CDP Research: Developing Hormonal Contraception Methods for Men

Currently, the only reversible male contraceptive method is the male condom. Although condoms also protect against sexually transmitted infections, the failure rate is relatively high, and the method is not acceptable to many men.

Hormonal approaches to male contraception effectively inhibit sperm production. Testosterone (T) is synthesized in testes in very high amounts, more than 50-fold higher than T circulating in blood. This high T level is needed for sperm production. Progestins use negative feedback on the hypothalamic-pituitary-gonadal axis to inhibit luteinizing hormone (LH) and follicle-stimulating hormone gonadotropin secretion. Inhibiting LH stops testicular T synthesis needed for spermatogenesis. T in serum must be replaced to maintain normal sexual function.

The challenge that has prevented development of a male pill is that oral T is cleared very rapidly, requiring multiple doses per day. Commercial transdermal T delivery for hypogonadal therapy has been hugely successful, but earlier pharmaceutical programs in male contraception were abandoned.

Contraceptive Development Program (CDP) research has broken new ground with products administered via transdermal, oral, or injectable routes of delivery. These successful approaches have used progestins to achieve sperm suppression consistent with contraceptive effectiveness (sperm <1 million/ml) and T delivered by injections, implants, or transdermal gels to maintain all other functions. New progestogenic androgens on the horizon may provide contraception with a single agent. Non-hormonal approaches that inhibit sperm production or sperm function are still in preclinical phase of research.

Nestorone®/T (Nes/T) Gel

Daily Transdermal Application

CDP research demonstrated that a potent progestin, Nestorone®, combined with T in a gel formulation, caused gonadotropin suppression with resultant inhibition of testicular T production. Daily application of Nes/T gel suppressed sperm production but maintained other androgen-dependent functions and was fully reversible after treatment ended.

ClinicalTrials.gov Identifier: NCT03452111

Status: CDP researchers, in collaboration with the Population Council, are evaluating the combined Nes/T gel for contraceptive effectiveness in couples who are willing to use this method for pregnancy prevention. Enrollment is ongoing at selected Contraceptive Clinical Trials Network sites in the United States, United Kingdom, Sweden, Italy, Chile, and Kenya.

Related Publications (from earlier studies):

  1. Anawalt, B. D., Roth, M. Y., Ceponis, J., Surampudi, V., Amory, J. K., Swerdloff, R. S., Liu, P. Y., Dart, C., Bremner, W. J., Sitruk-Ware, R., Kumar, N., Blithe, D. L., Page, S. T., & Wang, C. (2019). Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men. Andrology, 7(6), 878–887. PMID: 30969032. PMCID: PMC6768743
  2. Roth, M. Y., Shih, G., Ilani, N., Wang, C., Page, S. T., Bremner, W. J., Swerdloff, R. S., Sitruk-Ware, R., Blithe, D. L., & Amory, J. K. (2014). Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial. Contraception, 90(4), 407–412. PMID: 24981149. PMCID: PMC4269220
  3. Ilani, N., Roth, M. Y., Amory, J. K., Swerdloff, R. S., Dart, C., Page, S. T., Bremner, W. J., Sitruk-Ware, R., Kumar, N., Blithe, D. L., & Wang, C. (2012). A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. The Journal of Clinical Endocrinology and Metabolism, 97(10), 3476–3486. PMID: 22791756. PMCID: PMC3462927

Novel Progestogenic Androgens for Hormonal Male Contraception

Novel agents, Dimethandrolone (DMA) and 11ß-Methyl Nortestosterone (11ß-MNT), have been developed to have both androgenic and progestational activities, properties that may maximize gonadotropin suppression, while maintaining libido and other androgen-dependent functions. CDP is evaluating two pro-drugs (modified agents) to determine if they suppress testicular T production, while maintaining androgen-dependent functions.

Dimethandrolone Undecanoate (DMAU): Daily Oral Dosing

DMAU is an ester of the active compound DMA. First-in-human, single, oral-dosing trials indicated that the drug was well tolerated and well absorbed when taken with food. Daily oral dosing for 28 days demonstrated effective gonadotropin suppression and inhibition of testicular T production. Androgen-dependent functions (libido, ejaculation, etc.) were maintained and side effects were minimal.

ClinicalTrials.gov Identifiers: NCT01382069; NCT03455075

Status: CDP researchers are evaluating longer use of oral DMAU to demonstrate sperm suppression and recovery in a multicenter, randomized, placebo-controlled, double-blind trial of spermatogenesis suppression after oral administration of DMAU alone or with Levonorgestrel for 12 weeks versus placebo alone in normal men.

