Understanding the Role of PGE2 and CD55 in the Pathogenesis of Endometriosis May Lead to New Treatments

Cleveland Clinic researchers found that high levels of prostaglandin E2 (PGE2) may induce the formation of endometriosis through a novel pathway involving the complement regulatory protein CD55. The study will be presented at the American Society for Reproductive Medicine’s 2019 Scientific Congress and Expo, held October 14-16 in Philadelphia.

“Endometriosis is a complex and enigmatic disease with many factors and contributors. There almost certainly isn’t one single factor driving it, but evidence does suggest that PGE2 is critical,” states Ofer Reizes, PhD, the Laura J. Fogarty Endowed Chair for Uterine Cancer Research in Cleveland Clinic’s Lerner Research Institute and senior author on the study.

PGE2 is widely regarded as central to the pathogenesis of endometriosis. Observational studies analyzing peritoneal fluid have shown that patients with endometriosis have increased levels of PGE2 compared to healthy control women. Furthermore, treatment with drugs that diminish PGE2 have been shown to improve symptoms in humans and decrease lesion size in animal models.

PGE2 seems to alter CD55 expression levels

Investigators first localized the presence of CD55 protein in specimen from eutopic and ectopic endometrium of human pathology specimen using immunohistochemistry. They then performed CD55 expression analysis on endometrial stromal (T-HESC) and endometriotic epithelial (12Z) cell cultured in flasks and treated with increasing doses of PGE2 and determined ability of the cells to adhere to tissue culture surfaces, a necessary step for endometriosis formation.

“Our data suggest that CD55 has a role in the pathogenesis of endometriosis,” states Elliott Richards, MD, a fellow in Cleveland Clinic’s Ob/Gyn & Women’s Health Institute. “CD55 is an important regulator of the complement system, part of the body’s innate immune system. For decades it was thought that CD55 action was pretty much limited to complement regulation outside the cell surface. Recent studies in other diseases and organ systems, however, show that CD55 can have other functions in the cell. We investigated whether this was the case in endometriosis, since it is one of the genes misregulated in patients with the disease. We found that CD55 may play a role in cell adhesion in the early formation of endometriosis. What is most interesting is that PGE2 seems to alter CD55 expression levels, which may explain how the misregulation works.”

Dr. Richards cautions that these findings are preliminary, as this study includes only in vitro data. “Experiments using these cell lines can give clues as to what may be happening, but endometriosis lesion formation involves very complex biology. We can’t definitively say whether these processes in cell lines would happen the same way in the tissue in the body. The next step is to perform experiments in animal models. We have nearly completed these animal experiments and are in the process of analyzing the data,” Dr. Richards notes.

Toward new treatments for endometriosis

Patients with endometriosis report a lower health-related quality of life, with symptoms of chronic pelvic pain, dysmenorrhea, dyspareunia, gastrointestinal symptoms and infertility. “Endometriosis is estrogen-dependent and generally occurs between menarche and menopause. Nonsurgical treatments to date have focused on hormonal suppression,” states Jeffrey M. Goldberg, MD, Program Director for the Reproductive Endocrinology & Infertility Fellowship and a co-author on the study. “The results of this, and other ongoing studies, may provide us with a molecular pathway to better understand the pathogenesis of this disease state, with the ultimate goal of creating new non-hormonal treatment options for endometriosis.”