{"paper_id":"b1add4e6-7ce1-4daf-90f8-da8a22192749","body_text":"Clin. Exp. Obstet. Gynecol. 2023; 50(1): 10\nhttps://doi.org/10.31083/j.ceog5001010\nCopyright: © 2023 The Author(s). Published by IMR Press.\nThis is an open access article under the CC BY 4.0 license .\nPublisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nReview\nEndometriosis as an Infectious Disease: Association with Chronic\nEndometritis\nKotaro Kitaya1,*\n , Takako Mihara1, Masaya Mihara 1\n1Infertility Center, Kouseikai Mihara Hospital/Katsura Mihara Clinic, 615-8227 Kyoto, Japan\n*Correspondence: kitaya@koto.kpu-m.ac.jp (Kotaro Kitaya)\nAcademic Editors: Felice Sorrentino and Giuseppe Ricci\nSubmitted: 14 June 2022 Revised: 7 September 2022 Accepted: 9 September 2022 Published: 11 January 2023\nAbstract\nObjectives: Recent studies focus on immunological, infectious, and inflammatory aspects of endometriosis. Meanwhile, chronic en-\ndometritis (CE) is an immunological, infectious, and inflammatory disorder of the eutopic endometrium with unusual stromal plasmacyte\ninfiltration. Mechanism: In this review article, we aimed to gain a better understanding of the relationships between endometriosis and\nCE. Findings in Brief : Accumulating evidence supports the idea that CE is associated with infertility of unknown etiology, repeated\nimplantation failure in an in vitro fertilization-embryo transfer program, recurrent pregnancy loss, as well as several perinatal/neonatal\ncomplications. Endometrial biopsy/histopathologic examinations and/or hysteroscopy are required to make a definitive diagnosis of\nCE. Conclusions: While endometriosis has been long considered a cause of infertility, CE is also an emerging issue that may reduce\nfecundity in women of reproductive age. Endometriosis and CE share characteristics of endometrial proliferative nature. The potential\nrelationships between these two diseases of the uterine lining warrant future studies.\nKeywords: antibiotic treatment; chronic endometritis; endometriosis; microbiota; progesterone resistance\n1. Introduction\nChronic endometritis (CE) is an endometrial in-\nflammatory disorder, which is characterized by asymp-\ntomatic nature and unusual Clusterof Differentiation 138(+)\n(CD138(+)) endometrial stromal plasmacyte (ESPC) infil-\ntration [1]. The major cause of CE is thought to be intrauter-\nine infection represented by common bacteria (such as Es-\ncherichia coli , Enterococcus faecalis , Streptococcus, and\nStaphylococcus), Mycoplasma/Ureaplasma, and Mycobac-\nterium [2,3], as antibiotic treatments against these microor-\nganisms are effective for the elimination of ESPCs in the\naffected patients [ 4,5]. Other causes such as local dysbio-\nsis, however, may be involved in the pathogenesis of CE\n[6]. Accumulating evidence support that CE is associated\nwith infertility of unknown etiology (28%), repeated im-\nplantation failure in an in vitro fertilization-embryo transfer\nprogram (14%–31%), recurrent pregnancy loss (9%–13%),\nas well as several perinatal/neonatal complications [ 6–10].\nEndometriosis involves endocrinological, genetic,\nand epigenetic factors in its etiology and pathogenesis [ 11].\nRecent studies focus on immunological, infectious, and in-\nflammatory aspects of endometriosis and demonstrate the\ncommon characteristics between endometriosis and CE.\nThis review aimed to gain a better understanding of the rela-\ntionships between these two infertility-associated diseases.\n2. Prevalence of CE in Women with\nEndometriosis\nStudies reported that CE is identified in 3%–53% of\npatients with endometriosis (Table 1, Ref. [ 12–17]). These\ninterstudy variances are due to the differences in the diag-\nnostic criteria (ESPC density and microscopic fields ob-\nserved) and methodology to detect CD138(+) ESPCs (the\nclones, concentrations, incubation temperatures, and dura-\ntion of the primary antibody as well as specimen conditions)\nbetween the studies.\nIn 2011, we first investigated the prevalence of CE\nin the archival full-thickness eutopic endometrial tissues\nof women undergoing hysterectomy due to benign uter-\nine corpus diseases, such as leiomyoma, adenomyosis,\nand endometriosis. Histopathologic CE (defined as five\nCD138(+) ESPCs in 10 high power fields (HPFs), 400 mag-\nnification) was detected in 5.0% of the endometriosis group\nand 11.7% of the non-endometriosis group [ 12], although\nthe results were inconclusive due to the small sample size.\nIn 2014, Takebayashi et al . [ 13], retrospectively\nsearched for CE using a larger number of the eutopic en-\ndometrium obtained from the hysterectomized specimens.\nIn contrast to 27.0% of the non-endometriosis group, CE\nwas detected in 52.9% of the endometriosis group ( p =\n0.031), which is the highest number among the studies pub-\nlished so far. There were no relationships between CE\nand age, body mass index (BMI), gravidity, and parity.\nThey further compared the prevalence of CE in women with\nleiomyoma and adenomyosis. According to stepwise lo-\ngistic regression analysis, there were no significant associ-\nations between CE and these two frequent uterine benign\ndiseases, along with carcinoma in situ of the uterine cervix.\nAdditionally, CE was unrelated to the stage of endometrio-\nsis (according to the revised American Society for Repro-\n\nTable 1. Studies on the prevalence of histopathologic CE in women with endometriosis.