Belly gel, ultrasonic sperm, and forgetful testicles: the search for a male contraceptive continues

by Lindsay Miller on October 12, 2012

For decades, scientists have struggled to develop an effective and reversible form of male contraception. Currently, men have five main birth control options: abstinence, condoms, “outercourse” (google it), vasectomy, and withdrawal. So men who want to have complete, penetrative, vaginal intercourse really only have two main contraceptive options for themselves: condoms and vasectomy. Condoms, as they are typically used, are only about 82% effective. That is, over the course of a year, 18% of sexually active women whose partners use condoms in a “typical” manner will become pregnant. Vasectomy, a surgical procedure in which the tubes that carry sperm are tied or sealed, is almost 100% effective; however, it requires a greater up-front expense, carries the risk of surgical complications, and may not always be (affordably) reversible.

So, economic and social considerations aside, why don’t we have a male birth control pill yet?

Image courtesy of dream designs / FreeDigitalPhotos.net

Well, for starters, there are a lot of sperm to “stop.” During their reproductive years, men are continuously producing sperm, and in large quantities too. It is estimated that men’s bodies produce around 1,500 sperm cells every second. Yes, that’s right, every second. On average, each ejaculation contains roughly 100 million sperm per millileter, which means about 200-600 million sperm per ejaculation depending on the volume.

Hormonal methods (1) of male birth control have been moderately successful, but still there exist many drawbacks. These methods (and the forms in which they are typically delivered) can lead to a host of short-term side effects–like pain from the injection or skin irritation from the gel–as well as long-term side effects–such as suppression of HDL (the “good” cholesterol). Hormonal methods also fail to suppress sperm production in some men, so it would not be an effective option for all men.

Ultrasound (2), a non-hormonal method, was proven successful in reducing sperm count and motility, but not all studies of ultrasound as a male contraceptive have demonstrated reversibility. Moreover, those who receive the ultrasound treatment have no feasible or concrete way of knowing when the sperm-reducing effect is wearing off.

The RISUG involves an injection of a synthetic polymer into the vas deferens, or the “sperm ducts.” Image courtesy of Microsoft Image Gallery

RISUG (Reversible Inhibition of Sperm Under Guidance), recently touted as the “best birth control in the world,” is nearly 100% effective, fully reversible, and already approved in several countries. But, like vasectomy, it involves a surgical procedure, albeit a minor one, which may be a deterrent for some men.

So the search has continued…

Earlier this year, scientists stumbled upon a new approach. The best part is that they weren’t even trying…to find a male contraceptive, at least. The small molecule “JQ1” (named after the scientist who discovered it, Ju Qin) was initially studied and developed as an inhibitor of the Brd4 gene, which codes for the “bromodomain-containing 4″ protein, or BRD4. The suppression of the Brd4 gene by JQ1 has proven effective in stopping growth and division of cancerous acute myeloid leukemia (3) cells.

Scientists Matzuk and Bradner went on to test whether or not JQ1 could serve as an inhibitor to other members of the bromodomain-containing protein family, particularly the bromodomain testis-specific protein (BRDT). The BRDT protein plays a role in the remodeling of chromatin in sperm cells, a process which is crucial for the production of healthy sperm. As the researchers (4) had anticipated, mice that were injected with JQ1–which inhibits the BRDT protein– had a 90% reduction in sperm count and, of the remaining sperm, all but 5% had impaired motility.  It’s almost as though JQ1 makes the testicular proteins “forget” how to produce quality swimmers!

So what makes this finding especially exciting for those in the male birth control business?

1) JQ1 didn’t cause any harmful side-effects in the mice, and it had no negative effect on mating behaviors or testosterone levels.

2) The effects of JQ1 were reversible. Once mice were no longer being injected with JQ1, they regained their full fertility.

3) The estimated dosage of JQ1 required for humans is small enough that it could be delivered in the form of a small pill, which would make it a painless and potentially desirable form of birth control.

But things that sound too good to be true usually are, and this seems to be the case here, as well. Firstly, the study was preliminary and only performed on a small sample of mice. Secondly, since JQ1 binds to a variety of bromodomain-containing proteins, it is not specific enough to only target the testis-specific bromodomain-containing proteins involved in the production of sperm. And ultimately, the long-term effects of many of these experimental male contraceptives are still unknown.

Looks like it may be a while before we see men with their little black pill packs.

 

 

Sources:

(1) Page, S.T., Armory, J.K., & Brenmer, W.J. (2008). Advances in male contraception. Endocrine Reviews, 29, 465-493.

(2) Tsuruta, J.K., Dayton, P.A., Gallippi, C.M., O’Rand, M.G., Streicker, M.A., Gessner, R.C., Gregory, T.S., Silva, E.J., Hamil, K.G., Moser, G.J., Sokal, D.C. (2012). Therapeutic ultrasound as a potential male contraceptive: power, frequency and temperature required to deplete rat testes of meiotic cells and epididymides of sperm determined using a commercially available system. Reproductive Biology and Endocrinology, 10(7).

(3) Zuber J., Shi J., Wang E., Rappaport A.R., Herrmann H., Sison E.A., Magoon D., Qi J., Blatt K., Wunderlich M. (2011). RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature, 478:524–528.

(4) 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.

Elizabeth Fryer October 12, 2012 at 2:58 pm

Wow. What research. It is amazing that there is not a male birth control. There hasn’t been a political push for one, as historically “it’s the woman’s job to take care of that kind of stuff (said by a man wearing a smirk, with a beer in one hand and a cigar in the other).”

I really found this so interesting—though my hopes were dashed when I got to the “too good to be true” paragraph.

It’s a pleasure to read your writing because you punctuate so well.

Keep it up. :)

Robyn Sussel October 14, 2012 at 5:23 pm

Well done Lindsay. My only bit of constructive criticism would be to go for a shorter title. Just “The Search for Male Contraceptive Continues” may have been enough…

Liz Borkowski October 15, 2012 at 5:31 pm

Fascinating post! And you did a great job giving a reality check about how close we really are to the male contraceptive ideal.

One thing that’s implicit in your post and that it might be worth making explicit is what the ideal male contraceptive will be like. It probably can go without saying that we want it to be safe and effective, since that’s the aim for all drugs. But you also seem to assume that reversibility is a desired characteristic of birth control, but I suspect that some people (e.g., couples who already have as many kids as they think they can handle) would prefer a permanent fix that doesn’t involve surgery. If scientists are directing their attention mainly to contraceptives that work on a temporary basis, it might be worth mentioning their rationale for doing so.

I also wonder if the ideal male contraceptive would really be something that requires remembering to do something (e.g., take a pill) every day – did any of the researchers discuss the pros and cons of different dosing schedules?

Margaret October 16, 2012 at 8:30 pm

Lindsay,
Interesting article. I know I have had this conversation with men before. What kind of birth control would they accept? Oddly enough most of them would not accept one that messed with their hormones. Which is what women have had to deal with if they wanted birth control.

Thanks for making me think a little today!
Margaret

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