The role of bacterial contamination in the development of endometriosis

Smolnova T.Yu., Dmitrieva I.E., Pavlovich S.V., Chuprynin V.D., Priputnevich T.V.

1) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
The current concepts of the etiology and mechanisms of endometriosis, including the new theory of bacterial contamination, are analyzed. The review includes data from foreign and Russian articles published in the PubMed, UpToDate and eLibrary databases over the past 10 years. Antimicrobial peptide (AMP), in particular secretory leukocyte protease inhibitor (SLPI) and β-defensin, are elements of the local line of epithelial defense against an infectious agent. Their level in the endometrium and other tissues of the female genital tract decreases during menstruation under cyclic hormonal fluctuations, which increases the risk of bacterial contamination of menstrual blood and genital tract tissues. In addition, a change in AMP secretion may play a role in the implantation of endometrioid heterotopias through the influence on the synthesis and activity of matrix metalloproteinases and transcription nuclear factor kappa B (NF-κB). As the disease progresses, there are elevated levels of SLPI and β-defensins. AMPs are present in virtually all human epithelial tissues; and a decrease in their secretion by epithelial cells is one of the components in the development of common forms of endometriosis. The results of ongoing studies confirm the role of AMP as a trigger in the development of endometriosis, which exacerbates bacterial contamination during menstruation and forms a vicious circle in the pathogenesis of common forms of endometriosis.


common forms of endometriosis
Escherichia coli
antimicrobial peptides
secretory protease inhibitor


