{"paper_id":"d74bf194-6926-4d6b-a903-83a7f4f9a030","body_text":"RESEARCH Open Access\n© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, \nsharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and \nthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included \nin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The \nCreative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available \nin this article, unless otherwise stated in a credit line to the data.\nLiu et al. BMC Women's Health          (2022) 22:435 \nhttps://doi.org/10.1186/s12905-022-02033-0\nBMC Women's Health\n†Yue Liu and Xin Yu contributed equally to this work\n*Correspondence:\nDacheng Qu\nqdc3253859@163.com\n1Department of Obstetrics and Gynecology, Affiliated Hospital of North \nSichuan Medical College, No 63, Wenhua Road, Nanchong, China\n2Non-invasive and Microinvasive Laboratory of Gynecology, Affiliated \nHospital of North Sichuan Medical College, 637000 Nanchong, China\n3Department of Obstetrics and Gynecology, LongQuanYi District of \nmaternity and child health care hospital, Chengdu, China\nAbstract\nBackground To assess the efficacy of dysdrogesterone in the treatment of chronic endometritis (CE) treated with \nantibiotic in premenopausal women with endometrial polyps (EPs).\nMethods Routine detection of endometrium was simultaneously conducted to determine whether there was CE by \nsyndecan-1 (CD138), while women underwent hysteroscopic polypectomy in our hospital. Antibiotic was given for \nthe treatment of CE. A total of 235 premenopausal women with CE who underwent hysteroscopic polypectomy were \nenrolled in the retrospective observational study. In the control group, single antibiotic was given for the treatment \nof CE form January 2016 to December 2018, and in the treatment group additional dydrogesterone was used from \nJanuary 2019 to November 2020. Comparison of cure rates of CE with different treatment regimens was performed.\nResults The cure rates of CE in dydrogesterone and antibiotic combination group and the single antibiotic group \nwere 85.2% and 74.3%, respectively, with overall cure rate of 80.0% (188/235). The combination group showed better \neffects regarding the cure rate of CE (P < .05). Multivariate analysis confirmed that the cure rate of CE was not affected \nby age, body mass index, number of EPs, the status of estrogen receptor and the status of progesterone receptor. \nConversely, dydrogesterone and endometrial scratching were beneficial factors for cure rate increase with antibiotic \ntreatment.\nConclusion Combination of dydrogesterone and antibiotic was more effective for cure rate of CE than antibiotic \nalone in premenopausal women after hysteroscopic polypectomy. Endometrial scratching also contributed to the \ncure rate increase with antibiotic treatment.\nKeywords Antibiotic, Chronic endometritis, Combination, Dydrogesterone, Endometrial scratching\nAdditional dydrogesterone for the treatment \nof chronic endometritis treated with antibiotic \nin premenopausal women with endometrial \npolyps: a retrospective cohort study\nYue Liu1,2†, Xin Yu3†, Jing Huang1, Chengchao Du1, Honggui Zhou1,2, Yamei Yang1 and Dacheng Qu1,2*\n\nPage 2 of 7\nLiu et al. BMC Women's Health          (2022) 22:435 \nBackground\nEndometrial polyps (EPs) is common benign gynecologi -\ncal protrusions which represent a localized hyperplastic \novergrowth of stroma and endometrial glands; the preva -\nlence of EPs ranges from 7.8 to 34.9% across different \npopulations [1]. Previous studies have indicated that EPs \nis the result of hormonal dysfunction, although inflam -\nmatory factors such as chronic endometritis (CE) are also \nthought to play important roles in the development of \nEPs [2]. The prevalence of CE in premenopausal women \nwith abnormal bleeding or reproductive failure on EPs \nwas 28.7% [3].