Pathogenesis of pain in endometriosis

DOI

https://dx.doi.org/10.18565/aig.2022.9.12-18

Timofeeva Yu.S., Marinkin I.О., Кuleshov V.M., Aidagulovа S.V.
Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk, Russia

The review analyzes foreign and Russian articles on theoretical issues of the pathogenesis of pain in endometriosis. The current concepts are that inflammation, neuroangiogenesis, and neurogenic inflammation, which underlie peripheral and central sensitization, as well as the advancing interorgan sensitization, are involved in the pathogenesis of pain in endometriosis. The review considers the molecular mechanisms underlying the above pathological phenomena causing deterioration in quality of life in patients with endometriosis in some cases even after surgical excision of heterotopias. By now, it has not been possible to identify endometriosis-specific pain; the disease can take both its asymptomatic course and its course with the only pain symptom of varying intensity, as well as with their combinations. The study of the pathogenesis of endometriosis is still relevant; there are many questions to be answered in order to improve quality of life in patients and to relieve the pain syndrome that is present in almost half of the cases of endometriosis.
Conclusion: The pathogenesis of pain in endometriosis includes the following components: a biochemical signal that is converted through activation of nociceptors into a nerve signal that is modulated at the spinal level and sent to the brain neurons with pain fixation. The nature of the pain syndrome largely depends on the prevalence of endometrioid heterotopias, the duration of the disease and the individual characteristics of the patients. The nature of pain syndrome largely depends on the prevalence of endometrioid heterotopias, the duration of the disease, and the individual characteristics of the patients.

endometriosis

pain

pathogenesis

inflammation

sensitization

Full text (in Russian)

