The Endometriotic Nodule Has Lower T-cadherin, E-cadherin, Progesterone Receptor and Oestrogen Receptor Than Endometrioma Tissue

The Endometriotic Nodule Has Lower T-cadherin, E-cadherin, Progesterone Receptor and Oestrogen Receptor Than Endometrioma Tissue | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research The Endometriotic Nodule Has Lower T-cadherin, E-cadherin, Progesterone Receptor and Oestrogen Receptor Than Endometrioma Tissue Ismail Biyik, Uzeyir Kalkan, Sercan Simsek This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-151163/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To compare the T-cadherin, E-cadherin, PR and ER staining levels of endometriotic nodules, ovarian endometriomas and normal endometrial tissues. Methods: Endometriotic nodules of 24 cases, endometrioma of 30 cases and normal endometrial tissues of 30 cases were examined. T-cadherin, E-cadherin, ER-α and PR-α staining levels of endometriotic nodular tissues, endometrioma tissues and endometrial tissues were compared immunohistochemically. H -score was calculated to compare the expression of T-cadherin, E-cadherin, ER-α, PR-α in IHC staining based on the percentage of cells stained at each intensity level. Results: T-cadherin, E-cadherin, ER and PR H-score were found lowest in endometriotic nodule tissue and the highest in endometrial tissue (p <0.0001, <0.0001, <0.0001 and <0.0001, respectively). In correlation analysis, a positive correlation was found between T-cadherin, E-cadherin, PR and ER H-score (p 0.05). Conclusions: T-cadherin, E-cadherin, ER and PR H -score were found lowest in endometriotic nodule tissue, the highest in endometrium tissue. The finding of lower expression of PR-α in endometriotic nodule in our study may be related to decrease in progesterone effect which could not inhibit the decrease in the expression of T-cadherin and E-cadherin, thus the invasiveness of endometriotic nodule. These findings suggest that endometriotic nodule and ovarian endometrioma tissues have a different biology. Endocrinology & Metabolism T-cadherin E-cadherin progesterone receptor oestrogen receptor endometriosis endometriotic nodule endometrioma Figures Figure 1 Figure 2 Introduction: Endometriosis affects 7–10% of women of reproductive age [ 1 , 2 ]. The prevalence of endometriosis increases up to 40–50% in patients with infertility and pelvic pain [ 3 – 5 ]. Endometriosis is categorised into three classes as peritoneal, ovarian and deep infiltrative endometriosis (DIE) by the American Society of Reproductive Medicine (ASRM) [ 6 ]. DIE is diagnosed when the depth of endometriotic foci exceed the peritoneal surface by more than 5 mm [ 7 ]. Deep infiltrative endometriosis can affect the bladder, ureter, vagina or uterosacral ligaments. It is believed that each of the three classes of lesions have a separate pathogenesis [ 8 ]. Different genetic mutations were found in endometriotic nodules from peritoneal and ovarian endometriosis lesions [ 9 ]. Although endometriosis is a benign disease, it shows features similar to malignant diseases such as cellular invasion, metastasis to lymph nodes and distant organs, abnormal morphology, migration towards nerve bundles, unregulated cell proliferation, neoangiogenesis, DNA aneuploidy and loss of heterozygosity [ 10 ]. The epithelial-mesenchymal transition (EMT) is one of the most important events in cancer invasion [ 11 ]. Similar to cancer invasion, the EMT process is thought to play a role in the pathogenesis of pelvic endometriosis [ 12 ]. The cadherin family is a transmembrane glycoprotein family involved in cellular events such as cell-cell adhesion, cell recognition and signalling [ 13 ]. There is serious evidence that cadherin molecules play a role in tumour development, invasion and metastasis [ 14 – 16 ]. For instance, E-cadherin down-regulation has been associated with a poor prognosis in prostate cancer [ 17 ]. In addition, E-cadherin is a tumour suppressor molecule that is important in the EMT process [ 18 ]. T-cadherin is structurally different from other cadherin molecules [ 19 ]. Like E-cadherin, T-cadherin is thought to be a tumour suppressor molecule. In previous studies, T-cadherin down-regulation has been shown in lung, ovarian, bladder, cervical and prostate cancers. It has been shown that the invasive potential and growth rate of cells in breast cancer slows down with T-cadherin overexpression [ 20 ]. In the literature examining T-cadherin level in endometriosis tissue, T-cadherin level was found to be low in endometriosis tissue [ 21 ]. It was shown that the expression of E-cadherin was decreased in endometriotic nodule tissue [ 22 ]. In fact, in samples taken from invasive parts of endometriotic nodules close to the rectum, E-cadherin levels were significantly lower in glands located at the front of the lesions [ 23 ]. In healthy endometrial tissue, oestrogen receptors (ER) and progesterone receptors (PR) are densely expressed on endometrial cells, similar to endometrial cells in endometriosis tissue. However, the density of these receptors is less than in healthy endometrial tissue [ 23 ]. Drugs containing progesterone are frequently used in the medical treatment of endometriosis. Especially in individuals with high endometriosis stage and endometriotic nodules, a significant proportion of patients do not respond to progesterone treatment [ 24 ]. As a cause of this unresponsiveness, it is thought that there may be mechanisms such as cells having a small number of progesterone receptors that create resistance to progesterone, and abnormalities in post-receptor mechanisms [ 25 , 26 ]. Deficient methylation of the ERβ promoter results in pathological overexpression of ER-β in endometriotic stromal cells. High levels of ER-β suppress ER-α expression. A severely high ER-β to ER-α ratio in endometriotic stromal cells is associated with suppressed progesterone receptor contributing to progesterone resistance [ 27 ]. Studies examining endometriotic nodule tissue in the literature suggest that nodule tissue is biologically different from ovarian endometrioma tissue in many ways. Progesterone was shown to supress the EMT process in in vitro studies [ 28 – 32 ]. Progesterone was also shown to supress the EMT processes in endometrium cancer tissue. [ 30 ], and increase the expression of E-cadherin in Ishikawa cells [ 33 ]. In the single study that investigated the T-cadherine levels in endometriosis tissue in literature it was reported that the decreased T-cadherine expression may be linked to progesterone resistance but noticed that it was a subject of future studies [ 21 ]. In the present study we aimed to investigate the relationship of T-cadherin, E-cadherin, PR-α ve ER-α levels and their receptors in endometrioma, endometriotic nodule and normal endometriosis tissues. Material And Methods: Ethical approval Ethical approval was obtained from the Non-invasive Research Ethics Committee of Kütahya Health Sciences University, Kütahya, Turkey (Research number: 2020 / 07-10). The study protocols were in accordance with the Helsinki Committee requirements. Patients and tissue sample collection In this case-control study, subjects who underwent endometriosis surgery at Kütahya Health Sciences University Evliya Çelebi Training and Research Hospital and Söke Private Egemed Hospital between July 2016 and July 2020 constituted the study group and patients who had endometrial sampling before myomectomy constituted the control group. 20 cases in which endometriotic nodule tissue was examined were included in the 1st group, 30 cases in which ovarian endometrioma tissue was examined were included in the 2nd group, and 30 cases in which endometrial sampling tissue was examined (after which there was no intraoperative endometriosis performed before abdominal myomectomy) were included in the 3rd group. As the inclusion criteria for the study, women who did not use an intrauterine device and did not receive hormonal treatment for the last 3 months were accepted. Subjects with malignancy, those receiving immunosuppressive therapy, and those using drugs such as gonadotropin-releasing hormone agonist or danazol effective on ER and PR were not included in the study. Demographic data of the cases (age, preoperative VAS score in cases with nodules) and surgical information (endometriosis stage according to ASRM classification, endometrioma diameter, nodule diameter in cases with nodules, presence of adhesion) were recorded. T-cadherin, E-cadherin, ER-α and PR-α staining levels of groups were compared immunohistochemically. In this study, endometriosis was defined as the presence of endometrial glands and stroma-like lesions outside of the uterus [ 2 ]. DIE diagnosis was made according to criteria of histopathologically fibrous/muscular infiltration of organs and anatomical structures containing endometrial tissue below the peritoneum, regardless of the depth of infiltration [ 34 ]. Deep infiltrating endometriosis was grafted beneath the peritoneum in five different sites in the pelvic area: upper and lower parts of both uterosacral ligaments close to the ureters [ 10 ] and rectovaginal septum [ 7 ]. Sections taken from the endometriotic nodule were taken from the side facing the bowel segment for the rectovaginal nodule. Sections for other nodules were taken from the opposite side of the uterus. Immunohistochemical examination (IHC) : All tissue samples were fixed with 10% formaldehyde solution and embedded in paraffin blocks. Blocks that contained placenta samples representing the diagnosis were chosen. All blocks were sectioned with 4 mm thickness. Sections were deparaffinised in xylene solution and rehydrated in decreasing concentrations of ethanol. After a washing step in phosphate buffer solution (PBS), sections were incubated in 3% H2O2 solution for 10 min to inhibit endogenous peroxidase activity. Sections were boiled in 0.06% trypsin/EDTA (0.25 mM) solution at 850 W for 5 min and then at 350 W for 5 min. in a microwave. Then, sections were incubated with primary antibodies at 4 C for a 24 h. period. The primary antibodies used were monoclonal anti-T-cadherin (CDH13) antibody (Sigma-Aldrich Corp., USA, 1:100 dilution), anti-E-cadherin antibody (Sigma-Aldrich Corp., USA, 1:100 dilution), anti-ER-α antibody (Sigma-Aldrich Corp., USA, 1:100 dilution) and anti-PR-α antibody (Sigma-Aldrich Corp., USA, 1:100 dilution). Antibodies were boiled with citrate buffer solution in a microwave oven. All sections were washed with PBS and then incubated with horseradish peroxidase-conjugated goat anti-rabbit IgG for a 60 min. period. Diaminobenzidine chromogen was then added, and Mayer haematoxylin was used for counterstaining. Imaging analysis : An Olympus BX53 light microscope was used for evaluation, and each section was photographed with an Olympos DP27 digital camera. Five high magnification views were randomly selected in each immunohistochemical section. According to the proportion of positive cells and staining intensity of positive cells, we made a semi-quantitative score grade. The staining intensity level scoring was described as nonstaining for 0 points, faint staining for 1 point, moderate staining for 2 points and strong staining for 3 points. Immunoreactivity was assessed using a four-tiered scale: 0–5% (0), 6–20% (+ 1), 21 50% (+ 2), 51–100% (+ 3). H -score was calculated to compare the expression of T-cadherin in IHC staining based on the percentage of cells stained at each intensity level, ranging from 0 for negative staining to 3 for the most intense staining using the following formula: H -score = (% cells with intensity level 1 ∗ 1) + (% cells with intensity level 2 ∗ 2) + (% cells with intensity level 3 ∗ 3) [ 35 ]. Statistical analysis : For data analysis, the Statistical Package for the Social Sciences (SPSS), version 21.0 (SPSS Inc., Chicago, IL) and R statistical computing software (version 3.6.1, https://www.r-project.org/ ) were used. Data are presented as mean ± SD and median [25th percentile; 75th percentile]. Conformity to normal distribution was evaluated with the Kolmogorov-Smirnov test or Shapiro-Wilk tests. Differences of continuous variables between groups were evaluated with ANOVA or Kruskal Wallis test. In post-hoc analysis Tukey's test was used. Relationships between categorical data and groups were analyzed by Chi-Square test. Correlation between variables was