\nArticle/Ethnicity/Study pe-\nriod/design\nPrevalence of\nhistopathologic CE\nin endometriosis vs\ncontrol group (p-value)\nAge (years) in en-\ndometriosis vs con-\ntrol group\nBMI (kg/m 2) (en-\ndometriosis group vs\ncontrol group)\nSamples and\npreparations\nDetection system for\nESPC/clone, concentra-\ntion, incubation time, and\ntemperature of primary anti-\nbody against CD138\nDiagnostic criteria for\nCE\nStage of endometriosis (Re-\nvised American Society for\nReproductive Medicine clas-\nsification)\nKitaya K et al . [ 12]\n/Japan/January 2002–\nDecember 2010/retrospec-\ntive\n5.00% (1/20) vs\n11.68% (25/214)\n(non-endometriosis,\nendometrial benign\ndiseases) (p = 0.7072)\nInformation unavail-\nable\nInformation unavail-\nable\nHysterectomy\nspecimens\nImmunohistochemistry,\nparaffin-embedded 4- µm\nsections /B-A38 (Nichirei\nCorp., Tokyo, Japan), stock\nsolution, 60 min, room tem-\nperature\n5 or more ESPCs in 10\nhigh power fields (HPFs)\nInformation unavailable\nTakebayashi A et al. [13]/Ja-\npan/April 2001–December 2-\n012/retrospective\n52.94% (18/34) vs 27.02%\n(10/37) (non-endometrio-\nsis, endometrial benign d-\niseases) (p = 0.0311)\n44.15, 3.65 vs 43.15,\n2.75 (mean and SD)\n(p = 0.711)\n22.08, 4.83 vs 21.60,\n3.14 (mean and SD)\n(p = 0.940)\nHysterectomy\nspecimens\nImmunohistochemistry, para-\nffin-embedded 4-µm sections/\nB-A38, stock solution, 60 m-\nin, room temperature\n1 or more ESPCs in 10 H-\nPFs (400-fold magnifica-\ntion)\nStage I–IV\nNo relationship between the\nprevalence of CE and stage\nKhan KN et al . [ 14]\n/Japan/June 2012–December\n2013/retrospective\n3.08% (2/65) vs\n0% (0/55) (non-\nendometriosis, infer-\ntility/dysmenorrhea) (p =\n0.4993)\n21–51 vs 22–51\n(range)\nInformation unavail-\nable\nCurettage speci-\nmens\nImmunohistochemistry,\nparaffin-embedded 5- µm\nsections /ab34164 (Ab-\ncam, Tokyo, Japan), 1:200,\novernight, 4 °C\n1 or more ESPCs in 15\nHPFs (100-fold magnifi-\ncation) in 3 or more sec-\ntions\nInformation unavailable\nCicinelli E et al . [ 16]\n/Italy/January 2010–June\n2016/retrospective\n38.46% (30/78) vs\n14.10% (11/78) (non-\nendometriosis, endome-\ntrial benign diseases) ( p\n< 0.001)\n44.3, 2.8 vs 44.0, 2.3\n(mean and SD) ( p >\n0.05)\n27.3, 4.2 vs 27.2, 4.3\n(mean and SD) ( p >\n0.05)\nHysterectomy\nspecimens\nImmunohistochemistry,\nparaffin-embedded 4- µm\nsections /MI15 Cell Marque\n(Biocare Medical, Concord,\nCA)/not available\n1 or more ESPCs in 10\nHPFs (100-fold magnifi-\ncation)\nStage IV\nFreitag N et al .\n[17]/Germany (>90%\nCaucasian)/January 2013–\nFebruary 2017/retrospective\n12.90% (8/62) vs\n10.00% (5/50) (non-\nendometriosis, infertil-\nity) (p = 0.634)\n26–48 (range) Information unavail-\nable\nPipelle suction\nspecimens\nImmunohistochemistry,\nparaffin-embedded/Other\ninformation not available\n(sent to laboratory)\n5 or more ESPC per mm2\nsection\nInformation unavailable\nKhan KN et al. [ 15]/Japan/A-\npril 2015–February 2017/Pro-\nspective, non-randomized\n≥22.6% (≥12/53) Not e-\nxamined prior to treatment\n33.4% (7/21) (Untreated e-\nndometriosis) vs ≥23.4%\n(≥11/47) Not examined p-\nrior to treatment 27.3% (3/\n11) (Untreated endometri-\nosis)\n18–51 vs 26–51\n(range)\nInformation unavail-\nable\nCurettage speci-\nmens\nImmunohistochemistry, para-\nffin-embedded 5-µm sections/\nab34164, 1:200, overnight, 4\n°C\n1 or more ESPCs in 5 H-\nPFs (200-fold magnifica-\ntion)\nStage I–IV\nNo relationship between the\nprevalence of CE and stage\n2\n\n\nductive Medicine classification) [ 11]. The higher preva-\nlence of CE in this study is due to the diagnostic criteria\n(defined as one CD138(+) ESPCs in 10 HPFs, 400 magni-\nfication). When the researchers adopted the cut-off index of\n6 ESPCs in one HPF, the overall prevalence was still higher\nin the endometriosis group than in the non-endometriosis\ngroup (29.41% vs 5.4%, p = 0.0101). Additionally, they\nfound that all women with endometriosis enrolled had more\nthan 11 ESPCs in one HPF.\nIn the same year, Khan et al. [ 14] also retrospectively\ncompared the prevalence of CE in women with and with-\nout endometriosis using endometrial curettage biopsy spec-\nimens collected during laparoscopy. They defined CE as\nthe presence of one or more CD138(+) ESPCs (without neu-\ntrophils) in five non-overlapping power fields ( ×100 mag-\nnification) in three or more 5- µm thickness sections. CE\nwas detected in 3.1% (2/65 patients) with endometriosis,\nbut not in any non-endometriosis patients (no statistical dif-\nference). However, the prevalence is much different from\nanother prospective non-randomized study published in\n2021 (endometriosis group 22.6%~ and non-endometriosis\ngroup 23.4%~) [ 15], even with the same sample prepa-\nration and examination methods. The discrepancies be-\ntween the two studies may be due to the presence or ab-\nsence of (i) histopathologic examinations for CE before la-\nparoscopy, (ii) preoperative administration of the oral an-\ntibiotic agents (levofloxacin, 500 mg, once), and/or in-\ntramuscular gonadotropin-releasing hormone agonist (1.88\nmg per month, three times), and (iii) the difference in age\nof the women enrolled in the study. Again, no relationship\nwas found between the prevalence of CE and the stage of\nendometriosis.\nIn 2017, Cicinelli et al . [ 16] retrospectively com-\npared the prevalence of CE in the endometrial tissues in\nthe hysterectomized specimens of patients with and with-\nout endometriosis. Histopathologic CE was significantly\nmore frequent in the stage IV endometriosis group than in\nthe non-endometriosis group (38.5% vs 14.1%, p < 0.001).\nThe concomitance of CE and endometriosis was observed\nin more than one-third of women. There were no significant\nassociations between CE and age, BMI, and the presence of\nuterine leiomyoma/adenomyosis, but multiparity was found\nas a factor lowering the prevalence of CE in women with\nendometriosis.