A Proposed Platform for Phenotyping Endometriosis-Associated Pain: Unifying Peripheral and Central Pain Mechanisms

In: Current Obstetrics and Gynecology Reports · 2020 · vol. 9(3) , pp. 89–97 · doi:10.1007/s13669-020-00288-8 · W3031200642
article OA: closed CC0 ⤵ 7 in-corpus citations
Full text JSON View on OpenAlex View at publisher
AI-generated summary by claude@2026-06+body, 2026-06-12

This review identifies peripheral and central pain factors in endometriosis and proposes a four-type pain classification based on lesion characteristics, comorbidities, and central sensitization.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

AI-generated deep summary by claude@2026-06, 2026-06-06 · read from full text

This paper is a review proposing a platform for phenotyping endometriosis-associated pain by unifying peripheral and central pain mechanisms. It synthesizes evidence that pain development and persistence reflect an interplay between peripheral factors (lesion anatomy such as superficial/deep/ovarian features, local inflammation, neurogenesis and peripheral nerve sensitization, uterine factors including eutopic neuroinflammation with concurrent adenomyosis, and adjacent pelvic pain generators) and central factors (central nervous system/cross-organ sensitization, systemic pain conditions like fibromyalgia, and psychosocial comorbidities). The authors propose four endometriosis pain sub-types—type I (lesion-related), type II (comorbidity-driven), type III (central), and type IV (mixed)—and explicitly note that the classification requires further study and validation. This paper is centrally about endometriosis — it proposes a peripheral-to-central phenotyping and classification framework for endometriosis-associated pain.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Full text 14,332 characters · extracted from oa-doi-fallback · 2 sections · click to expand

