{"paper_id":"7290b1cf-5a23-47b0-970e-fd01f87eb867","body_text":"Comment\nhttps://doi.org/10.1038/s41467-023-43913-9\nTime for global health policy and research\nleaders to prioritize endometriosis\nLinda C. Giudice, Andrew W. Horne & Stacey A. Missmer\n Check for updates\nEndometriosis is an incurable, under-diagnosed,\nsystemic inflammatory disease affecting millions\nworld-wide. Common symptoms include life-\nimpacting pain, gastrointestinal/urinary symp-\ntoms, excessive fatigue, and infertility. Global\npublic health policies are urgently needed to\npromote awareness, implement multi-\ndisciplinary care, and fund research for aetiol-\nogy, biomarker discovery, and effective\ntherapies for symptoms associated with\nendometriosis.\nPatient and public health impact of underinvestment in\nendometriosis\nDefined by endometrium (uterine lining)-like tissue outside the uterus,\nendometriosis is a little known, common, hormone-dependent,\ninflammatory disorder currently diagnosed by surgical or radiologic\nvisualisation of disease\n1. While mainly associated with life-impacting\npelvic pain, painful menstruation and sexual intercourse, infertility,\nfatigue, and depression, those affected also have higher risk of non-\nreproductive sequelae, including high blood pressure, cardiovascular\ndisease, autoimmune conditions, gastrointestinal and urologic symp-\ntoms, multifocal pain, migraines, and ovarian and breast cancer\n1\n(Fig. 1). Endometriosis affects ~10% of persons with a uterus, commonly\nstriking teens and persisting across the reproductive life span (and\nsometimes beyond), greatly impacting personal relationships, educa-\ntional and employment opportunities, and quality of life\n2,3.R i s ko f\ndeveloping disease is ~50% genetic, with no speci fic “endometriosis\ngene” or consistently identified environmental triggers1.\nReliance on surgery and marginal advances in medical therapies\nfor symptom relief maintain delayed diagnosis and insufficient care for\nmany1. Moreover, menstrual stigma, pain in women, sexism, and\nracism are impediments globally for life-improving care 3,4.L a c ko f\nawareness and/or discomfort regarding menstrual health remains\nsurprisingly prevalent among healthcare providers\n3,4.\nClinical specialties are commonly siloed, which diminishes\nrecognizing and addressing endometriosis in clinical practices and\nspecialist care outside gynecology\n1,3. Siloed structures also negatively\nimpact awareness and applying cutting-edge technologies to multi-\ndisciplinary scientific discovery of causes, diagnostics, and treatments\nfor endometriosis\n3–5. Impediments to determining aetiology and\npathophysiology, classifying clinically-relevant subphenotypes, diag-\nnosing, and treating endometriosis include socio-cultural factors that\ncontinue its obscurity among practitioners and the public\n1,3,4.H e r ew e\nsummarize challenges in endometriosis care and advancing research\nin this space.\nA primary hypothesis for pelvic endometriosis establishment is\nthrough transplantation of endometrial tissue re fluxed through the\noviducts during menses, attaching to and invading pelvic organs, and\neliciting a profound in flammatory response and fibrosis\n1.T h i si s\nreplicated in experimental rodent models that utilize seeding with\nheterologous or homologous endometriotic tissue 7.H o w e v e r ,t h i s\nparadigm is insuf ficient, as nearly all persons with uteri experience\n“retrograde menstruation” and rodents do not menstruate. Thus\ngenetic, epigenetic, hormonal, immunologic factors, endometrial\nstem cells, and coelomic metaplasia, have been implicated in estab-\nlishment/survival of lesions (with pathway-informative somatic muta-\ntions)—complementing the theory that retrograde menstruation plays\na causal role\n1,4. While mechanisms underlying this complex patho-\nphysiology are slowly being elucidated, a comprehensive under-\nstanding of disease origins is wanting. This has stalled comprehensive\nanimal models with disease fidelity—hampering research on endome-\ntriosis overall\n6.