Chronic endometritis (CE) is an inflammatory disorder of the endometrium, whose pathogenesis has not been fully elucidated. Although CE may be asymptomatic or it may present with subtle symptoms, it may cause significant adverse outcomes on human reproduction including an increased risk of recurrent miscarriages (RM) and recurrent implantation failure (RIF). The diagnostic procedure includes hysteroscopy with a targeted biopsy from areas suspected of having abnormalities. Histopathological assessment involves the identification of immunohistochemical markers for plasma cells, such as CD138 and MUM-1. The treatment of CE in women with a history of RIF may increase clinical pregnancy rates, implantation rates and ongoing pregnancy rates/live birth rates. It mainly concerns antibiotic therapy, with doxycycline as the first-line treatment. Surgical removal is necessary in cases of lesions such as fibroids, polyps or severe intrauterine adhesions. We aimed to summarize current knowledge in the field of the effective diagnosis and treatment of CE.
CritchleyHODMaybinJAArmstrongGM, et al. Physiology of the Endometrium and Regulation of Menstruation. Physiol Rev2020; 100: 1149–1179. https://doi.org/10.1152/physrev.00031.2019
3.
GreenwoodSMMoranJJ.Chronic endometritis: morphologic and clinical observations. Obstet Gynecol1981, 58, 176–184.
4.
BuzzaccariniGVitaglianoAAndrisaniA, et al. Chronic endometritis and altered embryo implantation: a unified pathophysiological theory from a literature systematic review. J Assist Reprod Genet2020; 37(12): 2897–2911. https://doi.org/10.1007/s10815-020-01955-8
5.
BenderARChristiansenOBElsonJ, et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open2023; 2023(1): hoad002.
6.
CimadomoDde Los SantosMJGriesingerG, et al. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open2023; 2023(3): hoad023.
7.
KitayaKMatsubayashiHTakayaY, et al. Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol2017; 78: e12719.
8.
Johnston-MacAnannyEBHartnettJEngmannLL, et al. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril2010; 93(2): 437–441.
9.
CicinelliEMatteoMTinelliR, et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod Sci2014; 21(5): 640–647. https://doi.org/10.1093/humrep/deu292
10.
ChenPChenPGuoY, et al. Interaction between chronic endometritis caused endometrial microbiota disorder and endometrial immune environment change in recurrent implantation failure. Front Immunol2021; 12: 748447.
11.
McQueenDBBernardiLAStephensonMD.Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise. Fertil Steril2014; 101(4): 1026–1030. https://doi.org/10.1016/j.fertnstert.2013.12.031
12.
McQueenDBPerfettoCOHazardFK, et al. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril2015; 104(4): 927–931. https://doi.org/10.1016/j.fertnstert.2015.06.044
13.
CicinelliEMatteoMTinelliR, et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod2015; 30(2): 323–330. https://doi.org/10.1093/humrep/deu292
14.
VitaglianoALaganàASDe ZieglerD, et al. Chronic endometritis in infertile women: impact of untreated disease, plasma cell count and antibiotic therapy on IVF outcome – a systematic review and meta-analysis. Diagnostics (Basel)2022; 12(9): 2250. https://doi.org/10.3390/diagnostics12092250
15.
TanakaSESakurabaYKitayaK, et al. Differential vaginal microbiota profiling in lactic-acid-producing bacteria between infertile women with and without chronic endometritis. Diagnostics (Basel)2022; 12(4): 878. https://doi.org/10.3390/diagnostics12040878
16.
MorenoICodoñerFMVilellaF, et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol2016, 215, 684–703.
17.
LiuYKoEY-LWongKK-W, et al. Endometrial microbiota in infertile women with and without chronic endometritis as diagnosed using a quantitative and reference range-based method. Fertil Steril2019, 112, 707–717.e1.
18.
LozanoFMBernabeuALledoB, et al. Characterization of the vaginal and endometrial microbiome in patients with chronic endometritis. Eur J Obstet Gynecol Reprod Biol2021, 263, 25–32.
19.
FangR-LChenL-XShuW-S, et al. Barcoded sequencing reveals diverse intrauterine microbiomes in patients suffering with endometrial polyps. Am J Transl Res2016; 8: 1581–1592.
20.
ChenCSongXWeiW, et al. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun2017; 8: 875.
21.
LiFChenCWeiW, et al. The metagenome of the female upper reproductive tract. GigaScience2018; 7: giy107.
22.
KitayaKTakeuchiTMizutaS, et al. Endometritis: new time, new concepts. Fertil Steril2018; 110: 344–350.
23.
Sola-LeyvaAAndrés-LeónEMolinaNM, et al. Mapping the entire functionally active endometrial microbiota. Hum Reprod2021, 36, 1021–1031.
24.
CicinelliEDe ZieglerDNicolettiR, et al. Chronic endometritis: correlation among hysteroscopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril2008; 89(3): 677–684. https://doi.org/10.1016/j.fertnstert.2007.03.074
25.
KumarPShahNPSinghalA, et al. Association of tuberculous endometritis with infertility and other gynecological complaints of women in India. J Clin Microbiol2008; 46(12): 4068–4070. https://doi.org/10.1128/JCM.01162-08
26.
KurodaKYamanakaATakamizawaS, et al. Prevalence of and risk factors for chronic endometritis in patients with intrauterine disorders after hysteroscopic surgery. Fertil Steril2022; 118(3): 568–575. https://doi.org/10.1016/j.fertnstert.2022.05.029
27.
CicinelliERestaLNicolettiR, et al. Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis. Hum Reprod2005; 20: 1386–1389. https://doi.org/10.1093/humrep/deh779
28.
