Induction of the epithelial-mesenchymal transition in the endometrium by chronic endometritis in infertile patients

Induction of the epithelial-mesenchymal transition in the endometrium by chronic endometritis in infertile patients | 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 article Induction of the epithelial-mesenchymal transition in the endometrium by chronic endometritis in infertile patients Mitsuaki Ishida, Akie Takebayashi, Fuminori Kimura, Jun Kitazawa, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-33791/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Apr, 2021 Read the published version in PLOS ONE → Version 1 posted You are reading this latest preprint version Abstract Background The purpose of the present study was to evaluate the relationship between chronic endometritis (CE) and the epithelial-mesenchymal transition (EMT) in the eutopic endometrium of infertile patients in the implantation phase. Methods Endometrial biopsy specimens from 74 infertility patients were enrolled. The presence of CE was investigated by immunostaining for CD138. Immunohistochemical staining for E-cadherin, N-cadherin, Slug, and Snail was performed, and expression profiles were statistically analyzed according to the presence of CE. When loss of E-cadherin expression and/or positive N-cadherin expression was detected, the specimen was considered EMT-positive. EMT-positive cases were also statistically analyzed according to the presence of CE. Patients’ characteristics were compared between the EMT-positive and EMT-negative groups. Logistic regression analysis was also performed with variables including age, body mass index (BMI), gravidity, parity, and each factor causing infertility to examine the independent effect of each variable on EMT-positive status. Results Loss of E-cadherin expression, N-cadherin expression and EMT-positive were significant in CE patients (p = 0.0037, 0.0039 and < 0.0001, respectively). Slug, cytoplasmic Snail, and nuclear Snail expression were significant in CE patients (p = 0.0008, 0.0004 and 0.028, respectively). Differences were detected in unexplained infertility and CE between EMT-positive and EMT-negative cases. Unexplained infertility and CE were identified as variables related to EMT-positive status on logistic analysis. Conclusion The EMT was frequent in the eutopic endometrium in infertile patients with CE. Since the EMT is associated with unexplained infertility and CE, the EMT appears to be involved in altered mechanisms of implantation. Obstetrics & Gynecology cadherin chronic endometritis epithelial-mesenchymal transition infertility Figures Figure 1 Background Chronic endometritis (CE) is a persistent chronic inflammatory process of the endometrium. CE is defined as infiltration of plasma cells in the endometrial stroma [1-4], and immunostaining for CD138, a plasma cell marker, has been reported to be a useful method for demonstrating plasma cells in the endometrial stroma [2, 5]. CE is usually asymptomatic or presents only with subtle symptoms, including abnormal uterine bleeding, dyspareunia, leucorrhea, and pelvic pain [1-3]. However, recent studies have focused on the association between CE and various gynecological conditions, and they have shown that CE has a positive relationship with infertility and implantation failure [6-8]. CE has also been shown to modify the function of endometrial cells and affect deciuda [9-12]. The epithelial-mesenchymal transition (EMT) is a process by which polarized epithelial cells lose polarity and intercellular contraction and acquire mesenchymal cell motility [13]. It is well known that the EMT plays crucial roles not only in normal embryological development, but also in several pathological conditions such as wound healing, fibrosis, and cancer development 12 . Focusing on the endometrium during the implantation phase, it has been shown that the mesenchymal-epithelial transition (MET), which is the reverse process to that of EMT, is induced in the endometrium and promotes the acceptance of embryos to the uterus [14, 15]. On the other hand, it has been found that the EMT also plays an important role in implantation [16, 17]. To date, no studies have evaluated the status of the endometrial EMT in the implantation phase in humans. Thus, the occurrence of the EMT with or without CE was analyzed in infertile patients to elucidate the pathophysiology of CE causing impaired implantation. In addition, the effect of the EMT on infertility was evaluated by examining which infertility cause was associated with the occurrence of the EMT in the endometrium. Methods Ethics This study conformed to the Clinical Research Guideline of Shiga University of Medical Science and was approved by the research ethics committee. Written, informed consent to participate in this study was obtained from all patients. This study included only patients over the age of 20. Patients and endometrial sampling A total of 74 infertile patients referred to the Department of Obstetrics and Gynecology of Shiga University of Medical Science from April 2015 to March 2018 were enrolled. They were all free from immune diseases, cancer, and diseases increasing susceptibility to infections, and they were not taking anti-inflammatory drugs or corticosteroids. Patients given 7 or more days of antibiotics for the treatment of CE before endometrial sampling were excluded. The ovulation day was determined by a urine ovulation test and ultrasonography, and the endometrium was collected 7-9 days after ovulation. On the day of endometrial sampling, the patients’ blood was sampled to measure serum levels of estradiol (E 2 ) and progesterone (P 4 ). Patients with E 2 <50 pg/mL and P4 <8 ng/mL were excluded. Endometrial tissue obtained by the first curettage from each patient was used in this study. Clinical information including age, gravidity, parity, body mass index(BMI), serum levels of E 2 and P 4 , and cause of infertility were obtained from the clinical records. Immunohistochemistry Formalin-fixed, paraffin-embedded tissue blocks of the resected and biopsied specimens were cut into 3-µm-thick sections, deparaffinized, and rehydrated. Each section was used for immunostaining. Immunohistochemical analyses were performed using an autostainer (Benchmark XT system; Roche Diagnostics, Basel, Switzerland) according to the manufacturer’s instructions. The primary antibodies used in this study were as follows: a mouse monoclonal antibody against CD138 (clone B-A38, Cell Marque, CA, USA); a mouse monoclonal antibody against E-cadherin (clone 36, Roche Diagnostics); a mouse monoclonal antibody against N-cadherin (clone 6G11, DAKO Japan Co. Ltd., Kyoto, Japan); a rabbit polyclonal antibody against Slug (ab38551, Abcam, Cambridge, UK); and a rabbit polyclonal antibody against Snail (ab180714, Abcam). Analyses of immunostaining In this study, the number of CD138-immunoreactive cells was counted under high-power fields (magnification x 400) in 10 non-overlapping, random endometrial stromal areas in all resected and biopsied endometrial tissues. CE was diagnosed when one or more CD138-positive plasma cells were detected in the endometrial stroma [18, 19]. Membranous immunoreactivity for E- and N-cadherin was evaluated as positive staining. When one or more cell clusters were not stained with E-cadherin in the epithelium, it was considered loss of E-cadherin. When one or more cell clusters were stained with N-cadherin in the epithelium, it was considered N-cadherin-positive. Nuclear immunoreactivity for Slug was evaluated as positive staining, and positive staining in the endometrial glandular cells and stromal cells was analyzed separately. Moreover, nuclear or cytoplasmic immunoreactivity for Snail was evaluated as positive staining, and both of them were analyzed separately. Statistical analysis Statistical analysis was performed using Graph Pad Prism 5 (GraphPad Software Inc., La Jolla, CA). Each dataset was checked for a normal distribution using the Kolmogorov-Smirnov test, and Student’s t -test or the non-parametric Mann-Whitney U test was used to test for significance depending on the distribution pattern. The significance of differences in loss of E-cadherin expression, N-cadherin expression, loss of E-cadherin expression and/or N-cadherin expression, stromal Slug expression, cytoplasmic Snail expression, nuclear Snail expression, and both stromal Slug and cytoplasmic Snail expressions between the CE-positive group and CE-negative group was examined using Fisher analysis. When loss of E-cadherin expression and/or positive N-cadherin expression was detected, the specimen was designated EMT-positive. Patients’ characteristics including age, gravidity, parity, BMI, E 