\nCE is a persistent localized inflammatory condition of \nendometrium characterized by the presence of plasma \ncell infiltrate in the stroma [ 4, 5]. CE is usually asymp -\ntomatic or presents only with subtle symptoms such as \nabnormal uterine bleeding, pelvic pain, dyspareunia, and \nleucorrhea; which are very similar to the symptoms of \nEPs [ 6]. CE is associated with infertility, recurrent mis -\ncarriage and recurrent implantation failure [ 7, 8]. How -\never, the spontaneous cure rate of CE was very low, 12.7% \nreported in a randomized clinical trial [ 9]. Many studies \nhave shown that the cure rate of CE ranged widely from \n27.9 to 92.3% with one course antibiotic because of differ-\nent treatment regimens and different diagnostic creteria \n[10– 13].\nDydrogesterone is a selective progesterone receptor \nagonist with excellent oral bioavailability and potent pro -\ngestogenic activity, while having no androgenic, gluco -\ncorticoid or estrogenic activity, making it a good option \nfor progestin therapy [ 14]. The safety of dydrogester -\none has been confirmed in previous literature [ 15]. The \ntransformation dose of dydrogesterone required for the \nsecretory transformation of estrogenized human endo -\nmetrium was 140  mg, leading to effective shedding of \nendometrium [ 16]. It can theoretically remove plasma \ncells and pathogenic bacteria in superficial layer. Our pre-\nvious study had showed that addition of dydrogesterone \nwas effective for the treatment of chronic endometritis \nwith antibiotic treatment in premenopausal women [ 17]. \nHysteroscopic resection has long been considered as the \ngold standard for the treatment of EPs [18]. Post hystero-\nscopic progesterone hormone therapy, dydrogesterone of \n10 mg twice a day, from day 15 to day 24 of the menstrual \ncycle, had favorable clinical effect in treating EPs as it can \neffectively prevent the recurrence of EPs, relieve the level \nof hemoglobin and reduce endometrial thickness [19].\nIn the retrospective study we investigated whether \naddition of dydrogesterone with antibiotic treatment \nincreases the cure rate of CE in premenopausal women \nwho underwent hysteroscopic polypectomy.\nMethods\nParticipants\nThis retrospective study was conducted from January \n2016 to November 2020 in the Department of Obstet -\nrics and Gynecology of the Affiliated Hospital of North \nSichuan Medical College in Nanchong, China. Women \ndiagnosed with CE by CD138 while underwent hystero -\nscopic polypectomy in proliferative phase were enrolled \nin this study. The study was approved by the Institutional \nReview Board of the Affiliated Hospital of North Sichuan \nMedical College. All patients signed the written informed \nconsent form before participation in the study.\nThe inclusion criteria were EPs with CE diagnosed by \nCD138; agreement to undergo hysteroscopy, hystero -\nscopic resection, and endometrial biopsy; no contrain -\ndications to dydrogesterone or doxycycline; no severe \nsystemic diseases. The exclusion criteria were history \nor presence of endometrial carcinoma; use of hormone \nreplacement therapy or hormonal therapy in the preced -\ning 3 months.\nProcedure\nIn the retrospective observational study, single antibiotic \nwas given for the treatment of CE previously, and addi -\ntion of dydrogesterone was used to prevent recurrence \nof EPs in women with CE with antibiotic treatment. The \nassignment of the medical intervention is not at the dis -\ncretion of the investigator. From January 2016 to Decem-\nber 2018, women with CE who underwent hysteroscopic \npolypectomy were given single antibiotic for the treat -\nment of CE, oral doxycycline 200  mg daily for 14 days. \nFrom January 2019 to November 2020, women with CE \nwho underwent hysteroscopic polypectomy were given \none course of dydrogesterone to prevent recurrence of \nEPs, oral dydrogesterone of 10 mg twice a day, from day \n15 to day 24 of the menstrual cycle, except for the above \nantibiotic, oral doxycycline 200 mg daily for 14 days. In \nboth groups, antibiotic was given once CE was diagnosed \nby CD138. A second look hysteroscopy was performed \nand endometrial biopsy sample was obtained after com -\npletion of therapy in the next proliferative phase to assess \nthe response to treatment. Comparison of cure rates of \nCE with different treatment regimens was performed.