\nAs many of these studies enrolled women undergo-\ning pelvic surgery (hysterectomy or laparoscopy) and diag-\nnosed with endometriosis during the operation, the preva-\nlence of CE in women with suspected endometriosis (so-\ncalled “clinical endometriosis”) remains unknown and thus\nawaits further studies.\n3. Microbiota in Reproductive Tract in\nEndometriosis and CE\nWhile there are three major theories underlying the on-\nset of endometriosis (i.e., retrograde menstrual blood flow,\ncoelomic metaplasia, and Mullerian remnants), a single\none is unable to explain the whole entity of the disease.\nGiven the immunological and inflammatory natures of en-\ndometriosis, it is conceivable that bacterial infection and\ntheir metabolites are involved in this pathology [ 18].\nRecent advances in next-generation sequencing meth-\nods enabled us to analyze the local microbiota in various\ntissues and organs. In 2011, Human Microbiome Project\nrevealed that the microbiota in the human vagina is domi-\nnated by four Lactobacillus species (L. iners, L. crispatus,\nL. gasseri, and L. jensenii), along with lower proportions of\nlactic acid bacteria, indicating the essential role of lactate\nin the integrity of this organ [ 19,20]. However, it remained\nundetermined if these results go for the whole female repro-\nductive tract. In 2017, Chen et al . [ 21] comprehensively\ninvestigated the microbiota throughout the female repro-\nductive tract in Chinese women of reproductive age. They\ndemonstrated that each reproductive organ has its unique\nmicrobiota, and the local microbiota is affected by multiple\nfactors, such as age, body temperature, menstrual cycle, fe-\ncundability/infertility, and anemia.\nStudies have demonstrated conflicting findings on the\nmicrobiota in the reproductive tract, particularly on Lacto-\nbacillus, in women with endometriosis. While some re-\nsearchers reported a decrease in Lactobacillus in the en-\ndometrial and vaginal microbiota [ 22,23], others claimed\nthe opposite result [ 24–26]. Interestingly, Khan et al. [ 22]\nfound that the administration of gonadotropin-releasing\nhormone agonist, one of the therapeutic agents against en-\ndometriosis, changed the microbiota in the uterine cav-\nity, resulting in a further decrease in Lactobacillus. Ad-\nditionally, Le et al . [ 25], and Chang et al . [ 26] reported\nthat surgical intervention and hormonal therapy altered the\nabundance of vaginal bacterial communities in the affected\nwomen with endometriosis. For example, the proportion\nof Lactobacillus in the vaginal microbiota was lower in pa-\ntients using monophasic oral contraceptives than in the non-\nusers. The mechanisms underlying these medical interven-\ntions that affected the local microbiota in women with en-\ndometriosis remain unelucidated. Regarding other bacte-\nrial genera/species, the consequences are quite inconsistent\namong the studies [ 22–28]. These discrepancies are likely\nto result from the conditions for examinations such as types\nof local disinfectants, sampling device, and route. Taken to-\ngether, the bacterial genera/species and/or microbial com-\nmunities in the female reproductive tract that are unique to\nendometriosis remains open so far and further studies are\nrequired.\nMeanwhile, studies on CE share some common find-\nings on the microbiota in the reproductive tract in the af-\nfected women. For example, bacterial taxa such as Bifi-\ndobacterium, Gardnerella, Lactobacillus, Prevotella, and\nStreptococcus were found to be predominant in the endome-\ntrial microbiota in women with CE [ 29–35]. By contrast,\na number of studies failed to find unique bacterial gen-\n3\n\nera/species and microbial communities and/or differences\nin diversity and taxonomical composition in the endome-\ntrial and vaginal microbiota between women with and with-\nout CE [ 36–38]. The results of the endometrial micro-\nbiome analysis must be interpreted with precautions, as\nthe estimated bacterial load in the vaginal cavity is shown\nto be 100- to 10,000-fold more than those in the uterine\ncavity [ 21]. No matter how local cleansing and disinfec-\ntion are well performed before sampling, the contamina-\ntion of the vaginal bacteria into endometrial bacteria is in-\nevitable in the course of the transvaginal procedure. In-\ndeed, the studies using the samples obtained via the trans-\nperitoneo-myometrial route (laparoscopy or laparotomy)\nand transvaginal route disclosed quite different findings\non endometrial microbiota, particularly about the compo-\nsitions of Lactobacillus species [ 21,39,40]. We recently\nreported that the vaginal microbiota in infertile women\nwith CE is characterized by the reduction of lactic-acid-\nproducing bacteria other than Lactobacillus, such as Strep-\ntococcus, Enterococcus, Atopobium, and Bifidobacterium\n[41]. The vaginal microbiome analysis should be noticed\nin future studies in this field.\n4. Inflammatory Profiling of CE in Women\nwith Endometriosis\nNon-pathological human endometrium contains a\nwide variety of leukocyte subsets. One of the physiological\nroles of these local leukocytes is the clearance of endome-\ntrial cell debris shed over the course of the menstrual pe-\nriod. The density and proportion of endometrial leukocytes\nsignificantly fluctuate throughout the menstrual cycle. Af-\nter ovulation, the subpopulations of macrophages, natural\nkiller cells, and neutrophils increase in density in the en-\ndometrium [42].