2 and P 4 levels, cause of infertility, and CE were compared between the EMT-positive and EMT-negative groups. In addition, since this was a retrospective study, multivariate logistic regression analysis was performed for 8 explanatory variables, including 7 infertility factors (male factor, tubal factor, endometriosis, ovarian factor, fertilization failure, immune factor and unexplained infertility) and CE with respect to the objective variable, EMT-positive. SSPS statistics version 25 was used for this analysis. Odds ratios and P values were calculated. A significant difference was defined as a P value <0.05 in all analyses. Results CE was identified in 40 of 74 cases (54.1%). Age, gravidity, parity, BMI, and E 2 and P 4 levels were not different between the CE and Non-CE groups (Tables I). Regarding causes of infertility, among ovarian factor, tubal factor, endometriosis, male factor, fertilization failure, immune factor, and unexplained fertility, ovarian factor was higher in the Non-CE group, and unexplained infertility tended to be higher in the CE group, although there were no differences in other factors between the groups (Tables I). Comparison of cadherin expression profiles between the CE and Non-CE groups Table Ⅱ summarizes the immunohistochemical results of the CE and Non-CE groups. Loss of E-cadherin expression in the endometrial glands was observed in 14 of 40 and 2 of 34 cases in the CE and Non-CE groups, respectively (p = 0.0037) (Fig. 1 A, B). N-cadherin-positive glandular cells were seen in 22 and 7 cases in the CE and Non-CE groups, respectively (p = 0.0039) (Fig. 1 C, D). Loss of E-cadherin expression and/or N-cadherin expression was observed in 26 and 8 cases in the CE and Non-CE groups, respectively (p = 0.0005). Comparison of EMT marker expressions between the CE and Non-CE groups Table Ⅲ summarizes the associations between CE and expression profiles of Slug and Snail. Slug expression in the stromal cells was seen in 39 of 40 and 23 of 34 cases in the CE and Non-CE groups, respectively (p = 0.0008) (Fig. 1 E, F). No cases showing Slug expression in the endometrial glandular cells were present in both groups. Cytoplasmic Snail expression was noted in 31 and 12 cases in the CE and Non-CE groups, respectively (p = 0.004) (Fig. 1 G, H), and nuclear Snail expression was seen in 6 and 0 cases, respectively (p = 0.028). Both stromal Slug and cytoplasmic Snail expressions were seen in 30 and 8 cases, respectively (p < 0.0001). Analysis of the variables related to EMT-positive status Table Ⅳ summarizes patients’ characteristics in the EMT-positive and EMT-negative groups. Age, gravidity, parity, BMI, E 2 and P 4 levels were not different between the EMT-positive and EMT-negative groups. Regarding causes of infertility, among ovarian factor, tubal factor, endometriosis, male factor, fertilization failure, anti-sperm antibody, and unexplained fertility, only unexplained infertility was higher in the EMT-positive group; there were no differences in the other factors between the groups. Regarding gynecological disease, among uterine fibroids, adenomyosis, endometrial polyps, and CE, only CE was higher in the EMT-positive group. Unexplained infertility and CE were identified as variables related to EMT-positive on multivariate logistic analysis (Table Ⅴ) . Discussion In the present study, the effect of CE on the endometrial EMT in infertile patients was investigated, and it was found that the EMT occurred frequently in CE patients, and EMT-related transcription factor was also induced in CE patients at a high frequency. The risk factors for EMT were also investigated among the characteristics of infertile patients, and it was found that CE was associated with the highest risk for the induction of the EMT. Thus, CE is closely related to the induction of the EMT in the implantation phase endometrium of infertile patients. To the best of our knowledge, this is the first report on the impact of CE on the occurrence of the EMT in the endometrium in the world. One of the key functions of the endometrium is for embryos to implant and be nourished for the establishment and maintenance of pregnancy. The process of embryo implantation has long been classified into three phases: apposition, attachment, and penetration [ 20 – 22 ]. Apposition is defined as unstable adhesion of the blastocyst to the endometrial surface when blastocysts and the endometrial apical surface face each other. During this stage, the trophoblasts come close to the luminal epithelium. Then, trophoblasts begin to invade the endometrial surface, called the attachment phase. At this stage, the embryo and endometrium begin cross talk. A local increase in stromal vascular permeability at the blastocyst attachment site occurs, and rapid morphological changes in the endometrium are initiated. Penetration is a phase that involves the invasion of the embryo into the stromal area through the luminal epithelium to establish a closer relationship with the mother. It has been reported that the EMT and the MET are involved at the time of this attachment or penetration [ 14 , 16 ]. Decidualization is the process by which the fibroblast-like endometrial stromal cells differentiate into polygonal epithelial-like cells during implantation [ 23 , 24 ]. Zhang et al. showed that decidualization induced the MET by showing downregulated Snail and upregulated E-cadherin in mouse models [ 15 ]. E-cadherin has also been reported to be expressed in the mouse uterus at the start of implantation [ 16 , 17 ]. It is expressed in stroma before the trophoblastic cell invasion. On the other hand, some reports suggested that the EMT occurred in vivo and in vitro during the implantation process. The upregulation of N-cadherin and vimentin with downregulation of E-cadherin and cytokeratin was shown in the in vitro implantation model. Increased expressions of N-cadherin and TWIST2 (twist family basic helix-loop-helix transcription factor 2: a key transcription factor for Epithelial-mesenchymal transition) were detected at the implantation sites of trophoblasts. The immunohistochemical analysis for TWIST2 suggested that it was extensively expressed in endometrial glandular epithelium and luminal epithelium at implantation sites. The implantation rate of embryos was lower after the administration of TWIST2-siRNA interference, which prevented the EMT via decreased TWIST2 expression 17 . These findings suggest that the EMT is involved in receptivity of the uterine endometrium to the embryo. Thus, the endometrial cell possesses the ability to transform between epithelial and mesenchymal phenotypes by undergoing timely switches between the EMT and the MET and develop healthy gland and stromal structure for successful implantation of embryos 24 . CE is known to cause impaired implantation [ 6 , 7 ]. In the present study, it was shown that CE frequently induces the EMT in the endometrium at the implantation phase. Implantation might be impaired due to abnormal EMT induction by CE or due to the presence of such an environment that induces an abnormal EMT. In the present study, unexplained infertility was shown to be associated with the induction of the EMT in the endometrium. The EMT was found in 68% (13/19) of unexplained infertility cases. This rate is higher than that found in CE patients (65%, 26/40), and it was also significantly higher compared with infertility patients with other than unexplained infertility (21/55, P = 0.033). Patients with unexplained infertility include a high proportion of patients diagnosed with implantation failure and endometriosis [ 26 – 28 ]. The high frequency of the EMT in unexplained infertility suggests that the EMT may be associated with implantation failure and endometriosis. The present study found no relationship between CE and endometriosis in infertility patients. In our previous report, we showed that patients with endometriosis had a high frequency of CE in resected uterine specimens. Endometriosis was diagnosed in the present study when endometriosis was detected by laparoscopy or laparotomy in the past three years or ovarian chocolate cysts were detected by ultrasonography or MRI. Since laparoscopic or laparotomy was not performed for all patients, a definitive diagnosis of early endometriosis was not obtained. This might be a cause of the difference between the present study and the previous study. Endometrial cancer and endometriosis, as well as CE, are known to be frequent in infertile patients [ 4 – 8 , 29 – 32 ]. Considering that CE is frequently found in infertile patients, CE, by triggering the EMT, might be the cause of the increased prevalence of endometrial cancer and endometriosis in infertile