Chronic endometritis – diagnosing difficulties (review)

Igor O. Borovikov , Lidiya A. Papoyan , Daria V. Revenko , Kirill E. Golubchenko , Daria V. Ilyina , Karina M. Syrko

For citation:

Abstract

Background. The relevance of the problem is associated with the lack of a unified strategy for managing patients with repeated implantation failures during assisted reproductive technology procedures due to chronic endometritis. Currently, anamnestic-visual (the presence of a female factor of infertility, a change in the thickness of the endometrium during sonography and a relatively specific hysteroscopic picture of chronic inflammation of the inner layer of the uterus) and immunohistochemical (the main one is the detection of plasma cells in the endometrial epithelium) markers of this pathology are mainly used, while their accuracy is still the subject of many discussions and does not allow methods for eliminating infertility. The article is devoted to a review analysis of diagnostic procedures and approaches to the treatment of chronic endometritis in women with repeated implantation failures within the framework of reproductive medicine in general and reproductive immunology.

Objectives. Critical analysis of the main diagnostic methods for assessing the receptivity of the endometrium in chronic endometritis. Methods. An analysis of data from Russian- and English-language scientific literature devoted to studies to assess methods for diagnosing chronic endometritis in women with reproductive disorders.

Results. More than 80 studies were analyzed in this publication. The main methods of diagnosis of chronic endometritis both in retrospective and in the modern aspect are evaluated.

Conclusion. Now, in reproductive medicine, there are no highly specific methods for diagnosing chronic endometritis, which, on the one hand, necessitates an integrated approach to assessing the implantation properties of the endometrium, and, on the other hand, stimulates a more in-depth study of new aspects of the pathogenesis of this pathology and the search for more accurate diagnostic markers.

Keywords: infertility, chronic endometritis, repeated implantation failures, reproductive immunology, diagnostics, plasma cells.

References

1. Demirdag E, Guler I, Cevher Akdulum MF et al. Subsequent IVF outcomes following antibiotic therapy for chronic endometritis in patients with recurrent implantation failure. J Obstet Gynaecol Res 2022;47(12):4350-6. DOI: 10.1111/jog.15037

2. Murtinger M, Wirleitner B, Spitzer D et al. Diagnosing chronic endometritis: when simplification fails to clarify. Hum Reprod Open 2022;7(3):hoac023. DOI: 10.1093/hropen/hoac023

3. Darici E, Blockeel C, Mackens S. Should we stop screening for chronic endometritis? Reprod Biomed Online 2022;16:S1472-6483(22)00493-X. DOI: 10.1016/j.rbmo.2022.07.008

4. Giaimo S. Medawar and Hamilton on the selective forces in the evolution of ageing. Hist Philos Life Sci 2021;43(4):124. DOI: 10.1007/s40656-021-00476-6

5. Hennessy M, Dennehy R, Meaney S et al. Clinical practice guidelines for recurrent miscarriage in high-income countries: a systematic review. Reprod Biomed Online 2021;42:1146-71. DOI: 10.1016/j.rbmo. 2021.02.014

6. Toth B, Würfel W, Bohlmann M et al. Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050). Geburtshilfe Frauenheilkd 2018;78:364-81. DOI: 10.1055/a-0586-4568

7. Привычный выкидыш (МКБ-10: O26.2, N96). Клинические рекомендации Российского общества акушеров-гинекологов (РОАГ). Год утверждения (частота пересмотра): 2021. URL: https://roag-portal.ru/recommendations_obstetrics Habitual miscarriage (ICD-10: O26.2, N96). Clinical recommendations of the Russian Society of Obstetricians and Gynecologists (ROAG). Year of approval (frequency of revision): 2021. URL: https://roag-portal.ru/recommendations_obstetrics (in Russian).