\nThis postovulatory rise of macrophages, however,\nis not seen in the eutopic endometrium of women\nwith endometriosis, whereas an unusual hormonal cycle-\nindependent global augmentation of macrophages (in par-\nticular of M1 macrophages) is observed [ 43]. By contrast,\nin the ectopic endometrium of women with endometriosis, a\nlarge number of angiogenesis-supportive M2 macrophages\nare detectable in the endometriotic lesions [ 44]. These\nendometrial macrophages are thought to induce the pro-\nliferation of endometriotic cells. The postovulatory nu-\nmerical increase of eutopic endometrial natural killer cells\nis maintained in women with endometriosis, but their cy-\ntolytic activity is impaired. In parallel, the lowered activ-\nity of cytotoxic T lymphocytes, as well as the expansion of\neosinophils, neutrophils, and mast cells, are reported in the\nperitoneal fluid in women with endometriosis [45]. Such an\naberrant local immunological microenvironment is thought\nto allow the proliferation and survival of ectopic endome-\ntrial tissues. Another immunological feature of the eutopic\nendometrium of women with endometriosis is the appear-\nance of plasmacytes and CD20(+)/CD5(+)/HLA-DR(+) B\ncells, which are typical immunocompetent cells observed\nin CE, but are rare immunocompetent cells in the non-\npathological eutopic endometrium [ 45]. On the contrary,\nendometrial immunoglobulin profiling remains undetailed.\nEarly studies demonstrate a higher expression rate of IgG\nin eutopic endometrium with endometriosis compared with\nthose without endometriosis, but subclass analysis has not\nbeen performed [46].\nMeanwhile, the menstrual cycle-dependent fluctua-\ntion of the endometrial leukocyte subpopulations remains\ncontroversial in CE. Several studies did not find any dif-\nferences [45,47], but others showed an increase in the pro-\nportion of local macrophages, M2 macrophages, and im-\nmature/mature dendritic cells [48]. Regarding mucosal im-\nmunoglobulin expression, the densities of endometrial IgM,\nIgA1, IgA2, IgG1, and IgG2 subclasses were shown to be\nhigher in CE than in non-CE and healthy controls with the\npredominance of IgG2+ stromal cells [ 49].\nWe demonstrated that several pro-inflammatory\nmolecules involved in the selective extravasation of B\ncells, such as chemokines (Chemokine (C-X-C motif)\nligand (CXCL1) and CXCL13) and endothelial adhesion\nmolecule 1 (ELAM1) are aberrantly expressed in endothe-\nlial and epithelial cells of the endometrium in women\nwith CE [ 47]. These pro-inflammatory molecules are\ninduced in endometrial cells by microbial antigens such\nas lipopolysaccharide. In addition, the concentration of\ninterleukin (IL)-6 and tumor necrosis factor (TNF)- α is\nmarkedly higher in the menstrual effluents of women with\nCE compared with those without CE [ 49]. IL-6 is known\nas a differentiation factor of mature B cells in various\ntissues. TNF- α raises estrogen biosynthesis in endometrial\nglandular cells, which may drive the uterine lining to the\nproliferative phenotype that may cause the occurrence of\nendometrial micropolyposis, a hysteroscopic finding that\nis often seen in CE [ 50,51].\nAlthough it remains fully elucidated if these hypothe-\nses apply to the eutopic endometrium of endometriosis,\nstudies suggest that these unusual plasmacytes and B cells\nare potentially involved in the proliferation and survival\nof the other endometrial cell components. For example,\nthe endometrium with local polyps and micropolyps own\nproliferative nature and contains a larger number of ES-\nPCs than the non-pathologic endometrium [ 52]. One of the\nhistopathological characteristics of CE is delayed endome-\ntrial differentiation in the mid-secretory phase, when blasto-\ncysts start to implant in this mucosal tissue. We found that\napproximately one-third of the endometrium with CE ex-\nhibit “out-of-phase” morphology, such as pseudostratifica-\ntion and mitotic nuclei in both glandular and surface epithe-\nlial cells [47]. Additionally, the expression levels of the an-\ntiapoptotic genes (BCL2 and BAX ), proliferation-associated\nnuclear marker (Ki-67), and ovarian steroid receptors (es-\ntrogen receptor-α, and -β, progesterone receptor-A, and -B)\nare unusually upregulated in the secretory phase endometr-\n4\n\n\nTable 2. Studies on the use of metronidazole against CE.\nArticle/Ethnicity/Study pe-\nriod/Study design\nDose Indications Age (years) BMI (kg/m2) Samples/Detection system for\nESPC/clone, dilution, incu-\nbation time, and temperature\nof primary antibody against\nCD138\nDiagnostic criteria for\nCE\nThe cure rate of\nhistopathologic\nCE\nJohnston-MacAnanny\nEB et al ., [ 58] /United\nStates/January 2001–\nDecember 2007/Retro-\nspective\n1000 mg/day, 14 days (500\nmg, twice) in combination\nwith ciprofloxacin 1000\nmg/day, 14 days\nRIF (two failed ET cy-\ncles), second-line against\ndoxycycline-resistant CE\n34.50, 3.27 (mean\nand SD)\nInformation unavail-\nable\nPipelle suction specimens/\nImmunohistochemistry,\nparaffin-embedded sec-\ntions/MI15 Cell Marque\n(Biocare Medical, Concord,\nCA)/not available Biocare\nMedical, Concord, CA) /1:100\ndilution/60 min/Room air?\n1 or more ESPCs in 1\nHPF observed\n100% (3/3)\nMcQueen DB et al . [ 8]\n/United States (Cau-\ncasian and African-\nAmerican)/July 2004–\nFebruary 2012/Prospective\n1000 mg/day, 14 days (500\nmg, twice) in combina-\ntion with or ofloxacin 800\nmg/day, 14 days\nRecurrent pregnancy\nloss, first-line\n22.08, 4.83 (mean\nand SD)\n25.8, 6.4, 20–47\n(mean, SD and\nrange)\nNot detailed Not detailed 73.1% (19/26)\nY ang R et al . [ 62] /Chi-\nnese/January 2009–January\n2010/Prospective\n1000 mg/day, 14 days (500\nmg, twice) in combina-\ntion with levofloxacin 500\nmg/day, 14 days\nRIF (three failed ET cy-\ncles or 6 or more high-\nquality transferred em-\nbryos), first-line\nNot detailed (Two\ncombined studies\nare reported in one\narticle)\nNot detailed (Two\ncombined studies\nare reported in one\narticle)\nPipelle suction specimens/ Im-\nmunohistochemistry\n1 or more ESPCs in the\nsection observed\nNot re-examined\nTersoglio AE et al .