{"paper_id":"73aa6127-29e4-43f6-84d5-8872f431955c","body_text":"W G Foster and M Leonardi Endometriosis C39–C41\n2:4\nCOMMENTARY\nEndometriosis – novel approaches and \ncontroversies debated\nW G Foster  and M Leonardi\nDepartment of Obstetrics & Gynecology, McMaster University, Hamilton, Ontario, Canada\nCorrespondence should be addressed to W G Foster: fosterw@mcmaster.ca\nThis paper forms part of a special series on Endometriosis. The guest editors for this section were Dr Mathew Leonardi (McMaster University, Canada) \nand Dr Warren (Lauren) Foster (McMaster University, Canada).\nReproduction and Fertility (2021) 2 C39–C41\nDefined by the extrauterine growth of estrogen-\ndependent endometrial-like epithelial and stromal cells, \nendometriosis is a common gynecological and systemic \ninflammatory disease affecting approximately 179 million \npeople assigned female at birth (predominately cisgender \nwomen) worldwide. Although most frequently detected \nin the pelvic cavity, endometriotic lesions can be found \nthroughout the body. Three main phenotypes include \nendometriomas, superficial, and deep endometriosis. \nLesion appearance is variable and dependent on the tissue \non which it grows. Hallmark features of endometriosis \ninclude pelvic pain and infertility; however, some people \nwith endometriosis remain asymptomatic. Endometriosis \nis a disease whose impact on the health care system exceeds \nthat of caring for women with Crohn’s disease, asthma, \nmigraines, and rheumatoid arthritis ( Simoens  et  al. 2007, \n2 011, 2012, Klein et al. 2014). Although a relatively common \ndisease with a high economic burden, endometriosis \nremains underfunded and under-researched (As-Sanie et al. \n2019). While important advances have been made over the \nyears in defining the pathophysiology of endometriosis, \nthe cause of endometriosis remains ill-defined, diagnosis \ncontinues to present challenges and therapeutic options \nare suboptimal. Patients frequently report dissatisfaction \nwith current therapeutic options prompting the search \nfor alternative treatments including non-hormonal \nalternatives. In a special series that will be running \nin Reproduction and Fertility  over the coming months, \ninternational experts have been recruited to provide \ninsights and perspectives into the latest advances in \nendometriosis research and treatment. We strive to succeed \nwith this special series in summarizing the current state \nof ‘leading edge’ research and opinion in endometriosis. \nThough not exhaustive, the topics and authors capture \nthis moment in time in endometriosis research.\nAlthough widely recognized to be an estrogen-\ndependent disease, numerous physiological pathways are \nknown to be dysregulated in people with endometriosis \nincluding cell adherence, attachment, proliferation, \napoptosis, angiogenesis, and tissue remodeling enzyme \nexpression ( Hey-Cunningham  et  al.  2013 ). That \nendometriosis may have a heritable component is not \na new concept ( Saha  et  al. 2015); however, specific gene \nmutations and gene regulation continue to be explored. \nIndeed, the mechanisms regulating different pathways \ndysregulated in endometriotic tissues are beginning \nto be teased apart with increasing attention focused \non mechanisms regulating gene expression including \nchromatin architecture, long ncRNA, micro-RNA, and \npiwi-RNA. The role of gonadal steroids in modulating the \nexpression of epigenetic regulators of gene expression in \nendometriosis is poorly understood. Early in this special \nseries, the relationship between gonadal steroids and \ngenomic regulation is reviewed by Dr Philippa Saunders. \nGiven the prominent role of estrogen and the use of \nandrogens as a therapeutic option in endometriosis \nsuggests that hormone replacement therapy is a potential \nmodifying factor in the transgender population that \nis beginning to receive attention. The prevalence of \nendometriosis and its implication in transgender men is \nsummarized by Dr Cecile Ferrando in her review of this \nunderserved population.