Endometrium is derived from intermediate mesoderm via mesenchymal to epithelial transition (MET) during development of the urogenital system. By retaining some imprint of their mesenchymal origin, endometrial epithelial cells may be particularly prone to return to this state, via epithelial to mesenchymal transition (EMT). We hypothesized that pelvic endometriosis originates from retrograde menstruation of endometrial tissue and that EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis. We investigated commonly used molecular markers for EMT, including cytokeratin, E-cadherin, N-cadherin, vimentin, S100A4 and dephosphorylated beta-catenin by immunohistochemistry in different forms of pelvic endometriosis: deep infiltrating endometriosis, ovarian endometriosis and superficial peritoneal endometriosis (red and black lesions), as well as samples of menstrual endometrium, other benign ovarian cysts (mucinous and serous cyst adenoma), and abdominal scar endometriosis for comparison. Epithelial cells of red peritoneal lesions and ovarian endometriosis showed less epithelial marker (cytokeratin, P < 0.0001) expression and more mesenchymal marker (vimentin and/or S100A4, P < 0.0001) expression than those of menstrual endometrium. In contrast, epithelial cells of black peritoneal lesions and deep infiltrating endometriosis showed more epithelial marker (E-cadherin) expression than those of menstrual endometrium (P < 0.03), red peritoneal lesions (P < 0.0001) and ovarian endometriosis (P< 0.0001), but maintained expression of some mesenchymal markers (vimentin, S100A4). In addition, dephosphorylated beta-catenin protein expression was significantly higher in epithelial cells of deep infiltrating endometriosis (P < 0.0001) than in epithelial cells of red and black peritoneal lesions and ovarian endometriosis. EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis.

During the development and progression of endometriotic lesions, excess fibrosis may lead to scarring, chronic pain, and altered tissue function. However, the cellular and molecular mechanisms of fibrosis in endometriosis remain to be clarified. The objective of the present study was to investigate whether the Wnt/β-catenin signaling pathway was involved in regulating the cellular and molecular mechanisms of fibrosis in endometriosis in vitro and to evaluate whether fibrosis could be prevented by targeting the Wnt/β-catenin pathway in a xenograft model of endometriosis in immunodeficient nude mice. Seventy patients (40 with and 30 without endometriosis) with normal menstrual cycles were recruited. In vitro effects of small-molecule antagonists of the Tcf/β-catenin complex (PKF 115-584 and CGP049090) on fibrotic markers (alpha smooth muscle actin, type I collagen, connective tissue growth factor, fibronectin) and collagen gel contraction were evaluated in endometrial and endometriotic stromal cells from patients with endometriosis. In vitro effects of activation of the Wnt/β-catenin signaling pathway by treatment with recombinant Wnt3a on profibrotic responses were evaluated in endometrial stromal cells of patients without endometriosis. The effects of CGP049090 treatment on the fibrosis of endometriotic implants were evaluated in a xenograft model of endometriosis in immunodeficient nude mice. Treatment with PKF 115-584 and CGP049090 significantly decreased the expression of alpha smooth muscle actin, type I collagen, connective tissue growth factor and fibronectin mRNAs in both endometriotic and endometrial stromal cells with or without transforming growth factor-β1 stimulation. Both endometriotic and endometrial stromal cell-mediated contraction of collagen gels was significantly decreased by treatment with PKF 115-584 and CGP049090 as compared to that of untreated cells. The animal experiments showed that CGP049090 prevented the progression of fibrosis and reversed established fibrosis in endometriosis. Aberrant activation of the Wnt/β-catenin pathway may be involved in mediating fibrogenesis in endometriosis.

Context: Only a few, small, human studies on E-cadherin and β-catenin expression in normal cycling human endometrium have been reported. It remains unclear whether expression of these molecules might be altered in the endometrium of infertile patients with endometriosis. Objectives: The aim of the present study was to investigate E-cadherin and β-catenin expression in the endometrium of infertile patients with endometriosis, those with uterine fibromas, and patients with unexplained infertility. Design: Expression levels of E-cadherin and β-catenin mRNA and/or protein in the endometrium of infertile patients with endometriosis (n = 151), those with uterine fibromas (n = 41), patients with unexplained infertility (n = 9), as well as healthy fertile controls (n = 57) were measured. This study utilized laser capture microdissection, real-time RT-PCR, and immunohistochemistry. Results: No significant differences in E-cadherin or β-catenin mRNA expression in microdissected epithelial cells were observed among the different groups throughout the menstrual cycle. However, very low or no protein expression of E-cadherin, total β-catenin, or dephosphorylated β-catenin in luminal and glandular epithelial cells was detected in the mid-secretory endometrium of healthy fertile controls. E-cadherin, total β-catenin, and dephosphorylated β-catenin protein expression in the mid-secretory endometrium of infertile patients with endometriosis or unexplained infertility was significantly higher compared to that of healthy fertile controls in both luminal and glandular epithelial cells. Conclusions: These findings suggest that impaired down-regulation of E-cadherin and β-catenin protein expression, along with Wnt/β-catenin signaling pathway activation during the window of implantation, might be one of the potential molecular mechanisms of infertility in patients with endometriosis.

The aim of this study was to investigate HOXA-10 expression in endometrium from infertile patients with different forms of endometriosis; with uterine fibromas, or with unexplained infertility and from normal fertile women. Expression levels of HOXA-10 mRNA and protein in endometrium were measured during the mid-secretory phase. This study utilized laser capture microdissection, real-time RT–PCR and immunohistochemistry. HOXA-10 mRNA and protein expression levels in endometrial stromal cells were significantly lower in infertile patients with different types of endometriosis (deep infiltrating endometriosis, ovarian endometriosis and superficial peritoneal endometriosis), with uterine myoma, and unexplained infertility patients as compared with healthy fertile controls. HOXA-10 mRNA expression levels of microdissected glandular epithelial cells were significantly lower than those of microdissected stromal cells, without significant differences among the different groups. No protein expression was detected in glandular epithelial cells. The percentage of patients with altered protein expression of HOXA-10 in stromal cells were significantly higher in patients with only superficial peritoneal endometriosis (100%, 20/20, P < 0.05) compared with the other infertile groups (deep infiltrating endometriosis: 72.7%, 16/22; ovarian endometriosis: 70.0%, 14/20; uterine myoma: 68.8%, 11/16; unexplained infertility: 55.6%, 5/9). The present findings suggested that altered expression of HOXA-10 in endometrial stromal cells during the window of implantation may be one of the potential molecular mechanisms of infertility in infertile patients, particularly in patients with only superficial peritoneal endometriosis. One of the underlying causes of infertility in patients with only superficial endometriosis may be altered expression of HOXA-10 in endometrial stromal cells.