Ontogeny and expression profiles of steroid hormone receptors in a mouse model of endometriosis

Abstract

Endometriosis is a chronic incurable disorder of unknown etiology affecting a large proportion of women in reproductive age. In order to understand the pathogenesis and preclinical testing of drugs,animal models that recapitulate the key features of the disorder are highly desirous. Herein, we describe the ontogeny of the ectopic endometrial lesion in a mouse model where uterine tissue was ligated to the intestinal mesentery and the animals were followed up from day 5 to day 60 post-surgery. Out of 60 animals that underwent surgery, 58 developed endometriosis using this strategy. Most lesions were pale, fluid filled while red lesions were seen in ~10% of animals. Histologically, in most animals there was one large cystic gland with well differentiated epithelium, in 13% of animals there was mixed phenotype (well and poorly differentiated). There was extensive stromal compaction and increased number of macrophages in ectopic lesions. During the course of endometriosis, there was an increase in number of PCNA positive epithelial and stromal cells. The epithelial cells at all the time point were cytokeratin positive and the stroma was vimentin positive. However, at day 30 and 60, the stromal cells were also cytokeratin positive. The mRNA levels of estrogen receptors Esr1 and Gper1 were reduced while those of Esr2 were elevated as compared to normal endometrium, the levels of progesterone receptor (Pgr) were found to be downregulated in ectopic lesions as compared to control. However, these differences were not statistically significant due to high biological variability. Low abundance of Cyp19a1 transcripts (aromatase gene) were only detected in the ectopic endometrium. Immunohistochemically, the expression of ER and ER{beta} was significantly reduced only in stromal cells; the epithelial cell staining was maintained. GPER1 and PR immunoreactivity was significantly low in both epithelial and stromal cells. The immunostaining of all the steroid receptors was highly heterogeneous in the ectopic tissues with some areas of sections had stained intensely while others had negligible staining. We propose that temporal and spatial difference in the expression of steroid hormone receptors during the course of endometriosis development coupled with micro-heterogeneity may alter the effectiveness of steroid hormone analogues resulting in variable outcomes and often failure of therapy.