evaluated using Pearson or Spearman's correlation coefficient. A value of p < 0.05 was considered statistically significant. Results: Mean age of the 84 women included in the study was 34.39 ∓ 7.18 years. There was no significant difference in age of the groups in terms of BMI data (p > 0.05). T-cadherin, E-cadherin, ER and PR H-score were lowest in endometriotic nodule tissue and highest in endometrial tissue (p < 0.0001, < 0.0001, < 0.0001, < 0.0001, respectively). Demographics, T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor H-score levels of groups are given in Table 1. Additionally, T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor H-score of groups are given in Fig. 1. Endometrioma size was 7.06 ∓ 2.56 cm. There was no difference in CA125 levels between the endometriotic nodule group and the endometrioma group (70.29 ∓ 44.76 vs 66.56 ∓ 37.35; p = 0.807). There was no difference between the endometriotic nodule group and the endometrioma group in terms of visual analogue score (VAS) in the preoperative period (8 [ 6 – 10 ] vs 8 [ 6 – 10 ]; p = 0.292). A positive correlation was found between T-cadherin, E-cadherin, PR and ER H-score in correlation analysis (p 0.05). T-cadherin, E-cadherin, PR and ER staining levels of the groups in terms of immunohistochemistry are given in Fig. 2. Discussion: 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 [ 23 ]. 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 [ 22 ]. 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 [ 39 ]. 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 [ 21 ]. 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 [ 24 ]. 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 [ 43 ]. 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 [ 27 ]. 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 [ 44 ]. 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 [ 45 ]. 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 [ 46 ]. 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. Abbreviations: PR: progesterone receptor; ER: oestrogen receptor; DIE: deep infiltrative endometriosis; ASRM: American Society of Reproductive Medicine; EMT: epithelial-mesenchymal transition; VAS: visual analog scale; IHC: Immunohistochemical examination; PBS: in phosphate buffer solution; EDTA: Ethylenediaminetetraacetic acid Declarations: Acknowledgement We are grateful to Mr. Omer Faruk Ciftci for his assistance in editing the pictures and Assistant Profesor Onur Ince for her help in statistical analysis in our study. Authorship Contributions I.B. designed the study, performed experiments, acquired, analyzed and interpreted the data and produced the article. U.K. designed the study and analyzed and interpreted the data. S.S. performed experiments, interpreted the data and drafted the article. All authors critically revised the article and approved the final version. Funding No financial support was received for this study. Availability of data and materials All data generated or analyzed during this study are included in this published article. Ethics approval and consent to participate All procedures performed in studies involving humans were in accordance with the ethical standards of the institution or practice at which studies were conducted (Institutional Ethical Committee of the Kütahya Health Sciences University, School of Medicine-(Research number: 2020 / 07-10) Consent for publication: All patients gave written informed consent for publication. Competing interests No authors have any conflict of interest to report. References: Wheeler JM. Epidemiology of endometriosis-associated infertility. Reprod Med. 1989;34(1):41-6. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;13-19;364(9447):1789-99. Gordts S, Puttemans P, Gordts S, et al. Transvaginal endoscopy and small ovarian endometriomas: unravelling the missing link? Gynecol Surg. 2014;11(1):3-7. Meuleman C, Vandenabeele B, Fieuws S, et al. 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Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2020 Mar 9. doi: 10.5507/bp.2020.006. Epub ahead of print. Zanatta A, Pereira RM, Rocha AM, et al. The relationship among HOXA10, estrogen receptor α, progesterone receptor, and progesterone receptor B proteins in rectosigmoid endometriosis: a tissue microarray study. Reprod Sci. 2015;22(1):31-7. Donnez J, Nisolle M, Smoes P, et al. Peritoneal endometriosis and "endometriotic" nodules of the rectovaginal septum are two different entities. Fertil Steril. 1996;66(3):362-8. Liu X, Zhang Q, Guo SW. Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis. Reprod Sci. 2018;25(3):329-340. Tables: Table 1 Demographic, T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor H-score levels of groups Endometriotic nodule (n = 24) Endometrioma (n = 30) Endometrium (n = 30) P value Age (years) a 35,62 ∓ 57,56 32,60 ∓ 9,06 35,20 ∓ 3,87 0.231 35 [ 31 , 5 – 39 , 5 ] 23,15 [ 26 – 39 ] 36 [ 33 – 38 ] BMI (kg/m2) a 26,89 ∓ 4,68 24,88 ∓ 4,24 26,34 ∓ 4,46 0.227 28,05 [ 22 , 15 – 30 , 25 ] 35 [ 21 , 5 – 29 , 1 ] 25,94 [22,95 − 30,04] T-cadherin H-score a 26,21 ∓ 28,92 121,47 ∓ 57,82 200,17 ∓ 78,48 < 0.0001* 20 [ 10 – 30 ] 120 [70–160] 220 [180–270] E-cadherin H-score a 25,00 ∓ 20,43 121,00 ∓ 59,50 246,00 ∓ 70,00 < 0.0001* 20 [ 10 – 35 ] 105 80–170] 280 [200–300] PR H-score b 42,92 ∓ 40,80 137,67 ∓ 68,36 294,33 ∓ 45,46 < 0.0001* 30 [10–90] 105 [80–160] 300 [290–300] ER H-score b 42,08 ∓ 40,54 120,00 ∓ 72,25 277,33 ∓ 32,16 < 0.0001* 25 [10–70] 100 [60–160] 295 [260–300] BMI: body mass index; PR: progesterone receptor; ER: oestrogen receptor. Data are presented as mean ± SD, median [interquartile range] or number (percentage) a: ANOVA test; b: Kruskal Wallis test All of the pairwise comparisons of T-cadherin, E-cadherin, PR and ER H-score between groups were statistically significant (< 0.0001 for all). Statistically, significant comparisons were marked with * Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-151163","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":8592728,"identity":"c8c19678-f4f8-42ec-bf44-69fbebf45b04","order_by":0,"name":"Ismail