LiuYYuXHuangJ, et al. Additional dydrogesterone for the treatment of chronic endometritis treated with antibiotic in premenopausal women with endometrial polyps: a retrospective cohort study. BMC Womens Health2022; 22(1): 435. https://doi.org/10.1186/s12905-022-02033-0
29.
SunYZhangJBaiW.Higher prevalence of endometrial polyps in patients with fallopian tube obstruction: a case-control study. J Minim Invasive Gynecol2019; 26: 935–940.
30.
XiangRLiMGuZ, et al. Chronic endometritis positively correlates with the aggravation of intrauterine adhesions but has limited effects on reproductive prognosis with antibiotic application. Int J Gynaecol Obstet2023; 160(3): 986–992. https://doi.org/10.1002/ijgo.14434
TortorellaCPiazzollaGMatteoM, et al. Interleukin-6, interleukin-1β, and tumor necrosis factor α in menstrual effluents as biomarkers of chronic endometritis. Fertil Steril2014; 101: 242–247.
33.
CicinelliETrojanoGMastromauroM, et al. Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link. Fertil Steril2017; 108(2): 289–295.e1. https://doi.org/10.1016/j.fertnstert.2017.05.016
34.
FreitagNPourSJFehmTN, et al. Are uterine natural killer and plasma cells in infertility patients associated with endometriosis, repeated implantation failure, or recurrent pregnancy loss?Arch Gynecol Obstet2020; 302(6): 1487–1494. https://doi.org/10.1007/s00404-020-05679-z
35.
RyanETolaniATZhangJ, et al. The menstrual cycle phase impacts the detection of plasma cells and the diagnosis of chronic endometritis in endometrial biopsy specimens. Fertil Steril2022; 118(4): 787–794. https://doi.org/10.1016/j.fertnstert.2022.07.011
36.
CravelloLPorcuGD’ErcoleC, et al. Identification and treatment of endometritis. Contracept Fertil Sex1997; 25: 585–586.
37.
LiuYChenXHuangJ, et al. Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without reproductive failure. Fertil Steril2018; 109(5): 832–839.
38.
HangYLiWYLuJ.Hysteroscopic endometrial biopsy with immunohistochemistry in the diagnosis of endometritis. Chin Med J (Engl)2020; 134(9): 1116–1118. https://doi.org/10.1097/CM9.0000000000001275
39.
UranishiMIidaSSandaT, et al. Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-γ (MIG) gene expression in B-cell malignancy. Leukemia2005; 19: 1471–1478.
40.
CicinelliEHaimovichSDe ZieglerD, et al. MUM-1 immunohistochemistry has high accuracy and reliability in the diagnosis of chronic endometritis: a multi-centre comparative study with CD-138 immunostaining. J Assist Reprod Genet2022; 39(1): 219–226. https://doi.org/10.1007/s10815-021-02356-1
41.
KlimaszykKBednarek-RajewskaHSvarre NielsenE, et al. Significance of multiple myeloma oncogene 1 immunohistochemistry in chronic endometritis detection in patients with recurrent pregnancy losses: an observational study. J Physiol Pharmacol2023; 74(6): 647–653. https://doi.org/10.26402/jpp.2023.6.05
42.
ParksRNKimCJAl-SafiZA, et al. Multiple myeloma 1 transcription factor is superior to CD138 as a marker of plasma cells in endometrium. Int J Surg Pathol2019; 27(4): 372–379. https://doi.org/10.1177/1066896918814307
43.
XiongZZhangWLiuS, et al. The combination of CD138/MUM1 dual-staining and artificial intelligence for plasma cell counting in the diagnosis of chronic endometritis. Am J Reprod Immunol2023; 89(3): e13671. https://doi.org/10.1111/aji.13671
44.
InkiP.Expression of syndecan-1 in female reproductive tract tissues and cultured keratinocytes. Mol Hum Reprod1997; 3(4): 299–305. https://doi.org/10.1093/molehr/3.4.299
45.
KitayaKYasuoT.Inter-observer and intra-observer variability in immunohistochemical detection of endometrial stromal plasmacytes in chronic endometritis. Exp Ther Med2013; 5(2): 485–488. https://doi.org/10.3892/etm.2012.824
46.
ZhangYXuHLiuY, et al. Confirmation of chronic endometritis in repeated implantation failure and success outcome in IVF-ET after intrauterine delivery of the combined administration of antibiotic and dexamethasone. Am J Reprod Immunol2019; 82(5): e13177. https://doi.org/10.1111/aji.13177
47.
LiuWHuangJSunL, et al. New biopsy after antibiotic treatment: effect on outcomes of assisted reproduction in patients with infertility and chronic endometritis. Reprod Biomed Online2022; 45(6): 1167–1175.
48.
ChengXHuangZXiaoZ, et al. Does antibiotic therapy for chronic endometritis improve clinical outcomes of patients with recurrent implantation failure in subsequent IVF cycles? A systematic review and meta-analysis. J Assist Reprod Genet2022; 39: 1797–1813.
49.
KitayaKTanakaSESakurabaY, et al. Multi-drug-resistant chronic endometritis in infertile women with repeated implantation failure: trend over the decade and pilot study for third-line oral antibiotic treatment. J Assist Reprod Genet2022; 39: 1839–1848. https://doi.org/10.1007/s10815-022-02528-7
50.
KitayaKIshikawaT.Lincomycin administration against persistent multi-drug resistant chronic endometritis in infertile women with a history of repeated implantation failure. Appl Microbiol2022; 2: 554–560.
51.
KurodaKTakamizawaSMotoyamaH, et al. Analysis of the therapeutic effects of hysteroscopic polypectomy with and without doxycycline treatment on chronic endometritis with endometrial polyps. Am J Reprod Immunol2021; 85: e13392.
