Endometriotic-like Lesion Formation in Estrogen Receptor Deficient Mice.

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 sought to generate 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 expressing a GFP transgene or a Luciferase transgene is dispersed into the peritoneal cavity of a recipient host. Wild-type, αERKO or βERKO mice were used as recipient hosts. Lesions were established under vehicle or estradiol treatment conditions for three weeks (GFP donor) or for three months (Luciferase donor). Mice injected with GFP donor tissue were visualized at necropsy under a fluorescence dissecting scope to observe short term lesion formation, while mice injected with Luciferase donor tissue were imaged weekly for three months for luciferase activity to quantitate lesion growth using the IVIS Spectrum system. 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. Histological examination of these lesions revealed that they are cystic, have extensive blood supplies, and have the appearance of glandular epithelium and stroma, similar to human endometriotic lesions. WT, αERKO and βERKO mice injected with WT uterine tissue all demonstrate lesion establishment indicating establishment of lesions does not require host ERα or ERβ. The size and proliferation of the lesions was dependent on estrogen treatment indicating a potential role for ERα or ERβ in the lesion growth. In comparison to their vehicle-treated counterparts, endometriotic lesions removed from estrogen-treated mice exhibit more extensive glandular structures, are more fluid filled, and often contain more blood and macrophages. Immunohistochemistry confirmed that the removed lesions were donor-derived and also demonstrated that the lesions express ERα and progesterone receptor (PR) in a manner responsive to hormone treatment. Chemokine and cytokine analysis is underway to examine the immune milieu from these mice under the endometriosis-like disease condition. In sum, this syngeneic mouse model of endometriosis established lesions similar to human pathobiology in an immune-competent environment and suggests that lesion formation is independent of host genotype. (poster)