Biyik","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYDCCA4xtDAkMEgb8EmCuhAzxWiRnMDA2ALXwEKGFgQ1EGRjcAGthIKyF7/bhtgcP2yyMjW83H390o8aCh4H98NEN+LRInktsN0hskzAzu3MssTnnGNBhPGlpN/BpMTjD2CYB1GJjdiPHsDmHDahFgseMOC3GM0Ba/pGgxcxAAqglt40ILZJnGNsNEs5JGEvcSEucndsnwcNGyC98Z9ifPfxRVmfYPyP5wOecb3Vy/OyHj+HVAgaMbEgcNpzKUMAf4pSNglEwCkbBCAUAu9RHkUIErlkAAAAASUVORK5CYII=","orcid":"","institution":"Kutahya Saglik Bilimleri Universitesi Tip Fakultesi","correspondingAuthor":true,"prefix":"","firstName":"Ismail","middleName":"","lastName":"Biyik","suffix":""},{"id":8592729,"identity":"1c1836bf-1a02-4149-a8af-3e8fdd3f72c7","order_by":1,"name":"Uzeyir Kalkan","email":"","orcid":"","institution":"Koc University: Koc Universitesi","correspondingAuthor":false,"prefix":"","firstName":"Uzeyir","middleName":"","lastName":"Kalkan","suffix":""},{"id":8592730,"identity":"5b967509-db67-406c-bb2e-6330c737b6b0","order_by":2,"name":"Sercan Simsek","email":"","orcid":"","institution":"Evliya Çelebi Training and Research Hospital: Kutahya Saglik Bilimleri Universitesi Evliya Celebi Yerleske","correspondingAuthor":false,"prefix":"","firstName":"Sercan","middleName":"","lastName":"Simsek","suffix":""}],"badges":[],"createdAt":"2021-01-19 23:05:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-151163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-151163/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":5165395,"identity":"0d3d012c-f050-4789-b8c4-05aeb05a951d","added_by":"auto","created_at":"2021-01-21 19:31:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":104519,"visible":true,"origin":"","legend":"Comparison of the endometrial gland and stromal cells T-cadherin, E-cadherin, ER and PR H-scores among groups (ER: oestrogen receptor, PR: progesterone receptor).","description":"","filename":"Onlineendometriosisplot.png","url":"https://assets-eu.researchsquare.com/files/rs-151163/v1/4259c81eafbe5778450bec5b.png"},{"id":5165396,"identity":"fd5585c0-77c9-45b8-865f-0286d60c0ed0","added_by":"auto","created_at":"2021-01-21 19:31:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":8233362,"visible":true,"origin":"","legend":"In immunhistological examination, T-cadherin staining in endometrial gland and stromal cells in A) Endometriotic nodule tissue showed low or no staining in endometrial gland and stromal cells, B) Endometrioma tissue showed moderate staining in endometrial gland and stromal cells, C) Normal endometrium tissue showing high staining was observed in endometrial gland and stromal cells; E-cadherin staining in endometrial gland and stromal cells in D) Endometriotic nodule tissue showed low or no staining in endometrial gland and stromal cells, E) Endometrioma tissue showed moderate staining in endometrial gland and stromal cells, F) Normal endometrium tissue showing high staining was observed in endometrial gland and stromal cells; PR staining in endometrial gland and stromal cells; G) Endometriotic nodule tissue showed low or no nuclear staining in endometrial gland and stromal cells, H) Endometrioma tissue showed moderate nuclear staining in endometrial gland and stromal cells, I) Normal endometrium tissue showing high nuclear staining was observed in endometrial gland and stromal cells; ER staining in endometrial gland and stromal cells; J) Endometriotic nodule tissue showed low or no nuclear staining in endometrial gland and stromal cells, K) Endometrioma tissue showed moderate nuclear staining in endometrial gland and stromal cells, L) Normal endometrium tissue showing high nuclear staining was observed in endometrial gland and stromal cells. (x200)","description":"","filename":"Immun.jpg","url":"https://assets-eu.researchsquare.com/files/rs-151163/v1/1b88881e030728d1fc7d88d6.jpg"},{"id":13650414,"identity":"475d3c07-fa8e-4464-b16e-1db95ee00b70","added_by":"auto","created_at":"2021-09-17 09:41:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":805246,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-151163/v1/085586fa-7199-4627-ac8c-c3e36e7f422f.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe Endometriotic Nodule Has Lower T-cadherin, E-cadherin, Progesterone Receptor and Oestrogen Receptor Than Endometrioma Tissue\u003c/p\u003e","fulltext":[{"header":"Introduction:","content":" \u003cp\u003eEndometriosis affects 7\u0026ndash;10% of women of reproductive age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The prevalence of endometriosis increases up to 40\u0026ndash;50% in patients with infertility and pelvic pain [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Endometriosis is categorised into three classes as peritoneal, ovarian and deep infiltrative endometriosis (DIE) by the American Society of Reproductive Medicine (ASRM) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. DIE is diagnosed when the depth of endometriotic foci exceed the peritoneal surface by more than 5\u0026nbsp;mm [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Deep infiltrative endometriosis can affect the bladder, ureter, vagina or uterosacral ligaments. It is believed that each of the three classes of lesions have a separate pathogenesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Different genetic mutations were found in endometriotic nodules from peritoneal and ovarian endometriosis lesions [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough endometriosis is a benign disease, it shows features similar to malignant diseases such as cellular invasion, metastasis to lymph nodes and distant organs, abnormal morphology, migration towards nerve bundles, unregulated cell proliferation, neoangiogenesis, DNA aneuploidy and loss of heterozygosity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The epithelial-mesenchymal transition (EMT) is one of the most important events in cancer invasion [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Similar to cancer invasion, the EMT process is thought to play a role in the pathogenesis of pelvic endometriosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe cadherin family is a transmembrane glycoprotein family involved in cellular events such as cell-cell adhesion, cell recognition and signalling [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. There is serious evidence that cadherin molecules play a role in tumour development, invasion and