  1. Dunselman G.A., Vermeulen N., Becker C., Calhaz-Jorge C., D’Hooghe T., De Bie B., Heikinheimo O., Horne A.W., Kiesel L., Nap A., Prentice A., Saridogan E., Soriano D., Nelen W.; European Society of Human Reproduction and Embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014; 29(3): 400–12. doi: 10.1093/humrep/det457.
  2. Schenken R.S., Barbieri R.L., Eckler K. Endometriosis: Pathogenesis, clinical features, and diagnosis. UpToDate. 2019.
  3. Kuohung W., Hornstein M.D., Barbieri R.L., Eckler K. Causes of female infertility. UpToDate .2017.
  4. Sampson J.A. Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. Am J Pathol. 1927; 3(2): 93–110.43. PMCID: PMC1931779
  5. Fauser B.C., Diedrich K., Bouchard P., Domínguez F., Matzuk M., Franks S., Hamamah S., Simón C., Devroey P., Ezcurra D., Howles C.M.; Evian Annual Reproduction (EVAR) Workshop Group 2010. Contemporary genetic technologies and female reproduction. Hum Reprod Update. 2011; 17(6): 829–47. doi: 10.1093/humupd/dmr033.
  6. Konrad L., Dietze R., Kudipudi P.K., Horne F., Meinhold-Heerlein I. Endometriosis in MRKH Cases as a Proof for the Coelomic Metaplasia Hypothesis? Reproduction. 2019; pii: REP-19-0106. doi: 10.1530/REP-19-0106
  7. Moore J.G., Binstock M.A., Growdon W.A. The clinical implications of retroperitoneal endometriosis. Am J Obstet Gynecol. 1988;158(6 Pt 1):1291–8. doi: 10.1016/0002-9378(88)90359-6
  8. Hey-Cunningham A.J., Fazleabas A.T., Braundmeier A.G., Markham R., Fraser I.S., Berbic M. Endometrial stromal cells and immune cell populations within lymph nodes in a nonhuman primate model of endometriosis. Reprod Sci. 2011; 18(8):747–54. doi: 10.1177/1933719110397210.
  9. Sasson I.E., Taylor H.S. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106–15. doi: 10.1196/annals.1434.014
  10. Koninckx P.R., Ussia A., Adamyan L., Wattiez A., Gomel V., Martin D.C. Pathogenesis of endometriosis: the genetic/epigenetic theory. Fertil Steril. 2019;111(2):327–340. doi: 10.1016/j.fertnstert.2018.10.013
  11. Xie Q., He H., Wu Y.H., Zou L.J., She X.L., Xia X.M., Wu X.Q. Eutopic endometrium from patients with endometriosis modulates the expression of CD36 and SIRP-α in macrophages. J Obstet Gynaecol Res. 2019; 45(5):1045–7. doi: 10.1111/jog.13938
  12. Oosterlynck D.J., Cornillie F.J., Waer M., Vandeputte M., Koninckx P.R. Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium. Fertil Steril. 1991; 56(1): 45–51.doi: 10.1016/s0015-0282(16)54414-8
  13. Crain D.A., Janssen S.J., Edwards T.M., Heindel J., Ho S.M., Hunt P., Iguchi T., Juul A., McLachlan J.A., Schwartz J., Skakkebaek N., Soto A.M., Swan S., Walker C., Woodruff T.K., Woodruff T.J., Giudice L.C., Guillette L.J. Jr. Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril. 2008; 90(4): 911–40. doi: 10.1016/j.fertnstert.2008.08.067.
  14. Kodati V.L., Govindan S., Movva S., Ponnala S., Hasan Q. Role of Shigella infection in endometriosis: a novel hypothesis. Med Hypotheses. 2008; 70(2): 239–43. doi: 10.1016/j.mehy.2007.06.012
  15. Khan K.N., Fujishita A., Hiraki K., Kitajima M., Nakashima M., Fushiki S., Kitawaki J. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018;17(2):125–133. doi: 10.1002/rmb2.12083
  16. Thompson R.C., Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci U S A. 1986; 83(18): 6692–6.doi: 10.1073/pnas.83.18.6692
  17. King A.E., Critchley H.O., Kelly R.W. Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role. Mol Hum Reprod. 2000; 6(2): 191–6. doi: 10.1093/molehr/6.2.191
  18. Wira C.R., Fahey J.V., Rodriguez-Garcia M., Shen Z., Patel M.V. Regulation of mucosal immunity in the female reproductive tract: the role of sex hormones in immune protection against sexually transmitted pathogens. Am J Reprod Immunol. 2014; 72(2): 236–58. doi: 10.1111/aji.12252
  19. Hiemstra P.S., Maassen R.J., Stolk J., Heinzel-Wieland R., Steffens G.J., Dijkman J.H. Antibacterial activity of antileukoprotease. Infect Immun. 1996; 64(11): 4520–4. PMCID: PMC174407
  20. Wira C.R., Ghosh M., Smith J.M., Shen L., Connor R.I., Sundstrom P., Frechette G.M., Hill E.T., Fahey J.V. Epithelial cell secretions from the human female reproductive tract inhibit sexually transmitted pathogens and Candida albicans but not Lactobacillus. Mucosal Immunol. 2011; 4(3): 335–42. doi: 10.1038/mi.2010.72
  21. King A.E., Fleming D.C., Critchley H.O., Kelly R.W. Regulation of natural antibiotic expression by inflammatory mediators and mimics of infection in human endometrial epithelial cells. Mol Hum Reprod. 2002; 8(4): 341–9.doi: 10.1093/molehr/8.4.341
  22. Ohlsson S., Ljungkrantz I., Ohlsson K., Segelmark M., Wieslander J. Novel distribution of the secretory leucocyte proteinase inhibitor in kidney. Mediators Inflamm. 2001; 10(6): 347–50. doi: 10.1080/09629350120102389
  23. Ganesan S., Comstock A.T., Sajjan U.S. Barrier function of airway tract epithelium. Tissue Barriers. 2013;1(4): e24997. doi: 10.4161/tisb.24997.
  24. Si-Tahar M., Merlin D., Sitaraman S., Madara J.L. Constitutive and regulated secretion of secretory leukocyte proteinase inhibitor by human intestinal epithelial cells. Gastroenterology. 2000;118(6):1061–71.doi: 10.1016/s0016-5085(00)70359-3
  25. Gallo R.L., Nizet, V.. Endogenous production of antimicrobial peptides in innate immunity and human disease. Current Allergy and Asthma Reports, 2003; 3(5):402–409. doi: 10.1007/s11882-003-0074-x
  26. Zhang Y., DeWitt D.L., McNeely T.B., Wahl S.M., Wahl L.M. Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E2, and matrix metalloproteinases. J Clin Invest. 1997; 99(5): 894–900. doi: 10.1172/JCI119254
  27. Matsuba S., Yabe-Wada T., Takeda K., Sato T., Suyama M., Takai T., Kikuchi T., Nukiwa T., Nakamura A. Identification of Secretory Leukoprotease Inhibitor As an Endogenous Negative Regulator in Allergic Effector Cells. Front Immunol. 2017; 8: 1538. doi: 10.3389/fimmu.2017.01538
  28. Chegini N., Gold L.I., Williams R.S. Localization of transforming growth factor beta isoforms TGF-beta 1, TGF-beta 2, and TGF-beta 3 in surgically induced endometriosis in the rat. Obstet Gynecol. 1994; 83: 455–461. PMID: 8127541
