{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:44:09Z","timestamp":1793043849563,"version":"4.5.0"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Riga Stradins University, Riga, Latvia","id":[{"id":"https:\/\/ror.org\/03nadks56","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometriosis is a complex disease, which is defined by abnormal growth of endometrial tissue outside the uterus. It affects about 10% of women of reproductive age all over the world. Endometriosis causes symptoms that notably worsen patient\u2019s well-being\u2014such as severe pelvic pain, dysfunction of the organs of pelvic cavity, infertility and secondary mental issues. The diagnosis of endometriosis is quite often delayed because of nonspecific manifestations. Since the disease was defined, several different pathogenetic pathways have been considered, including retrograde menstruation, benign metastasis, immune dysregulation, coelomic metaplasia, hormonal disbalance, involvement of stem cells and alterations in epigenetic regulation, but the true pathogenesis of endometriosis remains poorly understood. The knowledge of the exact mechanism of the origin and progression of this disease is significant for the appropriate treatment. Therefore, this review reports the main pathogenetic theories of endometriosis based on current studies.<\/jats:p>","DOI":"10.3390\/ijms24054254","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T02:07:44Z","timestamp":1676945264000},"page":"4254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":318,"title":["The Main Theories on the Pathogenesis of Endometriosis"],"prefix":"10.3390","volume":"24","author":[{"given":"Jelizaveta","family":"Lamceva","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romans","family":"Uljanovs","sequence":"additional","affiliation":[{"name":"Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7393-9524","authenticated-orcid":false,"given":"Ilze","family":"Strumfa","sequence":"additional","affiliation":[{"name":"Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"ref_1","unstructured":"(2022, September 27). World Health Organization. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/endometriosis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1016\/j.cell.2021.04.041","article-title":"Endometriosis: Etiology, pathobiology, and therapeutic prospects","volume":"184","author":"Saunders","year":"2021","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Smolarz, B., Szy\u0142\u0142o, K., and Romanowicz, H. (2021). Endometriosis: Epidemiology, classification, pathogenesis, treatment and genetics (Review of literature). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910554"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.fertnstert.2017.01.009","article-title":"Biomarkers in endometriosis: Challenges and opportunities","volume":"107","author":"Ahn","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/j.cell.2019.11.033","article-title":"SnapShot: Endometriosis","volume":"179","author":"Horne","year":"2019","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1146\/annurev-pathmechdis-012419-032654","article-title":"The origin and pathogenesis of endometriosis","volume":"15","author":"Wang","year":"2020","journal-title":"Annu. Rev. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.rbmo.2019.10.007","article-title":"Pathogenesis of endometriosis: Look no further than John Sampson","volume":"40","author":"Yovich","year":"2020","journal-title":"Reprod. Biomed. Online"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0002-9378(40)91238-8","article-title":"The development of the implantation theory for the origin of peritoneal endometriosis","volume":"40","author":"Sampson","year":"1940","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/S0015-0282(97)00191-X","article-title":"Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities","volume":"68","author":"Nisolle","year":"1997","journal-title":"Fertil. Steril."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/jog.13559","article-title":"Involvement of immune cells in the pathogenesis of endometriosis","volume":"44","author":"Izumi","year":"2018","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1093\/humupd\/8.1.84","article-title":"Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons","volume":"8","author":"Debrock","year":"2002","journal-title":"Hum. Reprod. Update"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"879015","DOI":"10.3389\/fmed.2022.879015","article-title":"New insights in pathogenesis of endometriosis","volume":"9","author":"Signorile","year":"2022","journal-title":"Front. Med."},{"key":"ref_13","first-page":"93","article-title":"Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation","volume":"3","author":"Sampson","year":"1927","journal-title":"Am. J. Pathol."},{"key":"ref_14","first-page":"1","article-title":"The role of the lymphatic system in endometriosis: A comprehensive review of the literature","volume":"64","author":"Jerman","year":"2015","journal-title":"Biol. Reprod."