metastasis [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. For instance, E-cadherin down-regulation has been associated with a poor prognosis in prostate cancer [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition, E-cadherin is a tumour suppressor molecule that is important in the EMT process [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. T-cadherin is structurally different from other cadherin molecules [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Like E-cadherin, T-cadherin is thought to be a tumour suppressor molecule. In previous studies, T-cadherin down-regulation has been shown in lung, ovarian, bladder, cervical and prostate cancers. It has been shown that the invasive potential and growth rate of cells in breast cancer slows down with T-cadherin overexpression [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the literature examining T-cadherin level in endometriosis tissue, T-cadherin level was found to be low in endometriosis tissue [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. It was shown that the expression of E-cadherin was decreased in endometriotic nodule tissue [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In fact, in samples taken from invasive parts of endometriotic nodules close to the rectum, E-cadherin levels were significantly lower in glands located at the front of the lesions [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn healthy endometrial tissue, oestrogen receptors (ER) and progesterone receptors (PR) are densely expressed on endometrial cells, similar to endometrial cells in endometriosis tissue. However, the density of these receptors is less than in healthy endometrial tissue [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Drugs containing progesterone are frequently used in the medical treatment of endometriosis. Especially in individuals with high endometriosis stage and endometriotic nodules, a significant proportion of patients do not respond to progesterone treatment [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. As a cause of this unresponsiveness, it is thought that there may be mechanisms such as cells having a small number of progesterone receptors that create resistance to progesterone, and abnormalities in post-receptor mechanisms [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Deficient methylation of the ERβ promoter results in pathological overexpression of ER-β in endometriotic stromal cells. High levels of ER-β suppress ER-α expression. A severely high ER-β to ER-α ratio in endometriotic stromal cells is associated with suppressed progesterone receptor contributing to progesterone resistance [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Studies examining endometriotic nodule tissue in the literature suggest that nodule tissue is biologically different from ovarian endometrioma tissue in many ways. Progesterone was shown to supress the EMT process in in vitro studies [\u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Progesterone was also shown to supress the EMT processes in endometrium cancer tissue. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and increase the expression of E-cadherin in Ishikawa cells [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the single study that investigated the T-cadherine levels in endometriosis tissue in literature it was reported that the decreased T-cadherine expression may be linked to progesterone resistance but noticed that it was a subject of future studies [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present study we aimed to investigate the relationship of T-cadherin, E-cadherin, PR-α ve ER-α levels and their receptors in endometrioma, endometriotic nodule and normal endometriosis tissues.\u003c/p\u003e "},{"header":"Material And Methods:","content":"\u003cp\u003e\u003cem\u003eEthical approval \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from the Non-invasive Research Ethics Committee of K\u0026uuml;tahya Health Sciences University, K\u0026uuml;tahya, Turkey (Research number: 2020 / 07-10). The study protocols were in accordance with the Helsinki Committee requirements.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePatients and tissue sample collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn this case-control study, subjects who underwent endometriosis surgery at K\u0026uuml;tahya Health Sciences University Evliya \u0026Ccedil;elebi Training and Research Hospital and S\u0026ouml;ke Private Egemed Hospital between July 2016 and July 2020 constituted the study group and patients who had endometrial sampling before myomectomy constituted the control group. 20 cases in which endometriotic nodule tissue was examined were included in the 1st group, 30 cases in which ovarian endometrioma tissue was examined were included in the 2nd group, and 30 cases in which endometrial sampling tissue was examined (after which there was no intraoperative endometriosis performed before abdominal myomectomy) were included in the 3rd group.\u003c/p\u003e\n\u003cp\u003eAs the inclusion criteria for the study, women who did not use an intrauterine device and did not receive hormonal treatment for the last 3 months were accepted. Subjects with malignancy, those receiving immunosuppressive therapy, and those using drugs such as gonadotropin-releasing hormone agonist or danazol effective on ER and PR were not included in the study. Demographic data of the cases (age, preoperative VAS score in cases with nodules) and surgical information (endometriosis stage according to ASRM classification, endometrioma diameter, nodule diameter in cases with nodules, presence of adhesion) were recorded. T-cadherin, E-cadherin, ER-\u0026alpha; and PR-\u0026alpha; staining levels of groups were compared immunohistochemically.