\nThe reproductive and gastrointestinal tract microbiome \nhas been described by several investigators and dysbiosis has \n-21-0097ID: XX-XXXX; \n2 4\nThis work is licensed under a Creative Commons \nAttribution 4.0 International License.\nhttps://raf.bioscientifica.com © 2021 The authors\n\b Published\bby\bBioscientifica\bLtdhttps://doi.org/10.1530/RAF-21-0097\n Downloaded from Bioscientifica.com at 06/07/2026 01:14:03PM\nvia Open Access. This work is licensed under a Creative Commons Attribution\n4.0 International License.\nhttp://creativecommons.org/licenses/by/4.0/\n\n\nW G Foster and M Leonardi Endometriosis\nC402:4\nhttps://raf.bioscientifica.com © 2021 The authors\n\b Published\bby\bBioscientifica\bLtd\nbeen linked with endometriosis (Franasiak  et  al. 2016, Laschke \n& Menger 2016, Hernandes et al. 2020, Leonardi et al. 2020a). \nIn addition, the role of the microbiome in disease, cancer, and \nmodulating behavior has received increasing attention. Dr \nMauricio Abrão reviews recent advances in the microbiome \nand its potential role in the pathogenesis of endometriosis. \nDysregulation of the immune function and inflammation \nare well known in patients with endometriosis. Moreover, \nchronic inflammatory conditions are linked with increased \nrisk of cardiovascular disease and stroke ( Appelman  et  al. \n2015) prompting interest in health sequelae arising from \nendometriosis (Mu  et  al. 2016). Elucidating the long-term \nhealth consequences of endometriosis will be discussed by \nDr Stacey Missmer in her review.\nArriving at a diagnosis of endometriosis continues \nto challenge both patients and health care providers. \nChallenges in arriving at a diagnosis of endometriosis \ninclude early age at onset of symptoms, normalization of \npain, and symptom suppression through intermittent use of \noral contraceptive pills (Ballard et al. 2006, Nnoaham et al. \n2 011). Though actively being challenged, the gold standard \nfor diagnosis remains laparoscopic visualization and \nhistological confirmation of endometriotic implants, \nwith diagnostic delays of 5.3–12 years from the onset of \nthe first symptom to surgical diagnosis ( Simoens  et  al. \n2007, 2012, Singh  et  al. 2020 ). Although risks to patients \nfrom laparoscopy are rare, they are significant if they \noccur ( Slack  et  al. 2007) and patients with endometriosis \ncan expect to undergo multiple diagnostic and operative \nlaparoscopies over the course of their disease ( Jarrell 2010, \nAgarwal  et  al. 2021). Diagnostic delay, cost, surgical risk, \nand poor correlation between symptoms and extent of \ndisease are the basis for arguments to shift away from a \nsurgical diagnosis ( Taylor et al. 2018, Agarwal et al. 2019). \nIdeally, a diagnosis can be achieved in an accurate and \nreliable manner, with non-invasive imaging providing the \nmost optimistic method to visualize disease directly. Recent \nadvances in ultrasound and MRI techniques have brought \nthe diagnosis of endometriomas and deep endometriosis \ninto the realm of possibility. In this special series, Dr \nStephano Guerriero will be providing an overview of recent \nadvances and emerging techniques. However, diagnosis \nremains elusive to many currently and imaging may not be \na panacea. Thus, there is an urgent unmet need to identify \nnovel clinical markers of endometriosis ( Nisenblat  et  al. \n2016, Rogers et al. 2017, Agarwal et al. 2019).