ATLANTA — Phase 1 results from ENDO 2022 have shown that potential once-daily male oral contraceptives have cleared a first clinical hurdle. They showed a level of testosterone suppression sufficient to produce a contraceptive effect, without causing symptomatic hypergonadism.
Tamar Jacobsohn
Two pills are currently in development. The studies suggest that either one or both of the two might provide an acceptable balance of efficacy and tolerance, according to Tamar Jacobsohn (BS), a researcher in Contraceptive Development Program, Eunice Shriver National Institute of Child Health and Human Development in Bethesda.
The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both drugs are bifunctional and have both androgenic as well as progestogenic properties. Prodrugs should be cleaved immediately after ingestion to release active hormones over 24 hours. This allows for once-daily dosing.
Jacobsohn explained that these steroids are potent androgens. They suppress gonadotropin secretion which leads to markedly decreased serum testosterone production.
She noted, however, that this research is still in its infancy. The phase 1 trials have demonstrated that the pills are safe and effective. However, due to the biology of suppressing sperm formation, men will need to use these pills every day for approximately 3 months starting with contraceptive treatment. After that, adequate sperm suppression can be achieved.
She noted that while we are working towards a phase 2 trial with a contraceptive efficacy endpoint in it, there are many steps to get there.
Arthi Thirumalai MBBS, an assistant professor of medicine at University of Washington School of Medicine, Seattle, stated that there is a significant unmet need for male contraceptive methods.
Dr Arthi Thirumalai
Thirumalai, senior author of a 2020 review paper on male contraception, stated in an interview that hormonal methods to lower testosterone levels and suppress sperm formation are appealing due to their ease of use, efficacy and reversibility.
Thirumalai, a participant in numerous clinical and experimental studies on male contraception methods, stated that “we hope that oral formulations are possible to address this need.” Jacobsohn actually has many coauthors who have provided data.
Jacobsohn stressed that “Development and use of an effective, reversible method for male contraception will improve reproductive options and women’s health, decrease unintended pregnancies, and allow men to take an increasing active role in family planning.”
Phase 1 studies revealed that both MNTDC and DMAU might offer sufficient hormone suppression to decrease sperm count without causing hypogonadism symptoms. Each drug was subject to a phase I study with varying doses. The endpoint for testosterone suppression was determined.
The two placebo-controlled Phase 1a studies were presented as a poster Monday. Healthy male subjects were randomly assigned to either two pills of active treatment, four pills, or placebo. The combined study resulted in 39 subjects receiving DMAU, 30 receiving 11b-MNTDC and 28 receiving placebo.
Testosterone levels were used to evaluate efficacy. The majority of the patient questionnaires were used to determine tolerance.
The testosterone levels in the placebo group remained constant at 400 to 600 ng/dL after 7 days. All subjects who were given active agents, regardless of dose or agent, had levels below 100 ng/dL.
Jacobsohn reported that there was less testosterone suppression on 200 mg and 400 mg daily from day 7 to 28 (92.7 ng/dL) compared with 49.6 (P.001). However, both levels remained below the target of 100ng/dL.
Tolerability was not affected by the degree of testosterone suppression.
Jacobson presented P values of these outcomes for subjects who received active therapy relative to placebo. These numbers ranged from 0.48 to 0.85.
There were no adverse effects. She said that hypogonadism had mild side effects, but they were “all resolved by end of study.”
Thirumalai stated that a male contraceptive is needed. She said that although condoms have a high failure rate, vasectomy can be reverted even if most men agree that it is possible to prevent pregnancy.
Thirumalai’s previous review article revealed that at least 30 years have passed since clinical trials of hormonal suppression for male contraception. Finding an effective treatment that is well tolerated has been the challenge.
The answer may lie in drugs that combine progestogenic and androgenic activity. The manipulation of hormones that lower testosterone can reduce sperm production without affecting a man’s ability ejaculate. According to Thirumalai’s review, zero sperm production does not seem to be the goal.
Studies suggest that ejaculate containing less than 1,000,000 sperm/mL (normally between 15 and 200 million sperm/mL) has an antipregnancy effect similar to female oral contraceptives.
Clinical trials that prove this is possible have not been conducted.
Jacobsohn stated that the sperm half-life lasts about three months. Patients would have to continue hormonal therapy for approximately the same time period before they can achieve reliable contraception.
Jacobsohn stated that although the efficacy endpoint in this study (of 28 days duration) does not guarantee effective contraception, it is an important step in clinical development.
Jacobsohn, Thirumalai do not report any relevant financial relationships.
Annual Meeting of Endocrine Society #ENDO2022: PMON261. To be presented June 13, 20,22.
Follow us on Twitter or Facebook for more endocrinology and diabetes news