\u003c/p\u003e\n\u003cp\u003eIn this study, endometriosis was defined as the presence of endometrial glands and stroma-like lesions outside of the uterus [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. DIE diagnosis was made according to criteria of histopathologically fibrous/muscular infiltration of organs and anatomical structures containing endometrial tissue below the peritoneum, regardless of the depth of infiltration [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eDeep infiltrating endometriosis was grafted beneath the peritoneum in five different sites in the pelvic area: upper and lower parts of both uterosacral ligaments close to the ureters [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e] and rectovaginal septum [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Sections taken from the endometriotic nodule were taken from the side facing the bowel segment for the rectovaginal nodule. Sections for other nodules were taken from the opposite side of the uterus.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eImmunohistochemical examination (IHC)\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eAll tissue samples were fixed with 10% formaldehyde solution and embedded in paraffin blocks. Blocks that contained placenta samples representing the diagnosis were chosen. All blocks were sectioned with 4\u0026nbsp;mm thickness. Sections were deparaffinised in xylene solution and rehydrated in decreasing concentrations of ethanol. After a washing step in phosphate buffer solution (PBS), sections were incubated in 3% H2O2 solution for 10\u0026nbsp;min to inhibit endogenous peroxidase activity. Sections were boiled in 0.06% trypsin/EDTA (0.25\u0026nbsp;mM) solution at 850\u0026nbsp;W for 5\u0026nbsp;min and then at 350\u0026nbsp;W for 5\u0026nbsp;min. in a microwave. Then, sections were incubated with primary antibodies at 4\u0026nbsp;C for a 24\u0026nbsp;h. period. The primary antibodies used were monoclonal anti-T-cadherin (CDH13) antibody (Sigma-Aldrich Corp., USA, 1:100 dilution), anti-E-cadherin antibody (Sigma-Aldrich Corp., USA, 1:100 dilution), anti-ER-\u0026alpha; antibody (Sigma-Aldrich Corp., USA, 1:100 dilution) and anti-PR-\u0026alpha; antibody (Sigma-Aldrich Corp., USA, 1:100 dilution). Antibodies were boiled with citrate buffer solution in a microwave oven. All sections were washed with PBS and then incubated with horseradish peroxidase-conjugated goat anti-rabbit IgG for a 60\u0026nbsp;min. period. Diaminobenzidine chromogen was then added, and Mayer haematoxylin was used for counterstaining.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eImaging analysis\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eAn Olympus BX53 light microscope was used for evaluation, and each section was photographed with an Olympos DP27 digital camera. Five high magnification views were randomly selected in each immunohistochemical section. According to the proportion of positive cells and staining intensity of positive cells, we made a semi-quantitative score grade. The staining intensity level scoring was described as nonstaining for 0 points, faint staining for 1 point, moderate staining for 2 points and strong staining for 3 points. Immunoreactivity was assessed using a four-tiered scale: 0\u0026ndash;5% (0), 6\u0026ndash;20% (+\u0026thinsp;1), 21 50% (+\u0026thinsp;2), 51\u0026ndash;100% (+\u0026thinsp;3). \u003cem\u003eH\u003c/em\u003e-score was calculated to compare the expression of T-cadherin in IHC staining based on the percentage of cells stained at each intensity level, ranging from 0 for negative staining to 3 for the most intense staining using the following formula: \u003cem\u003eH\u003c/em\u003e-score = (% cells with intensity level 1 \u0026lowast; 1) + (% cells with intensity level 2 \u0026lowast; 2) + (% cells with intensity level 3 \u0026lowast; 3) [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eFor data analysis, the Statistical Package for the Social Sciences (SPSS), version 21.0 (SPSS Inc., Chicago, IL) and R statistical computing software (version 3.6.1, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003c/span\u003e) were used. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and median [25th percentile; 75th percentile]. Conformity to normal distribution was evaluated with the Kolmogorov-Smirnov test or Shapiro-Wilk tests. Differences of continuous variables between groups were evaluated with ANOVA or Kruskal Wallis test. In post-hoc analysis Tukey's test was used. Relationships between categorical data and groups were analyzed by Chi-Square test. Correlation between variables was evaluated using Pearson or Spearman's correlation coefficient. A value of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results:","content":"\u003cp\u003eMean age of the 84 women included in the study was 34.39\u0026thinsp;∓\u0026thinsp;7.18\u0026nbsp;years. There was no significant difference in age of the groups in terms of BMI data (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). T-cadherin, E-cadherin, ER and PR H-score were lowest in endometriotic nodule tissue and highest in endometrial tissue (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, \u0026lt;\u0026thinsp;0.0001, \u0026lt;\u0026thinsp;0.0001, \u0026lt;\u0026thinsp;0.0001, respectively). Demographics, T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor H-score levels of groups are given in Table\u0026nbsp;1. Additionally, T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor H-score of groups are given in Fig.\u0026nbsp;1.\u003c/p\u003e\n\u003cp\u003eEndometrioma size was 7.06\u0026thinsp;∓\u0026thinsp;2.56\u0026nbsp;cm. There was no difference in CA125 levels between the endometriotic nodule group and the endometrioma group (70.29\u0026thinsp;∓\u0026thinsp;44.76 vs 66.56\u0026thinsp;∓\u0026thinsp;37.35; p\u0026thinsp;=\u0026thinsp;0.807). There was no difference between the endometriotic nodule group and the endometrioma group in terms of visual analogue score (VAS) in the preoperative period (8 [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e] vs 8 [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]; p\u0026thinsp;=\u0026thinsp;0.292).\u003c/p\u003e\n\u003cp\u003eA positive correlation was found between T-cadherin, E-cadherin, PR and ER H-score in correlation analysis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for each). No correlation was found between age, BMI, VAS score, CA125, endometrioma size and severity of dysmenorrhea, dyspareunia or dystonia (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003eT-cadherin, E-cadherin, PR and ER staining levels of the groups in terms of immunohistochemistry are given in Fig.