\nMechanisms underlying endometriosis-associated pain are\ncomplex7. Key to establishing lesions and activating peripheral pain\npathways are new blood vessels and nerve sprouting\n(neuroangiogenesis)\n7. Also, in the central nervous system, brain\nvolume and regional biochemical alterations accompany chronic\nendometriosis-related pain\n7. Endometriosis is also associated with\ninfertility—attributed to scarred Fallopian tubes, diminished egg\nquality, and/or disrupted hormone signaling within the uterus 1,3,4.\nImproved understanding of endometriosis pathogenesis and its com-\nplex and heterogenous manifestations and physiologic impacts are\nessential to develop improved diagnostics and patient-centred\ntherapies.\nHeterogeneous presentation of endometriosis impedes\ndiagnosis and treatment\nMost pelvic endometriosis comprises three subtypes: super ficial\nperitoneal, ovarian cysts ( “endometrioma”), and deep disease 1.\nSymptom manifestation and severity vary, and underdiagnosis is\ncommon due to erroneous symptom normalization and overlap with\nother diseases\n8. Recently, re fined imaging techniques identify, with\nhigh accuracy, ovarian and deep disease, but reliance on surgical\nvisualisation for the most common superficial peritoneal lesions con-\ntinues to impede timely diagnosis 3,4. Surgery or imaging requires\naccess to healthcare services, which varies signi ficantly across socio-\neconomic and racial/ethnically underserved groups and\ngeographies\n4,9. Average diagnostic delay is 7 years after symptom\nonset, with delays >10 years not uncommon4,9. There remains no reli-\nable non-invasive biomarker of any endometriosis subtype4.\nTreatment of pain symptoms falls broadly into surgical removal of\ndisease and associated adhesions and hormonal suppressive therapies,\nnature communications         (2023) 14:8028 | 1\n1234567890():,;\n1234567890():,;\n\nincluding combined oral contraceptive steroids, progestins, gonado-\ntropin releasing hormone analogues, androgens and aromatase\ninhibitors10. Medical therapies that decrease oestrogen (or counter\noestrogen action) are prescribed, because steroids play a key role in\nthe pathophysiology of endometriosis\n1.U n f o r t u n a t e l y ,b o t ha p p r o a -\nches are suboptimal. Surgery is associated with recurrence rates up to\n50% within 5 years, and contraceptive hormone treatments often have\nunacceptable side effects and are counterproductive to fertility\ngoals\n10.G e o g r a p h i ca n dfinancial barriers to accessing treatment from\nendometriosis-trained healthcare providers are common9. Surveys of\npatients consistently highlight symptom relief and improved medical\ntherapies that do not limit fertility as a top priority for research\n3. His-\ntorically, pharmaceutical companies were reluctant to develop new\ndrugs for endometriosis, and focus has been on variations of hormo-\nnal, anti-in flammatory, or repurposed therapies\n11,l a c k i n gr e v o l u -\ntionary impact. While novel treatment discovery is essential, clinical\ntrials for endometriosis have been plagued by widespread variations in\noutcome reporting, and only a fraction of completed trials is\npublished\n11.\nEmerging chronic pelvic pain-focused therapies that include\nconsiderations of neuropathic and nociceptive pathways have not\nbeen adequately studied\n12. Those with persistent/recurrent pain have a\nhigh rate of hysterectomy12 which does not eliminate pain recurrence\nand may heighten risks for multiple conditions later in life1,10.F u r t h e r ,\ncommonly reported life-impacting concerns including fatigue and\nimpaired sexual functioning have yet to be targeted for treatment\namong patients with endometriosis. A critical impediment to dis-\ncovery of novel diagnostics and treatments and personalized approa-\nches is the lack of a prognostically correlated classi fication of the\nhighly heterogenous presentation of endometriosis lesion types and\nsymptoms, which includes variation and evolution within patients\nacross the life-course\n3,4.