Editing Endometriosis (section)

===Formation===
The main theories for the formation of the ectopic endometrium-like tissue include retrograde menstruation, Müllerianosis, coelomic metaplasia, vascular dissemination of [[stem cell]]s, and surgical transplantation, which were postulated as early as 1870. Each is further described below.<ref name=zondervan32212520/><ref name="vanderLinden1996">{{cite journal | vauthors = van der Linden PJ | title = Theories on the pathogenesis of endometriosis | journal = Human Reproduction | volume = 11 | issue = Suppl 3 | pages = 53–65 | date = November 1996 | pmid = 9147102 | doi = 10.1093/humrep/11.suppl_3.53 | doi-access = free | title-link = doi }}</ref><ref name=hufnagelpmc4986990>{{cite journal | vauthors = Hufnagel D, Li F, Cosar E, Krikun G, Taylor HS | title = The Role of Stem Cells in the Etiology and Pathophysiology of Endometriosis | journal = Seminars in Reproductive Medicine | volume = 33 | issue = 5 | pages = 333–40 | date = September 2015 | pmid = 26375413 | pmc = 4986990 | doi = 10.1055/s-0035-1564609 }}</ref>

====Retrograde menstruation theory====
The theory of retrograde menstruation (also called the ''implantation theory'' or ''transplantation theory'') is the most commonly accepted theory for the dissemination and transformation of ectopic endometrium into endometriosis. It suggests that during a woman's [[menstruation|menstrual flow]], some of the endometrial debris flow backward through the fallopian tubes and into the peritoneal cavity, attaching itself to the [[peritoneum|peritoneal surface]] (the lining of the abdominal cavity) where it can proceed to invade the tissue as or transform into endometriosis. It is unclear at what stage the transformation of endometrium, or any cell of origin such as stem cells or coelomic cells (see those theories below), to endometriosis begins.<ref name="Fauser2011">{{cite journal | vauthors = Fauser BC, Diedrich K, Bouchard P, Domínguez F, Matzuk M, Franks S, Hamamah S, Simón C, Devroey P, Ezcurra D, Howles CM | title = Contemporary genetic technologies and female reproduction | journal = Human Reproduction Update | volume = 17 | issue = 6 | pages = 829–47 | year = 2011 | pmid = 21896560 | pmc = 3191938 | doi = 10.1093/humupd/dmr033 }}</ref><ref name="vanderLinden1996"/><ref name="koninckx1999">{{cite journal | vauthors = Koninckx PR, Barlow D, Kennedy S | title = Implantation versus infiltration: the Sampson versus the endometriotic disease theory | journal = Gynecologic and Obstetric Investigation | volume = 47 | issue = Supplement 1 | pages = 3–9; discussion 9–10 | date = 1999 | pmid = 10087422 | doi = 10.1159/000052853 | s2cid = 29718095 }}</ref>

Proofs in support of the theory are based on retrospective epidemiological studies that an association with endometrial implants attached to the peritoneal cavity, which would develop into endometrial lesions and retrograde menstruation; and the fact that animals like rodents and non-human primates whose endometrium is not shed during the estrous cycle don't develop naturally endometriosis contrary to animals that have a natural menstrual cycle like rhesus monkeys and baboons.<ref name="Malvezzi Marengo Podgaec Piccinato p. ">{{cite journal | vauthors = Malvezzi H, Marengo EB, Podgaec S, Piccinato CA | title = Endometriosis: current challenges in modeling a multifactorial disease of unknown etiology | journal = Journal of Translational Medicine | volume = 18 | issue = 1 | page = 311 | date = August 2020 | pmid = 32787880 | pmc = 7425005 | doi = 10.1186/s12967-020-02471-0 | publisher = Springer Science and Business Media LLC | doi-access = free | title-link = doi }}</ref>