8. Benner M, Ferwerda G, Joosten I, van der Molen RG. How uterine microbiota might be responsible for a receptive, fertile endometrium. Hum Reprod Update 2018;24:393-415. DOI: 10.1093/humupd/ dmy012

9. Barrios De Tomasi J, Opata MM, Mowa CN. Immunity in the Cervix: Interphase between Immune and Cervical Epithelial Cells. J Immunol Res 2019;7693183. DOI: 10.1155/2019/7693183

10. Shen M, O'Donnell E, Leon G et al. The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review. Hum Reprod Open 2021;1:hoab043. DOI: 10.1093/hropen/hoab043

11. Мелкозерова О.А., Башмакова Н.В., Есарева А.В. Проблемы коммуникации эмбриона и эндометрия: маркеры нарушений и механизмы влияния. Российский вестник акушера-гинеколога. 2016;16(5):29-36. DOI: 10.17116/rosakush201616529-36 Melkozerova O.A., Bashmakova N.V., Kesareva A.V. Problems of communication between the embryo and endometrium: markers of disorders and mechanisms of influence. Russian Bulletin of the obstetrician-gynecologist. 2016;16(5):29-36. DOI: 10.17116/rosakush201616529-36 (in Russian).

12. de Ziegler D. Chronic endometritis and embryo implantation: the great illusion. Fertil Steril 2022;118(4):637-8. DOI: 10.1016/j.fertnstert. 2022.08.017

13. Donald A, Shaw WF. The symptoms and treatment of chronic endometritis, with special reference to the results of curetting. Proc R Soc Med 1911;4:37-52

14. Hitschmann F, Adler L. Die Lehre von der Endometritits. Z Geburtshilfe Gynäkol 1907;60:63-86.

15. Ruge C. Zur Aetiologie und Anatomie der Endometritits. Z Geburtshilfe Gynäkol 1880;5:317-23.

16. Wu D, Kimura F, Zheng L et al. Chronic endometritis modifies decidualization in human endometrial stromal cells. Reprod Biol Endocrinol 2017;15:16. DOI: 10.1186/s12958-017-0233-x

17. Di Pietro C, Cicinelli E, Guglielmino MR et al. Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol 2013;69:509-17. DOI: 10.1111/aji.12076

18. Buzzaccarini G, Vitagliano A, Andrisani A et al. Chronic endometritis and altered embryo implantation: a unified pathophysiological theory from a literature systematic review. J Assist Reprod Genet 2020;37:2897-911. DOI: 10.1007/s10815-020-01955-8

19. Chen P, Chen P, Guo Y et al. Interaction between chronic endometritis caused endometrial microbiota disorder and endometrial immune environment change in recurrent implantation failure. Front Immunol 2021;12:748447. DOI: 10.3389/fimmu.2021.748447

20. Kitazawa J, Kimura F, Nakamura A et al. Alteration in endometrial helper T-cell subgroups in chronic endometritis. Am J Reprod Immunol 2021;85:e13372. DOI: 10.1111/aji.13372

21. Wang WJ, Zhang H, Chen ZQ et al. Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis. Reprod Biol Endocrinol 2019;17:2. DOI: 10.1186/s12958-018-0444-9

22. Tanaka SE, Sakuraba Y, Kitaya K, Ishikawa T. Differential vaginal microbiota profiling in lactic-acid-producing bacteria between infertile women with and without chronic endometritis. Diagnostics (Basel) 2022;12:878. DOI: 10.3390/diagnostics12040878

23. Mount S, Mead P, Cooper K. Chlamydia trachomatis in the endometrium: can surgical pathologists identify plasma cells? Adv Anat Pathol 2001;8:327-9. DOI: 10.1097/00125480-200111000-00002

24. Herlihy NS, Klimczak AM, Titus S et al. The role of endometrial staining for CD138 as a marker of chronic endometritis in predicting live birth. J Assist Reprod Genet 2022;39(2):473-9. DOI: 10.1007/s10815-021-02374-z

25. Jain M, Samokhodskaya L, Mladova E, Panina O. Mucosal biomarkers for endometrial receptivity: A promising yet underexplored aspect of reproductive medicine. Syst Biol Reprod Med 2022;68(1):13-24. DOI: 10.1080/19396368.2021.1985186

26. Margulies SL, Dhingra I, Flores V et al. The diagnostic criteria for chronic endometritis: a survey of pathologists. Int J Gynecol Pathol 2021;40:556-62. DOI: 10.1097/PGP.0000000000000737

27. Groth JV. Chronic endometritis and the plasma cell, fact versus fiction. Fertil Steril 2018;109:788. DOI: 10.1016/j.fertnstert.2018.02.116

28. Яковчук Е.К., Сулима А.Н., Рыбалка А.Н. и др. Хронический эндометрит: современное состояние проблемы, основные аспекты патогенеза, влияние на репродуктивную функцию. Российский вестник акушера-гинеколога. 2016;16(5):37-41. DOI: 10.17116/ rosakush201616537-41 Yakovchuk E.K., Sulima A.N., Rybalka A.N. et al. Chronic endometritis: current state of the problem, main aspects of pathogenesis, impact on reproductive function. Russian Bulletin of the obstetrician-gynecologist. 2016;16(5):37-41. DOI: 10.17116/rosakush201616537-41 (in Russian).