\nHysteroscopic polypectomy, hysteroscopy and \nendometrial biopsy\nHysteroscopic polypectomy was conducted in the prolif -\nerative phase under intravenous anesthesia using a bipo -\nlar resection system, containing a 3-mm 15° inside rigid \nhysteroscope and an 8.5-mm outside sheath (Olympus, \nTokyo, Japan). Endometrial biopsies were performed to \nexclude endometrial lesions using a unelectrified plasma \ncutting ring away from the local polyps. Second look out -\npatient hysteroscopy was conducted in the proliferative \n\nPage 3 of 7\nLiu et al. BMC Women's Health          (2022) 22:435 \nphase without any anesthesia using a 3-mm 30° inside \nrigid hysteroscope and an 4.5-mm outside sheath (Olym -\npus, Tokyo, Japan). Endometrial biopsies were obtained \nwith the use of a metal curette, from the hysteroscopic \nfeatures area, if not, from the upper uterine cavity blindly.\nEndometrial scratching\nEndometrial scratching was performed in women with \nchildbearing desire, using a unelectrified plasma cutting \nring while hysteroscopic polypectomy. The scratching \nwas performed once in each quadrant of the endome -\ntrium, away from the local EPs.\nDiagnosis of CE and immunohistochemistry\nCurrently, there is no consensus on the diagnostic cri -\nteria of CE. CD138 was the preferred immunohisto -\nchemical stain to identify plasma cells [ 3, 17, 20– 22]. \nPathologists have different views on the diagnosis of \nCE: how many CD 138 + cells/HPF [ 21]. However, CE \ndecreased the pregnancy rate and the live birth rate when \nCE was diagnosed as the presence of ≥ 1 plasma cells in \n10 high-power fields [22]. In the present study, according \nto the clinically relevant CE, CE was diagnosed by CD138 \nwith one or more plasma cell identified per 10 high \npower fields (Fig.  1), as widely used in other studies [ 3, \n17, 20– 22]. At least 50 high-power fields were examined \nper specimen. Endometrial samples for routine histologic \nanalysis and immunohistochemistry were conducted \nas previously described [ 20]. The anti-CD138 monoclo -\nnal antibody used in our study was MI15 Cell Marque \n(Fuzhou Maixin Biotechnology Co., Ltd., Fuzhou, China).\nSlides immunostained for ER (estrogen receptor) and \nPR (progesterone receptor) were scored using the Allred \nScore [23, 24]. The clone of anti-ER and anti-PR mono -\nclonal antibody used in our study were SP1 and SP2 \n(Fuzhou Maixin Biotechnology Co., Ltd.). ER and PR \nwere classified as being positive if Allred score equal or \nmore than 3.\nStatistical analyses\nAll analyses were conducted with the use of SPSS version \n22.0 and a P value of < 0.05 was considered to be repre -\nsent statistical significance. After analyzing the distribu -\ntion of our data and confirming that age and body mass \nindex (BMI) in the population were not normally distrib -\nuted, we adopted a nonparametric method to analyze the \nage and BMI. Data are expressed as median (interquartile \nrange) or percentage. The other intergroup differences \nwere compared using Chi-squared test. Chi-square test \nwas used to compare the conversion of CD138 between \ngroups and subgroups. Logistic regression was carried \nout to investigate the factors associated with cure rate of \nCE.