\n[59] /Argentina/2010–\n2013/Prospective\n1000 mg/day, 14 days (500\nmg, twice) in combination\nwith ciprofloxacin 1000\nmg/day, 14 days and prece-\ndent 200 mg/day doxycycline\nalong with prednisone 4–8\nmg/day\nRIF (two or more failed\nET cycles), first-line\n36, 4.08 (mean and\nSD)\nInformation unavail-\nable\nNot detailed 1 or more ESPCs in 1\nHPF observed\n64.3% (9/14)\nKitaya K et al .\n[10]/Japan/November\n2011–July 2014/Prospective\n500 mg/day, 14 days (250\nmg, twice) in combination\nwith ciprofloxacin 400\nmg/day, 14 days\nRIF (three or more 6 or\nmore high-quality trans-\nferred embryos and/or\nblastocysts), second-line\nagainst doxycycline-\nresistant CE\n38.1, 3.8 (mean and\nSD)\n21.1, 1.9 (mean and\nSD)\nCurette biopsy speci-\nmens/Immunohistochemistry,\nparaffin-embedded 4- µm sec-\ntions /B-A38 (Nichirei Corp.,\nTokyo, Japan), stock solution,\n60 min, room temperature\nendometrial stromal\nplasmacyte density index\n(sum of ESPC counts\ndivided by the number of\nHPF evaluated) 0.25 or\nmore\n88.9% (8/9)\nGay C et al. [ 63]/France/Jan-\nuary 2013–January 2018/Re-\ntrospective\n1000 mg/day, 14 days (500\nmg, twice) in combination\nwith doxycycline 200 mg/d-\nay, 14 days (Antibiotic was\nchosen according to antibio-\ngram if bacteria were ident-\nified.)\nRecurrent pregnancy loss,\nfirst-line\n33 (9) 24 (3)\nPipelle suction specimens/Imm-\nunohistochemistry, not detailed\n1 or more ESPCs in 1 H-\nPF observed Not detailed\nmedian and (in-\nterquartile range)\nmedian and (in-\nterquartile range)\n5\n\nium with CE [ 53–56]. Meanwhile, the expression of the\ngenes potentially associated with embryo receptivity ( in-\nterleukin 11 (IL11), Chemokine Ligand 4 (CCL4) , insulin-\nlike growth factors 1 (IGF1) , and caspase 8 (CASP8) ) and\ndecidualization ( prolactin (PRL) and Insulin-like growth\nfactor-binding protein 1 (IGFBP1)) are impaired in this pe-\nriod [53,56].\nThese findings indicate that the endometrium with CE\nis unable to respond correctly to ovarian steroids and mod-\nulate its component cells into a receptive phenotype, impli-\ncating the potential relationship between progesterone re-\nsistance and CE, which is also seen in endometriosis [ 57].\n5. Antibiotic Treatment against CE and\nEndometriosis\nAs a bacterial infectious disease, antibiotic treatments\nhave been utilized in the treatment of CE. Indeed, recent\nstudies demonstrated that antibiotic treatments are supe-\nrior to follow-up observations in the cure rate of CE [ 4,5].\nAdditionally, some studies suggest an improved live birth\nrate in subsequent embryo transfer cycles after the cure of\nCE, although there are no published randomized controlled\nstudies [ 7,9,58–60]. Considering the broad antibacterial\nspectrum covering from common bacteria to mycoplasma,\nthe antibiotic agents such as oral doxycycline, fluoro-\nquinolones (ofloxacin, levofloxacin, and ciprofloxacin), ni-\ntroimidazole (tinidazole and metronidazole) have been pre-\nferred in the treatment against CE [7,9,58–63]. Meanwhile,\nsome studies adopted an antibiogram-oriented choice of an-\ntibiotic agents [ 6]. Antibiotic resistance is a global prob-\nlem in the treatment of bacterial infectious diseases. CE is\nno exception anymore. We recently demonstrated the in-\ncrease in multi-drug-resistant CE in infertile women with\na history of repeated implantation failure (7.8% of whole\nCE cases), along with the effectiveness of azithromycin or\nmoxifloxacin against multi-drug-resistant CE [ 37].\nAlthough there is currently no literature that demon-\nstrated the effectiveness and safety of antibiotic treatment\nagainst endometriosis in humans, animal studies suggest the\npotential of some antibiotic agents, particularly metronida-\nzole, which has been utilized for the treatment of CE (Ta-\nble 2, Ref. [ 8,10,58,59,62,63]), as a promising therapeutic\ndrug against endometriosis.\nUsing a mouse model, Chadchan et al . [ 64] investi-\ngated the effect of 21-day oral water-solubilized adminis-\ntration of the broad-spectrum antibiotics (0.5 mg/mL van-\ncomycin, 1 mg/mL neomycin, 1 mg/mL metronidazole, and\n1 mg/mL ampicillin, V ancomycin, Neomycin, Metronida-\nzole, and Ampicillin (VNMA)) on endometriosis lesions.\nOf them, metronidazole significantly reduced the volumes\nand weights of the ectopic endometriosis lesions, along\nwith amelioration of pelvic inflammatory responses (sup-\npression of macrophage proliferation and production of cy-\ntokines such as IL-1 β, IL-6, and TNF- α). Interestingly,\noral administration of feces from mice with endometriosis\nexacerbates the growth and inflammation of the endometri-\notic lesions in metronidazole-treated mice, indicating a key\nrole of gut bacteria in the promotion and progression of en-\ndometriosis in these mice. Furthermore, Lu et al. [ 65] re-\nported the effectiveness of the vaginal administration of the\nVNMA mixture (once every 3 days for 21 days) via an ab-\nsorbable gel sponge on endometriosis lesions. While the\ndisorder of the vaginal microbiota potentially promoted the\nprogression of endometriosis, antibiotic treatment was ca-\npable of reducing the volume of the endometriotic lesions\nvia regulation of the nuclear factor-kappa B signaling path-\nway.\nThus, antibiotic treatment can be a potential therapeu-\ntic option against endometriosis, although more basic stud-\nies are required prior to application to humans.