An oral contraceptive for men, or a male version of the pill, is currently unavailable, but scientists are poised to finally deliver one that is safe and effective1, 2. In August, a research team led by Dr. James E. Bradner published a paper in the journal Cell reporting that the drug JQ1 blocks sperm production in male mice and may be suited for human trials.
Sperm production in humans and other mammals is known as spermatogenesis. In the past, scientists investigating potential male pills have disrupted spermatogenesis via hormone regulation, often by targeting testosterone levels. The best of these treatments successfully lower sperm count, but also produce side effects because they alter hormone levels that are crucial for the health of many male tissues. Recently, scientists have changed their approach to identify a marketable male pill: instead of looking for ways to alter hormone levels, they seek a drug that will bind and repress the activity of a protein located only in the testes and devoted solely to spermatogenesis.
Using this approach, Dr. Bradner’s team identified a protein called BRDT as a target because it is essential to spermatogenesis and is located only in the testes. After studying an array of available drugs, they earmarked JQ1 as a likely inhibitor of BRDT and thus a strong candidate for the male pill.
JQ1 was originally identified as a treatment option for cancers including those of the breast, prostate and colon, among others3, 4. Dr. Bradner’s team was the first research group that recognized JQ1’s potential to be a type of male birth control. Experiments support their hypothesis: it does bind to BRDT in a manner that blocks sperm production. Dr. Bradner’s team found that mice treated daily with this drug over a period of six weeks have an 89% lower sperm count than untreated control mice. The treated mice also have decreased sperm motility and testes mass. Significantly, their hormone levels, which are essential for normal health, are unaffected by JQ1-treatment.
Dr. Bradner’s team also performed an eight-month experiment with 14 male mice and 28 female mice to monitor fertility during a period of JQ1-treatment and after treatment ended. The male mice were divided into three treatment groups: the first group (three males) was given a low-dose, the second group (four males) was given a high-dose, and the third group (seven males) was not given the drug. Each male mouse was caged with two females. Encouragingly, Dr. Bradner’s team observed that the low-dose group sired a total of only two pups; male mice on the high-dose regimen sired no offspring; and each of the males not administered JQ1 produced litters of regular sizes (six to nine pups). These data show that JQ1 is an effective contraceptive agent, especially at high-doses.
Importantly, male mice receiving a low-dose regain their fertility one month after treatment ends; male mice receiving a high-dose require two months in post-treatment to regain their fertility. Furthermore, female mice, impregnated by male mice that are far enough into post-treatment so as not to experience contraception, have normal litter sizes. The pups of these litters are healthy and grow to be fertile adults; they are indistinguishable from the offspring of control males.
Male mice treated with JQ1 do not incur permanent physical changes: sperm count, sperm motility, testes mass and fertility return to normal within weeks during post-treatment. However, the possibility of long-term effects has not been completely disproved, and the dose-level required to sustain infertility is unacceptably high. These results spur Dr. Bradner’s team to continue studying the safety of JQ1. Currently, they are modifying the drug for enhanced specificity towards BRDT and thereby a decreased dose-requirement to achieve infertility and an increased likelihood of efficacy in clinical trials with humans.
Scientists could jump the queue and gain early insights to JQ1’s contraceptive effect next year when it is scheduled to enter human clinical trials as an anti-cancer drug. In the meantime, stay tuned; a male pill could be unveiled in the near future.
1. Matzuk M.M., McKeown M.R., Filippakopoulos P., Li Q., Ma L., Agno J.E., Lemieux M.E., Picaud S., Yu R.N., Qi J., Knapp S., Bradner J.E. (2012). Small-molecule inhibition of BRDT for male contraception. Cell. 150, 673-684.
2. Kean S. (2012). Contraception research. Reinventing the pill: male birth control. Science. 338, 318-320.
3.Delmore J.E., Issa G.C., Lemieux M.E., Rahl P.B., Shi J., Jacobs H.M., Kastritis E., Gilpatrick T., Paranal R.M., Qi J., Chesi M., Schinzel A.C., Mckeown M.R., Heffernan T.P., Vakoc C.R., Bergsagel P.L., Ghobrial I.M., Richardson P.G., Young R.A., Hahn W.C., Anderson K.C., Kung A.L., Bradner J.E., Mitsiades C.S. (2011). BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 146, 904-917.
4. Toyoshima M., Howie H.L., Imakura M., Walsh R.M., Annis J.E., Chang A.N., Frazier J., Chau B.N., Loboda A., Linsley P.S., Cleary M.A., Park J.R., Grandori C. (2012). Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci USA. 109, 9545-9550.