\nThose with endometriosis report dissatisfaction with \ntheir care, and treatment options remain suboptimal. \nHistorically, endometriosis has been treated in acute care \nor surgical model; however, persistent pelvic pain and \nrecurrence of disease and/or pain following surgical removal \nof lesions brings attention to the need to readdress the current \napproach to care. Specifically, Dr Sanjay Agarwal introduces \nthe concept of a chronic care model for the management of \npeople with endometriosis. Alongside the changing model of \ncare, there is an obvious need for novel medical treatments, \nespecially in the non-hormonal category, which is being \nreviewed by Dr Hiroshi Kobayashi in this issue. Alternatives \nto current medical and surgical treatment options are also \nreceiving attention (Leonardi  et  al. 2020b). Environmental \nfactors and diet are well-established modifiers of health \nand disease; however, the role of diet as a therapeutic \noption in endometriosis is emerging as a potential option \nworthy of consideration. In this series, Dr Annemiek Nap \nwill be discussing the role of diet in endometriosis as a \nnovel approach to managing endometriosis symptoms. \nEnvironmental conditions and diet also differ across racial \ngroups. The impact of race on disease extends beyond diet; \nunderstanding the prevalence of endometriosis among \nracial groups and diagnostic and treatment considerations is \nan issue explored by Dr Olga Bougie.\nFinally, we will be concluding this special series with \na debate presenting opposing viewpoints on the future \nof diagnostic laparoscopy as a diagnostic test . Arguments \nin favor of diagnostic laparoscopy will be presented by Dr \nGeorge Condous and the contrary arguments presented \nby Dr Kelly Wright. The role of diagnostic laparoscopy as a \nstand-alone diagnostic test for endometriosis has become \ncontroversial in recent years, often being used at the same \ntime as operative laparoscopy for the surgical treatment \nof endometriosis. While many advocate for a reduction in \nthe number of laparoscopies in favor of a clinical diagnosis \nand presumptive management of disease, others maintain \nthat laparoscopy is a valuable tool that should remain \nprominent in the diagnosis of people with endometriosis.\nDeclaration of interest\nThe\b authors\b declare\b that\b there\b is\b no\b conflict\b of\b interest\b that\b could\b be\b\nperceived as prejudicing the impartiality of this commentary.\nFunding\nThis\bwork\bdid\bnot\breceive\bany\bspecific\bgrant\bfrom\bany\bfunding\bagency\bin\bthe\b\npublic,\bcommercial\bor\bnot-for-profit\bsector.\nAuthor contribution statement\nBoth authors jointly conceived of the concepts for this manuscript, \ncontributed\bequally\bto\bthe\bwritten\bdocument,\band\bjointly\bapproved\bthe\bfinal\b\nmanuscript for submission.\nThis work is licensed under a Creative Commons \nAttribution 4.0 International License.\nhttps://doi.org/10.1530/RAF-21-0097\n Downloaded from Bioscientifica.com at 06/07/2026 01:14:03PM\nvia Open Access. This work is licensed under a Creative Commons Attribution\n4.0 International License.\nhttp://creativecommons.org/licenses/by/4.0/\n\n\nW G Foster and M Leonardi Endometriosis\nC412:4\nReferences\nAgarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, \nMissmer SA, Singh SS & T aylor HS 2019 Clinical diagnosis \nof endometriosis: a call to action. American Journal of Obstetrics \nand Gynecology 220 354.e1–354.e12. (https://doi.org/10.1016/j.\najog.2018.12.039)\nAgarwal SK, Antunez-Flores O, Foster WG, Hermes A, \nGolshan S, Soliman AM, Arnold A & Luna R 2021 Real-world \ncharacteristics of women with endometriosis-related pain entering a \nmultidisciplinary endometriosis program. BMC Women’s Health 21 19. \n(https://doi.org/10.1 186/s12905-020-01 139-7)\nAppelman Y, van Rijn BB, T en Haaf ME, Boersma E & Peters SA \n2015 Sex differences in cardiovascular risk factors and disease \nprevention. Atherosclerosis 241 21 1–218. 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(https://doi.org/10.1002/ijgo.12521)\nReceived in final form 29 October 2021\nAccepted 5 November 2021\nAccepted Manuscript published online 5 November 2021\nThis work is licensed under a Creative Commons \nAttribution 4.0 International License.\nhttps://doi.org/10.1530/RAF-21-0097\nhttps://raf.bioscientifica.com © 2021 The authors\n\b Published\bby\bBioscientifica\bLtd Downloaded from Bioscientifica.com at 06/07/2026 01:14:03PM\nvia Open Access. This work is licensed under a Creative Commons Attribution\n4.0 International License.\nhttp://creativecommons.org/licenses/by/4.0/","source_license":"CC0","license_restricted":false}