\nResults\nComparison of general and clinical features of patients\nDuring the 5-year study period, A total of 251 premeno -\npausal women with CE who underwent hysteroscopic \npolypectomy were enrolled in this study. Sixteen cases \nwere excluded for various reasons. Finally, 235 cases were \nenrolled in the statistical analysis, including 122 cases \nwith dydrogesterone and doxycycline, and 113 cases with \ndoxycycline alone (Fig.  2). The demographic details and \nclinical features of the two groups are shown in Table  1. \nThe demographic details and clinical features of the two \ngroups were not statistically significant (P > .05).\nComparison of cure rate of CE between the two groups\nThe conversion of CD138 from positive to negative indi -\ncated the cure rate of CE. After treatment, the overall \ncure rate of CE in the population was 80.0% (188/235). \nThe dydrogesterone and antibiotic group showed bet -\nter effects regarding the cure rate of CE (Fig.  3, P < .05). \nThe cure rate of CE was 85.2% (104/122) in the dydro -\ngesterone and antibiotic combination group vs. 74.3% \n(84/113) in the single antibiotic group (Fig.  3, P = .037). \nAmong patients with endometrial scratching, the cure \nrate of CE was 88.2% (67/76) in the dydrogesterone and \nantibiotic combination group vs. 80.3% (53/66) in the \nsingle antibiotic group (P = .197), while without endome -\ntrial scratching, the cure rate of CE was 80.4% (37/46) in \nthe dydrogesterone and antibiotic combination group vs. \n66.0% (31/47) in the single antibiotic group (P = .115).\nComparison of cure rate of CE between subgroups in the \ntreatment group\nIn the treatment group, the cure rates of CE were 83.9% \n(73/87) in women with solitary EP and 88.6% (31/35) in \nwomen with multiple EPs, respectively (Fig.  3, P = .586). \nFig. 1 Diagnostic criteria of CE. CE was diagnosed by CD138 with one \nor more plasma cell identified per 10 high power fields. At least 50 high-\npower fields were examined per specimen\n \n\nPage 4 of 7\nLiu et al. BMC Women's Health          (2022) 22:435 \nThis may suggest that the effect of dydrogesterone was \nnot associated with the number of EPs. The cure rates \nof CE were 84.6% (88/104) in women with ER positive \nand 88.9% (16/18) in women with ER negative, respec -\ntively (Fig.  3). The cure rates of CE were 84.6% (88/104) \nin women with PR positive and 88.9% (16/18) in women \nwith PR negative, respectively (Fig.  3). The influence of \nstatus of ER or PR was undefined because of high expres -\nsion of ER and PR in women with CE and EPs.\nFactors associated with cure rate of chronic endometritis\nMultivariate analysis confirmed that addition of dydro -\ngesterone was a beneficial factor for cure rate increase \nwith antibiotic treatment (Table  2; OR, 2.10 [95% CI, \n1.06–4.15]; P = .032). In addition, endometrial scratch -\ning also contributed to cure rate increase with antibi -\notic treatment (Table  2; OR, 2.24 [95% CI, 1.14–4.39]; \nP = .019). The cure rates of CE with and without endo -\nmetrial scratching were 84.5% (120/142) and 71.8% \n(68/93), respectively (P = .033). endometrial scratching \nTable 1 Baseline demographic and clinical characteristics of the \nenrolled patients\nCharacteristics Dydroges-\nterone and an-\ntibiotic group \n(n = 122)\nAntibi-\notic group \n(n = 113)\nP \nvalue\nAge, y (median (Q3-Q1)) 32 (6) 34 (8) 0.081\nBMI, kg/m2 (median (Q3-Q1)) 22.0 (3.7) 22.3 (4.6) 0.673\nPolyp number, n (%) 0.714\nOne 35 (28.7%) 30 (26.5%)\nTwo or more 87 (71.3%) 83 (73.5%)\nEndometrial scratching, n (%) 0.543\nYes 76 (62.3%) 66 (58.4%)\nNo 46 (37.7%) 47 (41.6%)\nER status, n (%) 0.061\nPositive 104 (85.2%) 105 (92.9%)\nNegative 18 (14.8%) 8 (7.1%)\nPR status, n (%) 0.462\nPositive 104 (85.2%) 100 (88.5%)\nNegative 18 (14.8%) 13 (11.5%)\nNote: BMI - body mass index; ER - estrogen receptor; PR - progesterone receptor\nFig. 2 Flow diagram\n \n\nPage 5 of 7\nLiu et al. BMC Women's Health          (2022) 22:435 \nwas effective for the treatment of CE. However, in the \ntreatment group, the cure rates of CE with and without \nendometrial scratching were 88.2% (67/76) and 80.4% \n(37/46), respectively (Fig.  3, P = .244). This finding may \nFig. 3 Comparison of the cure rate of CE between