Researchers Identify A Possible Cause of Infertility In Some Women With Endometriosis

NIH funded researchers report that some women who have infertility as a result of endometriosis lack molecules in the uterus that allow the embryo to attach to the uterine wall. The researchers suspect that because the embryo cannot attach to the uterine wall, a pregnancy cannot become established, and infertility results. Endometriosis is a major cause of infertility, occurring in from 35-50 percent of women who have difficulty becoming pregnant.

The finding appears in the July 2003 issue of Endocrinology. The researchers also reported that a number of genes present in the uteri of endometriosis patients appear to be functioning inappropriately. Many of the genes identified in this study had not been shown previously to contribute to endometriosis and the infertility that commonly accompanies the disorder.

"The causes of endometriosis and of the infertility that's associated with it have eluded scientists for many years," said Duane Alexander, M.D., Director of the National Institute of Child Health and Human Development (NICHD). "This study provides a better understanding of this disease, and may lead to new therapies to treat women who have the disorder." The NICHD and the Office of Research on Women's Health provided part of the funding for the study.

The research builds upon an earlier NICHD funded study, which reported that the molecule L-selectin, needs to be present on the uterine wall before an embryo can attach itself to the uterus and a pregnancy can begin. [A news release describing this earlier finding appears on the NICHD web site at http://www.nichd.nih.gov/new/releases/embryo.cfm]

In the current study, researchers found that at the time the uterus is most receptive to the embryo, women with infertility because of endometriosis have very low levels of an enzyme that is involved in synthesizing the ligand for L-selectin. The ligand is a rubber-band like molecule that tethers L-selectin to the wall of the uterus. Because the women lack the enzyme that makes the L-selectin ligand, the embryo may not be able to attach to the uterine wall, and a pregnancy could not begin.

Endometriosis is a disorder in which endometrial tissue �� tissue that normally lines the inside of the uterus �� begins growing in other areas within a woman's abdomen �� on the fallopian tubes, on the outside of the uterus, the ovaries, or intestines. This disorder affects 10-15 percent of women of reproductive age and often causes pelvic pain.

To conduct the study, researchers at Stanford University, the University of California in San Francisco, Vanderbilt University, and the University of North Carolina in Chapel Hill, collected samples of endometrium from 15 non-pregnant volunteers, eight with endometriosis and seven without. They did this during the "window of implantation," the days of a woman's menstrual cycle (day 20-24 of a 28-day cycle) when the uterus is receptive to an embryo.

The scientists in this study used a new technology called microarray analysis, which makes it possible to screen a large number of genes at one time. This allows researchers to identify genes much more quickly than do traditional methods that look for only one gene at a time. The researchers measured gene expression �� the turning on or off of a particular gene, like a light switch turns a light on or off.

They analyzed over 12,000 genes. They found 91 genes that had more than a two-fold increase in gene expression in women with endometriosis, compared to those without the disease, and 115 genes that had more than a two-fold decrease in expression in women with endometriosis compared to those without. These genes are likely to play a role in the development of endometriosis in the pelvis and its associated infertility.

In addition, the researchers found three groups of genes that appear to play a role in endometriosis. One group of genes increased in expression during the window of implantation in women without endometriosis, but significantly decreased at this time in women with the disease. The gene for the enzyme needed to synthesize the ligand for L-selectin appeared in this group. The second group of genes normally decreased, but instead increased in women with endometriosis. The third group of genes consisted of only one gene, which normally decreased during the window of implantation, but in women with endometriosis, it decreased even further.

The researchers' data support the theory that having certain genes present in the incorrect amount contributes to the development of endometriosis. It may also create an inhospitable environment for an embryo to attach to the uterus. The findings also add weight to the hypothesis that the endometrium of women with endometriosis is abnormal.

"This study's findings support the theory that women who have this abnormal tissue are prone to develop endometriosis and its infertility," said the study's senior author, Linda Giudice, M.D., PhD., Stanford Professor of Obstetrics and Gynecology and Director of the Center for Research on Women's Health and Reproductive Medicine at Stanford.

Dr. Giudice explained that the study's findings might lead to a new way to screen women for the disease. Currently, diagnosis requires a laparoscopy (a procedure in which a small incision is made in the abdomen) or laparotomy (a larger incision is made), usually with a general anesthetic. This new research may one day enable scientists to develop a less invasive test, based on the detection of abnormal gene activity.

Dr. Giudice emphasized that the study's findings need to be verified in larger studies of women who have endometriosis. Nonetheless, she said, "This now offers an opportunity to create drugs to correct this error in gene expression, and therefore a treatment for endometriosis-related infertility."

More information about endometriosis is available from the NICHD publication Endometriosis, at http://www.nichd.nih.gov/publications/pubs/endometriosis.pdf. For additional information about endometriosis, contact the Endometriosis Association, 8585 North 76th Place, Milwaukee, WI 53223; phone: 414-355-2200; http://www.EndometriosisAssn.org/.

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 NICHDClearinghouse@mail.nih.gov.

Under the leadership of the NIH's Associate Director for Research on Women's Health, the Office of Research on Women's Health (ORWH) advises the NIH Director and staff on matters relating to research on women's health; strengthens and enhances research related to diseases, disorders, and conditions that affect women; ensures that research conducted and supported by NIH adequately addresses issues regarding women's health; ensures that women are appropriately represented in biomedical and biobehavioral research studies supported by NIH; develops opportunities for and supports recruitment, retention, re-entry, and advancement of women in biomedical careers; and supports research on women's health issues. The ORWH works in partnership with the NIH institutes and centers to ensure that women's health research is part of the scientific framework at NIH and throughout the scientific community. Information about women's health and ORWH is available at: http://www4.od.nih.gov/orwh/.