Endometriosis is a heterogeneous disease including peritoneal, ovarian and deep infiltrative endometriosis. It is likely that the biology of these lesions and therefore the treatment modalities to be applied are different. Therefore, it is very important to understand well the characteristics of the lesions. In the present study, there was no significant difference in terms of demographic data of the groups. T-cadherin, E-cadherin, ER and PR H-score were lowest in endometriotic nodule tissue and highest in endometrial tissue. A positive correlation was found between T-cadherin, E-cadherin, PR-α and ER-α H-score in correlation analysis. However, no correlation was found between age, BMI, VAS score, CA125, endometrioma size and severity of dysmenorrhea, dyspareunia or dystonia.
Solares JG and et al. examined rectovaginal endometriotic nodules of 17 DIE cases. Samples taken from the closest (most invasive) part of the tissues to the rectum and the middle (less invasive) part were examined immunohistochemically in terms of beta-catenin, E-cadherin, N-cadherin, MMP-9, nerve growth factor (NGF) and nerve fibre density (NFD). In sections taken from more invasive parts of tissues that were close to the rectum, thinning and increased proliferation rates were shown in the endometrial glands. Also, it was shown that while N-cadherin and MMP-9 levels increased, E-cadherin staining decreased . In various studies, it has been shown that NFD is increased in DIE cases compared to peritoneal and ovarian endometriosis cases [26, 36–38]. In a study conducted by Donnez et al. in a baboon model, it was shown that E-cadherin expression is reduced in the invasive part of the deep nodular endometriotic lesion . However, Orellana et al. found E-cadherin expression in the deep nodular endometriotic lesion invasive part to be similar to the non-invasive part in the baboon model . In the only study examining T-cadherin level in endometriosis tissue, T-cadherin level was found to be low in endometriosis tissue. In the same study, 40 endometriosis tissues were examined, and it was not clearly stated how many of these tissues were DIE tissues. In the cell culture phase of the study, it was shown that T-cadherin inhibits invasion and migration of endometrial stromal cells in endometriosis . In the current study, E-cadherin level was found to be low in endometriotic nodule tissue, in accordance with the literature. As additional information for the literature, T-cadherin and E-cadherin levels were found to be less than endometrioma tissue in endometriotic nodule tissue. Generally, T-cadherin and E-cadherin levels of endometriosis lesions were found to be lower than normal endometrial tissue.
Progesterone containing drugs are frequently used in the medical treatment of endometriosis. In particular, a significant proportion of patients with high endometriosis stage and endometriotic nodules do not respond to progesterone treatment . As the cause of this unresponsiveness, it is thought that there may be mechanisms, such as cells having a small number of progesterone receptors that creates resistance to progesterone, and abnormalities in post-receptor mechanisms [25, 26]. While there is a reduction in the size of ovarian endometriomas with hormonal treatment [40, 41], the resistance of endometriotic nodule tissue to medical treatments suggests that the biology of these two tissues is different [24, 42]. Studies show that oestrogen and progesterone receptors in endometriosis tissue are less than in normal endometrial tissue . Deficient methylation of the ER-β promoter results in pathological overexpression of ER-β in endometriotic stromal cells. High levels of ER-β suppress ER-α expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor contributing to progesterone resistance . In the present study we found decresed levels of ER-α and PR receptors in endometriosis tissues but more pronounced in endometriotic nodule tissue similar to previous reports. Also, in the present study, PR and ER levels were found to be lower in both endometriotic tissue and endometrioma tissue than in normal endometrium.
Zanatta et al. found that expression of ER-α (in 16 of 18 patients), PR (in 17 of 18 patients), and PR-B (17 of 18 patients) was moderate to strong in the glands and stroma of nodules during both phases in rectosigmoid endometriosis tissue. However, in that study, endometriotic nodules, ovarian endometrioma and eutopic endometrium tissues were not compared . Donnez et al. found cytokeratin and vimentin content, as well as ER and PR content, to be significantly lower in both types of lesion when compared with eutopic endometrium in a study in which 52 peritoneal endometriotic implants and 68 endometriotic nodules of rectovaginal septum were examined. Vimentin immunoreactivity in the epithelium, as well as the ER and PR content, were significantly lower in nodules when compared with black peritoneal lesions . Liu et al. found that E-cadherin levels were the lowest in endometriotic nodule tissue in the control group in their study, in which they examined 25 endometriomas, 20 DIE nodules and 25 eutopic endometrial tissues. They found the highest ER-beta staining level in the ovarian endometrioma group and the lowest in the eutopic endometrium tissue. In contrast, they found the highest PR-B staining level in eutopic endometrium tissue and the lowest in endometriotic nodule tissue . In the current study, similar to the study conducted by Liu et al., the highest PR level was found in the normal endometrium group and the lowest in the endometriotic nodule tissue. The staining order of ER levels in tissues was different from the study conducted by Liu et al. This difference may be due to assessment of ER-α in the present study versus ER-β staining in the study conducted by Liu et al. In addition, a positive correlation was found between the staining levels of T-cadherin, E-cadherin and ER-α and PR-α levels in the current study. The fact that T-cadherin and E-cadherin staining levels and ER-α and PR-α levels were lower in ovarian endometrioma and normal endometrial tissues than in endometriotic nodule tissue, which is the most severe form of endometriosis, suggests that these molecules and receptors may have an effect on the invasive character.
In further studies in endometriotic nodule and endometrioma tissue, over-expression or knockout of T-cadherin and E-cadherin may indicate whether they are part of the complex mechanisms that regulate invasion. Also, functional studies evaluating the amount of PR and ER-α and post-receptor mechanisms would contribute to understanding the biology of endometriotic nodule tissue. In the present study, although there was a correlation between T-cadherin, E-cadherin, PR and ER staining levels, the functional relationship between these molecules needs to be explained. In future cell and tissue culture studies dealing with PR, ER, T-cadherin and E- cadherin expressions, it could be shown that progesterone may supress the EMT process by upregulating the cadherin expression mechanisms.
In conclusion, we found T-cadherin, E-cadherin, ER and PR H-scores to be lowest in endometriotic nodule tissue and highest in endometrial tissue. A positive correlation was found between T-cadherin, E-cadherin, PR and ER H-scores in correlation analysis. These findings suggest that endometriotic nodules and ovarian endometrioma tissues have a different biology. In the present study, lower PR-α, ER-α, T-cadherin and E- cadherin expressions and lower progesterone effect that could not inhibit the decrease in cadherin expressions may explain the invasiveness of endometrial nodule.