\u0026nbsp;2.\u003c/p\u003e"},{"header":"Discussion:","content":"\u003cp\u003eEndometriosis 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-\u0026alpha; and ER-\u0026alpha; 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.\u003c/p\u003e\n\u003cp\u003eSolares 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 [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. In various studies, it has been shown that NFD is increased in DIE cases compared to peritoneal and ovarian endometriosis cases [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]. 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 [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. 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 [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]. 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 [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. 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.\u003c/p\u003e\n\u003cp\u003eProgesterone 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 [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. 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 [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. While there is a reduction in the size of ovarian endometriomas with hormonal treatment [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e], the resistance of endometriotic nodule tissue to medical treatments suggests that the biology of these two tissues is different [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e]. Studies show that oestrogen and progesterone receptors in endometriosis tissue are less than in normal endometrial tissue [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]. Deficient methylation of the ER-\u0026beta; promoter results in pathological overexpression of ER-\u0026beta; in endometriotic stromal cells. High levels of ER-\u0026beta; suppress ER-\u0026alpha; expression. A severely high ER\u0026beta;-to-ER\u0026alpha; ratio in endometriotic stromal cells is associated with suppressed progesterone receptor contributing to progesterone resistance [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the present study we found decresed levels of ER-\u0026alpha; 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.\u003c/p\u003e\n\u003cp\u003eZanatta et al. found that expression of ER-\u0026alpha; (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 [\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e]. 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 [\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]. 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 [\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e]. 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-\u0026alpha; in the present study versus ER-\u0026beta; 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-\u0026alpha; and PR-\u0026alpha; levels in the current study. The fact that T-cadherin and E-cadherin staining levels and ER-\u0026alpha; and PR-\u0026alpha; 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.\u003c/p\u003e\n\u003cp\u003eIn 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-\u0026alpha; 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.\u003c/p\u003e\n\u003cp\u003eIn 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-\u0026alpha;, ER-\u0026alpha;, 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.\u003c/p\u003e"},{"header":"Abbreviations:","content":"\u003cp\u003ePR: progesterone receptor; ER: oestrogen receptor; DIE: deep infiltrative endometriosis; ASRM: American Society of Reproductive Medicine; EMT: epithelial-mesenchymal transition; VAS: visual analog scale; IHC: Immunohistochemical examination; PBS: in phosphate buffer solution; EDTA: Ethylenediaminetetraacetic acid\u003c/p\u003e"},{"header":"Declarations:","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to Mr. Omer Faruk Ciftci for his assistance in editing the pictures and Assistant Profesor Onur Ince for her help in statistical analysis in our study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship Contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI.B. designed the study, performed experiments, acquired, analyzed and interpreted the data and produced the article. U.K. designed the study and analyzed and interpreted the data. S.S. performed experiments, interpreted the data and drafted the article. All authors critically revised the article and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving humans were in accordance with the ethical standards of the institution or practice at which studies were conducted (Institutional Ethical Committee of the K\u0026uuml;tahya Health Sciences University, School of Medicine-(Research number: 2020 / 07-10)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients gave written informed consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo authors have any conflict of interest to report.\u003c/p\u003e"},{"header":"References:","content":"\u003col\u003e\n\u003cli\u003eWheeler JM. 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Reprod Sci. 2018;25(3):329-340.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables:","content":"\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDemographic, T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor H-score levels of groups\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEndometriotic nodule\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEndometrioma\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEndometrium\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP value\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (years)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35,62\u0026thinsp;∓\u0026thinsp;57,56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32,60\u0026thinsp;∓\u0026thinsp;9,06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35,20\u0026thinsp;∓\u0026thinsp;3,87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.231\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23,15 [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 [\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI (kg/m2) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26,89\u0026thinsp;∓\u0026thinsp;4,68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24,88\u0026thinsp;∓\u0026thinsp;4,24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26,34\u0026thinsp;∓\u0026thinsp;4,46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.227\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28,05 [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25,94 [22,95\u0026thinsp;\u0026minus;\u0026thinsp;30,04]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT-cadherin H-score \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26,21\u0026thinsp;∓\u0026thinsp;28,92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121,47\u0026thinsp;∓\u0026thinsp;57,82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e200,17\u0026thinsp;∓\u0026thinsp;78,48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e120 [70\u0026ndash;160]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e220 [180\u0026ndash;270]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eE-cadherin H-score \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25,00\u0026thinsp;∓\u0026thinsp;20,43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121,00\u0026thinsp;∓\u0026thinsp;59,50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e246,00\u0026thinsp;∓\u0026thinsp;70,00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 80\u0026ndash;170]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e280 [200\u0026ndash;300]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePR H-score\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42,92\u0026thinsp;∓\u0026thinsp;40,80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137,67\u0026thinsp;∓\u0026thinsp;68,36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e294,33\u0026thinsp;∓\u0026thinsp;45,46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 [10\u0026ndash;90]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 [80\u0026ndash;160]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e300 [290\u0026ndash;300]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eER H-score\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42,08\u0026thinsp;∓\u0026thinsp;40,54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e120,00\u0026thinsp;∓\u0026thinsp;72,25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e277,33\u0026thinsp;∓\u0026thinsp;32,16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 [10\u0026ndash;70]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100 [60\u0026ndash;160]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e295 [260\u0026ndash;300]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eBMI: body mass index; PR: progesterone receptor; ER: oestrogen receptor.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, median [interquartile range] or number (percentage)\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003ea: ANOVA test; b: Kruskal Wallis test\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eAll of the pairwise comparisons of T-cadherin, E-cadherin, PR and ER H-score between groups were statistically significant (\u0026lt;\u0026thinsp;0.0001 for all).\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eStatistically, significant comparisons were marked with *\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"T-cadherin, E-cadherin, progesterone receptor, oestrogen receptor, endometriosis, endometriotic nodule, endometrioma","lastPublishedDoi":"10.21203/rs.3.rs-151163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-151163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTo compare the T-cadherin, E-cadherin, PR and ER staining levels of endometriotic nodules, ovarian endometriomas and normal endometrial tissues.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eEndometriotic nodules of 24 cases, endometrioma of 30 cases and normal endometrial tissues of 30 cases were examined. T-cadherin, E-cadherin, ER-α and PR-α staining levels of endometriotic nodular tissues, endometrioma tissues and endometrial tissues were compared immunohistochemically. \u003cem\u003eH\u003c/em\u003e-score was calculated to compare the expression of T-cadherin, E-cadherin, ER-α, PR-α in IHC staining based on the percentage of cells stained at each intensity level.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eT-cadherin, E-cadherin, ER and PR H-score were found lowest in endometriotic nodule tissue and the highest in endometrial tissue (p \u0026lt;0.0001, \u0026lt;0.0001, \u0026lt;0.0001 and \u0026lt;0.0001, respectively). In correlation analysis, a positive correlation was found between T-cadherin, E-cadherin, PR and ER H-score (p \u0026lt;0.0001 for each). No correlation was found between age, BMI, VAS score, CA125, endometrioma size and the severity of dysmenorrhea, dyspareunia and dystonia (p\u0026gt; 0.05).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eT-cadherin, E-cadherin, ER and PR \u003cem\u003eH\u003c/em\u003e-score were found lowest in endometriotic nodule tissue, the highest in endometrium tissue. The finding of lower expression of PR-α in endometriotic nodule in our study may be related to decrease in progesterone effect which could not inhibit the decrease in the expression of T-cadherin and E-cadherin, thus the invasiveness of endometriotic nodule. These findings suggest that endometriotic nodule and ovarian endometrioma tissues have a different biology.\u003c/p\u003e","manuscriptTitle":"The Endometriotic Nodule Has Lower T-cadherin, E-cadherin, Progesterone Receptor and Oestrogen Receptor Than Endometrioma Tissue","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-01-21 19:28:51","doi":"10.21203/rs.3.rs-151163/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5f1062a-3450-4cbc-998a-fb119719ab08","owner":[],"postedDate":"January 21st, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2011902,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2021-01-21T19:28:52+00:00","versionOfRecord":[],"versionCreatedAt":"2021-01-21 19:28:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-151163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-151163","identity":"rs-151163","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}