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‘Tremendous progress’ made in development of male contraceptive
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CHICAGO — At least four hormonal and two nonhormonal contraceptives for use by men are in the clinical pathway, with first-in-man studies begun or completed, and testing for safety, effectiveness and reversibility underway, Diana Lynn Blithe, PhD, announced during a presentation at the Presidential Plenary session here.
“Developing a male contraceptive method is very challenging, but tremendous progress is being made,” Blithe, director of the NICHD Contraceptive Clinical Trials Network and chief of the Contraceptive Development Program at NIH, told Endocrine Today. “[The audience] might be surprised to know there are so many leads in the pipeline.”
Men are already using contraception, Blithe said, but the most effective — vasectomy — is not reversible, and the reversible methods — condoms and withdrawal — are not reliably effective.
“If you can get a drug over the valley of death and into clinical research, if it’s a female contraceptive, at least we have a plan,” Blithe said.
Contraceptives for use by women must be tested over 20,000 menstrual cycles for safety, and 400 women must use the method for 1 year to assess effectiveness.
“But the road to a male contraceptive product is not quite so straightforward,” Blithe said. “We know that we have to identify the drug, but how high is that bar of safety? Men don’t bear that risk for pregnancy or childbirth so that risk-and-benefit relationship is a little bit harder to calculate.”
Nonhormonal methods in the works include bromodomain inhibitors and a retinoic acid pathway, Blithe said. Bromodomain proteins regulate apoptosis, migration and evasion in cells, and their overexpression can lead to cancers. Antitumor inhibitors have shown promise in cancer trials, and BRDT, a testis-specific inhibitor of a bromodomain involved in spermatogenesis, is being investigated as a reversible contraceptive.
“This work is ongoing and shows great promise,” Blithe said.
Another compound in the group referred to as BDADs was explored as a possible male contraceptive in the 1950s, but the agent had unacceptable side effects. A similar BDAD is being examined currently and shows promise, Blithe said.
Hormonal methods of preventing spermatogenesis currently under investigation include a topical gel combining progestin and testosterone that has been shown to fully suppress sperm production in 90% of trial participants by 12 weeks of daily use and is fully reversible, Blithe said. Researchers will next recruit 420 couples to use the method for 1 year, with cumulative pregnancy rate as the primary endpoint.
Two agents are under investigation as possible contraceptive pills or capsules for men.
“We’re looking for safe, orally active, lasts for 24 hours so it can be a single dose,” said Blithe. “So, we’re going to ask the questions: Does the progestin activity shut down the gonadotropins and the endogenous testosterone production, and does the androgen activity maintain androgenic function?”
Dimethandrolone undecanoate (DMAU) and 11beta-methyl-nortestosterone-dodecylcarbonate are good candidates, Blithe said. The next stage of testing for these agents is to recruit participants for daily oral use for 28 days to evaluate safety and side effects, with effectiveness trials to follow.
A first-in-man study has recently begun evaluating DMAU as a monthly or longer-term injectable agent in castor oil, Blithe said.
“More than half of men asked say they would be willing to use a male contraceptive method,” Blithe said. “When you ask them, ‘How would you like that contraceptive to be delivered?’ most say they would like a pill. But a lot of them say they would be willing to use an injection or an implant or a gel.”
And, Blithe said, describing a recent discussion she had with university students, “Everyone likes to talk about male contraception, and the young women indicated particularly to the young men that they would be more interested in a man who was using male contraception.” – Jill Rollet
Reference:
Blithe, DL. PL01. Presented at: The Endocrine Society Annual Meeting; March 17-20, 2018; Chicago.
Disclosure: Blithe reports she has a financial relationship with HRA Pharmaceuticals.
Perspective
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Glenn R. Cunningham, MD
The FDA approved the first oral hormonal contraceptive for women on May 9, 1960. However, condoms and coitus interruptus remain the only reversible forms of male contraception in April 2018, and neither is as effective as oral contraceptives are for women. Development of a safe, reliable and reversible male contraceptive has proven difficult. Moreover, the pharmaceutical industry has been reluctant to engage in this effort.
Administration of testosterone to fertile men will suppress spermatogenesis, but reliable contraception requires that sperm counts be suppressed to 1 million/mL semen or lower. Suppression of sperm counts by testosterone alone is less effective in white than in Asian men. Greater suppression is achieved when a progestin is coupled with testosterone. The progestin provides additional and more complete suppression of gonadotropins, intra-testicular testosterone and spermatogenesis. Exogenous testosterone is required to maintain androgenic functions.
Most men would prefer daily oral administration of testosterone and progestin; however, testosterone, per se, is rapidly metabolized by the liver when it is administered orally. When testosterone is given with oil and administered orally in a capsule, it is absorbed by the lymphatics in the gut, bypassing metabolism by the liver. Transdermal and injectable routes of administration also are effective, but less acceptable to most men. The Contraceptive Clinical Trials Network (CCTN) is preparing to determine the contraceptive efficacy of a transdermal gel containing testosterone and Nesterone, a 19-nor-progestin that does not bind to androgen receptors.
Some derivatives of 19-nor-testosterone have affinity for both androgen and progesterone receptors, and they can be given orally. The CCTN is exploring the possibility that a derivative of 19-nor-testosterone can provide sufficient progestin activity to suppress gonadotropins, intra-testicular testosterone and spermatogenesis and also maintain normal androgenic effects. This is an intriguing approach, but these studies remain in the early phases.
Limitations of using hormonal agents for male contraception include the time that it takes to adequately suppress spermatogenesis and the time required for recovery. Although there is considerable biological variability, most studies indicate a minimum of 3 months before sperm counts are suppressed sufficiently to ensure contraception and at least that long before fertility can be restored when the contraceptive is stopped.
The male reproductive process may be susceptible to agents that impair fertility by disrupting spermatogenesis or by agents that impair sperm maturation in the epididymis. Theoretically, such agents would act more quickly, and fertility would be restored more quickly. Obviously, they would have to be selective and safe. At this time, hormonal approaches to male contraception appear closer to reality.
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