Enzyme Essential To Sperm Movement Provides Target for New Contraceptive Approach
A team of researchers has determined that an enzyme in sperm is
necessary for sperm movement. Mice bred to lack this enzyme produce
sperm that cannot swim toward egg cells to fertilize them.
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
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
"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