Адамян Л.В., Куликов В.И., Андреева Е.Н. Эндометриозы. Руководство для врачей. М.: Медицина; 2006. 416с. [Adamyan L.V., Kulikov V.I., Andreeva E.N. Endometriosis: A guide for doctors. M.: Medicine, 2006. 416p. (in Russian)].
Сухих Г.Т., Адамян Л.В., Серов В.Н., Андреева Е.Н., Баранов И.И., Дубровина С.О., Козаченко А.В., Кулешов В.М., Подзолкова Н.М., Прилепская В.Н., Радзинский В.Е., Сонова М.М., Тихомиров А.Л., Уварова Е.В., Чернуха Г.Е., Ших Е.В., Ярмолинская М.И. Резолюция совещания экспертов на тему «Возможности персонализации гормональной терапии эндометриоза с использованием препарата дидрогестерон. Утверждение протокола многоцентрового открытого наблюдательного исследования по применению дидрогестерона для лечения эндометриоза в России (исследование «ОРХИДЕЯ»)». Проблемы репродукции. 2018; 24(5): 41-4. [Sukhikh G.T., Adamyan L.V., Serov V.N., Andreeva E.N., Baranov I.I., Dubrovina S.O., Kozachenko A.V., Kuleshov V.M., Podzolkova N.M., Prilepskaya V.N., Radzinsky V.E., Sonova M.M., Tikhomirov A.L., Uvarova E.V., Chernukha G.E., Shikh E.V., Yarmolinskaya M.I. Resolution of the expert meeting on the topic "Possibilities of personalization of hormonal therapy of endometriosis using the drug didrogesterone. Approval of the protocol of a multicenter open observational study on the use of didrogesterone for the treatment of endometriosis in Russia (the ORCHID study)". Problems of Reproduction. 2018; 24(5): 41-4. (in Russian)].
Маринкин И.О., Феофилов И.В. Успешное хирургическое лечение эндометриоза мочевого пузыря. Акушерство и гинекология. 2018; 4: 150-4. [Marinkin I.O., Feofilov I.V. Successful surgical treatment for bladder endometriosis. Obstetrics and Gynecology. 2018; 4: 150-4. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.4.150-154.
Bulun S.E., Yilmaz B.D., Sison C., Miyazaki K., Bernardi L., Liu S. et al. Endometriosis. Endocr. Rev. 2019; 40(4): 1048-79. https://dx.doi.org/10.1210/er.2018-00242.
Mechsner S. Endometriosis, an ongoing pain-step-by-step treatment. J. Clin. Med. 2022; 11(2): 467. https://dx.doi.org/10.3390/jcm11020467.
Ярмолинская М.И., Айламазян Э.К. Генитальный эндометриоз. Различные грани проблемы. М.: ЭКО-Вектор; 2017. [Yarmolinskaya M.I., Aylamazyan E.K. Genital endometriosis. Various facets of the problem. M.: ECO-Vector; 2017. (in Russian)].
Дубровина С.О., Берлим Ю.Д. Медикаментозное лечение боли, связанной с эндометриозом. Акушерство и гинекология. 2019; 2: 34-40. [Dubrovina S.O., Berlim Yu.D. Drug treatment for endometriosis-related pain. Obstetrics and Gynecology. 2019; 2: 34-40. (in Russian)]. https://dx.doi.org/10.18565/aig.2019.2.34-40.
Rogers P.A., Adamson G.D., Al-Jefout M., Becker C.M., D'Hooghe T.M., Dunselman G.A. et al.; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod. Sci. 2017; 24(2): 202-26. https://dx.doi.org/10.1177/1933719116654991.
Tempest N., Efstathiou E., Petros Z., Hapangama D.K. Laparoscopic outcomes after normal clinical and ultrasound findings in young women with chronic pelvic pain: A cross-sectional study. J. Clin. Med. 2020; 9(8): 2593.https://dx.doi.org/10.3390/jcm9082593.
Morotti M., Vincent K., Becker C.M. Mechanisms of pain in endometriosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017; 209: 8-13. https://dx.doi.org/10.1016/j.ejogrb.2016.07.497.
Patel B.G., Lenk E.E., Lebovic D.I., Shu Y., Yu J., Taylor R.N. Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways. Best Pract. Res. Clin. Obstet. Gynaecol. 2018; 50: 50-60. https://dx.doi.org/10.1016/j.bpobgyn.2018.01.006.
Zheng P., Zhang W., Leng J., Lang J. Research on central sensitization of endometriosis-associated pain: A systematic review of the literature. J. Pain Res. 2019; 12: 1447-56. https://dx.doi.org/10.2147/JPR.S197667. eCollection 2019.
Laux-Biehlmann A., d'Hooghe T., Zollner T.M. Menstruation pulls the trigger for inflammation and pain in endometriosis. Trends Pharmacol. Sci. 2015; 36(5):270-6. https://dx.doi.org/10.1016/j.tips.2015.03.004.
Halme J., Hammond M.G., Hulka J.F., Raj S.G., Talbert L.M. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet. Gynecol. 1984; 64(2): 151-4.
Nanda A., Thangapandi K., Banerjee P., Dutta M., Wangdi I., Sharma P. et al. Cytokines, angiogenesis, and extracellular matrix degradation are augmented by oxidative stress in endometriosis. Ann. Lab. Med. 2020; 40(5): 390-7.https://dx.doi.org/10.3343/alm.2020.40.5.390.
