How Embryos ‘Take Hold’ May Give Answers to Treating Infertility

(HealthDay News) – Ever since scientists learned how a new embryo attaches to the mother's uterus, they have attempted to use that information in concert with new methods to treat infertility.

The findings, first published in 2003, found that proteins called selectins were the “glue” responsible for the fertilized egg attaching to the wall of the uterus.

This discovery was extremely important, because failure of the embryo to "implant," or attach to the uterus, is responsible for about three quarters of miscarriages.

"You could envision a test for a couple who have otherwise unexplained infertility so that perhaps a cause of infertility would be elucidated," says Dr. Richard Grazi, Director of Reproductive Endocrinology, Maimonides Medical Center in Brooklyn, N.Y. "In about 20 percent of couples who have infertility, it's unexplained. That doesn't mean there's no reason. It just means we don't know what the reason is yet."

Normally, a woman's egg is fertilized by the male sperm at the end of the uterine tube, explains Susan Fisher, senior author of the study and a developmental biologist at the University of California, San Francisco. The developing embryo then transits the tube and enters the uterine cavity. In order for the embryo to successfully grab hold in the uterus, both it and the uterine lining must be ready -- and the window of opportunity is extremely small. "It's all a matter of timing," Fisher says.

What, then, allows successful sticking to take place?

Fisher and her colleagues have uncovered a sort of intricate mating dance that seems to occur between the embryo and the uterine wall.

Human embryos, it turns out, are covered with the proteins called selectins, which are attracted to carbohydrates. Every month after ovulation, the lining of the uterus expresses carbohydrates, which are drawn to a protein called L-selectin on the outer walls of the embryo.

This mutual attraction causes the L-selectin of the embryo to bind briefly with the carbohydrates of the uterine lining, separate and then bind again, slowing the embryo's rate of progress through the uterus. Eventually, the embryo comes to rest against the uterine wall and taps into the mother's bloodstream to form the placenta. Think of a plane landing on a runway: The wheels touch the ground several times before coming to a final stop.

"It's not surprising that there is communication between the implanting embryo and the endometrial surface, and we know that there's some type of signaling that's involved in the implantation process," Grazi says. "What's exciting about it is that they've been able to identify a specific molecular substance that is involved that can a) be tested for and, b) possibly in the future be controlled."

A similar principle is at work in the body's blood system: The sticking mechanism allows leukocytes (white blood cells, which fight infection) to slow down and stop before they exit the bloodstream destined for inflamed tissue.

In addition to shedding light on the mechanisms involved in miscarriage and infertility, this research may help us understand preeclampsia, a potentially fatal form of high blood pressure that occurs in about 10 percent of pregnancies. According to the study authors, in preeclampsia, the placenta does not attach fully to the uterine wall, depriving the fetus of oxygen and endangering the mother's life. This process may also involve the same interaction of carbohydrates and proteins.

"Certainly once you figure out what controls the secretion of these carbohydrates you can possibly control them, but obviously it's just one piece of information," Grazi says. "There are a lot of other putative implantation molecules that are involved, so this may be just one."

Any number of things might be affecting the embryo's ability to attach to the uterus. Women with sexually transmitted diseases, for instance, have a lower rate of being able to get pregnant, Fisher says. We know now that infection causes the L-selectin to shed, which means it lacks the ability to connect with the uterine lining. "You can imagine that if you have anything from chlamydia to gonorrhea that you might knock this part of implantation out," she says.

Fisher's next focus of research is on what happens "downstream" from the L-selectin or the proteins on the embryo. When L-selectin binds to the carbohydrates in the immune system, it triggers a set of signals that allow the leukocyte to stop and stick to a blood vessel, then leave the vessel for the inflamed tissue, where it's needed. Fisher wants to prove that the same thing is happening in the process of embryo attachment.

"That would mean if we could give an embryo or a placental cell those signals artificially, we might be able to get over a major hurdle to implantation and trigger downstream events," Fisher says.

In the nearer term, the University of California, San Francisco is exploring how to use L-selectin to help determine if a woman is infertile and to locate the exact cause.

On the Web

The U.S. Department of Health and Human Services’ 4women.gov Internet location has an excellent Web site devoted to research into the causes of both fertility and infertility.

SOURCES: Susan J. Fisher, Ph.D., Professor, Oral Biology, Professor of Pharmaceutical Chemistry, Professor of Anatomy and Faculty Director, Biomolecular Resource Center, University of California, San Francisco; Richard Grazi, M.D., Director, Reproductive Endocrinology, Maimonides Medical Center, Brooklyn, N.Y.; Jan. 17, 2003 Science
Publication date: March 1, 2007
Author: Amanda Gardner, HealthDay Reporter
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