the treatment and control groups as well as subgroups in each group. (A) Comparison of the cure rate \nof CE between the treatment and control groups (*P < .05). (B) Comparison of the cure rate of CE among patients with different number of EPs in each \ngroup (#P > .05). C and D. Comparison of the cure rate of CE in according to ER and PR status of patients in each group (#P > .05 and #P > .05, respectively). \nE. Comparison of the cure rate of CE with or without endometrial scratching in each group (#P > .05)\n \n\nPage 6 of 7\nLiu et al. BMC Women's Health          (2022) 22:435 \nindicate that endometrial scratching did not function in \nwomen using dydrogesterone for CE. Conversely, multi -\nvariate analysis showed that the cure rate of CE was not \naffected by age, BMI, number of EPs, ER status and PR \nstatus.\nDiscussion\nIn this retrospective trial of 235 participants with CE \nwho underwent hysteroscopic polypectomy, combined \nadministration of dydrogesterone and antibiotic had a \nhigher cure rate of CE compared with the treatment of \nantibiotic alone. The finding supported a beneficial role \nof co-treatment with dydrogesterone and antibiotic in \npremenopausal patients with CE who underwent hys -\nteroscopic polypectomy.\nMany studies have shown that impaired inflammatory \nstate of the endometrium (IISE) is the main cause of most \nintrauterine diseases, such as EPs, unexplained infertil -\nity and endometrial cancer [25]. Unlike CE, IISE contains \ninfectious and non-infectious etiology [ 25]. Dydrogester-\none is effective in the treatment of EPs in premenopausal \nwomen [ 26]. Furthermore, it can effectively prevent the \nrecurrence of EPs after hysteroscopic polypectomy [ 19]. \nTo our knowledge, this is the first study to assess the \ntreatment of CE after hysteroscopic polypectomy with \ncombination of dydrogesterone and antibiotic.\nIn this study, women with combination of dydroges -\nterone and antibiotic had a higher cure rate of CE in one \ncourse compared with women with antibiotic alone. The \noverall cure rate of CE in premenopausal women was \n80.0%. The cure rate of CE with single doxycycline was \n74.3%, which is consistent with previous studies [ 10, 12, \n17]. With the use of dydrogesterone, the cure rate of CE \nreached to an elevated level of 85.2%. Multivariate analy -\nsis confirmed that dydrogesterone was a beneficial factor \nfor cure rate increase with antibiotic treatment (OR, 2.10 \n[95% CI, 1.06–4.15]; P = .032). The potential mechanisms \nunderlying the beneficial effect of dydrogesterone is cur -\nrently unknown. One of the possible explanation is that \ndydrogesterone application can remove plasma cells and \npathogenic bacteria in the superficial layer [ 16]. Syner -\ngistic effect occurred with the effect of dydrogesterone \nto reduce the severity of CE. In addition, dydrogesterone \nmay improve the local immune status within the endo -\nmetrium [14]. Furthermore, progesterone has been found \nto function in cell apoptosis of endometrium [27– 29].\nIt remains unclear if endometrial scratching improves \nthe chance of pregnancy and, if so, for whom [ 30]. The \nprocedure is painful, with patients reporting pain scores \nof 3–7 out of 10, causes bleeding, and carries a risk of \ninfection, it entails the inconvenience of attending an \nadditional clinic and additional charge [31]. In the current \nstudy, endometrial scratching was conducted while hys -\nteroscopic polypectomy under intravenous anesthesia, it \ncan ovoid the above hazard factors. Multivariate analysis \nconfirmed that endometrial scratching was a beneficial \nfactor for cure rate increase with antibiotic treatment \n(OR, 2.24 [95% CI, 1.14–4.39]; P = .019). This may be the \nexplanation that endometrial scratching improves the \nchance of pregnancy by curing the concealed CE. How -\never, with the use of dydrogesterone, the cure rates of \nCE with and without endometrial scratching were 88.2% \n(67/76) and 80.4% (37/46), respectively (P = .244). There \nwas no additive function with dydrogesterone and endo -\nmetrial scratching for the treatment of CE.