A step towards a contraceptive pill for men?
A fast-acting, time-limited drug shows promise in male mice
HOW OFTEN does locker-room talk involve nuanced discussion of the various types of contraceptives available, and the merits and difficulties associated with them all? In women’s locker rooms, the answer is “surprisingly frequently”. In men’s, “hardly ever”. Contraception has long been an overwhelmingly female issue.
At least in part, that is because men have little to discuss. Their choice is between condoms and vasectomy. Women, by contrast, may pick from a range which includes the Pill, vaginal rings, copper intrauterine devices, hormonal intrauterine devices, contraceptive sponges, cervical caps, spermicides, diaphragms, female condoms and tubal ligation. For decades, therefore, researchers have hunted for ways to level the playing field by extending men’s options. But none of the resulting injections, gels and hormonal pills has so far advanced beyond clinical trials.
Jochen Buck and Lonny Levin, who work at Weill Cornell Medicine, in New York, have now entered a new runner into the race. Their candidate, rather than requiring the consistent and long-term application associated with pills and gels, is fast-acting and temporary. In a paper published in Nature Communications they show that, in mice at least, it works within half an hour, rendering the animals temporarily infertile by stopping their sperm swimming, but with no perceptible changes in their behaviour or sexual performance. Importantly, within a day, their fertility returns.
The substance concerned, TDI-11861, belongs to a class of molecules called soluble adenylyl cyclase (sAC) inhibitors. sAC itself is found in nearly every body cell. It is a source of a messenger molecule called cAMP, and its activity is regulated by bicarbonate ions. A preponderance of those ions speeds up the rate at which sAC produces cAMP. A dearth slows it down.
The concentration of bicarbonate varies little from tissue to tissue with one notable exception. In the epididymis, the tube in which mature sperm are stored, it is a fifth of the usual level. The significance of this is that, at ejaculation, a tiny pellet of sperm is pushed forward and mixed with seminal fluid, suddenly quintupling the bicarbonate concentration. That causes sAC to produce a bunch of cAMP.
This increase in cAMP then activates the sperm, and lets them start swimming and searching for an egg to fertilise. TDI-11861 blocks the places on sAC where bicarbonate would normally bind, rendering it unresponsive to this rapid change in concentration. That stops them swimming.
Although TDI-11861 inhibits sAC everywhere in the body, Dr Buck and Dr Levin say this is not a cause for concern. Some men lack functioning sAC because of a mutation. That results in infertility and a slightly raised incidence of kidney stones, but otherwise they are completely normal. So, while sAC appears to be a unique link in the chain of sperm mobilisation, the body has built plenty of redundancy into its means of generating cAMP.
Whether Dr Buck’s and Dr Levin’s discovery will actually prove to be the long-sought breakthrough in the search for a Pill for men remains to be seen. More animal tests will be needed before trials on people can go ahead. The two researchers are, however, already looking at other sAC-inhibiting compounds, to determine which performs best.
One approach they use is X-ray crystallography, which shows how molecules fit together at an atomic level. With it, they have improved how well their compound binds to the right spot on sAC, and stays there—and they hope to do better still.
Right now, men have less control over family planning than women do, and sometimes feel little responsibility for it. That is surely not unconnected with the fact that, according to the United Nations Population Fund, nearly half of pregnancies—121m each year—are unplanned. “This”, Dr Levin says, referring to sAC inhibition, “gives men the ability to be a partner.” Who knows? Some of them might even give it a try. ■