29. Huang W, Liu B, He Y et al. Variation of diagnostic criteria in women with chronic endometritis and its effect on reproductive outcomes: a systematic review and meta-analysis. J Reprod Immunol 2020;140:103146. DOI: 10.1016/j.jri.2020.103146

30. Achilles SL, Amortegui AJ, Wiesenfeld HC. Endometrial plasma cells: do they indicate subclinical pelvic inflammatory disease? Sex Transm Dis 2005;32:185-8. DOI: 10.1097/01.olq.0000154491.47682.bf

31. McQueen DB, Bernardi LA, Stephenson MD. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise. Fertil Steril 2014;101:1026-30. DOI: 10.1016/j.fertnstert.2013.12.031

32. Li Y, Xu S, Yu S et al. Diagnosis of chronic endometritis: how many CD138+ cells/HPF in endometrial stroma affect pregnancy outcome of infertile women? Am J Reprod Immunol 2021;85:e13369. DOI: 10.1111/aji.13369

33. Gkrozou F, Dimakopoulos G, Vrekoussis T et al. Hysteroscopy in women with abnormal uterine bleeding: a meta-analysis on four major endometrial pathologies. Arch Gynecol Obstet 2015; 291:1347-54. DOI: 10.1007/s00404-014-3585-x

34. Cicinelli E, Bettocchi S, de Ziegler D et al. Chronic endometritis, a common disease hidden behind endometrial polyps in premenopausal women: first evidence from a case-control study. J Minim Invasive Gynecol 2019;26:1346-50. DOI: 10.1016/j.jmig.2019.01.012

35. Guo L, Gu F, Tan J et al. Multiple endometrial polyps is associated with higher risk of chronic endometritis in reproductive-aged women. J Obstet Gynaecol Res 2021;47:389-96. DOI: 10.1111/jog.14541

36. Kuroda K, Horikawa T, Moriyama A et al. Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes. Immun Inflamm Dis 2020;8:650-8. DOI: 10.1002/iid3.354

37. Оразов М.Р., Михалева Л.М., Семенов П.А. Хронический эндометрит: патогенез, диагностика, лечение и его связь с бесплодием. Клиническая и экспериментальная морфология. 2020;9(2):16-25. DOI: 10.31088/CEM2020.9.2.16-25 Orazov M.R., Mikhaleva L.M., Semenov P.A. Chronic endometritis: pathogenesis, diagnosis, treatment and its relation to infertility. Clinical and experimental morphology. 2020;9(2):16-25. DOI: 10.31088/CEM2020.9.2.16-25 (in Russian).

38. Краснопольская К.В., Назаренко Т.А., Ершова И.Ю. Современные подходы к оценке рецептивности эндометрия (обзор литературы). Проблемы репродукции. 2016;22(5):61-9. DOI: 10.17116/repro201622561-69 Krasnopolskaya K.V., Nazarenko T.A., Yershova I.Y. Modern approaches to assessing endometrial receptivity (literature review). Problems of reproduction. 2016;22(5):61-9. DOI: 10.17116/repro 201622561-69 (in Russian).

39. Tsonis O, Gkrozou F, Dimitriou E, Paschopoulos M. Hysteroscopic detection of chronic endometritis: Evaluating proposed hysteroscopic features suggestive of chronic endometritis. J Gynecol Obstet Hum Reprod 2021;50:102182. DOI: 10.1016/j.jogoh.2021.102182

40. Zolghadri J, Momtahan M, Aminian K et al. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 2011;155:217-20. DOI: 10.1016/j.ejogrb.2010.12.010

41. Wang S, Li F, Zhang W et al. Investigation of the Relationship between Chronic Endometritis Manifestations under Hysteroscope and CD138 Expression. Appl Bionics Biomech 2022;8323017. DOI: 10.1155/2022/ 8323017

