Male contraceptives are gaining momentum

Methods hold potential for greater safety

The first male contraceptives to make it to the market likely will be hormonal-based birth control, similar to what has worked well for female contraceptives for the past four decades. However, there are serious difficulties with hormonal contraceptives for men, so the possibilities that are beginning to excite researchers working in the contraceptive field are the nonhormonal methods.

"We have to consider all of the possibilities," says Deborah O’Brien, PhD, an associate professor at the University of North Carolina School of Medicine in the department of cell and developmental biology in Chapel Hill.

There is a need for a variety of contraceptive options for men and women, she says. "Non-hormonal and post-testicular methods are what we’re shooting for," she says. "We’d like to inhibit sperm specifically and not have side effects elsewhere."

O’Brien has been working on a contraceptive target involving novel sperm glycolytic enzymes.1

"There are two potential advantages of this kind of approach," O’Brien says. "One is they’re expressed only in germ cells, and two, enzymes are considered [potential] drugs by the pharmaceutical industry."

The hypothesis is that glycolysis is required for sperm motility and male fertility; so if a drug could inhibit glycolytic enzymes necessary for the production of sperm, then fertility would be compromised.1

"We have good evidence from studies that if we can eliminate one of the sperm-specific enzymes then sperm are infertile," O’Brien says. "We’ve proved proof of principle that it will work; it’s been done in mice."

O’Brien’s investigations have shown that the germ cell-specific isozyme, glyceraldehyde 3-phosphate dehydrogenase-S can be eliminated, resulting in sperm having no forward motility.1

"Researchers have a good idea of how you would go about designing inhibitors and other kinds of interactions — like protein interactions also are potential targets — but we don’t have drugs yet that work that way," O’Brien says. "We can conceive of ways to inhibit it, but it’s not like having an enzyme or [other products] already targeted in the pharmaceutical industry."

The bad news is that it will take a while to get from this proof of principle to actual male contraceptive drugs, O’Brien notes.

Another potential target for nonhormonal male contraceptives involves ion channels, which control the excitability of cells.

In 2001, Boston investigators discovered an ion channel, named CatSper for cation channel of sperm that was located only in mature sperm in the tail.2

"It was no where else in the body, and it didn’t get put into cell membranes by cells until the sperm were mature," says David E. Clapham, MD, PhD, one of the investigators and an Aldo R. Castaneda professor of cardiovascular research and an investigator at the Howard Hughes Medical Institute and professor of neurobiology at Harvard Medical School and the Children’s Hospital of Boston.

CatSper discovered accidentally

Clapham discovered CatSper by accident since he primarily works in cardiology and neurobiology. When he and co-investigators discovered the ion channel, they tracked it down to discover what it did and found that it was only present in sperm, which seemed to make it an obvious novel target for a contraceptive, he recalls.

"When we knocked out the ion channel in mice, the gene that encoded it, the mice were completely infertile," he recalls. "Then we studied the mice sperm and found they had a small defect in motility, but they’re mainly unable to hyperactivate, which is required for fertilization."

Hyperactivation gives sperm greater force that is needed to penetrate the protective cells around an egg and then penetrate the egg, Clapham points out.

Researchers hypothesize that CatSpers bring calcium into the sperm and that they are used to initiate movement and change of movement of the tail, he says.

"So the significance for contraception is that ion channels are good targets for drugs because they’re on the surface of cells," Clapham explains. "Since this channel is only present in mature sperm, if you blocked it specifically, it would not have effects on any other tissues."

As a specific blocker, the contraceptive would work only on cells that potentially would die or fertilize, so it would have no long-term effect on a man’s reproduction, he adds.

A biotechnology company named Hydra of Cambridge, MA, has licensed this potential target and is working on trying to develop a small molecule blocker of CatSper, Clapham says.

Comparable pharmaceutical solutions are the calcium channel-blocking drugs that are used to treat hypertension, he notes.

"The analogy here would be to find a small molecule that would block only this calcium channel and not any others, and that should block hyperactivation," Clapham explains.

While hormonal contraceptives for men are the furthest along in development, they are not as promising an approach for the long term, he says.

"I think that’s an unlikely approach because I don’t think many men will take a hormone that will affect their fertility for unknown duration and which has other side effects," Clapham says. "You have to worry if it’s going to be reversible and make sure it doesn’t affect your offspring."

All contraceptives have to have a very high safety margin because they’re used for changing a lifestyle and not for treating a disease, and so the approaches that are more likely to affect sperm formation in the long term are riskier, he says.

While research into male contraceptives is a positive development, there already are two male contraceptives that are cheap, safe, and effective, but they’ve been underutilized in the 100 years that they’ve been available: condoms and vasectomy, says Robert Hatcher, MD, MPH, senior author of Contraceptive Technology, and professor of gynecology and obstetrics at Emory University School of Medicine in Atlanta. He is the chairman of the editorial advisory board for Contraceptive Technologies Update.

"In the world today, there are only four nations, the Netherlands, Bhutan, New Zealand, and Great Britain, where more men get vasectomies than women get tubal sterilization in spite of the fact that vasectomy is less expensive, safer, and is the most effective contraceptive of all, and it can be verified with semen analysis," Hatcher says. Condoms have pretty good effectiveness against many sexually transmitted diseases and are very effective against HIV, for example, and they are the only means of preventing infections if you have high-risk couples, Hatcher says. "But what contribution is this method making in the world today?" he says. "In many locations, [it is] minimal, and in some societies, moderate, but in no place is it excellent."

Given the history of men not using condoms and vasectomy as much as they could, Hatcher says he doesn’t see much potential for the new male contraceptives.

References

1. O’Brien DA. Novel sperm glycolytic enzymes as contraceptive targets. Presented at the Future of Male Contraception conference. Seattle; Sept. 29-Oct. 2, 2004.

2. Clapham DE. The CatSper family of sperm-specific ion channels. Presented at the Future of Male Contraception conference. Seattle; Sept. 29-Oct. 2, 2004.