Male oral contraceptive may be on its way

Research published in the journal Cell this week suggests that a viable equivalent of the female oral contraceptive pill could be on the horizon for men. In vivo trials in mice and in vitro experiments with human cells have provided encouraging signs, fuelling hopes that a reliable alternative to condoms and vasectomies may become available in the not-too-distant future.

Professor Martin Matzuk from Baylor College of Medicine was involved in the study, along with lead author Dr James Bradner of the Dana-Farber Cancer Institute. I asked Professor Matzuk some questions about the research he and his colleagues are conducting, beginning with the issue of why it has proven so challenging to develop pharmacologic contraceptives for men.

"One of the reasons that the oral contraceptive pill for women has been successful is that the pill blocks the normal hormonal cycling in a woman," he started. "This causes a block in the normal ovarian process and prevents development and release of the oocyte, or egg, from the ovary. In addition, during each monthly menstrual cycle in a woman, only one oocyte is released."

In men, although hormones are important for fertility and masculinity, there is no equivalent of this cycling. Previous attempts to develop male contraceptives have largely focused on hormonal approaches or surgical interventions, with the latter usually irreversible and the former difficult to balance in terms of efficacy and side effects. There are many issues that must be addressed for a male ‘pill’ to be effective.

"Although giving testosterone-like drugs to men can affect fertility (and this is one form of contraception that is being developed), these drugs are not perfect at inducing a contraceptive effect," Professor Matzuk explained. "In addition, men produce millions of sperm each day, and therefore a male contraceptive must block this continuous daily onslaught of sperm from making their way into semen. Lastly, if you want the contraceptive drug to affect the more mature male germ cells, the drug must pass a physical boundary called the blood-testis boundary."

The tests carried out by Professor Matzuk and his colleagues tackle the problem from a new angle by targeting bromodomain testis-specific protein (BRDT) which is essential for fertility.

"In our current approach, as described in Cell, we were fortuitous to start with a drug that we believed would target BRDT, a protein which is specifically expressed in the male germline. This is the first example of a non-hormonal approach focused on the spermatogenic cells in the testis."

The drug Professor Matzuk refers to is a small molecule called JQ1, the BRDT-inhibiting effects of which resulted in the production of fewer and weaker sperm when administered to male mice. The author outlined the positive aspects of these results and why they are so promising.

"In our case, the treatment of mice reduced both sperm number and sperm motility, thereby having a double edged effect on the sperm. Another key factor is that we show that JQ1 is fairly safe in mice, and the effects of JQ1 are reversible.

"The drug is very effective and the effects are reproducible. Every animal that received JQ1 in our study showed an effect. In addition, it was reversible for every animal tested."

Significantly, the molecule was not seen to affect the libido or behaviour of the male mice it was trialled on. Nor did it have any apparent adverse effects on their offspring in mating studies which were carried out. The team is hopeful that the method will be readily translatable for human use.

"Our studies are proof-of-principle that BRDT is an excellent target and a drug such as JQ1 could block its function in vivo," Professor Matzuk stated. "Although our in vivo studies were performed in mice, our in vitro studies in the paper showed that the drug JQ1 bound with high affinity to the human BRDT protein. Thus, our studies with the human protein convinced us that any findings in mice would be efficacious in men. Furthermore, the mouse and human BRDT show high conservation."

If an effective, reversible, male oral contraceptive is developed, it could see a profound effect on the rate of unplanned pregnancies, but Professor Matzuk cautions that JQ1 is a lead compound and by no means the pill for men. Further work will be needed before a pharmacologic male birth control based on these findings can reach the market.

"Because our drug binds to some BRDT-related proteins, our goal is to develop a pill that blocks only BRDT (ie, is selective for BRDT) and has fewer theoretical side effects," he said. "This is the goal of our research now. Any selective drugs that are developed by our group would also need to be tested in other in vivo trials, including clinical trials in men."