Retrograde menstruation alone is not able to explain all instances of endometriosis, and additional factors such as genetics, immunology, stem cell migration, and coelomic metaplasia (see "Other theories" on this page) are needed to account for disseminated disease and why many individuals with retrograde menstruation are not diagnosed with endometriosis. In addition, endometriosis has shown up in people who have never experienced menstruation including cisgender men,<ref name="pmid445352">{{cite journal | vauthors = Pinkert TC, Catlow CE, Straus R | title = Endometriosis of the urinary bladder in a man with prostatic carcinoma | journal = Cancer | volume = 43 | issue = 4 | pages = 1562–7 | date = April 1979 | pmid = 445352 | doi = 10.1002/1097-0142(197904)43:4<1562::aid-cncr2820430451>3.0.co;2-w | doi-access = free | title-link = doi }}</ref> fetuses,<ref name="signorile2009"/> and prepubescent girls.<ref>{{cite journal | vauthors = Mok-Lin EY, Wolfberg A, Hollinquist H, Laufer MR | title = Endometriosis in a patient with Mayer-Rokitansky-Küster-Hauser syndrome and complete uterine agenesis: evidence to support the theory of coelomic metaplasia | journal = Journal of Pediatric and Adolescent Gynecology | volume = 23 | issue = 1 | pages = e35-7 | date = February 2010 | pmid = 19589710 | doi = 10.1016/j.jpag.2009.02.010 }}</ref><ref name="Marsh EE 2004">{{cite journal | vauthors = Marsh EE, Laufer MR | title = Endometriosis in premenarcheal girls who do not have an associated obstructive anomaly | journal = Fertility and Sterility | volume = 83 | issue = 3 | pages = 758–60 | date = March 2005 | pmid = 15749511 | doi = 10.1016/j.fertnstert.2004.08.025 | doi-access = free | title-link = doi }}</ref> Further theoretical additions are needed to complement the retrograde menstruation theory to explain why cases of endometriosis show up in the [[brain]]<ref>{{cite journal | vauthors = Thibodeau LL, Prioleau GR, Manuelidis EE, Merino MJ, Heafner MD | title = Cerebral endometriosis. Case report | journal = Journal of Neurosurgery | volume = 66 | issue = 4 | pages = 609–10 | date = April 1987 | pmid = 3559727 | doi = 10.3171/jns.1987.66.4.0609 | doi-access = free | title-link = doi }}</ref> and lungs.<ref>{{cite journal | vauthors = Rodman MH, Jones CW | title = Catamenial hemoptysis due to bronchial endometriosis | journal = The New England Journal of Medicine | volume = 266 | issue = 16 | pages = 805–8 | date = April 1962 | pmid = 14493132 | doi = 10.1056/nejm196204192661604 }}</ref>

Researchers are investigating the possibility that the immune system may be unable to cope with the cyclic onslaught of retrograde menstrual fluid. In this context there is interest in studying the relationship of endometriosis to [[autoimmune disease]], [[allergy|allergic]] reactions, and the impact of toxic materials.<ref name="Lino">{{cite journal|author-link1=Norbert Gleicher | vauthors = Gleicher N, el-Roeiy A, Confino E, Friberg J | title = Is endometriosis an autoimmune disease? | journal = Obstetrics and Gynecology | volume = 70 | issue = 1 | pages = 115–22 | date = July 1987 | pmid = 3110710 }}</ref><ref>{{cite journal | vauthors = Capellino S, Montagna P, Villaggio B, Sulli A, Soldano S, Ferrero S, Remorgida V, Cutolo M | title = Role of estrogens in inflammatory response: expression of estrogen receptors in peritoneal fluid macrophages from endometriosis | journal = Annals of the New York Academy of Sciences | volume = 1069 | pages = 263–7 | date = June 2006 | issue = 1 | pmid = 16855153 | doi = 10.1196/annals.1351.024 | bibcode = 2006NYASA1069..263C | s2cid = 35601442 }}</ref> It is still unclear what, if any, causal relationship exists between toxic materials or autoimmune disease and endometriosis. There are immune system changes in people with endometriosis, such as an increase in macrophage-derived secretion products, but it is unknown if these contribute to the disorder or are reactions to it.<ref name="Young2013">{{cite journal | vauthors = Young VJ, Brown JK, Saunders PT, Horne AW | title = The role of the peritoneum in the pathogenesis of endometriosis | journal = Human Reproduction Update | volume = 19 | issue = 5 | pages = 558–69 | year = 2013 | pmid = 23720497 | doi = 10.1093/humupd/dmt024 | doi-access = free | title-link = doi }}</ref>

