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. High testicular testosterone concentrations are needed to support sperm production; substantially lower testosterone levels in serum are sufficient to maintain other androgen-dependent functions. Reversible contraception can be achieved by giving exogenous hormones that suppress secretion of hypothalamic-pituitary hormones, which stimulate testicular testosterone production. Taking a progestin can suppress testicular testosterone and stop sperm production. Exogenous testosterone is required to replace normal blood levels to maintain other androgen-dependent functions.

The challenge that has prevented development of a male pill is that oral testosterone is cleared very rapidly, requiring multiple doses per day. Successful approaches have used progestins (oral, injectable, or implants) to achieve sperm suppression consistent with contraceptive effectiveness (sperm <1 million/ml) and testosterone 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®/Testosterone (Nes/Tes) Gel

Daily Transdermal Application

CDP research demonstrated that a potent progestin, Nestorone®, delivered in a gel formulation, caused gonadotropin suppression with resultant inhibition of testicular testosterone production. Daily application of Nestorone® and testosterone gels suppressed sperm production but maintained other androgen-dependent functions.1,2 All men recovered normal sperm production after treatment ended. Inhibition of spermatogenesis, followed by recovery, indicates that the regimen may be effective and reversible for male contraception.

Status: Program researchers, in collaboration with The Population Council, are moving to the next step: testing the combined Nes/Tes gel for contraceptive effectiveness in couples who are willing to use this method for pregnancy prevention. Enrollment is anticipated to begin in mid- to late 2018 at selected CCTN sites in the United States, United Kingdom, Sweden, Italy, Chile, and Kenya.

ClinicalTrials.gov Identifier: NCT03452111

Related Publications (from earlier studies):

  1. Roth MY, Shih G, Ilani N, Wang C, Page ST, Bremner WJ, Swerdloff RS, Sitruk-Ware R, Blithe DL, Amory JK. Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial. Contraception. 2014; 90(4):407-412. PMID: 24981149. PMCID: PMC4269220.
  2. Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Wang C. A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. The Journal of Clinical Endocrinology and Metabolism. 2012; 97(10):3476-3486. PMID: 22791756. PMCID: PMC3462927.

Novel Progestogenic Androgens for Hormonal Male Contraception

Novel agents, Dimethandrolone (DMA) and 11ß-Methyl Nortestosterone, 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 testosterone 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 tests 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 testosterone production. Androgen-dependent functions (libido, ejaculation, etc.) were maintained and side effects were minimal.

Status: CDP researchers are evaluating longer use of oral DMAU to demonstrate sperm suppression and recovery in the Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of Spermatogenesis Suppression After Oral Administration of DMAU Alone or with Levonorgestrel (LNG) for 12 Weeks versus Placebo Alone in Normal Men.

ClinicalTrials.gov Identifier: NCT03455075

Long-Acting Injectable

Although studies of oral DMAU appear promising, and most men say that they prefer a pill to other delivery methods. However, 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.

Status: A dose-escalation study, Injectable DMAU for Male Contraception: Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of Single IM or SC DMAU Injection Dose Escalation Study in Healthy Male Volunteers, is ongoing, in collaboration with the Los Angeles Biomedical Research Institute and the University of Washington.

ClinicalTrials.gov Identifier: NCT02927210

Related Publications (from earlier studies):

  1. Ayoub R, Page ST, Swerdloff RS, Liu PY, Amory JK, Leung A, Hull L, Blithe D, Christy A, Chao JH, Bremner WJ, Wang C. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology. 2017; 5(2):278-285. PMID: 27907978. PMCID: PMC5352517.
  2. Surampudi P, Page ST, Swerdloff RS, Nya-Ngatchou JJ, Liu PY, Amory JK, Leung A, Hull L, Blithe DL, Woo J, Bremner WJ, Wang C. Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. Andrology. 2014; 2(4):579-587. PMID: 24789057. PMCID: PMC4069217.

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

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

Status: Daily oral dosing for 28 days in the 28-Day Repeat-Dose, Dose Escalation Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics Study of 11β-MNTDC in Healthy Men study is ongoing to determine if 11ß-MNTDC can suppress gonadotropins and inhibit testicular testosterone production while maintaining androgen-dependent functions.

ClinicalTrials.gov Identifier: NCT03298373

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