Missing proteins in the uterus tied to infertility in women with endometriosis
CHAPEL HILL, Friday, June 30, 2000 — Proteins missing from cells lining the wombs of women with endometriosis may help explain their infertility, according to findings from a study headed by a University of North Carolina at Chapel Hillscientist.
The findings published in the July 1 issue of the medicaljournal Fertility and Sterility could add important clues to the link between infertility and endometriosis — a link that has been controversial. The research suggests that the cellular proteins alphav-beta3 and leukemia inhibitory factor (LIF) may serve as biomarkers for identifying women whose infertility is linked to their endometriosis and is most likely reversible with treatment.
In endometriosis, fragments of the uterine lining — the endometrium — implant elsewhere in the pelvis, such as on the vagina, ovaries, cervix, bladder and rectum. The condition exists in up to 40 percent of women with infertility, but the link between minimal or mild endometriosis and infertility remains unclear. As many as half of women with endometriosis will become pregnant without any treatment for the condition. Moreover, studies on the adverse effects of endometriosis on pregnancy rates have yielded conflicting results.
The new study headed by Dr. Bruce A. Lessey, associate professor of obstetrics and gynecology at the UNC-CH School of Medicine, suggests that a reduction of the proteins in question may interfere with embryo implantation in the uterine lining. Alphav-beta3 and LIF are present in uterine cells around day 20 of the typical 28-day menstrual cycle, suggesting they play an important role in the embryo’s subsequent attachment to the uterine lining.
Lessey, a member of the department’s reproductive endocrinology and infertility division, had previously identified alphav-beta 3 as one of a family of “cell adhesion” glycoproteins called integrins that may be vital to pregnancy. LIF recently was shown by study co-author Dr. Colin L. Stewart to be critical for implantation.
“We believe beta3 and LIF are markers of uterine receptivity, a sign that the uterus is ready for embryo attachment, and their absence might be used to identify infertile women with endometriosis who might benefit from medical or surgical treatment,” Lessey said.
Earlier findings by Lessey based on 113 infertile women diagnosed with minimal or mild endometriosis provided support for this belief. He compared fertility rates of 30 beta3 positives and 38 beta3 negatives. Neither group received subsequent therapy for their endometriosis. Of these women, 73 percent of the positives became pregnant within four years, compared to only 10 percent in the beta3-negative group.
In the new study, Lessey and his colleagues collected peritoneal (abdominal) fluid from women with minimal or mild endometriosis and from women without the uterine condition. Some women were fertile, others infertile. The fluid was injected into the abdomens of recently mated female mice around the time of embryo implantation.
“We saw a marked reduction of implantations in the mice that received the fluid from the infertile women with endometriosis.” Lessey said. “And when we looked at the level of utetrine beta3 integrin in the mice that got this peritoneal fluid, we noticed it was absent along with decreased levels of LIF.”
The impact on implantation and protein levels was least among mice who received abdominal fluid from fertile women without endometriosis.
Moreover, peritoneal fluid from a woman successfully treated for endometriosis and who eventually became pregnant had no effect on the mice.
“She had previously been missing beta3 but was successfully treated and had gotten it back before she conceived,” Lessey added. “Many doctors don’t believe that minimal amounts of endometriosis can cause infertility. This study would argue that even women with minimal disease appear to have peritoneal fluid that can affect implantation. I think this study offers a mechanism by which this may be happening.”
The research was funded in part by grants from the National Institute of Child Health and Human Development at the National Institutes of Health.
Others involved in the study are Drs. Maria J. Illera of the Universidad Complutense in Madrid, Spain; Lingwen Juan and Jane Ruman of the UNC-CH department of obstetrics and gynecology; Colin Stewart of the Laboratory of Cancer and Developmental Biology at the National Cancer Institute; and Emily Cullinan of Lexicon Genetics in The Woodlands, Texas.