42. Féghali J, Bakar J, Mayenga JM et al. Systematic hysteroscopy prior to in vitro fertilization. Gynecol Obstet Fertil 2003;31:127-31. DOI: 10.1016/s1297-9589(03)00007-9

43. Cicinelli E, Resta L, Nicoletti R et al. Detection of chronic endometritis at fluid hysteroscopy. J Minim Invasive Gynecol 2005;12:514-8. DOI: 10.1016/j.jmig.2005.07.394

44. Cicinelli E, Matteo M, Tinelli R et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 2015;30:323-30. DOI: 10.1093/humrep/deu292

45. Puente E, Alonso L, Laganà AS et al. Chronic endometritis: old problem, novel insights and future challenges. Int J Fertil Steril 2020;13:250-6. DOI: 10.22074/ijfs.2020.5779

46. La Marca A, Gaia G, Mignini Renzini M et al. Hysteroscopic findings in chronic endometritis. Minerva Obstet Gynecol 2021;73:790-805. DOI: 10.23736/S2724-606X.21.04970-8

47. Cicinelli E, Matteo M, Trojano G et al. Chronic endometritis in patients with unexplained infertility: Prevalence and effects of antibiotic treatment on spontaneous conception. Am J Reprod Immunol 2018;79:e12782. DOI: 10.1111/aji.12783

48. Zhang Y, Xu H, Liu Y 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 Immunol 2019;82:e13177. DOI: 10.1111/aji.13177

49. Kitaya K, Matsubayashi H, Takaya Y et al. Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol 2017;78:e12719. DOI: 10.1111/aji.12722

50. Sfakianoudis K., Simopoulou M., Nikas Y et al. Efficient treatment of chronic endometritis through a novel approach of intrauterine antibiotic infusion: a case series. BMC Women’s Health. 2018; 18: 197. DOI: 10.1186/s12905-018-0688-8

51. Negishi Y, Shima Y, Takeshita T, Morita R. Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation. Immunol Med 2021;44:98-115. DOI: 10.1080/25785826.2020.1809951

52. Kale MS, Korenstein D. Overdiagnosis in primary care: framing the problem and finding solutions. BMJ 2018;362:k2820. DOI: 10.1136/bmj.k2820

53. Rothberg MB, Class J, Bishop TF et al. The cost of defensive medicine on 3 hospital medicine services. JAMA Intern Med 2014;174:1867-8. DOI: 10.1001/jamainternmed.2014.4649

54. Johnston-MacAnanny EB, Hartnett J, Engmann LL et al. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril 2010;93:437-41. DOI: 10.1016/j.fertnstert.2008.12.131

55. McQueen DB, Perfetto CO, Hazard F.K et al. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril 2015;104:927-31. DOI: 10.1016/j.fertnstert.2015.06.044

56. Moynihan R, Doust J, Henry D. Preventing overdiagnosis: how to stop harming the healthy. BMJ 2012;344:e3502. DOI: 10.1001/10.1136/bmj.e3502

57. Murtinger M, Wirleitner B, Schuff M. Scoring of mosaic embryos after preimplantation genetic testing: a rollercoaster ride between fear, hope and embryo wastage. Reprod Biomed Online 2018;37:120-1. DOI: 10.1016/j.rbmo.2018.04.046

58. Gleicher N, Kushnir VA, Barad DH. How PGS/PGT-A laboratories succeeded in losing all credibility. Reprod Biomed Online 2018;37:242-5. DOI: 10.1016/j.rbmo.2018.06.019

59. Bulmer JN, Lash GE. Uterine natural killer cells: time for a re-appraisal? F1000Research 2019;8:999. DOI: 10.1016/10.12688/f1000research.19132.1

60. Bemark M, Angeletti D. Know your enemy or find your friend? – Induction of IgA at mucosal surfaces. Immunol Rev 2021;303:83-102. DOI: 0.1111/imr.13014

61. Nakagawa K, Kwak-Kim J, Ota K et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol 2015;73:353-61. DOI: 10.1111/aji.12338

62. Mascarenhas M, Jeve Y, Polanski L et al. Management of recurrent implantation failure: British Fertility Society policy and practice guideline. Hum Fertil (Camb) 2021;5:1-25. DOI: 10.1080/14647273. 2021.1905886 63. Chavan AR, Griffith OW, Wagner GP. The inflammation paradox in the evolution of mammalian pregnancy: turning a foe into a friend. Curr Opin Genet Dev 2017;47:24-32. DOI: 10.1016/j.gde.2017.08.004