patients. The EMT is thought to be a central process of cancer invasion and metastasis, and some recent studies demonstrated the association between endometriosis and the EMT [ 33 – 36 ]. Moreover, regardless of the factors that induce the EMT in stem cells (or non-stem cells), genetic or epigenetic changes caused by endogenous or external stimuli establish a partial EMT and make the hybrid (epithelial-mesenchymal) phenotype stable [ 37 , 38 ]. Whether the EMT or its reverse process the MET enables cells to obtain pluripotency still remains controversial [ 39 ], it is necessary to study whether CE affects the development of endometrial cancer or endometriosis through the EMT in the future. Conclusion This is the first report to demonstrate the association between CE and the endometrial EMT. The infertility caused by CE may be due to its high EMT frequency and its effect on endometrial function during implantation. Abbreviations BMI: body mass index, CE: Chronic endometritis, EMT: epithelial-mesenchymal transition, E 2 : estradiol, MET: mesenchymal-epithelial transition, P 4 : progesterone, TWIST2: twist family basic helix-loop-helix transcription factor 2 Declarations Ethics approval and consent to participate: This research was approved by the Ethics Committee of Shiga University of Medical Science (IRB-ethics committee approval number, R2014-090). Consent for publication: Informed written consent was obtained for publication. Availability of data and materials: We can provide the raw data. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request. Competing interests : No author has any conflict of interest to disclose. Funding : The Grants-in-Aid for Scientific Research of Japan Society for the Promotion of Science, Grant Number 16K11083 and 19K09752 (to F.K.), supported this study regarding the design of the study and data collection, analysis, interpretation of data and in writing the manuscript. Authors’ contributions Conceived the study: MI, FK; designed the experiments: MI; performed the experiment: MI, AT; analyzed the data: MI, FK; contributed reagents/materials/analysis tools: AT, FK, JK, TH, KT; wrote the manuscript: MI, FK. Final approval: KT, TM. All authors read and approved the final manuscript. Acknowledgements: Nothing to disclose. 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Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol. 2017;232:3261–72. Tables Table Ⅰ. Patients’ characteristics in the CE and Non-CE groups CE (40 cases) Non-CE (34 cases) p value Age (y.o) 37.08 36.35 0.43 Gravidity 0.63 0.62 0.97 Paritiy 0.3 0.29 0.96 Serum level of estradiol 135 135.9 0.95 Serum level of prgesterone 14.69 15.58 0.55 Infertiity cause Ovarian factor 0 5 0.017 Tubal factor 9 10 0.6 Endometriosis 10 9 0.79 Male factor 9 9 0.6 Fatilization failure 4 1 0.37 Immune factor 0 0 1 Unexplained 14 5 0.063 Gynecological disease Uterine fibroid 11 6 0.41 Adnoemyosis 0 1 0.46 Endometrial polyp 5 3 0.72 CE: chronic endometritis Table Ⅱ. Association between chronic endometritis and cadherin expression profiles in the specimens CE (40 cases) Non-CE (34 cases) p value Loss of E-cadherin expression 14 2 0.0037 N-cadherin expression 22 7 0.0039 Loss of E-cadherin expression and/or N-cadherin expression 26 8 0.0005 CE, chronic endometritis Table Ⅲ. Associations between chronic endometritis and EMT marker expression in the specimens CE (40 cases) Non-CE (34 cases) p value Stromal Slug expression 39 23 0.0008 Cytoplasmic Snail expression 31 12 0.0004 Nuclear Snail expression 6 0 0.028 Both stromal Slug + Cyto Snail 30 8 <0.0001 CE, chronic endometritis; EMT, epithelial-mesenchymal transition. Table Ⅳ. Patients’ characteristics in the EMT-positive and EMT-negative groups EMT+ (34cases) EMT- (40 cases) p value Age 37.59 36.03 0.087 Gravidity 0.68 0.58 0.65 Paritiy 0.32 0.28 0.67 Serum level of estradiol 129.1 140.7 0.47 Serum level of prgesterone 15.21 14.99 0.88 Infertiity cause Ovarian factor 1 5 0.21 Tubal factor 6 12 0.28 Endometriosis 11 6 0.78 Male factor 5 11 0.78 Fatilization failure 2 3 1 Anti-sperm antibody 0 1 1 Unknown 13 6 0.033 Gynecological disease Uterine fibroid 8 10 1 Adnoemyosis 0 1 1 Endometrial polyp 5 6 1 Chronic endometritis 26 14 0.0005 EMT: epithelial-mesenchymal transition. Table Ⅴ. Logistic regression analysis for the EMT Variable p value Odds ratio 95% CI Chronic endometritis 0.002 5.3 1.83-15.4 Unexplained infertility 0.046 3.72 1.03-13.5 EMT: epithelial-mesenchymal transition. 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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-33791","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":677220,"identity":"d8504697-deed-4199-bbe4-a07b14b5add1","order_by":0,"name":"Mitsuaki Ishida","email":"","orcid":"","institution":"Kansai Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Mitsuaki","middleName":"","lastName":"Ishida","suffix":""},{"id":677221,"identity":"ccf22014-075b-40c3-8dbc-189f2fc27275","order_by":1,"name":"Akie Takebayashi","email":"","orcid":"","institution":"Shiga Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Akie","middleName":"","lastName":"Takebayashi","suffix":""},{"id":677222,"identity":"420804f0-38c1-4bb0-a129-19064a73a564","order_by":2,"name":"Fuminori Kimura","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-9840-4227","institution":"Shiga Ika Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Fuminori","middleName":"","lastName":"Kimura","suffix":""},{"id":677223,"identity":"4b33fcf3-69ec-44be-9528-af509bbed788","order_by":3,"name":"Jun Kitazawa","email":"","orcid":"","institution":"Shiga Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Kitazawa","suffix":""},{"id":677224,"identity":"f17e945c-f7e3-4a3a-82d7-1d45e50ad880","order_by":4,"name":"Tetsuro Hanada","email":"","orcid":"","institution":"Shiga Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Tetsuro","middleName":"","lastName":"Hanada","suffix":""},{"id":677225,"identity":"60639752-18d6-4c16-a4e5-3926a258ac08","order_by":5,"name":"Koji Tsuta","email":"","orcid":"","institution":"Kansai Iryo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Tsuta","suffix":""},{"id":677226,"identity":"6971fe1c-2e8c-4bc7-8ea0-97a15cf5a53f","order_by":6,"name":"Takashi murakami","email":"","orcid":"","institution":"Shiga Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"murakami","suffix":""}],"badges":[],"createdAt":"2020-06-05 15:16:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-33791/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-33791/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1371/journal.pone.0249775","type":"published","date":"2021-04-07T21:08:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2626305,"identity":"32f58c71-96f3-48d0-93a4-baff46e1f647","added_by":"acdc","created_at":"2020-09-25 21:02:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":154159,"visible":true,"origin":"acdc-manuscripts-figure","legend":"Immunohistochemical results of the specimens. (A) E-cadherin was detected in the glandular cells in endometrial specimens. (B) A cluster of E-cadherin-negative in endometrial glandular cells was observed (arrows). When such a finding was detected, it was judged as loss of E-cadherin. (C) N-cadherin was not detected in the glandular cells in endometrial specimens. (D) N-cadherin-positive glandular cells was present in endometrial glandular cells. When the staining was observed, it was judged as N-cadherin positive. (E) Slug was not expressed in stromal cells of the endometrium. (F) Slug is expressed in the nuclei of endometria stromal cells. When the staining was observed, it was judged as slug positive. (G) Snail expression was not noted in the glandular cells of the endometrium. (H) Cytoplasmic Snail expression was noted in the glandular cells of the endometrium. When the staining was observed, it was judged as Snail positive. Bar is 100µm.","description":"{\"primaryId\":\"undefined\",\"secondaryId\":\"BMWH-D-20-00611\",\"acdcId\":\"undefined\",\"revision\":\"1\",\"timestamp\":\"2020-06-16T17:06:07\",\"document\":\"manuscripts\",\"linkRel\":\"figure\"}","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-33791/v1/figure_1.jpg"},{"id":13542397,"identity":"df8d67fa-01b6-4808-ab33-13b7b2a0b5ed","added_by":"auto","created_at":"2021-09-17 01:54:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":448155,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-33791/v1/d78b8339-308b-4800-b586-951d59fa899b.pdf"}],"financialInterests":"","formattedTitle":"Induction of the epithelial-mesenchymal transition in the endometrium by chronic endometritis in infertile patients","fulltext":[{"header":"Background","content":"\u003cp\u003eChronic endometritis (CE) is a persistent chronic inflammatory process of the endometrium. CE is defined as infiltration of plasma cells in the endometrial stroma [1-4], and immunostaining for CD138, a plasma cell marker, has been reported to be a useful method for demonstrating plasma cells in the endometrial stroma [2, 5]. CE is usually asymptomatic or presents only with subtle symptoms, including abnormal uterine bleeding, dyspareunia, leucorrhea, and pelvic pain [1-3]. However, recent studies have focused on the association between CE and various gynecological conditions, and they have shown that CE has a positive relationship with infertility and implantation failure [6-8]. CE has also been shown to modify the function of endometrial cells and affect deciuda [9-12].