11β -Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC): Daily Oral Dosing

11ß-MNTDC is a dodecylcarbonate pro-drug of the active compound, 11ß-MNT. First-in-human single dosing indicated that the drug was well tolerated and well absorbed if taken with food.

Daily oral dosing demonstrated that of 11ß-MNTDC suppressed gonadotropins and inhibited testicular T production while maintaining androgen-dependent functions during a 28-day treatment period.

ClinicalTrials.gov Identifier: NCT03298373

Status: Acceptability and willingness-to-use the method were very high with both DMAU and 11β-MNTDC, confirming in actual use what was projected from surveys based on hypothetical methods. Participants randomized to the active drugs had significantly higher willingness-to-use responses compared with placebo, suggesting a possible benefit to use of the drug. The duration of treatment was effective at inhibiting gonadotropins, but longer treatment is required to demonstrate sperm suppression. Results support further investigation as oral drugs.

DMAU: Long-Acting Injectable

Although studies of oral DMAU appear promising and most men say that they prefer a pill to other delivery methods, a substantial proportion of men would prefer an injectable formulation because it does not require remembering to take a pill every day. First-in-human testing of injectable DMAU dosing is underway. Single injections are evaluated in a dose-escalation design in which each group recovers before the next higher dose injections begin. This approach assures that safety and time-to-recovery are evaluated at a selected dose prior to increasing exposure to a higher level of drug.

ClinicalTrials.gov Identifier: NCT02927210

Status: A dose-escalation study of the safety and tolerability, pharmacokinetics, and pharmacodynamics of injectable DMAU for male contraception administered to healthy male volunteers as a single intramuscular or subcutaneous injection is ongoing, in collaboration with the Los Angeles Biomedical Research Institute and the University of Washington.

Related Publications (from earlier studies):

  1. Yuen, F., Thirumalai, A., Fernando, F. A., Swerdloff, R. S., Liu, P. Y., Pak, Y., Hull, L., Bross, R., Blithe, D. L., Long, J. E., Page, S. T., & Wang, C. (2021). Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β-MNTDC in healthy men. Andrology, 9(5), 1526–1539. PMID: 33908182
  2. Thirumalai, A., Yuen, F., Amory, J. K., Hoofnagle, A. N., Swerdloff, R. S., Liu, P. Y., Long, J. E., Blithe, D. L., Wang, C., & Page, S. T. (2021). Dimethandrolone undecanoate, a novel, nonaromatizable androgen, increases P1NP in healthy men over 28 days. The Journal of Clinical Endocrinology and Metabolism, 106(1), e171–e181. PMID: 33090208
  3. Nguyen, B. T., Yuen, F., Farrant, M., Thirumalai, A., Fernando, F., Amory, J. K., Swerdloff, R. S., Anawalt, B. D., Blithe, D. L., Long, J. E., Liu, P. Y., Page, S. T., & Wang, C. (2021). Acceptability of the oral hormonal male contraceptive prototype, 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), in a 28-day placebo-controlled trial. Contraception, 104(5), 531–537. PMID: 34153318
  4. Nguyen, B. T., Farrant, M. T., Anawalt, B. D., Yuen, F., Thirumalai, A., Amory, J. K., Swerdloff, R. S., Bremner, W. J., Liu, P. Y., Blithe, D. L., Page, S. T., & Wang, C. (2020). Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype. Contraception, 102(1), 52–57. PMID: 32298717. PMCID: PMC7287214
  5. Yuen, F., Thirumalai, A., Pham, C., Swerdloff, R. S., Anawalt, B. D., Liu, P. Y., Amory, J. K., Bremner, W. J., Dart, C., Wu, H., Hull, L., Blithe, D. L., Long, J., Wang, C., & Page, S. T. (2020). Daily oral administration of the novel androgen 11β-MNTDC markedly suppresses serum gonadotropins in healthy men. The Journal of Clinical Endocrinology and Metabolism, 105(3), e835–e847. PMID: 31976519. PMCID: PMC7049261
  6. Thirumalai, A., Ceponis, J., Amory, J. K., Swerdloff, R., Surampudi, V., Liu, P. Y., Bremner, W. J., Harvey, E., Blithe, D. L., Lee, M. S., Hull, L., Wang, C., & Page, S. T. (2019). Effects of 28 days of oral dimethandrolone undecanoate in healthy men: A prototype male pill. The Journal of Clinical Endocrinology and Metabolism, 104(2), 423–432. PMID: 30252061. PMCID: PMC6306388
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