64. Moffett A, Shreeve N. Local immune recognition of trophoblast in early human pregnancy: controversies and questions. Nat Rev Immunol 2022;3:1-14. DOI: 10.1038/s41577-022-00777-2

65. Cooper MA, Fehniger TA, Turner SC et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 2001;97:3146-51. DOI: 10.1182/blood.v97.10.3146

66. Koopman LA, Kopcow HD, Rybalov B et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003;198:1201-12. DOI: 10.1084/jem.20030305

67. Gaynor LM, Colucci F. Uterine natural killer cells: functional distinctions and influence on pregnancy in humans and mice. Front Immunol 2017;8:467. DOI: 10.3389/fimmu.2017.00467

68. Kanter JR, Mani S, Gordon SM, Mainigi M. Uterine natural killer cell biology and role in early pregnancy establishment and outcomes. F S Rev 2021;2(4):265-86. DOI: 10.1016/j.xfnr.2021.06.002

69. Pan D, Liu Q, Du L, Yang Y, Jiang G. Polarization disorder of decidual NK cells in unexplained recurrent spontaneous abortion revealed by single-cell transcriptome analysis. Reprod Biol Endocrinol 2022;20(1):108. DOI: 10.1186/s12958-022-00980-9

70. Vento-Tormo R, Efremova M, Botting R.A et al. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 2018;563:347-53. DOI: 10.1038/s41586-018-0698-6

71. Pioli PD. Plasma cells, the next generation: beyond antibody secretion. Front Immunol 2019;10:2768. DOI: 10.3389/fimmu.2019.02768

72. Shalapour S, Font-Burgada J, Di Caro G et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 2015;521:94-98. DOI: 10.1038/nature14395

73. Delaloy C, Schuh W, Jäck H.M et al. Single-cell resolution of plasma cell fate programming in health and disease. Eur J Immunol 2022;52:10-23. DOI: 10.1002/eji.202149216

74. Chen YQ, Fang RL, Luo YN, Luo CQ. Analysis of the diagnostic value of CD138 for chronic endometritis, the risk factors for the pathogenesis of chronic endometritis and the effect of chronic endometritis on pregnancy: a cohort study. BMC Womens Health 2016;16:60. DOI: 10.1186/s12905-016-0341-3

75. Monteiro RC. Immunoglobulin A as an anti-inflammatory agent. Clin Exp Immunol 2014;178(1):108-10. DOI: 10.1111/cei.12531

76. Kitaya K, Takeuchi T, Mizuta S et al. Endometritis: new time, new concepts. Fertil Steril 2018;110:344-50. DOI: 10.1016/j.fertnstert. 2018.04.012

77. Song D, Feng X, Zhang Q et al. Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure. Reprod Biomed Online 2018;36:78-83. DOI: 10.1016/j.rbmo.2017.09.008

78. Bouet PE, El Hachem H, Monceau E et al. Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis. Fertil Steril 2016;105:106-10. DOI: 10.1016/j.fertnstert.2015.09.025

79. Mitter VR, Meier S, Rau TT et al. Treatment following hysteroscopy and endometrial diagnostic biopsy increases the chance for live birth in women with chronic endometritis. Am J Reprod Immunol 2021;86(5):e13482. DOI: 0.1111/aji.13482

80. Singh N, Sethi A. Endometritis – Diagnosis, Treatment and its impact on fertility – A Scoping Review. JBRA Assist Reprod 2022;26(3):538-546. DOI: 10.5935/1518-0557.20220015

81. Gkrozou F, Tsonis O, Dimitriou E, Paschopoulos M. In women with chronic or subclinical endometritis is hysteroscopy suitable for setting the diagnosis? A systematic review. J Obstet Gynaecol Res 2020;46(9):1639-50. DOI: 10.1111/jog.14360

For citation:Borovikov I.O., Papoyan L.A., Revenko D.V., Golubchenko K.E., Ilyina D.V., Syrko K.M. Chronic endometritis – diagnosing difficulties (review). Clinical review for general practice. 2025; 6 (9): 12–18(In Russ.). DOI: 10.47407/kr2025.6.09.00p4533

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Clinical review for general practice