\u003c/p\u003e\n\u003cp\u003eThe epithelial-mesenchymal transition (EMT) is a process by which polarized epithelial cells lose polarity and intercellular contraction and acquire mesenchymal cell motility [13]. It is well known that the EMT plays crucial roles not only in normal embryological development, but also in several pathological conditions such as wound healing, fibrosis, and cancer development\u003csup\u003e12\u003c/sup\u003e. Focusing on the endometrium during the implantation phase, it has been shown that the mesenchymal-epithelial transition (MET), which is the reverse process to that of EMT, is induced in the endometrium and promotes the acceptance of embryos to the uterus [14, 15]. On the other hand, it has been found that the EMT also plays an important role in implantation [16, 17]. To date, no studies have evaluated the status of the endometrial EMT in the implantation phase in humans.\u003c/p\u003e\n\u003cp\u003eThus, the occurrence of the EMT with or without CE was analyzed in infertile patients to elucidate the pathophysiology of CE causing impaired implantation. In addition, the effect of the EMT on infertility was evaluated by examining which infertility cause was associated with the occurrence of the EMT in the endometrium.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eEthics\u003c/p\u003e\n\u003cp\u003eThis study conformed to the Clinical Research Guideline of Shiga University of Medical Science and was approved by the research ethics committee. Written, informed consent to participate in this study was obtained from all patients. This study included only patients over the age of 20.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients and endometrial sampling\u003c/p\u003e\n\u003cp\u003eA total of 74 infertile patients referred to the Department of Obstetrics and Gynecology of Shiga University of Medical Science from April 2015 to March 2018 were enrolled. They were all free from immune diseases, cancer, and diseases increasing susceptibility to infections, and they were not taking anti-inflammatory drugs or corticosteroids. Patients given 7 or more days of antibiotics for the treatment of CE before endometrial sampling were excluded. The ovulation day was determined by a urine ovulation test and ultrasonography, and the endometrium was collected 7-9 days after ovulation. On the day of endometrial sampling, the patients\u0026rsquo; blood was sampled to measure serum levels of estradiol (E\u003csub\u003e2\u003c/sub\u003e) and progesterone (P\u003csub\u003e4\u003c/sub\u003e). Patients with E\u003csub\u003e2\u003c/sub\u003e \u0026lt;50 pg/mL and P4 \u0026lt;8 ng/mL were excluded. Endometrial tissue obtained by the first curettage from each patient was used in this study. Clinical information including age, gravidity, parity, body mass index(BMI), serum levels of E\u003csub\u003e2\u003c/sub\u003e and P\u003csub\u003e4\u003c/sub\u003e, and cause of infertility were obtained from the clinical records.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eImmunohistochemistry\u003c/p\u003e\n\u003cp\u003eFormalin-fixed, paraffin-embedded tissue blocks of the resected and biopsied specimens were cut into 3-\u0026micro;m-thick sections, deparaffinized, and rehydrated. Each section was used for immunostaining. Immunohistochemical analyses were performed using an autostainer (Benchmark XT system; Roche Diagnostics, Basel, Switzerland) according to the manufacturer\u0026rsquo;s instructions. The primary antibodies used in this study were as follows: a mouse monoclonal antibody against CD138 (clone B-A38, Cell Marque, CA, USA); a mouse monoclonal antibody against E-cadherin (clone 36, Roche Diagnostics); a mouse monoclonal antibody against N-cadherin (clone 6G11, DAKO Japan Co. Ltd., Kyoto, Japan); a rabbit polyclonal antibody against Slug (ab38551, Abcam, Cambridge, UK); and a rabbit polyclonal antibody against Snail (ab180714, Abcam).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalyses of immunostaining\u003c/p\u003e\n\u003cp\u003eIn this study, the number of CD138-immunoreactive cells was counted under high-power fields (magnification x 400) in 10 non-overlapping, random endometrial stromal areas in all resected and biopsied endometrial tissues. CE was diagnosed when one or more CD138-positive plasma cells were detected in the endometrial stroma [18, 19].\u003c/p\u003e\n\u003cp\u003eMembranous immunoreactivity for E- and N-cadherin was evaluated as positive staining. When one or more cell clusters were not stained with E-cadherin in the epithelium, it was considered loss of E-cadherin. When one or more cell clusters were stained with N-cadherin in the epithelium, it was considered N-cadherin-positive.\u003c/p\u003e\n\u003cp\u003eNuclear immunoreactivity for Slug was evaluated as positive staining, and positive staining in the endometrial glandular cells and stromal cells was analyzed separately. Moreover, nuclear or cytoplasmic immunoreactivity for Snail was evaluated as positive staining, and both of them were analyzed separately.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using Graph Pad Prism 5 (GraphPad Software Inc., La Jolla, CA). Each dataset was checked for a normal distribution using the Kolmogorov-Smirnov test, and Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test or the non-parametric Mann-Whitney U test was used to test for significance depending on the distribution pattern. The significance of differences in loss of E-cadherin expression, N-cadherin expression, loss of E-cadherin expression and/or N-cadherin expression, stromal Slug expression, cytoplasmic Snail expression, nuclear Snail expression, and both stromal Slug and cytoplasmic Snail expressions between the CE-positive group and CE-negative group was examined using Fisher analysis.\u003c/p\u003e\n\u003cp\u003eWhen loss of E-cadherin expression and/or positive N-cadherin expression was detected, the specimen was designated EMT-positive. Patients\u0026rsquo; characteristics including age, gravidity, parity, BMI, E\u003csub\u003e2\u003c/sub\u003e and P\u003csub\u003e4\u003c/sub\u003e levels, cause of infertility, and CE were compared between the EMT-positive and EMT-negative groups.\u003c/p\u003e\n\u003cp\u003eIn addition, since this was a retrospective study, multivariate logistic regression analysis was performed for 8 explanatory variables, including 7 infertility factors (male factor, tubal factor, endometriosis, ovarian factor, fertilization failure, immune factor and unexplained infertility) and CE with respect to the objective variable, EMT-positive. SSPS statistics version 25 was used for this analysis. Odds ratios and P values were calculated. A significant difference was defined as a P value \u0026lt;0.05 in all analyses.\u003c/p\u003e"},{"header":"Results","content":" \u003cp\u003eCE was identified in 40 of 74 cases (54.1%). Age, gravidity, parity, BMI, and E\u003csub\u003e2\u003c/sub\u003e and P\u003csub\u003e4\u003c/sub\u003e levels were not different between the CE and Non-CE groups (Tables I). Regarding causes of infertility, among ovarian factor, tubal factor, endometriosis, male factor, fertilization failure, immune factor, and unexplained fertility, ovarian factor was higher in the Non-CE group, and unexplained infertility tended to be higher in the CE group, although there were no differences in other factors between the groups (Tables I).\u003c/p\u003e \u003cp\u003eComparison of cadherin expression profiles between the CE and Non-CE groups\u003c/p\u003e \u003cp\u003eTable Ⅱ summarizes the immunohistochemical results of the CE and Non-CE groups. Loss of E-cadherin expression in the endometrial glands was observed in 14 of 40 and 2 of 34 cases in the CE and Non-CE groups, respectively (p\u0026thinsp;=\u0026thinsp;0.0037) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, B). N-cadherin-positive glandular cells were seen in 22 and 7 cases in the CE and Non-CE groups, respectively (p\u0026thinsp;=\u0026thinsp;0.0039) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC, D). Loss of E-cadherin expression and/or N-cadherin expression was observed in 26 and 8 cases in the CE and Non-CE groups, respectively (p\u0026thinsp;=\u0026thinsp;0.0005).