DMA), the 17beta-undecanoic acid ester of dimethandrolone (DMAU; 7alpha,11beta-dimethyl-19-nortestosterone) is a potent androgen currently in development for therapeutic uses in men. Cleavage of the 17beta-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 11alpha-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, approximately 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.

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

“…For transient transfection experiments, cells were plated in 6-well dishes in phenol red-free DMEM supplemented with 10% dextran-coated charcoal-stripped (DCC-stripped) fetal bovine serum (FBS, Hyclone Laboratories, Inc., Logan, UT), 10 U/ml penicillin G, and 10 μg/ml streptomycin sulfate. Cells were transfected with 3XERE-LUC, a reporter plasmid containing three copies of an estrogen response element (ERE) upstream of the firefly luciferase (LUC) gene (a gift of Dr. Donald McDonnell, Duke University, Durham, NC) using FuGENE 6 (Roche, Indianapolis, IN) as described previously [3,15]. Data were expressed as relative light units (RLU) normalized for differences in protein content per well.…”

“…Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) is a potent orally active synthetic 19-norandrogen. We are currently assessing the 17β-undecanoic acid ester of DMA as a potential agent for androgen therapy [3]. Cleavage of the ester bond in the body liberates the biologically active unesterified DMA.…”

“…The enzyme complex, which is composed of 2 subunits, aromatase P450 and an NADPH cytochrome C reductase, is localized to the microsomal fraction of estrogen-producing cells. Aromatization of C19 androgens such as T and androstenedione (AD) to their C18 aromatic A-ring products, estradiol and estrone (E 1 ), respectively, takes place in three sequential steps [4][5][6]: (1) hydroxylation of the C19-methyl group; (2) a second hydroxylation of the C19-methyl group to form a 19-oxo-compound; (3) cleavage of the bond between C10 and C19 to yield formic acid and the aromatized A-ring product with loss of the hydrogen atoms at the 1β and 2β positions. Although the mechanism of action of human aromatase involves the C19-methyl group, published findings concerning the potential aromatization of 19-norandrogens in vitro and in vivo have been contradictory [7][8][9][10][11][12][13][14].…”

Does ethnicity matter in male hormonal contraceptive efficacy?

“…Dimethandrolone undecanoate, a derivative of 19-nortestosterone possesses both in vitro and in vitro androgenic and progestational activities with prostate sparing properties, 51,52 and may be one such compounds. There may be long-term issues with the use of these compounds due to lack of conversion to aromatic A-ring metabolites 53 and possible effects on lipid metabolism.…”

Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

“…Preliminary animal data suggest that due to its combined androgen and progestin effects, dimethandrolone undecanoate may offer a single, reversible contraceptive agent for men. 54 Newer delivery systems have been approved by the US Food and Drug Administration for the treatment of hypogonadism. Whether men would tolerate daily gel application of testosterone may be a barrier to its widespread use, however recent studies combining testosterone gel with other agents will be presented later.…”