Intact progesterone receptors are essential to counteract the proliferative effect of estrogen in a transgenic mouse model of endometriosis

Abstract

Objective: Estrogen and progesterone were found to be important in the pathogenesis of endometriosis. The genomic action of progesterone is mediated by its nuclear receptor (PR). It was proposed that there is a generalized resistance to progesterone action, which may be mediated by significantly decreased levels of PR in human endometriotic tissue. A mouse model endometriosis has been established whereby autologous uterine tissue is surgically transplanted to the peritoneum. The objectives of this study were to determine the effects of progesterone on the growth of ectopic uterine implants in ovariectomized mice with a disrupted gene for PR (PRKO). Design: The size of ectopic and eutopic uterine tissue in wild type (WT) and PRKO mice were compared between the groups subjected to treatments with progesterone or estrogen. Tissue proliferating cell nuclear antigen (PCNA) levels were compared among these groups. Materials/Methods: All mice were of the same C57BL6 background and ovariectomized at 6 months of age. WT littermates of PRKO mice served as controls. At the time of ovariectomy, endometriosis was induced surgically in the following groups of mice (n=5 in each group): 1-PRKO; 2-PRKO treated with estradiol (E); 3-PRKO treated with E and progesterone (P); 4-WT; 5-WT treated with E; 6-WT treated with P; 7-WT treated with E and P. One uterine horn was opened up, divided into 3 equal pieces and transplanted to the peritoneum to study the proliferation of ectopic uterine tissue. The remaining uterine horn was used as control eutopic uterine tissue.E (10g/d slow-release pellet) and P (250g/day slow-release pellet) were administrated subcutaneously for 2 months following surgery. Mice were euthanized at the end of this 2-month period, and lesions were assessed. ANOVA was used for statistical analyses. Results: The mean size of ectopic lesions in untreated PRKO mice was significantly larger than those in untreated WT mice (p <0.05). On the other hand, there was no significant difference between the eutopic uterine tissues of untreated WT and PRKO mice. P significantly suppressed the growth of ectopic lesions in untreated or E-treated WT mice (p <0.05). P, however, did not decrease the size of eutopic uterine tissue in untreated WT mice. The ectopic uterine tissues in untreated or E-treated PRKO mice were significantly larger than corresponding WT controls (p <0.0001). P did not suppress the E-dependent growth of ectopic uterine tissues in PRKO mice. These changes in ectopic lesion size were accompanied by parallel changes in tissue PCNA levels in that the addition of P effectively suppressed E-dependent increase in PCNA levels in WT tissues but not in PRKO tissues. Conclusions: E increases the size of ectopic uterine tissue via cell proliferation, whereas P suppresses this effect via a PR-mediated mechanism. Intact PR in ectopic uterine tissue is necessary to abolish E-dependent or independent proliferation. Thus, our findings support the hypothesis that progesterone resistance in human endometriotic tissue may in part be due to the lack of sufficient levels of functional PR in this tissue. Supported by: This project was supported by the NIH grant HD38691.