Endometriotic lesions differ in their biochemistry, hormonal response, immunology, and inflammatory response compared to the endometrium.<ref name=zondervan32212520/><ref name="pmid12372441">{{cite journal |vauthors=Redwine DB |title=Was Sampson wrong? |journal=Fertility and Sterility |volume=78 |issue=4 |pages=686–93 |date=October 2002 |pmid=12372441 |doi=10.1016/S0015-0282(02)03329-0 |doi-access=free |title-link=doi}}</ref> This is likely because the cells that give rise to endometriosis are a side population of cells.<ref name=Fauser2011/> Similarly, there are changes in, for example, the [[mesothelium]] of the peritoneum in people with endometriosis, such as loss of [[tight junction]]s. It is unknown if these are causes or effects of the disorder.<ref name=Young2013/>

In rare cases where [[imperforate hymen]] does not resolve itself before the first menstrual cycle and goes undetected, blood and endometrium are trapped within the uterus until the problem is resolved by surgical incision. Many health care practitioners never encounter this defect, and due to the [[flu-like symptoms]], it is often misdiagnosed or overlooked until multiple menstrual cycles have passed. By the time a correct diagnosis has been made, endometrium and other fluids have filled the uterus and Fallopian tubes with results similar to retrograde menstruation, resulting in endometriosis. The initial stage of endometriosis may vary based on the time elapsed between onset and surgical procedure.{{citation needed|date=March 2016}}

The theory of retrograde menstruation as a cause of endometriosis was first proposed by [[John A. Sampson]].<ref name="vanderLinden1996"/><ref name=sampson27ajppmcid>{{cite journal |vauthors=Sampson JA |title=Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation |journal=Am. J. Pathol. |volume=3 |issue=2 |pages=93–110.43 |date=March 1927 |pmid=19969738 |pmc=1931779 }}</ref>

