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Female Hormone Could Be Key to Male Contraceptive

Progesterone-sensing molecule that guides sperm to egg offers fertility solution.

By Ewen Callaway

A sperm's path to an egg is more a deadly obstacle course than a track sprint. The one ejaculated sperm cell in a million that is lucky enough to reach the fallopian tubes, where eggs await fertilization, must conquer thick, gelatinous layers of mucus and cells surrounding the egg to reach its prize.

Fortunately for the sperm, there is help. Two studies published today in Nature show how sperm sense progesterone, a female sex hormone, that has been released by cells surrounding the egg. The hormone may guide the sperm towards the egg as well as giving it a final push to get there, the research suggests. The findings could be used to design a new class of contraceptive drug.

"It really is a significant step forward in terms of how we understand what regulates sperm," says Steven Publicover, a reproductive biologist at the University of Birmingham, UK, who was not involved in either study.

In some previous experiments, ejaculated human sperm have been shown to swim towards areas with high levels of progesterone. The hormone also causes the cells to beat their whip-like tails more powerfully to make it through to the egg, a condition called hyperactivity. "We've got good reason to think that the response to progesterone matters, but it's bloody difficult to pin it down," says Publicover.

Changing channel

The latest studies, led by independent teams in Germany and the United States who agreed to publish their findings simultaneously, show that progesterone activates a molecular channel called CatSper, which floods sperm cells with calcium.

Mice without the channel are infertile, as are some men with mutations in the genes that make it, says Polina Lishko, a reproductive biologist at the University of California, San Francisco, who led one of the studies2. Sperm that don't make CatSper cannot become hyperactive.

Lishko and Kirichok's team developed a way of measuring the electrical currents within sperm that are created by ions like calcium, similar to how neuroscientists record the electrical activity of neurons. They found that adding progesterone to ejaculated human sperm boosts the current, and that treating sperm with drugs that block CatSper reduces it. Putting the cells into high-pH environments, like those found around the egg, also activated CatSper. A combination of high pH and high progesterone had an even stronger effect.

A second team, led by Benjamin Kaupp, a biophysicist at the Center of Advanced European Studies and Research in Bonn, Germany, came to the same conclusion in their own experiments. They also measured calcium levels within human sperm, and found that the effects of administering progesterone are almost instantaneous. Kaupp says that this quick action leaves little time for traditional molecular-signaling pathways to act, and suggests that CatSper itself detects the sex hormone and causes calcium levels to rise.

Problems with progesterone sensing could explain some cases of infertility, says Kaupp. "It could be that some eggs do not produce enough progesterone, or that some sperm are not as sensitive to progesterone as others."

Yet there would be little demand for infertility drugs that activate CatSper, says Kaupp, because infertility is already well-addressed by in vitro fertilization. More promising, say researchers, are drugs that stymie conception by hindering the channel's ability to sense progesterone -- or to work at all.

"The consequence for humans is that if you could block CatSper it would be an ideal contraceptive," says David Clapham, a biochemist at Children's Hospital Boston in Massachusetts, whose team discovered the channel and are looking for drugs that inhibit it. Sperm are the only cells known to make CatSper, so such a drug is unlikely to have many side effects. It would also, presumably, work regardless of whether it is men or women who take it because it could act on sperm regardless of their location, adds Lishko.

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