\nThere are limitations in this study which should be con-\nsidered. For example, in the retrospective review, we can \nnot cover plentiful enough impact factors for cure rate of \nCE, concealed factors need to be explored. Furthermore, \nonly women with CE on EPs were enrolled, women with \nCE on other diseases are needed for widely application. \nLarge, prospective studies will be necessary to confirm \nthe beneficial role of co-treatment with dydrogester -\none and antibiotic in patients with CE and the potential \nmechanisms.\nConclusion\nIn conclusion, combination of dydrogesterone and anti -\nbiotic was more effective for CE than antibiotic alone in \npremenopausal women after hysteroscopic polypectomy. \nSynergistic effect occurred with the effect of dydrogester-\none to reduce the severity of CE. With the same reason, \nendometrial scratching also contributed to the cure rate \nincrease with antibiotic treatment. However, there was \nno duplicate effect.\nAbbreviations\nEps  endometrial polyps\nCE  chronic endometritis\nER  estrogen receptor\nPR  progesterone receptor\nBMI  body mass index\nIISE  impaired inflammatory state of the endometrium\nAcknowledgements\nThe authors thank Wei Xu for processing statistical data.\nAuthor contributions\nConception and design: DQ; Acquisition of data: XY; Analysis and \nInterpretation of data: DQ; Drafting of the manuscript: DQ, YL; Critical revision \nof the manuscript for important intellectual content: DQ, JH; Statistical \nanalysis: DQ, CD; Obtaining funding: DQ; Administrative technical or material \nsupport: DQ, YY; Supervision: DQ; HZ. All authors read and approved the final \nmanuscript.\nTable 2 Multivariate logistic regression analysis of factors \nassociated with cure rate of chronic endometritis\nVariables Cure rate of CE\nOR (95% CI)\nP \nvalue\nTreatment (dydrogesterone and antibiotic) 2.10 (1.06–4.15) 0.032\nEndometrial scratching 2.24 (1.14–4.39) 0.019\n\nPage 7 of 7\nLiu et al. BMC Women's Health          (2022) 22:435 \nFunding\nThe work was supported by the Sichuan Science and Technology Program \n(2018SZ0264) and Bureau of Science and Technology Nanchong City \n(19SXHZ0338).\nData availability\nThe datasets used and/or analysed during the current study are available from \nthe corresponding author on reasonable request.\nDeclarations\nEthics approval and consent to participate\nThe study was approved by the Institutional Review Board of the Affiliated \nHospital of North Sichuan Medical College [2019ER(R)017]. All patients signed \nthe written informed consent form before participation in the study. All \nmethods were performed in accordance with the relevant guidelines and \nregulations.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare that they have no competing interests.\nReceived: 26 April 2022 / Accepted: 27 October 2022\nReferences\n1. Clark TJ, Stevenson H. Endometrial Polyps and Abnormal Uterine Bleeding \n(AUB-P): What is the relationship, how are they diagnosed and how are they \ntreated? Best Pract Res Clin Obstet Gynaecol. 2017;40:89–104.\n2. Indraccolo U, Di Iorio R, Matteo M, Corona G, Greco P , Indraccolo SR. The \npathogenesis of endometrial polyps: a systematic semi-quantitative review. \nEur J Gynaecol Oncol. 2013;34:5–22.\n3. Song D, Feng X, Zhang Q, Xia E, Xiao Y, Xie W, et al. Prevalence and confound-\ners of chronic endometritis in premenopausal women with abnormal bleed-\ning or reproductive failure. Reprod Biomed Online. 2018;36:78–83.\n4. Kitaya K, Takeuchi T, Mizuta S, Matsubayashi H, Ishikawa T. 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Fertil \nSteril. 2019;111:1094–101.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in \npublished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}