Establishment and Proliferation of Endometriotic-Like Lesions in Estrogen Receptor Deficient Mouse Models Is Host and Donor Specific.

Abstract

Endometriosis, a gynecological disease resulting from the ectopic invasion of endometrial tissue within the peritoneal cavity, affects approximately 10% of reproductive-aged women and is a significant source of pelvic pain, subfertility and/or infertility. Estrogen is an important factor in stimulating the growth of endometriosis, as evidenced by the aberrant levels of the estrogen receptor (ER) α and β, in women with this condition. Interestingly, immune responses also appear to be involved as patients with endometriosis often have a higher incidence of autoimmune disorders and have macrophages as the predominant cell type in their peritoneal fluid. In this study, we generated a laboratory model of endometriosis that reflects human pathobiology to facilitate the investigation into the roles of estrogen in causing endometriosis and to study lesion development and progression in an immune-competent host. In our homologous mouse model, uterine tissue from a syngeneic donor mouse is dispersed into the peritoneal cavity of a recipient host. Wild-type (WT) and mice lacking ERα and ERβ (αERKO or βERKO, respectively) were used as both donors and recipient hosts. Lesions were established under vehicle or estradiol treatment conditions for three weeks. Upon necroscopy, similar to what is observed in women, endometrial lesions were found outside the uterine cavity, including the peritoneal wall, rectovaginal septum and intestinal mesentery. Lesion gross anatomy suggests that WT uterine tissue injected into an αERKO and βERKO host develop the same number of lesions; however, the WT lesions in the αERKO host do not increase in size in response to estradiol treatment as the WT lesions in either the WT or βERKO host. Uterine tissue from αERKO or βERKO mice injected into a WT host suggests that βERKO tissue establishes and responds similar to WT tissue; however, a WT host injected with αERKO uterine tissue form one lesion at the injection site and this lesion does not respond to hormone treatment. Histological examination of the lesions revealed that they are cystic, have extensive blood supplies, and have the appearance of glandular epithelium and stroma, similar to human endometriotic lesions. However, the αERKO tissue injected into the WT host is disorganized, fibrous and necrotic. Immunohistochemistry (IHC) was used to access the progesterone receptor (PR) status of the lesions. Classically, PR is predominately expressed in the epithelium of the eutopic uterus, but in the presence of estradiol, the expression of PR is found more predominately in the stroma. We find that the PR expression in WT lesions developed in a WT and βERKO host respond to hormone similarly to the eutopic host uterus. The PR expression of WT lesions developed in an αERKO host did not respond to hormone as the PR expression remains localized to the epithelium. Tissue from a βERKO donor injected into a WT mouse exhibits the PR switch and as expected, like the αERKO uterus, the αERKO donor uterine tissue injected into a WT host does not respond to estradiol treatment. We find no differences in expression levels of ERα levels by IHC. In sum, this syngeneic mouse model of endometriosis establishes lesions similar to human pathobiology in an immune-competent environment and suggests that there is both host and donor specificity to the establishment, proliferation, and responsiveness of the endometriotic-like lesions. This provides a novel model system to examine the importance of hormonal responsiveness and the roles of ERα and ERβ in endometriosis. (poster)