Enzyme Essential To Sperm Movement Provides Target For New Contraceptive Approach

The enzyme, known as GAPDS, is essentially the same as an enzyme produced in human sperm. The researchers believe that designing a drug to disable the enzyme might provide the basis for an effective new form of male contraception. Similarly, an understanding of the enzyme and related chemical reactions might lead to insights into treatment for some forms of male infertility.

"Currently, attempts to design a male contraceptive involve manipulating male hormones," said Duane Alexander, M.D., Director of the NICHD. "This finding provides a promising new lead that might allow development of a contraceptive that targets only sperm and doesn't affect natural hormone levels."

Enzymes are chemical compounds that assist a chemical reaction.

The study was funded by the National Institute of Child Health and Human Development of the National Institutes of Health, and will appear in the Proceedings of the National Academy of Sciences Online Early Edition the week of November 15, 2004.

GAPDS, short for Glyceraldehyde 3-phosphate dehydrogenase-S, is a key enzyme in a series of biochemical reactions known as glycolysis. This series of reactions produces ATP, a kind of cellular fuel that supplies energy for the cell's activities. GAPDS is found only in sperm (the final "S" in the acronym stands for sperm) and the precursor cells that give rise to sperm. However, a related enzyme is present in virtually all the cells in the body.

GAPDS is found in the sperm's flagellum, the snake-like tail which whips back and forth to propel the sperm forward. In earlier studies, researchers found that glycolysis played a role in sperm movement, but did not know how much of the total amount of ATP in sperm resulted from glycolysis. Before the current study, most researchers believed that most of the ATP for the tail's movement came largely from cellular bodies called mitochondria, which are thought to generate more ATP than does glycolysis.

In the current study, Dr. Deborah O'Brien, Ph.D., of the University of North Carolina School of Medicine at Chapel Hill and her colleagues sought to determine if sperm require GAPDS and glycolysis in order to move forward and fertilize eggs. Using molecular genetic techniques, they generated a strain of mice that were genetically incapable of producing GAPDS. Although the mice mated normally with receptive female mice, the females did not become pregnant. When the researchers examined sperm from the mice under a microscope, the sperm showed only a slight side-to-side movement, but were incapable of moving forward.

"We were very surprised at this finding," Dr. O'Brien said. "It turned out that almost all of the sperm's motility and ATP production depended on this enzyme."

At this point, the researchers know that sperm lacking GAPDS can not swim forward toward the egg, but they did not conduct studies to determine whether the GAPDS-deficient sperm could fertilize eggs with which they are placed in contact.

Dr. O'Brien's study was funded as part of NICHD's Specialized Cooperative Centers Program in Reproduction Research, which seeks to identify compounds that might provide the basis for new forms of contraception and provide insights that might be helpful in treating infertility.

The human form of GAPDS is known as GAPD2, explained Louis De Paolo, Ph.D., of NICHD's Reproductive Sciences Branch, administrator of the Specialized Centers Program. A drug that interfered with the enzyme might provide an effective means of nonhormonal male contraception.

One possibility, he added, would be a drug that males could take to interfere with sperm motility. Another possibility would be a drug that could be deposited in the female reproductive tract, which could stop the movement of sperm when they come in contact with it.

Dr. De Paolo noted that current attempts to design a male contraceptive pill involve drugs that temporarily halt the functioning of the testes. These drugs not only suppress sperm production, but also the production of the male hormone testosterone, necessary for normal reproductive functioning. Such treatments typically involve replacing the missing testosterone through artificial means — a process that could increase the risk for prostate cancer. A drug that interfered with GAPD2 would leave testosterone levels unaffected, he said.

Similarly, studying the functioning of GAPD2 might provide insights that could lead to treatments for male infertility.

"One study showed that in a sample of infertile men, about 81 percent had sperm with defects in motility," Dr. De Paolo said.

Some of these men might have a genetic defect that interferes with normal production of GAPD2, he added. A drug that restored GAPD2 functioning might provide a treatment for their infertility. Similar molecular defects in the glycolysis pathway that produces ATP might also interfere with sperm movement, and might be the focus of other treatments.

"This finding has opened up several exciting new possibilities for future studies of male fertility regulation," he said.

The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Information Resource Center, 1-800-370-2943; e-mail NICHDInformationResourceCenter@mail.nih.gov.