Abstract

Purpose of the Review Endometriosis is defined by a finding of ectopic endometrial glands/stroma, and is characterized by a wide variability in pain symptoms. The goal of this review is to identify peripheral to central factors that can modulate pain output in a given patient with endometriosis. Based on this constellation of factors, we propose a pain classification for endometriosis. Recent Findings The development and persistence of endometriosis-associated pain is influenced by a complex interplay between local factors that then interact with central variables. Starting peripherally, endometriosis anatomic characteristics include anatomic sub-type (superficial, deep, ovarian) and location/depth/amount of disease. Other peripheral factors involve local inflammation, neurogenesis, and sensitization of peripheral nerve cells around endometriosis glands/stroma. Uterine factors are eutopic endometrial neuroinflammation and concurrent adenomyosis. Other anatomic factors include risk factors for pain such as a history of PID or previous surgeries. Beyond the gynecologic organs, adjacent pelvic structures such as musculoskeletal, gastrointestinal, and urological can serve as pain generators. Finally, centrally, there is central nervous system and/or cross-organ sensitization, presence of systemic pain conditions such as fibromyalgia, and psychosocial comorbidities. Summary Pain can be modulated by a combination of peripheral and central mechanisms, resulting in varied clinical presentations, even in those with the same endometriosis anatomic characteristics. Based on this complex interplay of features with peripheral and central factors, we propose four sub-types of endometriosis pain: type I (pain primarily due to endometriosis lesions and associated inflammation/neurogenesis), type II (pain primarily due to comorbid condition), type III (central pain), and type IV (combination of types I–III). Clinically, this classification could help identify which patients may not respond to conventional gynecologic management alone. In research studies, the classification could allow for patient sample stratification, since diagnostic markers or treatments may only be effective in certain sub-types. This phenotypic classification of endometriosis-associated pain requires further study and validation. Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance Montanari E, Dauser B, Keckstein J, Kirchner E, Nemeth Z, Hudelist G. Association between disease extent and pain symptoms in patients with deep infiltrating endometriosis. Reprod BioMed Online. 2019;39:845–51. Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22:266–71. Yosef A, Allaire C, Williams C, et al. Multifactorial contributors to the severity of chronic pelvic pain in women. Am J Obstet Gynecol. 2016;215:760 e1–e14. •• Horne AW, Daniels J, Hummelshoj L, Cox E, Cooper KG. Surgical removal of superficial peritoneal endometriosis for managing women with chronic pelvic pain: time for a rethink? BJOG. 2019;126:1414–6 Re-think of the relationship between superficial endometriosis and pain. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, et al. Endometriosis. Endo Reviews. 2019;40:1048–79. Morotti M, Vincent K, Brawn J, Zondervan KT, Becker CM. Peripheral changes in endometriosis-associated pain. Hum Reprod Update. 2014;20:717–36. McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015;26:1–10. Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015;22:1053–9. Hogg C, Horne AW, Greaves E. Endometriosis-associated macrophages: origin, phenotype, and function. Front Endocrinol (Lausanne). 2020;11:7. Fraser IS. Mysteries of endometriosis pain: Chien-Tien Hsu memorial lecture 2009. J Obstet Gynaecol Res. 2010;36:1–10. Williams CHL, Yosef A, Alotaibi F, Allaire C, Brotto L, Fraser IS, et al. Nerve bundles and deep dyspareunia in endometriosis. Reprod Sci. 2016;23(7):892–901. Peng B, Zhan H, Alotaibi F, Alkusayer GM, Bedaiwy MA, Yong PJ. Nerve growth factor is associated with sexual pain in women with endometriosis. Reprod Sci. 2018;25:540–9. McKinnon B, Bersinger NA, Wotzkow C, Mueller MD. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertil Steril. 2012;97:373–80. Mechsner S, Kaiser A, Kopf A, Gericke C, Ebert A, Bartley J. A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions. Fertil Steril. 2009;92:1856–61. Tulandi T, Felemban A, Chen MF. Nerve fibers and histopathology of endometriosis-harboring peritoneum. J Am Assoc Gynecol Laparoscopists. 2001;8:95–8. Barcena de Arellano ML, Arnold J, Lang H, Vercellino GF, Chiantera V, Schneider A, et al. Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine. 2013;62:253–61. Kajitani T, Maruyama T, Asada H, Uchida H, Oda H, Uchida S, et al. Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Endocr J. 2013;60:1155–64. •• Coxon L, Horne AW, Vincent K. Pathophysiology of endometriosis-associated pain: a review of pelvic and central nervous system mechanisms. Best Pract Res Clin Obstet Gynaecol. 2018;51:53–67 Recent review of pain mechanisms in endometriosis. Zakhari A, et al. Keep your landmarks close and the hypogastric nerve closer: an approach to nerve-sparing endometriosis surgery. J Minim Invasive Gynecol. 2019;3. Al-Jefout M, Dezarnaulds G, Cooper M, et al. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod. 2009;24:3019–24. Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79. Leyendecker G, et al. Uterine peristaltic activity and the development of endometriosis. Ann N Y Acad Sci. 2004;1034:338–55. Hellman KM, Kuhn CS, Tu FF, et al. Cine MRI during spontaneous cramps in women with menstrual pain. Am J Obstet Gynecol. 2018;218:506 e1–8. Tai FW, Chang CY, Chiang JH, Lin WC, Wan L. Association of pelvic inflammatory disease with risk of endometriosis: a nationwide cohort study involving 141,460 individuals. J Clin Med. 2018;7. Stratton P, Khachikyan I, Sinaii N, Ortiz R, Shah J. Association of chronic pelvic pain and endometriosis with signs of sensitization and myofascial pain. Obstet Gynecol. 2015;125:719–28. Yong PJ, Mui J, Allaire C, Williams C. Pelvic floor tenderness in the etiology of superficial dyspareunia. J Obstet Gynaecol Canada. 2014;36(11):1002–9. Orr NL, Noga H, Williams C, Allaire C, Bedaiwy MA, Lisonkova S, et al. Deep dyspareunia in endometriosis: role of the bladder and pelvic floor. J Sex Med. 2018;15:1158–66. Vleeming A, Albert HB, Ostgaard HC, Sturesson B, Stuge B. European guidelines for the diagnosis and treatment of pelvic girdle pain. Eur Spine J. 2008;17:794–819. •• Hellman KM, Datta A, Steiner ND, et al. Identification of experimental bladder sensitivity among dysmenorrhea sufferers. Am J Obstet Gynecol. 