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eComparison of EMT marker expressions between the CE and Non-CE groups\u003c/p\u003e \u003cp\u003eTable Ⅲ summarizes the associations between CE and expression profiles of Slug and Snail. Slug expression in the stromal cells was seen in 39 of 40 and 23 of 34 cases in the CE and Non-CE groups, respectively (p\u0026thinsp;=\u0026thinsp;0.0008) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, F). No cases showing Slug expression in the endometrial glandular cells were present in both groups. Cytoplasmic Snail expression was noted in 31 and 12 cases in the CE and Non-CE groups, respectively (p\u0026thinsp;=\u0026thinsp;0.004) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG, H), and nuclear Snail expression was seen in 6 and 0 cases, respectively (p\u0026thinsp;=\u0026thinsp;0.028). Both stromal Slug and cytoplasmic Snail expressions were seen in 30 and 8 cases, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eAnalysis of the variables related to EMT-positive status\u003c/p\u003e \u003cp\u003eTable Ⅳ summarizes patients\u0026rsquo; characteristics in the EMT-positive and EMT-negative groups. Age, gravidity, parity, BMI, E\u003csub\u003e2\u003c/sub\u003e and P\u003csub\u003e4\u003c/sub\u003e levels were not different between the EMT-positive and EMT-negative groups. Regarding causes of infertility, among ovarian factor, tubal factor, endometriosis, male factor, fertilization failure, anti-sperm antibody, and unexplained fertility, only unexplained infertility was higher in the EMT-positive group; there were no differences in the other factors between the groups. Regarding gynecological disease, among uterine fibroids, adenomyosis, endometrial polyps, and CE, only CE was higher in the EMT-positive group.\u003c/p\u003e \u003cp\u003eUnexplained infertility and CE were identified as variables related to EMT-positive on multivariate logistic analysis (Table Ⅴ)\u003c/p\u003e \u003cp\u003e.\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eIn the present study, the effect of CE on the endometrial EMT in infertile patients was investigated, and it was found that the EMT occurred frequently in CE patients, and EMT-related transcription factor was also induced in CE patients at a high frequency.\u003c/p\u003e \u003cp\u003eThe risk factors for EMT were also investigated among the characteristics of infertile patients, and it was found that CE was associated with the highest risk for the induction of the EMT. Thus, CE is closely related to the induction of the EMT in the implantation phase endometrium of infertile patients. To the best of our knowledge, this is the first report on the impact of CE on the occurrence of the EMT in the endometrium in the world.\u003c/p\u003e \u003cp\u003eOne of the key functions of the endometrium is for embryos to implant and be nourished for the establishment and maintenance of pregnancy. The process of embryo implantation has long been classified into three phases: apposition, attachment, and penetration [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Apposition is defined as unstable adhesion of the blastocyst to the endometrial surface when blastocysts and the endometrial apical surface face each other. During this stage, the trophoblasts come close to the luminal epithelium. Then, trophoblasts begin to invade the endometrial surface, called the attachment phase. At this stage, the embryo and endometrium begin cross talk. A local increase in stromal vascular permeability at the blastocyst attachment site occurs, and rapid morphological changes in the endometrium are initiated. Penetration is a phase that involves the invasion of the embryo into the stromal area through the luminal epithelium to establish a closer relationship with the mother. It has been reported that the EMT and the MET are involved at the time of this attachment or penetration [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Decidualization is the process by which the fibroblast-like endometrial stromal cells differentiate into polygonal epithelial-like cells during implantation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Zhang et al. showed that decidualization induced the MET by showing downregulated Snail and upregulated E-cadherin in mouse models [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. E-cadherin has also been reported to be expressed in the mouse uterus at the start of implantation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. It is expressed in stroma before the trophoblastic cell invasion. On the other hand, some reports suggested that the EMT occurred in vivo and in vitro during the implantation process. The upregulation of N-cadherin and vimentin with downregulation of E-cadherin and cytokeratin was shown in the in vitro implantation model. Increased expressions of N-cadherin and TWIST2 (twist family basic helix-loop-helix transcription factor 2: a key transcription factor for Epithelial-mesenchymal transition) were detected at the implantation sites of trophoblasts. The immunohistochemical analysis for TWIST2 suggested that it was extensively expressed in endometrial glandular epithelium and luminal epithelium at implantation sites. The implantation rate of embryos was lower after the administration of TWIST2-siRNA interference, which prevented the EMT via decreased TWIST2 expression\u003csup\u003e17\u003c/sup\u003e. These findings suggest that the EMT is involved in receptivity of the uterine endometrium to the embryo. Thus, the endometrial cell possesses the ability to transform between epithelial and mesenchymal phenotypes by undergoing timely switches between the EMT and the MET and develop healthy gland and stromal structure for successful implantation of embryos\u003csup\u003e24\u003c/sup\u003e. CE is known to cause impaired implantation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In the present study, it was shown that CE frequently induces the EMT in the endometrium at the implantation phase. Implantation might be impaired due to abnormal EMT induction by CE or due to the presence of such an environment that induces an abnormal EMT.\u003c/p\u003e \u003cp\u003eIn the present study, unexplained infertility was shown to be associated with the induction of the EMT in the endometrium. The EMT was found in 68% (13/19) of unexplained infertility cases. This rate is higher than that found in CE patients (65%, 26/40), and it was also significantly higher compared with infertility patients with other than unexplained infertility (21/55, P\u0026thinsp;=\u0026thinsp;0.033). Patients with unexplained infertility include a high proportion of patients diagnosed with implantation failure and endometriosis [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The high frequency of the EMT in unexplained infertility suggests that the EMT may be associated with implantation failure and endometriosis.\u003c/p\u003e \u003cp\u003eThe present study found no relationship between CE and endometriosis in infertility patients. In our previous report, we showed that patients with endometriosis had a high frequency of CE in resected uterine specimens. Endometriosis was diagnosed in the present study when endometriosis was detected by laparoscopy or laparotomy in the past three years or ovarian chocolate cysts were detected by ultrasonography or MRI. Since laparoscopic or laparotomy was not performed for all patients, a definitive diagnosis of early endometriosis was not obtained. This might be a cause of the difference between the present study and the previous study.\u003c/p\u003e \u003cp\u003eEndometrial cancer and endometriosis, as well as CE, are known to be frequent in infertile patients [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Considering that CE is frequently found in infertile patients, CE, by triggering the EMT, might be the cause of the increased prevalence of endometrial cancer and endometriosis in infertile patients. The EMT is thought to be a central process of cancer invasion and metastasis, and some recent studies demonstrated the association between endometriosis and the EMT [\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Moreover, regardless of the factors that induce the EMT in stem cells (or non-stem cells), genetic or epigenetic changes caused by endogenous or external stimuli establish a partial EMT and make the hybrid (epithelial-mesenchymal) phenotype stable [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Whether the EMT or its reverse process the MET enables cells to obtain pluripotency still remains controversial [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], it is necessary to study whether CE affects the development of endometrial cancer or endometriosis through the EMT in the future.