\nEndometriosis funding landscape and the socioeconomic\ncost of underinvestment\nThe first economic study (2011) revealed the average cost of endo-\nmetriosis was ~ €9579/woman/year ( €6298 lost work-productivity,\n€3113 direct health care costs) —similar to diabetes, Crohn ’sd i s e a s e ,\na n dr h e u m a t o i da r t h r i t i s13. However, unlike these well-known diseases\nwith similar socioeconomic impact and burden but considerably lower\nprevalence in the general population, there is relatively little invest-\nment in research into causes and disease mechanisms of\nendometriosis\n5. Recent governmental attention has included an\nincrease in NIH funding for endometriosis research to $16 M (0.04% of\nthe total NIH budget) for the year 2022 ($2/person with endometriosis/\nyear), while Crohn ’s disease received $90 M ($130/person with\nCrohn’s/year)\n14. Data consistently demonstrate that female-speci fic\nconditions are disproportionately underfunded 5. Further, female\nreproductive conditions are largely absent from open access reference\ndatabases on which much of advanced biomolecular data science\nrelies (e.g., ENCODE, NIH Roadmap epigenomics, GTEx, TissueNexus),\nimpeding novel discovery, although recent endometrium and endo-\nmetriosis single-cell transcriptomic data should soon appear in the\nHuman Cell Atlas\n4.\nCommitments to endometriosis research and care and mov-\ning forward\nDespite identification of endometriosis as a chronic inflammatory pain\ncondition with multi-systemic symptoms and co-morbidities 1,8,a sa\ndisease associated with menstruation and pelvic pain, it is still gen-\nerally considered a gynaecologic disorder. This reductive concept has\nresulted in lowered healthcare system and research prioritization,\nlimited integration, and impeded translation of rapidly developing\nscientific, multi-omic, genetic, bioengineering, and clinical discoveries\nin pain and in flammation. Their application would hasten identifying\nFig. 1 | Endometriosis is a global disease needing global solutions.Basic research\nis key to understanding its causes and molecular and genomic underpinnings,\nleading to novel diagnostics and therapeutics to alleviate symptoms and ultimately\ndiscover a cure. Education of professional and lay communities and leaders\nthroughout the world about endometriosis and its intersection with social deter-\nminants of health are key components to improve the lives of those affected.\nMoreover, multidisciplinary care is essential for holistic management of this com-\nplex and multi-dimensional disorder.\nComment\nnature communications         (2023) 14:8028 | 2\n\nshared and unique features of endometriosis, leading to novel ther-\napeutics and multi-disciplinary approaches to symptom management.\nEssential to improving diagnosis and care for endometriosis\npatients is ensuring they are heard and believed when expressing\ntheir symptoms to themselves, their personal support networks, and\nespecially to healthcare providers\n4,10. The 2021 WHO Endometriosis\nFact Sheet ( https://www.who.int/news-room/fact-sheets/detail/\nendometriosis) is a welcome leap forward to increase awareness\nglobally. We posit that education and improved awareness including\nmenstrual wellbeing curricula within schools for students of all gender\nidentities could overcome menstruation taboos, ensure under-\nstanding of a ‘normal’ period, and when to seek help for distressing\nsymptoms. Improved medical education regarding menstruation and\nendometriosis signs and symptoms could be ensured with thoughtful\ntargets, e.g., including questions about menstrual health and non-\nmalignant gynaecologic conditions on medical training board exam-\ninations, and larger scale initiatives such as revision of didactic\nteaching and medical curricula to prioritize menstrual health as critical\nto patient care.