\n6. Conclusions\nWhile endometriosis has been long considered a cause\nof infertility, CE is also an emerging issue that may reduce\nfecundity in women of reproductive age [ 66]. Endometrio-\nsis and CE share characteristics of endometrial prolifer-\native nature. Like endometrial polyps being often seen\nin endometriosis, endometrial micropolyposis is frequently\ncomplicated with CE [ 17,67]. The potential relationships\nbetween these two diseases of the uterine lining warrant fu-\nture studies.\nAuthor Contributions\nKK wrote the manuscript. TM and MM were involved\nin the discussion of the contents. All authors read and ap-\nproved the final manuscript.\nEthics Approval and Consent to Participate\nNot applicable.\nAcknowledgment\nNot applicable.\nFunding\nThis research received no external funding.\nConflict of Interest\nThe authors declare no conflict of interest.\nReferences\n[1] Kitaya K, Takeuchi T, Mizuta S, Matsubayashi H, Ishikawa T.\nEndometritis: new time, new concepts. Fertility and Sterility.\n2018; 110: 344–350.\n[2] Andrews WW, Goldenberg RL, Hauth JC, Cliver SP , Conner\nM, Goepfert AR. Endometrial microbial colonization and plasma\ncell endometritis after spontaneous or indicated preterm versus\nterm delivery. American Journal of Obstetrics and Gynecology.\n2005; 193: 739–745.\n[3] Cicinelli E, De Ziegler D, Nicoletti R, Colafiglio G, Saliani N,\nResta L, et al. Chronic endometritis: correlation among hystero-\nscopic, histologic, and bacteriologic findings in a prospective\ntrial with 2190 consecutive office hysteroscopies. Fertility and\nSterility. 2008; 89: 677–684.\n6\n\n\n[4] Cicinelli E, Resta L, Loizzi V , Pinto V , Santarsiero C, Cicinelli\nR, et al . Antibiotic therapy versus no treatment for chronic en-\ndometritis: a case-control study. Fertility and Sterility. 2021;\n115: 1541–1548.\n[5] Song D, He Y , Wang Y , Liu Z, Xia E, Huang X, et al. Impact of\nantibiotic therapy on the rate of negative test results for chronic\nendometritis: a prospective randomized control trial. Fertility\nand Sterility. 2021; 115: 1549–1556.\n[6] Moreno I, Cicinelli E, Garcia-Grau I, Gonzalez-Monfort M, Bau\nD, Vilella F, et al . The diagnosis of chronic endometritis in in-\nfertile asymptomatic women: a comparative study of histology,\nmicrobial cultures, hysteroscopy, and molecular microbiology.\nAmerican Journal of Obstetrics and Gynecology. 2018; 218:\n602.e1–602.e16.\n[7] Cicinelli E, Matteo M, Tinelli R, Lepera A, Alfonso R, Indrac-\ncolo U, et al. Prevalence of chronic endometritis in repeated un-\nexplained implantation failure and the IVF success rate after an-\ntibiotic therapy. Human Reproduction. 2015; 30: 323–330.\n[8] McQueen DB, Perfetto CO, Hazard FK, Lathi RB. Pregnancy\noutcomes in women with chronic endometritis and recurrent\npregnancy loss. Fertility and Sterility. 2015; 104: 927–931.\n[9] Bouet P , El Hachem H, Monceau E, Gariépy G, Kadoch I,\nSylvestre C. Chronic endometritis in women with recurrent preg-\nnancy loss and recurrent implantation failure: prevalence and\nrole of office hysteroscopy and immunohistochemistry in diag-\nnosis. Fertility and Sterility. 2016; 105: 106–110.\n[10] Kitaya K, Matsubayashi H, Takaya Y , Nishiyama R, Y amaguchi\nK, Takeuchi T, et al . Live birth rate following oral antibiotic\ntreatment for chronic endometritis in infertile women with re-\npeated implantation failure. American Journal of Reproductive\nImmunology. 2017; 78: e12719.\n[11] American Society for Reproductive Medicine. Revised Amer-\nican Society for Reproductive Medicine classification of en-\ndometriosis. Fertility and Sterility. 1996; 67: 817–821.\n[12] Kitaya K, Y asuo T. Immunohistochemistrical and Clinicopatho-\nlogical Characterization of Chronic Endometritis. American\nJournal of Reproductive Immunology. 2011; 66: 410–415.\n[13] Takebayashi A, Kimura F, Kishi Y , Ishida M, Takahashi A, Y a-\nmanaka A, et al . The association between endometriosis and\nchronic endometritis. PLoS ONE. 2014; 9: e88354.\n[14] Khan KN, Fujishita A, Kitajima M, Hiraki K, Nakashima M, Ma-\nsuzaki H. Intra-uterine microbial colonization and occurrence of\nendometritis in women with endometriosis. Human Reproduc-\ntion. 2014; 29: 2446–2456.\n[15] Khan KN, Fujishita A, Muto H, Masumoto H, Ogawa K, Koshiba\nA, et al . Levofloxacin or gonadotropin releasing hormone ag-\nonist treatment decreases intrauterine microbial colonization in\nhuman endometriosis. European Journal of Obstetrics and Gy-\nnecology and Reproductive Biology. 2021; 264: 103–116.\n[16] Cicinelli E, Trojano G, Mastromauro M, Vimercati A, Marinac-\ncio M, Mitola PC, et al. Higher prevalence of chronic endometri-\ntis in women with endometriosis: a possible etiopathogenetic\nlink. Fertility and Sterility. 2017; 108: 289–295.e1.\n[17] Freitag N, Pour SJ, Fehm TN, Toth B, Markert UR, Weber M,\net al. Are uterine natural killer and plasma cells in infertility pa-\ntients associated with endometriosis, repeated implantation fail-\nure, or recurrent pregnancy loss? Archives of Gynecology and\nObstetrics. 2020 ; 302: 1487–1494.\n[18] Medina-Bastidas D, Camacho-Arroyo I, García-Gómez E. Cur-\nrent findings in endometrial microbiome: impact on uterine dis-\neases. Reproduction. 2022; 163: R81–R96.\n[19] Ravel J, Gajer P , Abdo Z, Schneider GM, Koenig SSK, McCulle\nSL, et al. V aginal microbiome of reproductive-age women. Pro-\nceedings of the National Academy of Sciences of USA. 2011;\n108: 4680–4687.\n[20] V erstraelen H, Vilchez-V argas R, Desimpel F, Jauregui R,\nV ankeirsbilck N, Weyers S,et al. Characterisation of the human\nuterine microbiome in non-pregnant women through deep se-\nquencing of the V1-2 region of the 16S rRNA gene. PeerJ. 