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eThis is the first report to demonstrate the association between CE and the endometrial EMT. The infertility caused by CE may be due to its high EMT frequency and its effect on endometrial function during implantation.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eBMI: body mass index, CE: Chronic endometritis, EMT: epithelial-mesenchymal transition, E\u003csub\u003e2\u003c/sub\u003e: estradiol, MET: mesenchymal-epithelial transition, P\u003csub\u003e4\u003c/sub\u003e: progesterone, TWIST2: twist family basic helix-loop-helix transcription factor 2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate: \u003c/strong\u003eThis research was approved by the Ethics Committee of Shiga University of Medical Science (IRB-ethics committee approval number, R2014-090).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Informed written consent was obtained for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e We can provide the raw data. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: No author has any conflict of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e: \u003c/strong\u003eThe Grants-in-Aid for Scientific Research of Japan Society for the Promotion of Science, Grant Number 16K11083 and 19K09752 (to F.K.), supported this study regarding the design of the study and data collection, analysis, interpretation of data and in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceived the study: MI, FK; designed the experiments: MI; performed the experiment: MI, AT; analyzed the data: MI, FK; contributed reagents/materials/analysis tools: AT, FK, JK, TH, KT; wrote the manuscript: MI, FK. Final approval: KT, TM.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eNothing to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003eGreenwood SM, Moran JJ. Chronic endometritis: morphologic and clinical observation. Obstet Gynecol. 1981;58:176\u0026ndash;84.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKitaya K, Yasuo T. Immunohistochemical and clinicopathological characterization of chronic endometritis. Am J Reprod Immunol. 2011;66:410\u0026ndash;5.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eCrum CP, Egawa K, Fenoglio CM, Richart RM. Chronic endometritis: the role of immunohistochemistry in the detection of plasma cells. 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Studies using an in vitro model show evidence of involvement of epithelial-mesenchymal transition of human endometrial epithelial cells in human embryo implantation. J Biol Chem. 2012;287:4441\u0026ndash;50.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKasius JC, Broekmans FJ, Sie-Go DM, Bourgain C, Eijkemans MJ, Fauser BC, Devroey P, Fatemi HM. The reliability of the histological diagnosis of endometritis in asymptomatic IVF cases: a multicenter observer study. Hum Reprod. 2012;27:153\u0026ndash;8.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eTakebayashi A, Kimura F, Kishi Y, Ishida M, Takahashi A, Yamanaka A, et al. The association between endometriosis and chronic endometritis. PLoS ONE. 2014;9:e88354.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eEdwards RG. Human implantation: the last barrier in assisted reproduction technologies? 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Hum Reprod. 2016;31:1475\u0026ndash;82.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eL\u0026oacute;pez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1:303\u0026ndash;14.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eZhou C, Liu J, Tang Y, Liang X. Inflammation linking EMT and cancer stem cells. Oral Oncol. 2012;48:1068\u0026ndash;75.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eProestling K, Birner P, Gamperl S, Nirtl N, Marton E, Yerlikaya G, et al. Enhanced epithelial to mesenchymal transition (EMT) and upregulated MYC in ectopic lesions contribute independently to endometriosis. Reprod Biol Endocrinol. 2015;13:75.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eBartley J, J\u0026uuml;licher A, Hotz B, Mechsner S, Hotz H. Epithelial to mesenchymal transition (EMT) seems to be regulated differently in endometriosis and the endometrium. Arch Gynecol Obstet. 2014;289:871\u0026ndash;81.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eDenisov EV, Perelmuter VM. A fixed partial epithelial-mesenchymal transition (EMT) triggers carcinogenesis, whereas asymmetrical division of hybrid EMT cells drives cancer progression. Hepatology. 2018;68:807\u0026ndash;10.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eSingh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2020;29:4741\u0026ndash;51.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eChen T, You Y, Jiang H, Wang ZZ. Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol. 2017;232:3261\u0026ndash;72.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eTable Ⅰ. Patients\u0026rsquo; characteristics in the CE and Non-CE groups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 445.0pt; margin-left: 4.2pt; border-collapse: collapse;\" width=\"593\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 445.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" colspan=\"4\" width=\"593\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.6pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'MS PGothic', sans-serif;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eCE (40 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eNon-CE (34 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eAge (y.o)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e37.08\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e36.35\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.6pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eGravidity\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.63\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.62\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.97\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.6pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eParitiy\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.29\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.96\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.6pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eSerum level of estradiol\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e135\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e135.9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.6pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.95\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eSerum level of prgesterone\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e14.69\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e15.58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.55\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eInfertiity cause\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Ovarian factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.017\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Tubal factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e10\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Endometriosis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e10\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.79\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Male factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Fatilization failure\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.37\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Immune factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Unexplained \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.063\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eGynecological disease \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Uterine fibroid\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.41\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.95pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Adnoemyosis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 24.95pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.46\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 25.5pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"232\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Endometrial polyp\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"133\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"164\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"65\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.72\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 173.9pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"232\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 99.45pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"133\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 123.