\nOnce diagnosed, individuals with endometriosis require perso-\nnalised, multimodal, interdisciplinary treatment across the life-course\nto meet challenges of the evolving disease and changing patient\npriorities. First proposed in 2006, this novel care approach is optimally\ndelivered through specialist centres comprised of integrated services\nincluding gynaecologists, endometriosis specialist nurses, and experts\nin imaging, pain medicine, psychology, physiotherapy, fertility, col-\norectal surgery, urology, and gastroenterology\n15. Whilst specialist\ncentres have been successfully implemented in the UK and a few\nEuropean countries (e.g., Denmark, Germany, France), this is not\nstandard of care worldwide. Importantly, care delivery models incor-\nporating mobile and digital technologies, and including primary care\nproviders, specialists, pharmacy-based, community-based, and risk-\nprevention approaches, offer great opportunities and need develop-\nment and investment\n4. For example, the Australian National Action\nPlan for Endometriosis launched in 2018 with $58 M additional funding\nin 2022 supports a 4-year plan to fund research and establish specialist\nendometriosis and pelvic pain clinics in every state and territory.\nRestructuring similar models globally could fulfilp e r s o n a l i z e dc a r ei n\nall regions.\nAs delayed or undiagnosed endometriosis leads to compromised\nhealth, promoting awareness, improving access to care, and imple-\nmenting multidisciplinary care paradigms are urgently needed in glo-\nbal public health policies. Equally urgent and important are prioritizing\nand committing resources to support fundamental research and bio-\nmarker discovery to shorten the protracted time to diagnosis and\nprovide effective, long-term therapies for this chronic and debilitating\ndisorder to the benefit of millions world-wide.\nLinda C. Giudice 1 , Andrew W. Horne 2 &\nStacey A. Missmer 3,4\n1Distinguished Professor, Center for Reproductive Sciences, Center for\nReproductive Health, Department of Obstetrics, Gynecology and\nReproductive Sciences, University of California, San Francisco, San\nFrancisco, CA, USA.\n2Professor of Gynaecology and Reproductive\nSciences, EXPPECT Edinburgh and Centre for Reproductive Health,\nUniversity of Edinburgh, Edinburgh, UK.\n3Professor of Obstetrics,\nGynecology, and Reproductive Biology, Michigan State University,\nGrand Rapids, MI, USA.\n4Adjunct Professor of Epidemiology, Harvard\nT.H. Chan School of Public Health, Boston, MA, USA.\ne-mail: Linda.Giudice@ucsf.edu\nReceived: 16 November 2022; Accepted: 22 November 2023;\nReferences\n1. Saunders, P. T. K. & Horne, A. W. Endometriosis: etiology, pathobiology, and therapeutic\nprospects. Cell 184,2 8 0 7–2824 (2021).\n2. Missmer, S. A. et al. Impact of endometriosis on life-course potential: a narrative review. Int\nJ. Gen. Med 14,9 –25 (2021).\n3. As-Sanie, S. et al. Assessing research gaps and unmet needs in endometriosis. Am. J.\nObstet. Gynecol.221,8 6–94 (2019).\n4. Giudice, L. C., Oskotsky, T. T., Falako, S., Opoku-Anane, J. & Sirota, M. Endometriosis in the\nera of precision medicine and impact on sexual and reproductive health across the lifespan\nand in diverse populations.FASEB J. 37,e 2 3 1 3 0( 2 0 2 3 ) .\n5. Mirin, A. Gender disparity in the funding of diseases by the U.S. National Institutes of health.\nJ. Women’s Health (Larchmt.) 30,9 5 6–963 (2021).\n6. Simitsidellis, I., Gibson, D. A. & Saunders, P. T. K. Animal models of endometriosis: Repli-\ncating the aetiology and symptoms of the human disorder.Best. Pr. Res Clin. Endocrinol.\nMetab. 32,2 5 7–269 (2018).\n7. Coxon, L., Horne, A. W. & Vincent, K. Pathophysiology of endometriosis-associated pain: a\nreview of pelvic and central nervous system mechanisms.Best. Pr. Res Clin. Obstet.\nGynaecol. 51,5 3–67 (2018).\n8. Agarwal, S. K. et al. Clinical diagnosis of endometriosis: a call to action. Am. J. Obstet.\nGynecol. 220,3 5 4 . e 3 5 1–354.e312 (2019).\n9. Davenport, S., Smith, D. & Green, D. J. Barriers to a timely diagnosis of endometriosis: a\nqualitative systematic review.Obstet. Gynecol.142,5 7 1–583 (2023). 1Epub 2023 Jul 13.\nPMID: 37441792.\n10. Becker, C. et al. ESHRE guideline: endometriosis. Hum. Reprod. Open 2022,1 –26 (2022).\n11. Guo, S. W. & Groothuis, P. G. Is it time for a paradigm shift in drug research and development\nin endometriosis/adenomyosis?Hum. Reprod. Update 24,5 7 7–598 (2018).\n12. Lamvu, G., Carrillo, J., Ouyang, C. & Rapkin, A. Chronic pelvic pain in women: a review.JAMA\n325, 2381–2391 (2021).