2016;\n4: e1602.\n[21] Chen C, Song X, Wei W, Zhong H, Dai J, Lan Z,et al. The micro-\nbiota continuum along the female reproductive tract and its rela-\ntion to uterine-related diseases. Nature Communications. 2017;\n8: 875.\n[22] Khan KN, Fujishita A, Masumoto H, Muto H, Kitajima M, Ma-\nsuzaki H, et al . Molecular detection of intrauterine microbial\ncolonization in women with endometriosis. European Journal\nof Obstetrics and Gynecology and Reproductive Biology. 2016;\n199: 69–75.\n[23] Wei W, Zhang X, Tang H, Zeng L, Wu R. Microbiota com-\nposition and distribution along the female reproductive tract of\nwomen with endometriosis. Annals of Clinical Microbiology and\nAntimicrobials. 2020; 19: 15.\n[24] Hernandes C, Silveira P , Rodrigues SAF, Christoff AP , Mendes\nH, V alter de Oliveira LF, et al. Microbiome profile of deep en-\ndometriosis patients: comparison of vaginal fluid, endometrium,\nand lesion. Diagnostics. 2020; 10: 163.\n[25] Le N, Cregger M, Brown V , de Mola JL, Bremer P , Nguyen L,\net al. Association of microbial dynamics with urinary estrogens\nand estrogen metabolites in patients with endometriosis. PLoS\nONE. 2021; 16: e0261362.\n[26] Chang CYY , Chiang AJ, Lai MT, Y an MJ, Tseng CC, Lo LC,et\nal. A more diverse cervical microbiome associated with better\nclinical outcomes in patients with endometriosis: a pilot study.\nBiomedicines. 2022; 10: 174.\n[27] Wessels JM, Domínguez MA, Leyland NA, Agarwal SK, Foster\nWG. Endometrial microbiota is more diverse in people with en-\ndometriosis than symptomatic controls. Scientific Reports. 2021;\n11: 18877.\n[28] Y uan W, Wu Y , Chai X, Wu X. The colonized microbiota com-\nposition in the peritoneal fluid in women with endometriosis.\nArchives of Gynecology and Obstetrics. 2022; 305: 1573–1580.\n[29] Fang RL, Chen LX, Shu WS, Y ao SZ, Wang SW, Chen YQ.\nBarcoded sequencing reveals diverse intrauterine microbiomes\nin patients suffering with endometrial polyps. American Journal\nof Translational Research. 2016; 8: 1581–1592.\n[30] Bhide S, Flyckt R, Y ao M, Falcone T. Long-term impact of\nchronic pelvic pain on quality of life in women with and with-\nout endometriosis Clinical Experimental Obstetrics and Gyne-\ncology. 2021; 48: 851–859.\n[31] Chen W, Wei K, He X, Wei J, Y ang L, Li L, et al. Identification\nof uterine microbiota in infertile women receiving in vitro fertil-\nization with and without chronic endometritis. Frontiers in Cell\nand Developmental Biology 2021; 9: 693267.\n[32] Liu Y , Ko EY , Wong KK, Chen X, Cheung W, Law TS, et\nal. Endometrial microbiota in infertile women with and with-\nout chronic endometritis as diagnosed using a quantitative and\nreference range-based method. Fertility and Sterility. 2019; 112:\n707–717.e1.\n[33] Lozano FM, Bernabeu A, Lledo B, Morales R, Diaz M, Aranda\nFI, et al. Characterization of the vaginal and endometrial micro-\nbiome in patients with chronic endometritis. European Journal\nof Obstetrics and Gynecology and Reproductive Biology. 2021;\n263: 25–32.\n[34] Molina NM, Sola-Leyva A, Saez-Lara MJ, Plaza-Diaz J, Tubić-\nPavlović A, Romero B, et al. New opportunities for endometrial\nhealth by modifying uterine microbial composition: present or\nfuture? Biomolecules. 2020; 10: 593.\n[35] Chen P , Chen P , Guo Y , Fang C, Li T. Interaction between\nchronic endometritis caused endometrial microbiota disorder and\nendometrial immune environment change in recurrent implanta-\ntion failure. Frontiers in Immunology 2021; 12: 748447.\n[36] Lüll K, Saare M, Peters M, Kakhiani E, Zhdanova A, Salumets\nA, et al . Differences in microbial profile of endometrial fluid\nand tissue samples in women with in vitro fertilization failure\n7\n\nare driven by Lactobacillus abundance. Acta Obstetricia et Gy-\nnecologica Scandinavica 2022; 101: 212–220.\n[37] Kitaya K, Tanaka SE, Sakuraba Y , Ishikawa T. Multi-drug-\nresistant chronic endometritis in infertile women with repeated\nimplantation failure: trend over the decade and pilot study for\nthird-line oral antibiotic treatment. Journal of Assisted Repro-\nduction and Genetics. 2022; 39: 1839–1848.\n[38] Kitaya K, Ishikawa T. Lincomycin administration against persis-\ntent multi-drug-resistant chronic endometritis in infertile women\nwith a history of repeated implantation failure. Applied Micro-\nbiology. 2022; 2: 554–560.\n[39] Winters AD, Romero R, Gervasi MT, Gomez-Lopez N, Tran\nMR, Garcia-Flores V , et al . Does the endometrial cavity have\na molecular microbial signature? Scientific Reports. 2019; 9:\n9905.\n[40] Leoni C, Ceci O, Manzari C, Fosso B, V olpicella M, Ferrari A,\net al. Human endometrial microbiota at term of normal pregnan-\ncies. Genes. 2019; 10: E971.\n[41] Tanaka SE, Sakuraba Y , Kitaya K, Ishikawa T. Differential vagi-\nnal microbiota profiling in lactic-acid-producing bacteria be-\ntween infertile women with and without chronic endometritis.\nDiagnostics. 2022; 12: 878.\n[42] Kitaya K, Y amaguchi T, Y asuo T, Okubo T, Honjo H. Post-\novulatory rise of endometrial CD16(−) natural killer cells: in situ\nproliferation of residual cells or selective recruitment from circu-\nlating peripheral blood? Journal of Reproductive Immunology.\n2007; 76: 45–53.\n[43] Agostinis C, Balduit A, Mangogna A, Zito G, Romano F, Ricci\nG, et al. Immunological Basis of the Endometriosis: The Com-\nplement System as a Potential Therapeutic Target. Frontiers in\nImmunology. 2021; 11: 599117.\n[44] Laganà AS, Salmeri FM, Ban Frangež H, Ghezzi F, Vrtačnik-\nBokal E, Granese R. Evaluation of M1 and M2 macrophages in\novarian endometriomas from women affected by endometriosis\nat different stages of the disease. Gynecological Endocrinology.