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"164\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 48.55pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"65\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eCE: chronic endometritis\u003c/span\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u003cbr style=\"page-break-before: always;\" /\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eTable Ⅱ. Association between chronic endometritis and cadherin expression profiles in the specimens\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 460.0pt; border-collapse: collapse;\" width=\"613\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 171.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"228\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 107.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"143\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 96.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"128\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 86.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"115\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 171.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"228\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'MS PGothic', sans-serif;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"143\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eCE (40 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eNon-CE (34 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 86.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"115\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 171.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"228\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eLoss of E-cadherin expression\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"143\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 86.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"115\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.0037\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 171.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"228\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eN-cadherin expression\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"143\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e22\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 86.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"115\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.0039\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 171.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"228\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eLoss of E-cadherin expression and/or N-cadherin expression\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"143\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e26\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 86.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"115\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.0005\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 2.3pt;\"\u003e\n\u003ctd style=\"width: 171.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 2.3pt;\" width=\"228\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eCE, chronic endometritis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 2.3pt;\" width=\"143\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 96.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 2.3pt;\" width=\"128\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 86.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 2.3pt;\" width=\"115\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eTable Ⅲ. Associations between chronic endometritis and EMT marker expression in the specimens \u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 441.0pt; border-collapse: collapse;\" width=\"588\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 156.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"208\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'MS PGothic', sans-serif;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 103.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"137\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eCE (40 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eNon-CE (34 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 80.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"107\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 156.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"208\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eStromal Slug expression\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 103.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"137\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e39\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e23\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 80.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"107\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.0008\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 156.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"208\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eCytoplasmic Snail expression\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 103.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"137\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e31\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 80.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"107\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.0004\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 156.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"208\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eNuclear Snail expression\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 103.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"137\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 80.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"107\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e0.028\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 156.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"208\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eBoth stromal Slug + Cyto Snail \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 103.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"137\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e30\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 80.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"107\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003e\u0026lt;0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.0pt;\"\u003e\n\u003ctd style=\"width: 361.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" colspan=\"3\" width=\"481\"\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan style=\"font-size: 11pt; font-family: 'Times New Roman', serif;\"\u003eCE, chronic endometritis; EMT, epithelial-mesenchymal transition. \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 80.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 30.0pt;\" width=\"107\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eTable Ⅳ. Patients\u0026rsquo; characteristics in the EMT-positive and EMT-negative groups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 5.75in; border-collapse: collapse;\" width=\"552\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 15.0pt;\"\u003e\n\u003ctd style=\"width: 5.75in; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 15.0pt;\" colspan=\"4\" width=\"552\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 15.75pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 15.75pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'MS PGothic', sans-serif;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 15.75pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eEMT+ (34cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 15.75pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eEMT- (40 cases)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 15.75pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e37.59\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e36.03\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.087\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eGravidity\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.68\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.65\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eParitiy\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.32\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.28\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.67\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eSerum