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, J., Liu, Y., Du, K., Xiao, L., He, X., Dai, F., and Tang, J. (2022). Endometriosis in para-aortic lymph node resembling a malignancy: A case report and literature review. BMC Womens Health, 22.","DOI":"10.1186\/s12905-022-01659-4"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"213","DOI":"10.4103\/IJPM.IJPM_1022_19","article-title":"Gastrointestinal deep infiltrative endometriosis with lymph node involvement","volume":"64","author":"Parag","year":"2021","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"rjaa396","DOI":"10.1093\/jscr\/rjaa396","article-title":"A case of infiltrative cecal endometriosis with appendiceal obliteration and lymph node involvement","volume":"2020","author":"Law","year":"2020","journal-title":"J. Surg. Case. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/j.humpath.2004.07.020","article-title":"Vascular endothelial growth factor A and C gene expression in endometriosis","volume":"35","author":"Takehara","year":"2004","journal-title":"Hum. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1093\/humrep\/der230","article-title":"Lymphangiogenesis in deep infiltrating endometriosis","volume":"26","author":"Keichel","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kapoor, R., Stratopoulou, C.A., and Dolmans, M.M. (2021). Pathogenesis of endometriosis: New insights into prospective therapies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111700"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Abramiuk, M., Grywalska, E., Ma\u0142kowska, P., Sierawska, O., Hrynkiewicz, R., and Nied\u017awiedzka-Rystwej, P. (2022). The role of the immune system in the development of endometriosis. Cells, 11.","DOI":"10.3390\/cells11132028"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1093\/humupd\/dmz018","article-title":"The endometrial immune environment of women with endometriosis","volume":"25","author":"Houshdaran","year":"2019","journal-title":"Hum. Reprod. Update"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1093\/humrep\/den393","article-title":"Macrophage expression in endometrium of women with and without endometriosis","volume":"24","author":"Berbic","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1093\/humrep\/det003","article-title":"Suppression of annexin A2 by prostaglandin E\u2082 impairs phagocytic ability of peritoneal macrophages in women with endometriosis","volume":"28","author":"Wu","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"547","DOI":"10.2353\/ajpath.2009.081011","article-title":"Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease","volume":"175","author":"Bacci","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/aji.12540","article-title":"Neutrophil depletion reduces endometriotic lesion formation in mice","volume":"76","author":"Takamura","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jiang, I., Yong, P.J., Allaire, C., and Bedaiwy, M.A. (2021). Intricate connections between the microbiota and endometriosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115644"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.5301\/je.5000180","article-title":"Peripheral and endometrial dendritic cell populations during the normal cycle and in the presence of endometriosis","volume":"6","author":"Maridas","year":"2014","journal-title":"J. Endometr. Pelvic Pain Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.mce.2009.03.022","article-title":"Estrogen metabolism and action in endometriosis","volume":"307","author":"Rizner","year":"2009","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1055\/s-0033-1350702","article-title":"Cytotoxic T-cells in peripheral blood in women with endometriosis","volume":"73","author":"Slabe","year":"2013","journal-title":"Geburtshilfe. Frauenheilkd."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R41","DOI":"10.1530\/REP-19-0106","article-title":"Endometriosis in MRKH cases as a proof for the coelomic metaplasia hypothesis?","volume":"158","author":"Konrad","year":"2019","journal-title":"Reproduction"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1111\/j.1447-0756.2009.01025.x","article-title":"Endometriosis in a patient with Rokitansky-Kuster-Hauser syndrome","volume":"35","author":"Cho","year":"2009","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.2741\/e589","article-title":"Stem cell theory for the pathogenesis of endometriosis","volume":"4","author":"Maruyama","year":"2012","journal-title":"Front. Biosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.fertnstert.2017.08.036","article-title":"Pathogenesis of deep endometriosis","volume":"108","author":"Gordts","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1749-6632.2011.05969.x","article-title":"Stem cells in endometrium and their role in the pathogenesis of endometriosis","volume":"1221","author":"Figueira","year":"2011","journal-title":"Ann. N. Y. Acad Sci."