Second potential male birth control pill passes human safety tests

Organisation: Position: Deadline Date: Location:

A new experimental male oral contraceptive has been announced, called 11-beta-methyl-19-nortestosterone dodecylcarbonate, or 11-beta-MNTDC. It is a modified testosterone that has the combined actions of a male hormone (androgen) and a progesterone, said the study’s co-senior investigator, Dr Christina Wang, associate director, Clinical and Translational Science Institute at Los Angeles Biomed Research Institute (LA BioMed), Torrance. “Our results suggest that this pill, which combines two hormonal activities in one, will decrease sperm production while preserving libido,” Wang said.

The study took place in 40 healthy men at LA BioMed and the University of Washington in Seattle. Ten study participants randomly received a placebo capsule, or dummy drug. The other 30 men received 11-beta-MNTDC at one of two doses; 14 men received 200 milligrams, or mg, and 16 got the 400 mg dose. Subjects took the drug or placebo once daily with food for 28 days. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, which is developing 11-beta-MNTDC and other male contraceptives, funded this study.

Among men receiving 11-beta-MNTDC, the average circulating testosterone level dropped as low as in androgen deficiency, but the participants reportedly did not experience any severe side effects. Wang said drug side effects were few, mild and included fatigue, acne or headache in four to six men each. Five men reported mildly decreased sex drive, and two men described mild erectile dysfunction, but sexual activity was not decreased, she said. Furthermore, no participant stopped taking the drug because of side effects, and all passed safety tests.

Effects due to low testosterone were minimal, according to co-senior investigator, Dr Stephanie Page, professor of medicine at the University of Washington School of Medicine, because “11-beta-MNTDC mimics testosterone through the rest of the body but is not concentrated enough in the testes to support sperm production.”

Levels of two hormones required for sperm production dropped greatly compared to placebo, the researchers found. The drug effects were reversible after stopping treatment, Wang noted.

Because the drug would take at least three 60 to 90 days to affect sperm production, 28 days of treatment is too short an interval to observe optimal sperm suppression, Wang explained. They plan longer studies, and if the drug is effective, it will move to larger studies and then testing in sexually active couples.

“Safe, reversible hormonal male contraception should be available in about 10 years,” Wang predicted.

Wang said most men are open to using this type of male birth control. She cited a multinational survey of 9,000 men published in the journal Human Reproduction in February 2005 that found that 55% of men in stable relationships want to try new, hormonal male contraceptive methods if they are reversible.

This experimental contraceptive, 11-Beta-MNTDC, is a “sister compound” to dimethandrolone undecanoate, or DMAU, the first potential male birth control pill to undergo testing by the same research team.

Abstract
Context: 11β-Methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) is an orally bioavailable prodrug of 11β-methyl-19-nortestosterone (11β-MNT) with androgenic and progestational activity.
Objectives: (i) Quantify 11β-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11β-MNTDC in men.
Design and Setting: (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers.
Participants and Intervention: Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11β-MNTDC or placebo given with or without food.
Main Outcome Measures: (i) In vitro 11β-MNT/11β-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing.
Results: 11β-MNT avidly binds and activates human androgen and progesterone receptors, but 11β-MNTDC has minimal activity. Single oral doses of 11β-MNTDC were well tolerated without serious adverse events. Administration of 11β-MNTDC with food markedly increased average 11β-MNTDC and 11β-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05).
Conclusions: A single, oral dose of 11β-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11β-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

Authors
Sherry Wu, Fiona Yuen, Ronald S Swerdloff, Youngju Pak, Arthi Thirumalai, Peter Y Liu, John K Amory, Feng Bai, Laura Hull, Diana L Blithe, Bradley D Anawalt, Toufan Parman, Kyuri Kim, Min S Lee, William J Bremner, Stephanie T Page, Christina Wang

Endocrine Society material
The Journal of Clinical Endocrinology and Metabolism abstract


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