level of estradiol\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e129.1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e140.7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.47\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eSerum level of prgesterone\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e15.21\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e14.99\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.88\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eInfertiity cause\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Ovarian factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.21\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Tubal factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.28\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Endometriosis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.78\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Male factor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.78\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Fatilization failure\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Anti-sperm antibody\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Unknown\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e13\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.033\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eGynecological disease \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Uterine fibroid\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e10\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Adnoemyosis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Endometrial polyp\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.5pt;\"\u003e\n\u003ctd style=\"width: 169.65pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"226\"\u003e\n\u003cp style=\"margin-left: .2in; text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e\u0026nbsp;\u0026nbsp; Chronic endometritis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.85pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"129\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e26\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 101.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"135\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 46.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 13.5pt;\" width=\"61\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.0005\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eEMT: epithelial-mesenchymal transition.\u003cstrong\u003e\u003cbr style=\"page-break-before: always;\" /\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eTable Ⅴ. Logistic regression analysis for the EMT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 400.0pt; border-collapse: collapse;\" width=\"533\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 26.25pt;\"\u003e\n\u003ctd style=\"width: 109.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 26.25pt;\" width=\"145\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eVariable\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 83.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 26.25pt;\" width=\"111\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 26.25pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eOdds ratio\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.0pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 4.95pt 0in 4.95pt; height: 26.25pt;\" width=\"169\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e95% CI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 25.5pt;\"\u003e\n\u003ctd style=\"width: 109.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"145\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eChronic endometritis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 83.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"111\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.002\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e5.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 25.5pt;\" width=\"169\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1.83-15.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.25pt;\"\u003e\n\u003ctd style=\"width: 109.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 29.25pt;\" width=\"145\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eUnexplained infertility\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 83.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 29.25pt;\" width=\"111\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e0.046\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 29.25pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e3.72\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 4.95pt 0in 4.95pt; height: 29.25pt;\" width=\"169\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 11pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003e1.03-13.5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 12pt; line-height: 200%; font-family: 'Times New Roman', serif;\"\u003eEMT: epithelial-mesenchymal transition.\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"cadherin, chronic endometritis, epithelial-mesenchymal transition, infertility","lastPublishedDoi":"10.21203/rs.3.rs-33791/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-33791/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe purpose of the present study was to evaluate the relationship between chronic endometritis (CE) and the epithelial-mesenchymal transition (EMT) in the eutopic endometrium of infertile patients in the implantation phase.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eEndometrial biopsy specimens from 74 infertility patients were enrolled. The presence of CE was investigated by immunostaining for CD138. Immunohistochemical staining for E-cadherin, N-cadherin, Slug, and Snail was performed, and expression profiles were statistically analyzed according to the presence of CE. When loss of E-cadherin expression and/or positive N-cadherin expression was detected, the specimen was considered EMT-positive. EMT-positive cases were also statistically analyzed according to the presence of CE. Patients\u0026rsquo; characteristics were compared between the EMT-positive and EMT-negative groups. Logistic regression analysis was also performed with variables including age, body mass index (BMI), gravidity, parity, and each factor causing infertility to examine the independent effect of each variable on EMT-positive status.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eLoss of E-cadherin expression, N-cadherin expression and EMT-positive were significant in CE patients (p\u0026thinsp;=\u0026thinsp;0.0037, 0.0039 and \u0026lt;\u0026thinsp;0.0001, respectively). Slug, cytoplasmic Snail, and nuclear Snail expression were significant in CE patients (p\u0026thinsp;=\u0026thinsp;0.0008, 0.0004 and 0.028, respectively). Differences were detected in unexplained infertility and CE between EMT-positive and EMT-negative cases. Unexplained infertility and CE were identified as variables related to EMT-positive status on logistic analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe EMT was frequent in the eutopic endometrium in infertile patients with CE. Since the EMT is associated with unexplained infertility and CE, the EMT appears to be involved in altered mechanisms of implantation.\u003c/p\u003e","manuscriptTitle":"Induction of the epithelial-mesenchymal transition in the endometrium by chronic endometritis in infertile patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-06-17 19:34:16","doi":"10.21203/rs.3.rs-33791/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":"4f2995f1-086e-429e-ba3e-66650d116c71","owner":[],"postedDate":"June 17th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":122933,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2021-07-27T21:08:21+00:00","versionOfRecord":{"articleIdentity":"rs-33791","link":"https://doi.org/10.1371/journal.pone.0249775","journal":{"identity":"plos-one","isVorOnly":true,"title":"PLOS ONE"},"publishedOn":"2021-04-07 21:08:21","publishedOnDateReadable":"April 7th, 2021"},"versionCreatedAt":"2020-06-17 19:34:16","video":"","vorDoi":"10.1371/journal.pone.0249775","vorDoiUrl":"https://doi.org/10.1371/journal.pone.0249775","workflowStages":[]},"version":"v1","identity":"rs-33791","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-33791","identity":"rs-33791","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}