\n13. Simoens, S. et al. The burden of endometriosis: costs and quality of life of women with\nendometriosis and treated in referral centres.Hum. Reprod. 27,1 2 9 2–1299 (2012).\n14. Ellis, K., Munro, D. & Clarke, J. Endometriosis is undervalued. Front Glob. Women’s Health 3,\n902371, https://doi.org/10.3389/fgwh.2022.902371\n(2022).\n15. D ’Hooghe, T. & Hummelshoj, L. Multi-disciplinary centres/networks of excellence for\nendometriosis management and research: a proposal.Hum. Reprod.21, 2743–2748 (2006).\nAcknowledgements\nThe authors thank Kevin Kuan, University of Edinburgh, for Fig.1 graphic design and critical\ncontent editing.\nAuthor contributions\nL.C.G. conceived the topic and wrote the initial draft, which was extensively revised with A.W.H.\nand S.A.M.. L.C.G. contributed much of the scientific information about endometriosis patho-\ngenesis and pathophysiology. A.W.H. contributed key concepts about public health relevance\nand endometriosis clinical symptoms, clinical care, and health disparities. S.A.M. contributed\nkey concepts in the epidemiology of endometriosis, status of funding for research and multi-\ndisciplinary care models. L.C.G., A.W.H., and S.A.M. each provided references throughout the\nmanuscript and in areas of their expertise and assured accuracy of citations and worked as a\nteam on revising the manuscript resulting in its final form.\nCompeting interests\nL.C.G. is funded by the National Institutes of Health P01 HD106414, “UCSF Stanford Endo-\nmetriosis Center for Discovery, Innovation, Training and Community Engagement ”. She is co-\nauthor of patent filed by the Regents of the University of California, San Francisco, U.S.\nApplication Serial No. 63/149,022, “Endometriosis-Related Methods and Compositions ”.S h e\nis past-President of the World Endometriosis Society and the American Society for Repro-\nductive Medicine, and is a consultant for Celmatix, Myovant Sciences, and Gesynta Pharma.\nAH’s institution (University of Edinburgh) has received payment for consultancy and grant\nfunding from Roche Diagnostics to assist in the early development of a possible blood\ndiagnostic biomarker for endometriosis. A.W.H. ’s institution has received payment for con-\nsultancy fees from Gesynta and Joii. A.W.H. has received payment for a presentation from\nTheramex. A.W.H. ’s instutution has received grant funding from the MRC, NIHR, CSO and\nWellbeing of Women for endometriosis research. A.W.H. is listed as a co-inventor on a UK\nPatent Application (No· 2217921·2). A.W.H. is President-elect of the World Endometriosis\nSociety and co-Editor in chief of Reproduction and Fertility. AH has been a member of the\nNICE and ESHRE Endometriosis Guideline Groups. AH is a Trustee and Medical Advisor to\nComment\nnature communications         (2023) 14:8028 | 3\n\nEndometriosis UK. S.A.M. receives research support from National Institutes of Health, USA\nDepartment of Defense, AbbVie, and Marriott Family Foundations. She is President of the\nWorld Endometriosis Society, the Field Chief Editor for Frontiers in Reproductive Health and\nhas served on advisory boards for AbbVie, Roche, and Abbott.\nAdditional information\nCorrespondenceand requests for materials should be addressed to Linda C. Giudice.\nPeer review informationNature Communicationsthanks Serdar E. Bulun and Sarah Hawkes, for\ntheir contribution to the peer review of this work.\nReprints and permissions informationis available at\nhttp://www.nature.com/reprints\nPublisher’sn o t eSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.\nOpen Access This article is licensed under a Creative Commons Attribution 4.0 International\nLicense, which permits use, sharing, adaptation, distribution and reproduction in any medium or\nformat, as long as you give appropriate credit to the original author(s) and the source, provide a\nlink to the Creative Commons licence, and indicate if changes were made. The images or other\nthird party material in this article are included in the article’s Creative Commons licence, unless\nindicated otherwise in a credit line to the material. 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