  29. Young V.J., Brown J.K., Saunders P.T., Duncan W.C., Horne A.W. The peritoneum is both source and target of TGF-β in women with endometriosis. PLoS One. 2014; 9(9): e106773. doi: 10.1371/journal.pone.0106773
  30. Bruner K.L., Eisenberg E., Gorstein F., Osteen K.G. Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis. Steroids. 1999; 64(9): 648–53. doi: 10.1016/s0039-128x(99)00048-3
  31. Зайратьянц О.В., Адамян Л.В., Манукян Л.М., Калинин Д.В., Арсланян К.Н. Экспрессия моэзина, p21-активированной киназы 4 (PAK 4), матриксных металлопротеиназ (ММР 2, ММР 9) и CD34в эутопическом и эктопическом эндометрии при аденомиозе. Архив патологии. 2018; 80(6):14–21. [Zayratyants O.V., Adamyan L.V., Manukyan L.M., Kalinin D.V., Arslanyan K.N.The expression of moesin, p21-activated kinase 4 (PAK 4), matrix metalloproteinases (MMP 2, MMP 9), and CD34 in the eutopic and ectopic endometrium in adenomyosis. Archive of Pathology/Arkhiv Patologii. 2018; 80(6): 14. (in Russian)]. doi:10.17116/patol20188006114
  32. Адамян Л.В., Азнаурова Я.Б., Осипова А.А. Сравнительная характеристика эутопического эндометрия при эндометриозе и в отсутствие данного заболевания. Проблемы репродукции. 2018; 24(3): 10–15. [Adamyan L.V., Aznaurova Ya.B., Osipova A.A. Comparative analysis of eutopic endometrium from women with and without endometriosis. Russian Journal of Human Reproduction/Problemy reproduktsii. 2018; 24(3): 10–15. (in Russian)]. doi:10.17116/repro201824310
  33. Bruner K.L., Matrisian L.M., Rodgers W.H., Gorstein F., Osteen K.G. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997; 99(12): 2851–7. doi:10.1172/JCI119478
  34. Cui N., Wang H., Long Y., Su L., Liu D. Dexamethasone Suppressed LPS-Induced Matrix Metalloproteinase and Its Effect on Endothelial Glycocalyx Shedding. Mediators Inflamm. 2015; 2015: 912726. doi: 10.1155/2015/912726
  35. Zaga-Clavellina V., Garcia-Lopez G., Flores-Pliego A., Merchant-Larios H., Vadillo-Ortega F. In vitro secretion and activity profiles of matrix metalloproteinases, MMP-9 and MMP-2, in human term extra-placental membranes after exposure to Escherichia coli. Reprod Biol Endocrinol. 2011; 9:13. doi:10.1186/1477-7827-9-13
  36. Sallenave J.M., Shulmann J., Crossley J., Jordana M., Gauldie J. Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Am J Respir Cell Mol Biol. 1994;11(6):733–41. doi: 10.1165/ajrcmb.11.6.7946401
  37. Suzumori N., Sato M., Yoneda T., Ozaki Y., Takagi H., Suzumori K. Expression of secretory leukocyte protease inhibitor in women with endometriosis. Fertil Steril. 1999; 72(5): 857–67. doi: 10.1016/s0015-0282(99)00381-7
  38. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol. 2003; 3(9):710–20. doi: 10.1038/nri1180
  39. Gallo R.L., Nizet V. Endogenous production of antimicrobial peptides in innate immunity and human disease. Curr Allergy Asthma Rep. 2003; 3(5): 402–9. DOI: 10.1007/s11882-003-0074-x
  40. Selsted M.E., Tang Y.Q., Morris W.L., McGuire P.A., Novotny M.J., Smith W., Henschen A.H., Cullor J.S. Purification, primary structures, and antibacterial activities of beta-defensins, a new family of antimicrobial peptides from bovine neutrophils. J Biol Chem. 1996; 271(27): 16430. doi: 10.1074/jbc.271.27.16430
  41. Valore E.V., Park C.H., Quayle A.J., Wiles K.R., McCray P.B. Jr., Ganz T. Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest. 1998;101(8): 1633–42. doi: 10.1172/JCI1861
  42. Harder J., Bartels J., Christophers E., Schroder J.M. Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. J Biol Chem. 2001; 276(8): 5707–13. doi: 10.1074/jbc.M008557200
  43. Yang D., Chertov O., Bykovskaia S.N., Chen Q., Buffo M.J., Shogan J., Anderson M., Schröder J.M., Wang J.M., Howard O.M., Oppenheim J.J. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science. 1999; 286(5439): 525–8. doi: 10.1126/science.286.5439.525
  44. García J.R., Jaumann F., Schulz S., Krause A., Rodríguez-Jiménez J., Forssmann U., Adermann K., Klüver E., Vogelmeier C., Becker D., Hedrich R., Forssmann W.G., Bals R. Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res. 2001; 306(2): 257–64.
  45. Gupta S., Bhatia G., Sharma A., Saxena S. Host defense peptides: An insight into the antimicrobial world. J Oral Maxillofac Pathol. 2018; 22(2): 239–44. doi:10.4103/jomfp.JOMFP_113_16
  46. Hazlett L., Wu M. Defensins in innate immunity. Cell Tissue Res. 2011; 343(1):175–88. doi:10.1007/s00441-010-1022-4
  47. King A.E., Fleming D.C., Critchley H.O., Kelly R.W. Differential expression of the natural antimicrobials, beta-defensins 3 and 4, in human endometrium. J Reprod Immunol. 2003; 59(1):1–16. doi: 10.1016/s0165-0378(02)00083-9
  48. Fleming D.C., King A.E., Williams A.R., Critchley H.O., Kelly R.W. Hormonal contraception can suppress natural antimicrobial gene transcription in human endometrium. Fertil Steril. 2003; 79(4): 856–63. doi: 10.1016/s0015-0282(02)04930-0
  49. Каримова Г.Н. Совершенствование клинико-лабораторных подходов к прогнозированию, диагностике и тактике лечения пациенток с послеродовым эндометритом: дисс. ... кандидата медицинских наук: 14.01.01. Место защиты: Научный центр акушерства, гинекологии и перинатологии им. академика В.И. Кулакова, 2017. [Karimova G.N. Improving the clinical and laboratory approaches to predicting, diagnosing and treating patients with postpartum endometritis: a dissertation ... of a candidate of medical sciences: 14.01.01. Place of protection: Scientific Center for Obstetrics, Gynecology and Perinatology. Academician V.I. Kulakova, 2017. (in Russian)]
  50. Чупрынин В.Д., Смольнова Т.Ю., Мельников М.В., Чурсин В.В., Чурсин Д.В. Осложнения хирургического лечения колоректального эндометриоза у пациенток репродуктивного возраста. Материалы конгресса «Новые технологии в диагностике и лечениигинекологических заболеваний». М.: МЕДИ Экспо, 2018; 166–167. [Chuprynin V.D., Smolnova T.Yu., Melnikov M.V., Chursin V.V., Chursin D.V. Complications of surgical treatment of colorectal endometriosis in reproductive age patients. Materials of Congress «New technologies for diagnosis and treatment of gynecologic diseases». M.: MEDI Expo, 2018; 166–167. (in Russian)]. ISBN 978–5–906484–37–6