2018;219:84 e1–8 Identification of pain with bladder filling in some women with dysmenorrhea. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308:1587–9. Lee CE, Yong PJ, Williams C, Allaire C. Factors associated with severity of irritable bowel syndrome symptoms in patients with endometriosis. J Obstet Gynaecol Can. 2018;40:158–64. Roman H, Bubenheim M, Huet E, Bridoux V, Zacharopoulou C, Daraï E, et al. Conservative surgery versus colorectal resection in deep endometriosis infiltrating the rectum: a randomized trial. Hum Reprod. 2018;33:47–57. Bao C, Noga H, Allaire C, Williams C, Bedaiwy MA, Sadownik LA, et al. Provoked vestibulodynia in women with pelvic pain. Sex Med. 2019;7:227–34. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20:737–47. As-Sanie S, Harris RE, Harte SE, Tu FF, Neshewat G, Clauw DJ. Increased pressure pain sensitivity in women with chronic pelvic pain. Obstet Gynecol. 2013;122:1047–55. As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys A, et al. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain. 2012;153:1006–14. As-Sanie S, Kim J, Schmidt-Wilcke T, Sundgren PC, Clauw DJ, Napadow V, et al. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J Pain. 2016;17:1–13. Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M, et al. The immunopathophysiology of endometriosis. Trends Mol Med. 2018;24:748–62. Kaya S, Hermans L, Willems T, Roussel N, Meeus M. Central sensitization in urogynecological chronic pelvic pain: a systematic literature review. Pain physician. 2013;16:291–308. •• Allaire C, Williams C, Bodmer-Roy S, et al. Chronic pelvic pain in an interdisciplinary setting: 1-year prospective cohort. Am J Obstet Gynecol. 2018;218:114 e1–e12 An interdisciplinary approach to pelvic pain is associated with improvements in pain and quality-of-life, and reductions in health care utilization. Jarrell J, Ross S, Robert M, et al. Prediction of postoperative pain after gynecologic laparoscopy for nonacute pelvic pain. Am J Obstet Gynecol. 2014;211:360 e1–8. Martin CE, Johnson E, Wechter ME, Leserman J, Zolnoun DA. Catastrophizing: a predictor of persistent pain among women with endometriosis at 1 year. Hum Reprod. 2011;26:3078–84. Carey ET, Martin CE, Siedhoff MT, Bair ED, As-Sanie S. Biopsychosocial correlates of persistent postsurgical pain in women with endometriosis. Int J Gynaecol Obstet. 2014;124:169–73. Weijenborg PT, Ter Kuile MM, Gopie JP, Spinhoven P. Predictors of outcome in a cohort of women with chronic pelvic pain - a follow-up study. Eur J Pain. 2009;13:769–75. Yong PJ, Williams C, Yosef A, Wong F, Bedaiwy MA, Lisonkova S, et al. Anatomic sites and associated clinical factors for deep dyspareunia. Sex Med. 2017;5:e184–e95. Williams C, Long AJ, Noga H, Allaire C, Bedaiwy MA, Lisonkova S, et al. East and south east Asian ethnicity and moderate-to-severe endometriosis. J Minim Invasive Gynecol. 2019;26:507–15. Zondervan KT, et al. Beyond endometriosis genome-wide association study: from genomics to phenomics to the patient. Semin Reprod Med. 2016;34(4):242–54. As-Sanie S, Black R, Giudice LC, Gray Valbrun T, Gupta J, Jones B, et al. Assessing research gaps and unmet needs in endometriosis. Am J Obstet Gynecol. 2019;221:86–94. Arion K, Aksoy T, Allaire C, Noga H, Williams C, Bedaiwy MA, et al. Prediction of pouch of Douglas obliteration: point-of-care ultrasound versus pelvic examination. J Minim Invasive Gynecol. 2019;26:928–34. Guerriero S, Condous G, van den Bosch T, Valentin L, Leone FPG, van Schoubroeck D, et al. Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol. 2016;48:318–32. Yong PJ, Sutton C, Suen M, Williams C. Endovaginal ultrasound-assisted pain mapping in endometriosis and chronic pelvic pain. J Obstet Gynaecol. 2013;33:715–9. Tu FF, As-Sanie S. A modest proposal to investigate chronic uterine pain. Br J Obstet Gynaecol. 2017;124:182–4. Mui J, Allaire C, Williams C, Yong PJ. Abdominal wall pain in women with chronic pelvic pain. J Obstet Gynaecol Can. 2016;38:154–9. Hanno PM, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, FitzGerald MP, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol. 2011;185:2162–70. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology. 2016. Bornstein J, Goldstein AT, Stockdale CK, Bergeron S, Pukall C, Zolnoun D, et al. 2015 ISSVD, ISSWSH and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia. Obstet Gynecol. 2016;127:745–5. Nasr-Esfahani M, Jarrell J. Cotton-tipped applicator test: validity and reliability in chronic pelvic pain. Am J Obstet Gynecol. 2013;208:52 e1–5. Orr NLWK, Noga H, Allaire C, Williams C, Bedaiwy MA, Albert A, et al. Phenotyping sexual pain in endometriosis using the central sensitization inventory. J Sex Med. in press. As-Sanie S, Till SR, Mowers EL, Lim CS, Skinner BD, Fritsch L, et al. Opioid prescribing patterns, patient use, and postoperative pain after hysterectomy for benign indications. Obstet Gynecol. 2017;130:1261–8. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152:S2–15. Yong PJ. Deep dyspareunia in endometriosis: a proposed framework based on pain mechanisms and genito-pelvic pain penetration disorder. Sex Med Rev. 2017;5:495–507. Author information Authors and Affiliations Corresponding author Ethics declarations Conflict of Interest Dr. Yong and Dr. Williams have nothing to disclose. Dr. Bedaiwy reports personal fees from Abbvie, grants and personal fees from Allergan, outside the submitted work. Dr. Allaire reports personal fees from Abbvie, personal fees from Allergan, outside the submitted work. Human and Animal Rights This article does not contain any studies with human or animal subjects performed by any of the authors. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This article is part of the Topical Collection on Endometriosis Rights and permissions About this article Cite this article Yong, P.J., Williams, C., Bedaiwy, M.A. et al. A Proposed Platform for Phenotyping Endometriosis-Associated Pain: Unifying Peripheral and Central Pain Mechanisms. Curr Obstet Gynecol Rep 9, 89–97 (2020). https://doi.org/10.1007/s13669-020-00288-8 Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s13669-020-00288-8

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (61)

Cited by (7)

Source provenance

openalex
last seen: 2026-06-10T17:14:06.276822+00:00
License: CC0 · commercial use OK