====Other theories====
* Stem cells: Endometriosis may arise from stem cells from bone marrow and potentially other sources. In particular, this theory explains endometriosis found in areas remote from the pelvis, such as the brain or lungs.<ref name=hufnagelpmc4986990/> Stem cells may be from local cells such as the peritoneum (see coelomic metaplasia below) or cells disseminated in the bloodstream (see vascular dissemination below) such as those from the [[bone marrow]].<ref name="vanderLinden1996"/><ref name=hufnagelpmc4986990/><ref name=sampson27ajogdoi>{{cite journal | vauthors = Sampson JA |year= 1927 |title= Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity |journal= Am J Obstet Gynecol |volume= 14 |issue= 4 |pages= 422–469 |doi= 10.1016/S0002-9378(15)30003-X}}</ref>
* Vascular dissemination: Vascular dissemination is a 1927 theory that has been revived with new studies of bone marrow stem cells involved in pathogenesis.<ref name=hufnagelpmc4986990/><ref name=sampson27ajogdoi/>
* Environment: Environmental toxins (e.g., dioxin, [[nickel]]) may cause endometriosis.<ref name="Bruner-Tran_2008">{{cite journal | vauthors = Bruner-Tran KL, Yeaman GR, Crispens MA, Igarashi TM, Osteen KG | title = Dioxin may promote inflammation-related development of endometriosis | journal = Fertility and Sterility | volume = 89 | issue = 5 Suppl | pages = 1287–98 | date = May 2008 | pmid = 18394613 | pmc = 2430157 | doi = 10.1016/j.fertnstert.2008.02.102 }}</ref><ref>{{cite journal | vauthors = Yuk JS, Shin JS, Shin JY, Oh E, Kim H, Park WI | title = Nickel Allergy Is a Risk Factor for Endometriosis: An 11-Year Population-Based Nested Case-Control Study | journal = PLOS ONE | volume = 10 | issue = 10 | pages = e0139388 | date = 2015 | pmid = 26439741 | pmc = 4594920 | doi = 10.1371/journal.pone.0139388 | doi-access = free | title-link = doi | bibcode = 2015PLoSO..1039388Y }}</ref> Toxins such as [[dioxins and dioxin-like compounds]] tend to [[bioaccumulation|bioaccumulate]] within the human body. Further research is needed but "it is plausible that inflammatory-like processes, caused by dioxin-like environmental chemicals, can alter normal endometrial and immune cell physiology allowing persistence and development of endometrial tissue within the peritoneal cavity, normally cleared by immune system cells".<ref>{{cite journal | vauthors = Soave I, Caserta D, Wenger JM, Dessole S, Perino A, Marci R | title = Environment and Endometriosis: a toxic relationship | journal = European Review for Medical and Pharmacological Sciences | volume = 19 | issue = 11 | pages = 1964–72 | date = 2015 | pmid = 26125255 | url = https://pubmed.ncbi.nlm.nih.gov/26125255/ | archive-date = 21 July 2021 | access-date = 21 July 2021 | archive-url = https://web.archive.org/web/20210721001415/https://pubmed.ncbi.nlm.nih.gov/26125255/ | url-status = live }}</ref>
* Müllerianosis: A theory supported by foetal autopsy is that cells with the potential to become endometrial, which are laid down in tracts during embryonic development called the female reproductive (Müllerian) tract as it migrates downward at 8–10 weeks of embryonic life, could become dislocated from the migrating uterus and act like seeds or stem cells.<ref name="vanderLinden1996"/><ref name="signorile2009">{{cite journal | vauthors = Signorile PG, Baldi F, Bussani R, D'Armiento M, De Falco M, Baldi A | title = Ectopic endometrium in human foetuses is a common event and sustains the theory of müllerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer | journal = Journal of Experimental & Clinical Cancer Research | volume = 28 | page = 49 | date = April 2009 | issue = 1 | pmid = 19358700 | pmc = 2671494 | doi = 10.1186/1756-9966-28-49 | doi-access = free | title-link = doi }}</ref>
* Coelomic metaplasia: [[Coelomic]] cells which are the common ancestor of [[endometrial]] and [[peritoneal]] cells may undergo [[metaplasia]] (transformation) from one type of cell to the other, perhaps triggered by inflammation.<ref name="vanderLinden1996"/><ref name="aafp1999">{{cite journal | vauthors = Wellbery C | title = Diagnosis and treatment of endometriosis | journal = American Family Physician | volume = 60 | issue = 6 | pages = 1753–62, 1767–8 | date = October 1999 | pmid = 10537390 | url = http://www.aafp.org/afp/991015ap/1753.html | access-date = 26 July 2011 | publisher = American Academy of Family Physicians | url-status = live | archive-url = https://web.archive.org/web/20110606032508/http://www.aafp.org/afp/991015ap/1753.html | archive-date = 6 June 2011 }}</ref>