Received 03.10.2019

Accepted 04.10.2019

About the Authors

Tatiana Yu. Smolnova, MD., senior associate of the Surgery department of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynaecology and Perinatology. Tel.: 8 (926) 310-80-90. Email:
Akademika Oparina street, 4, Moscow, Russia, 117997.
Irina E. Dmitrieva, 1st year PhD candidate of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynaecology and Perinatology. Tel.: +7 (916)089-08-09.
Akademika Oparina street, 4, Moscow, Russia, 117997.
Stanislav V. Pavlovich, PhD/Med, scientific secretary and senior associate of the Pathologic Pregnancy department of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynaecology and Perinatology, associate professor of the Obstetrics, Gynaecology and Perinatology academic department of the Postgraduate Professional Medical Studies faculty of the I.M. Sechenov First Moscow State Medical University (Sechenov University). Tel.: +7 (916)189-37-18. Email:
Akademika Oparina street, 4, Moscow, Russia, 117997.
Vladimir D. Chuprynin, PhD/Med, head of the Surgery department of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynaecology and Perinatology
Tel.:+7 (495)438-78-33.
Akademika Oparina street, 4, Moscow, Russia, 117997.
Tatiana V. Priputnevich, MD, head of the Microbiology, Clinical Pharmacology and Epidemiology department of the V.I. Kulakov National Medical Research Center
for Obstetrics, Gynaecology and Perinatology.Tel.: +7(910)414-56-16.
Akademika Oparina street, 4, Moscow, Russia, 117997.

For citation: Smolnova T.Yu., Dmitrieva I.E., Pavlovich S.V., Chuprynin V.D., Priputnevich T.V. The role of bacterial contamination in the development of endometriosis.
Akusherstvo i Ginekologiya/Obstetrics and gynecology. 2020; 1: 47-53. (In Russian).

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.