Use of a murine endometriosis interna model for the characterization of compounds that effectively treat human endometriosis

Abstract

Endometriosis is a chronic, estrogen-dependent disease characterized by the presence of ectopic endometrium either in the pelvic cavity (endometriosis externa) or within the uterus (endometriosis interna, adenomyosis). Key symptoms are pelvic pain, dysmenorrhea and infertility. Established rodent animal models used for drug research in endometriosis have certain limitations. Since rodents do not menstruate, they cannot develop endometriosis externa spontaneously, but they suffer from endometriosis interna. There is growing evidence that human endometriosis externa and interna represent two faces of the same disease. Both are estrogen-dependent and respond to similar treatment paradigms. Here, we addressed the question whether a murine endometriosis interna model may also be suitable for the characterization of drugs employed in human endometriosis. We examined the effects of danazol, Faslodex and cetrorelix in SHN mice that developed endometriosis interna after pituitary grafting. The GnRH antagonist cetrorelix and the estrogen receptor antagonist Faslodex, which negatively interfered with estrogen-mediated signaling, completely inhibited endometriosis interna, whereas danazol, an androgenic progestin, showed significant therapeutic activity in the majority of SHN mice. We conclude that this murine endometriosis interna model may be a valuable complement to established endometriosis externa models to support drug research in human endometriosis.

Figure 1.

Uterine sections. Animals (A and B) remained unoperated or (C–F) received a pituitary graft under the kidney capsule. Two weeks later, animals (A–C) remained either untreated or were treated for 8 weeks with (D) danazol, (E) Faslodex or (F) cetrorelix. Asterisks indicate endometriotic foci invading the inner (IM) and/or outer muscular (OM) layer of the uterus. (A) Untreated control animals were either healthy or (B) suffered from severe endometriosis interna. (C) Pituitary grafting led to endometriosis interna in all animals. (D) Danazol treatment prevented endometriosis interna in the majority of animals. (E) Faslodex and (F) cetrorelix inhibited the disease in all animals. All images were taken at the same magnification.

Figure 2.

Disease scores and relative uterine weights. SHN mice remained unoperated (control) or received pituitary grafts followed by subsequent treatment with danazol, Faslodex or cetrorelix. Median disease scores are indicated as horizontal bars, a score of 0 indicates healthy animals. Asterisks indicate scores significantly different from the score of the pituitary-grafted group (^*p<0.05). (A) Uteri from unoperated control animals exhibited disease heterogeneity. Pituitary grafting provoked endometriosis interna in all animals. Danazol (median score 0, p<0.05 vs. pituitary-grafted group) faslodex (median score 0, p<0.05 vs. pituitary-grafted group) and cetrorelix (median score 0, p<0.05 vs. pituitary-grafted group) prevented the disease in pituitary-grafted animals. (B) Compared to the untreated control animals, uteri of pituitary-grafted animals exhibited reduced relative weight due to increased progestogenic activity. Danazol application did not further reduce relative uterine weight. Faslodex and cetrorelix abolished estrogenic activity in the uterus and severely reduced relative uterine weight. Data are given as the means ± standard deviation. ^*p<0.05 (vs. the control group).