},{"key":"ref_36","first-page":"51","article-title":"Somatic stem cells and their dysfunction in endometriosis","volume":"1","author":"Djokovic","year":"2014","journal-title":"Front. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cervell\u00f3, I., Mas, A., Gil-Sanchis, C., Peris, L., Faus, A., Saunders, P.T., Critchley, H.O., and Sim\u00f3n, C. (2011). Reconstruction of endometrium from human endometrial side population cell lines. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021221"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Marquardt, R.M., Kim, T.H., Shin, J.H., and Jeong, J.W. (2019). Progesterone and estrogen signaling in the endometrium: What goes wrong in endometriosis?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153822"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.3892\/mmr.2016.4925","article-title":"DNA methylation in endometriosis (Review)","volume":"13","author":"Koukoura","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2741\/4431","article-title":"Inflammation and endometriosis","volume":"21","author":"Jiang","year":"2016","journal-title":"Front. Biosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1210\/er.2012-1043","article-title":"Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer","volume":"34","author":"Kim","year":"2013","journal-title":"Endocr. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.biopha.2018.06.109","article-title":"Endometriosis: Perspective, lights, and shadows of etiology","volume":"106","author":"Asghari","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lagan\u00e0, A.S., Garzon, S., G\u00f6tte, M., Vigan\u00f2, P., Franchi, M., Ghezzi, F., and Martin, D.C. (2019). The pathogenesis of endometriosis: Molecular and cell biology insights. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225615"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.fertnstert.2020.08.1398","article-title":"Insight into epigenetics of human endometriosis organoids: DNA methylation analysis of HOX genes and their cofactors","volume":"115","author":"Esfandiari","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/humupd\/dmp034","article-title":"The role of microRNAs in endometriosis and associated reproductive conditions","volume":"16","author":"Teague","year":"2010","journal-title":"Hum Reprod. Update"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"102157","DOI":"10.1016\/j.jogoh.2021.102157","article-title":"Endometriosis, infertility and microRNA\u2019s: A review","volume":"50","author":"Raja","year":"2021","journal-title":"J. Gynecol. Obstet. Hum. Reprod."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"100112","DOI":"10.1016\/j.clinsp.2022.100112","article-title":"MiRNA-223 expression in patient-derived eutopic and ectopic endometrial stromal cells and its effect on epithelial-to-mesenchymal transition in endometriosis","volume":"77","author":"Xue","year":"2022","journal-title":"Clinics"},{"key":"ref_48","first-page":"117","article-title":"Serum exosomal miRNA from endometriosis patients correlates with disease severity","volume":"305","author":"Wu","year":"2022","journal-title":"Gynecol. Obstet."},{"key":"ref_49","first-page":"591","article-title":"Endometriosis and cancer","volume":"10","author":"Losan","year":"2014","journal-title":"Womens Health"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1056\/NEJMoa1614814","article-title":"Cancer-associated mutations in endometriosis without cancer","volume":"376","author":"Anglesio","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"102418","DOI":"10.1016\/j.jogoh.2022.102418","article-title":"Endometriosis and environmental factors: A critical review","volume":"51","author":"Coiplet","year":"2022","journal-title":"J. Gynecol. Obstet. Hum. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Kechagias, K.S., Katsikas Triantafyllidis, K., Kyriakidou, M., Giannos, P., Kalliala, I., Veroniki, A.A., Paraskevaidi, M., and Kyrgiou, M. (2021). The relation between caffeine consumption and endometriosis: An updated systematic review and meta-analysis. Nutrients, 13.","DOI":"10.3390\/nu13103457"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Polak, G., Banaszewska, B., Filip, M., Radwan, M., and Wdowiak, A. (2021). Environmental factors and endometriosis. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph182111025"},{"key":"ref_54","first-page":"374","article-title":"Role of genetic and environmental factors in the development of endometriosis","volume":"67","author":"Ballester","year":"2012","journal-title":"Rev. Med. Liege"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4254\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:44Z","timestamp":1760121464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,21]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054254"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054254","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,21]]}}}