New research has shown a promising avenue for creating a male version of ‘The Pill’, but independent experts caution that an effective contraceptive agent for males will still be some years away.
Researchers have identified a compound that may offer the first effective and hormone-free birth control pill for men. The study, published in the journal Cell today, shows that the small molecule makes male mice reversibly infertile without putting a damper on their sex drive. When the animals stop taking this new form of birth control, their sperm rebound and they are again able to sire perfectly healthy offspring.
“This compound produces a rapid and reversible decrease in sperm count and motility with profound effects on fertility,” said James Bradner of the Dana-Farber Cancer Institute, the lead author of the study.
Known as JQ1, the compound developed in the Bradner lab works by targeting a testis-specific protein called BRDT that is essential for fertility. When mice are given the BRDT-inhibiting molecule, they begin producing fewer sperm and those sperm they do produce don’t swim as well.
Mating studies confirm that JQ1 indeed works as effective contraception. Even better, those effects are complete and reversible and without adverse consequences for the animals’ testosterone levels or behaviour. The small molecule also comes without any apparent adverse effects on the males’ future offspring.
“Ever since my wife gave birth to twins a year and a half ago, I’ve been taking a gram a day” Bradner joked in an interview before clarifying that JQ1 was really just the first step in developing a safe contraceptive for men.
“There has not been a new reversible contraceptive for men since the development of the condom, centuries ago,” noted William Bremner from the University of Washington, Seattle in an accompanying commentary in which he refers to Matzuk and Bradner’s contraceptive method as “a breakthrough new approach”.
Our colleagues at the AusSMC collected the following expert commentary. Feel free to use these quotes in your reporting. If you would like to contact a New Zealand expert, please contact the SMC (04 499 5476; email@example.com).
Professor Moira O’Bryan, Senior Research Fellow of the NHMRC and Head of the Male Infertility and Germ Cell Biology Laboratory at Monash University in Victoria, comments:
“This is an exciting report that could have major scientific and social impacts. The authors have shown that administering ‘drug’ JQ1, which targets the way DNA is packaged into developing sperm cells, leads to reversible male infertility. Importantly the mice receiving the drug appear healthy, have normal hormone levels (and therefore behaviour) and are subsequently able to conceive apparently normal pups.
“Mechanistically, JQ1 inhibitors work by inhibiting a protein called BRDT and altering the way in which DNA interacts with its scaffold proteins (histones). This in turn dramatically alters which genes are produced in developing sperm cells and ultimately leads to sperm death. The elegance of the approach used in this study is that JQ1 does not affect the stem cells (spermatogonia) in the testis. As such, following drug removal, sperm production can rebound and fertility will return.
“The strong similarity between sperm production in the mouse and the human, and in particular histone function, suggest that a variation of JQ1 may ultimately result in a human contraceptive. Although there is undoubtedly an urgent need for additional contraceptive options, the path between this paper and a new product is likely to be long. The authors have already indicated that they are producing versions of JQ1 that will be more specific to sperm development. Several doses of drug will need to be tested and the method of delivery improved. Frequent injections are unlikely to be acceptable to many. It is also essential that the safety of any drug be tested first in mice then in other animals over many months, and then that is ultimately tested in small groups of human volunteers. Such a goal is however, well worth the effort.
“The medical and social costs of unplanned pregnancies are enormous and studies from both academics and drug companies have repeatedly shown that there is a strong desire for male-based contraceptives.”
Professor Robert McLachlan, Principal Research Fellow of the NH&MRC and Director of Clinical Research at Prince Henry’s Institute of Medical Research, comments:
“This exciting study has identified a novel target for male contraception that reversibly impairs sperm production in mice. The authors have ingeniously targeted a factor involved in DNA remodelling that is essential for successful sperm production. They have developed a small molecule, a drug called JQ1, that effectively blocks the cell division necessary for normal sperm production.
“The authors claim that for the mice injected with the drug there was no significant toxicity, no effects on testosterone or sexual behaviour, nor adverse effects in the first generation of offspring after reversal from the contraception. Because this system is highly conserved between mouse and man, the authors are optimistic that it would be applicable in humans.
Is it suitable for humans?
“First, there must be a long process of further research in animals. The development of a potential contraceptive is a very long and arduous process leading up to the first human studies.
“Key steps include:
- Extensive animal toxicology to ensure reversibility and specificity of its effect in mice and then in other mammals.
- Not all of the mice had their sperm count reduced to zero. For the drug to be clinically useful it will need to be shown to be (almost) universally effective.
- Despite the reproductive system being highly conserved between mouse and man, proof is needed of its effectiveness in human spermatogenesis.
- At whatever effective dose, research will need to confirm the authors’ assertion that the drug (JQ1) is free of adverse effects on other tissues and that it is fully reversible.
“Validation on a new class of drugs like this will take many years. Ultimately, the compound will need to face the challenge of male contraception efficacy trials involving hundreds of couples over several years in order to assess its true effectiveness. This requires industry partners, who at this point in time have been reluctant to engage in male contraceptive initiatives because of concerns such as side effects, efficacy and the size of the potential market.
“It will be fascinating to see how the drug ( JQ1) evolves, but we know that such pipelines may require 15 years of evaluation and there are many potential pitfalls along the journey.”