\n2020; 36: 441–444.\n[45] Shen M, O’Donnell E, Leon G, Kisovar A, Melo P , Zondervan K,\net al. The role of endometrial B cells in normal endometrium and\nbenign female reproductive pathologies: a systematic review.\nHuman Reproduction Open. 2022; 2022: hoab043.\n[46] Mathur S, Garza DE, Smith LF. Endometrial autoantigens elic-\niting immunoglobulin (Ig)G, IgA, and IgM responses in en-\ndometriosis. Fertility and Sterility. 1990; 54: 56–63.\n[47] Kitaya K, Y asuo T. Aberrant expression of selectin E, CXCL1,\nand CXCL13 in chronic endometritis. Modern Pathology. 2010;\n23: 1136–1146.\n[48] Li Y , Y u S, Huang C, Lian R, Chen C, Liu S, et al . Evaluation\nof peripheral and uterine immune status of chronic endometri-\ntis in patients with recurrent reproductive failure. Fertility and\nSterility. 2020; 113: 187–196.e1.\n[49] Kitaya K, Tada Y , Hayashi T, Taguchi S, Funabiki M, Naka-\nmura Y . Comprehensive Endometrial Immunoglobulin Subclass\nAnalysis in Infertile Women Suffering from Repeated Implan-\ntation Failure with or without Chronic Endometritis. American\nJournal of Reproductive Immunology. 2014; 72: 386–391.\n[50] Tortorella C, Piazzolla G, Matteo M, Pinto V , Tinelli R, Sabbà\nC, et al. Interleukin-6, interleukin-1β, and tumor necrosis factor\nα in menstrual effluents as biomarkers of chronic endometritis.\nFertility and Sterility. 2014; 101: 242–247.\n[51] Cicinelli E, Bettocchi S, de Ziegler D, Loizzi V , Cormio G, Mari-\nnaccio M, et al. Chronic Endometritis, a Common Disease Hid-\nden behind Endometrial Polyps in Premenopausal Women: first\nEvidence from a Case-Control Study. Journal of Minimally In-\nvasive Gynecology. 2019; 26: 1346–1350.\n[52] Kitaya K, Tada Y , Taguchi S, Funabiki M, Hayashi T, Naka-\nmura Y . Local mononuclear cell infiltrates in infertile patients\nwith endometrial macropolyps versus micropolyps. Human Re-\nproduction. 2012; 27: 3474–3480.\n[53] Di Pietro C, Cicinelli E, Guglielmino MR, Ragusa M, Fa-\nrina M, Palumbo MA, et al . Altered Transcriptional Regula-\ntion of Cytokines, Growth Factors, and Apoptotic Proteins in\nthe Endometrium of Infertile Women with Chronic Endometri-\ntis. American Journal of Reproductive Immunology. 2013; 69:\n509–517.\n[54] Mishra K, Wadhwa N, Guleria K, Agarwal S. ER, PR and Ki-\n67 expression status in granulomatous and chronic non-specific\nendometritis. Journal of Obstetrics and Gynaecology Research.\n2008; 34: 371–378.\n[55] Pickartz H, Beckmann R, Fleige B, Düe W, Gerdes J, Stein\nH. Steroid receptors and proliferative activity in non-neoplastic\nand neoplastic endometria. Virchows Archiv a Pathological\nAnatomy and Histopathology. 1990; 417: 163–171.\n[56] Wu D, Kimura F, Zheng L, Ishida M, Niwa Y , Hirata K, et\nal. Chronic endometritis modifies decidualization in human en-\ndometrial stromal cells. Reproductive Biology and Endocrinol-\nogy. 2017; 15: 16.\n[57] Burney RO, Talbi S, Hamilton AE, V o KC, Nyegaard M, Nezhat\nCR, et al . Gene Expression Analysis of Endometrium Reveals\nProgesterone Resistance and Candidate Susceptibility Genes in\nWomen with Endometriosis. Endocrinology. 2007; 148: 3814–\n3826.\n[58] Johnston-MacAnanny EB, Hartnett J, Engmann LL, Nulsen JC,\nSanders MM, Benadiva CA. Chronic endometritis is a frequent\nfinding in women with recurrent implantation failure after in\nvitro fertilization. Fertility and Sterility. 2010; 93: 437–441.\n[59] Tersoglio AE, Salatino DR, Reinchisi G, Gonzalez A, Tersoglio\nS, Marlia C. Repeated implantation failure in oocyte donation.\nWhat to do to improve the endometrial receptivity? JBRA As-\nsisted Reproduction. 2015; 19: 44–52.\n[60] Vitagliano A, Saccardi C, Noventa M, Di Spiezio Sardo A, Sac-\ncone G, Cicinelli E, et al. Effects of chronic endometritis therapy\non in vitro fertilization outcome in women with repeated implan-\ntation failure: a systematic review and meta-analysis. Fertility\nand Sterility. 2018; 110: 103–112.e1.\n[61] Kasius JC, Fatemi HM, Bourgain C, Sie-Go DMDS, Eijkemans\nRJC, Fauser BC, et al . The impact of chronic endometritis on\nreproductive outcome. Fertility and Sterility. 2011; 96: 1451–\n1456.\n[62] Y ang R, Du X, Wang Y , Song X, Y ang Y , Qiao J. The hys-\nteroscopy and histological diagnosis and treatment value of\nchronic endometritis in recurrent implantation failure patients.\nArchives of Gynecology and Obstetrics. 2014; 289: 1363–1369.\n[63] Gay C, Hamdaoui N, Pauly V , Rojat Habib M, Djemli A, Car-\nmassi M, et al . Impact of antibiotic treatment for chronic en-\ndometritis on unexplained recurrent pregnancy loss. Journal of\nGynecology Obstetrics and Human Reproduction. 2021; 50:\n102034.\n[64] Chadchan SB, Cheng M, Parnell LA, Yin Y , Schriefer A,\nMysorekar IU, et al . Antibiotic therapy with metronidazole re-\nduces endometriosis disease progression in mice: a potential role\nfor gut microbiota. Human Reproduction. 2019; 34: 1106–1116.\n[65] Lu F, Jing W, Zhong Y , Feng Y , Ma B, Xiong Y , et al . An-\ntibiotic Therapy and V aginal Microbiota Transplantation Reduce\nEndometriosis Disease Progression in Female Mice via NF-κB\nSignaling Pathway. Frontiers in Medicine. 2022; 9: 831115.\n[66] Sorrentino F, De Padova M, Falagario M, D’Alteri O MN, Di\nSpiezio Sardo A, Pacheco LA, et al. Endometriosis and adverse\npregnancy outcome. Minerva Obstetrics and Gynecology. 2022;\n74: 31–44.\n[67] Shen L, Wang Q, Huang W, Wang Q, Y uan Q, Huang Y , et\nal. High prevalence of endometrial polyps in endometriosis-\nassociated infertility. Fertility and Sterility. 2011; 95: 2722–\n2724.e1.\n8","source_license":"CC0","license_restricted":false}