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Men who lack sperm-shielding protein less fertile, study finds

Sperm from men with at least one copy of the gene DEFB126 show up in green on a monitor during research.

Image created by Theodore L. Tollner/Handout

The lack of a protein that normally protects sperm as they travel through a woman's cervix may play a key role in male infertility, according to a new international study co-authored by Canadian researchers.

The protein beta defensin 126 acts as a "Klingon cloaking device" that allows sperm to swim through cervical mucous and eventually join with an egg. Men with a gene mutation lack the protein, called DEFB126 for short, so their sperm have more trouble passing the mucous.

The findings, published Wednesday in the journal Science Translational Medicine, could lead to cost-saving approaches for diagnosing infertility, which affects about 14 per cent of couples worldwide.

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It's been widely estimated that in half of infertile couples the problem lies with the male partner, even though the sperm quality and quantity may appear normal.

"The World Health Organization defines infertility as the inability to conceive after 12 months of attempts in the absence of birth control. Our data suggest the likelihood or probability that couples [who]are unable to conceive in the 12-month window will increase significantly if men lack the normal gene for DEFB126," says Gary Cherr, senior author and professor of toxicology and nutrition at the University of California, Davis.

Observed under a microscope, sperm from men with the defective DEFB126 genes looked and swam like normal sperm but were far less adroit at breaking through an artificial gel designed to resemble human cervical mucous. When the protein was added to the semen, the sperm recovered their normal abilities.

The study, which involved DNA samples from men in the U.S., Britain, Japan, Africa and China, showed that half of them carried one defective copy of the mutation; a quarter had two defective copies.

The researchers also followed 500 newly married Chinese couples as they tried for their first child over 22 months.

"The rate of births among couples with the husband who had two copies of the DEFB126 mutation was 30 per cent lower than in the other couples in the study," said Scott Venners, assistant professor of health sciences at Simon Fraser University in British Columbia.

Still, some of the couples were able to overcome the mutation, conceiving just a little later than their unaffected counterparts.

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"If men have this mutation but they have very high sperm counts and very good quality sperm with good motility, there may not be much of an effect or very minor effect; essentially they can overcome the mutation," Dr. Cherr explained.

"However, if these men have marginal sperm counts and poor motility or poor morphology, then there may be a very dramatic impact if they also have this gene mutation."

Add to that other infertility factors - anti-sperm antibodies in the female, and menstrual cycle irregularity - and "the probability of conceiving within 12 months becomes increasingly small."

The researchers envision a home kit for determining the absence of DEFB126.

"Such a development," Dr. Cherr said, "would enable couples who are trying to become pregnant … to bypass extended clinical workups," and go directly to treatment such as artificial insemination, which involves injecting sperm into eggs removed from the woman, saving them the journey through the cervical mucous.

Ultimately, the researchers hope for treatment that would see DEFB126 added to defective sperm.

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"Then these sperm could be used either for artificial insemination, or perhaps even a home kit could be developed where the protein could be concentrated in a vaginally applied cream or gel. In this way the sperm would pick up the defense as they advanced into the cervix," said Dr. Cherr.

As for why so many of the men studied lacked the protein, the researchers suggest human sperm is typically of poorer quality than that of more promiscuous monkeys and mammals. Since humans breed mostly in long-term, monogamous relationships, less competition means sperm quality isn't as critical.

"As you move into primate groups where there is less competition from the standpoint of males per ovulation cycle, and you have males and females that ... select one another for a long period of time, then you do see sperm quality start to decrease," said Theodore Tollner, another study author and adjunct assistant professor of obstetrics and gynecology at UC Davis.

The researchers think their findings are particularly crucial given that human male fertility has declined worldwide in recent decades. While the gene mutation popped up in many countries and appeared to be quite old, new environmental stressors such as chemical exposure are being added to the mix, Dr. Cherr said.

"This is where this gene mutation may really be quite important with these other stresses layered on top."

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