* Vasculogenesis: Up to 37% of the microvascular [[endothelium]] of ectopic endometrial tissue originates from [[endothelial progenitor cell]]s, which result in ''de novo'' formation of microvessels by the process of [[vasculogenesis]] rather than the conventional process of [[angiogenesis]].<ref>{{cite journal | vauthors = Laschke MW, Giebels C, Menger MD | title = Vasculogenesis: a new piece of the endometriosis puzzle | journal = Human Reproduction Update | volume = 17 | issue = 5 | pages = 628–36 | year = 2011 | pmid = 21586449 | doi = 10.1093/humupd/dmr023 | doi-access = free | title-link = doi }}</ref>{{clarify|reason=what's the theory here? |date=March 2016}}
* Neural growth: An increased expression of new nerve fibres is found in endometriosis, but does not fully explain the formation of ectopic endometriotic tissue and is not definitely correlated with the amount of perceived pain.<ref name="MorottiVincent2014">{{cite journal | vauthors = Morotti M, Vincent K, Brawn J, Zondervan KT, Becker CM | title = Peripheral changes in endometriosis-associated pain | journal = Human Reproduction Update | volume = 20 | issue = 5 | pages = 717–36 | year = 2014 | pmid = 24859987 | pmc = 4337970 | doi = 10.1093/humupd/dmu021 }}</ref>{{clarify|reason=what's the theory here? |date=March 2016}}
* Autoimmune: [[Graves disease]] is an autoimmune disease characterized by hyperthyroidism, goiter, ophthalmopathy, and dermopathy. People with endometriosis had higher rates of Graves' disease. One of these potential links between Graves disease and endometriosis is [[autoimmunity]].<ref>{{cite journal | vauthors = Yuk JS, Park EJ, Seo YS, Kim HJ, Kwon SY, Park WI | title = Graves Disease Is Associated With Endometriosis: A 3-Year Population-Based Cross-Sectional Study | journal = Medicine | volume = 95 | issue = 10 | pages = e2975 | date = March 2016 | pmid = 26962803 | doi = 10.1097/MD.0000000000002975 | pmc = 4998884 }}</ref><ref>{{cite journal | vauthors = Giudice LC, Kao LC | title = Endometriosis | journal = Lancet | volume = 364 | issue = 9447 | pages = 1789–99 | date = 2004 | pmid = 15541453 | doi = 10.1016/S0140-6736(04)17403-5 | s2cid = 208788714 }}</ref>
* [[Oxidative stress]]: Influx of iron is associated with the local destruction of the peritoneal mesothelium, leading to the adhesion of [[Ectopic expression|ectopic]] endometriotic cells.<ref name=":3" /> Peritoneal iron overload has been suggested to be caused by the destruction of [[erythrocytes]], which contain the iron-binding protein hemoglobin, or a deficiency in the peritoneal [[Human iron metabolism|iron metabolism system.]]<ref name=":3">{{cite journal | vauthors = Scutiero G, Iannone P, Bernardi G, Bonaccorsi G, Spadaro S, Volta CA, Greco P, Nappi L | title = Oxidative Stress and Endometriosis: A Systematic Review of the Literature | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | page = 7265238 | date = 2017 | pmid = 29057034 | pmc = 5625949 | doi = 10.1155/2017/7265238 | doi-access = free | title-link = doi }}</ref> Oxidative stress activity and [[reactive oxygen species]] (ROS) (such as [[superoxide anion]]s and [[peroxide]] levels) are reported to be higher than normal in people with endometriosis.<ref name=":3" /> Oxidative stress and the presence of excess ROS can damage tissue and induce rapid [[cellular division]].<ref name=":3" /> Mechanistically, there are several cellular pathways by which oxidative stress may lead to or may induce proliferation of endometriotic lesions, including the [[Mitogen-activated protein kinase|mitogen activated protein]] (MAP) kinase pathway and the [[MAPK/ERK pathway|extracellular signal-related kinase]] (ERK) pathway.<ref name=":3" /> Activation of both of the MAP and ERK pathways lead to increased levels of [[c-Fos]] and [[C-jun|c-Jun]], which are [[Proto oncogenes|proto-oncogenes]] that are associated with [[High grade lesion|high-grade lesions]].<ref name=":3" />
* [[Human microbiome|Microbiome]]: Some studies have reported differences in gut microbial composition in individuals with endometriosis compared to healthy controls. These findings have led to suggestions that alterations in the gut microbiome may contribute to the pathophysiology of endometriosis, though further research is needed to clarify this relationship.<ref>{{Cite journal |last1=Torraco |first1=Astrid |last2=Di Nicolantonio |first2=Sara |last3=Cardisciani |first3=Martina |last4=Ortu |first4=Eleonora |last5=Pietropaoli |first5=Davide |last6=Altamura |first6=Serena |last7=Del Pinto |first7=Rita |date=2025-05-14 |title=Meta-Analysis of 16S rRNA Sequencing Reveals Altered Fecal but Not Vaginal Microbial Composition and Function in Women with Endometriosis |journal=Medicina |language=en |volume=61 |issue=5 |pages=888 |doi=10.3390/medicina61050888 |doi-access=free |issn=1648-9144}}</ref>