Wei Y., Liang Y., Lin H., Dai Y., Yao S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J. Neuroinflammation. 2020; 17(1): 80. https://dx.doi.org/10.1186/s12974-020-01752-1.
Scholl B., Bersinger N.A., Kuhn A., Mueller M.D. Correlation between symptoms of pain and peritoneal fluid inflammatory cytokine concentrations in endometriosis. Gynecol. Endocrinol. 2009; 25(11): 701-6.https://dx.doi.org/10.3109/09513590903159680.
Liang Y., Xie H., Wu J., Liu D., Yao S. Villainous role of estrogen in macrophage-nerve interaction in endometriosis. Reprod. Biol. Endocrinol. 2018; 16(1): 122. https://dx.doi.org/10.1186/s12958-018-0441-z.
Zhou J., Chern B.S.M., Barton-Smith P., Phoon J.W.L., Tan T.Y., Viardot-Foucault V. et al. Peritoneal fluid cytokines reveal new insights of endometriosis subphenotypes. Int. J. Mol. Sci. 2020; 21(10): 3515. https://dx.doi.org/10.3390/ijms21103515.
Grundy L., Erickson A., Brierley S.M. Visceral pain. Annu. Rev. Physiol. 2019; 81: 261-84. https://dx.doi.org/10.1146/annurev-physiol-020518-114525.
Vercellini P., Somigliana E., Viganò P., Abbiati A., Daguati R., Crosignani P.G. Endometriosis: current and future medical therapies. Best Pract. Res. Clin. Obstet. Gynaecol. 2008; 22(2): 275-306. https://dx.doi.org/10.1016/j.bpobgyn.2007.10.001.
Yosef A., Allaire C., Williams C., Ahmed A.G., Al-Hussaini T., Abdellah M.S. et al. Multifactorial contributors to the severity of chronic pelvic pain in women. Am. J. Obstet. Gynecol. 2016; 215(6): 760.e1-760.e14. https://dx.doi.org/10.1016/j.ajog.2016.07.023.
Miyashita M., Koga K., Takeuchi A., Makabe T., Taguchi A., Urata Y. et al. Expression of nerve injury-induced protein1 (Ninj1) in endometriosis. Reprod.. Sci. 2019; 26(8): 1105-10. https://dx.doi.org/10.1177/1933719118806395.
Skaper S.D. Neurotrophic factors: An overview. Methods Mol. Biol. 2018; 1727: 1-17. https://dx.doi.org/10.1007/978-1-4939-7571-6_1.
Tokushige N., Markham R., Russell P., Fraser I.S. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum. Reprod. 2006; 21(3): 782-7. https://dx.doi.org/10.1093/humrep/dei368.
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(10):1155-64.https://dx.doi.org/10.1507/endocrj.ej13-0027.
Tokushige N., Markham R., Russell P., Fraser I.S. Effects of hormonal treatment on nerve fibers in endometrium and myometrium in women with endometriosis. Fertil. Steril. 2008; 90(5): 1589-98. https://dx.doi.org/10.1016/j.fertnstert.2007.08.074.
Anaf V., El Nakadi I., De Moor V., Chapron C., Pistofidis G., Noel J.C. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol. Obstet. Invest. 2011; 71(2): 112-7. https://dx.doi.org/10.1159/000320750.
Pluchino N., Mamillapalli R., Wenger J.M., Ramyead L., Drakopoulos P., Tille J.C. et al. Estrogen receptor-alpha immunoreactivity predicts symptom severity and pain recurrence in deep endometriosis. Fertil. Steril. 2020; 113(6): 1224-31.e1. https://dx.doi.org/10.1016/j.fertnstert.2020.01.036.
Shimizu Y., Mita S., Takeuchi T., Notsu T., Mizuguchi K., Kyo S. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids. 2011; 76(1-2): 60-7. https://dx.doi.org/10.1016/j.steroids.2010.08.010.
Pavone M.E., Bulun S.E. Aromatase inhibitors for the treatment of endometriosis. Fertil. Steril. 2012; 98(6): 1370-9. https://dx.doi.org/10.1016/j.fertnstert.2012.08.053.
Patel B.G., Rudnicki M., Yu J., Shu Y., Taylor R.N. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet. Gynecol. Scand. 2017; 96(6): 623-32. https://dx.doi.org/10.1111/aogs.13156.
Reis F.M., Coutinho L.M., Vannuccini S., Batteux F., Chapron C., Petraglia F. Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure. Hum. Reprod. Update. 2020; 26(4): 565-85. https://dx.doi.org/ 10.1093/humupd/dmaa009.
Ярмолинская М.И., Хобец В.В., Ткаченко Н.Н., Толибова Г.Х., Траль Т.Г., Иванова А.О., Лысенко В.В. Значение окситоцина в патогенезе эндометриоз-ассоциированного болевого синдрома. Проблемы репродукции. 2021; 27(3): 36-43. [Yarmolinskaya M.I., Khobets V.V., Tkachenko N.N., Tolibova G.Kh., Tral T.G., Ivanova A.O., Lysenko V.V. Oxytocin significance in the pathogenesis of endometriosis-associated pain syndrome. Russian Journal of Human Reproduction. 2021; 27(3): 36 43. (in Russian)]. 10.17116/repro20212703136.
Forster R., Sarginson A., Velichkova A., Hogg C., Dorning A., Horne A.W. et al. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis. FASEB J. 2019; 33(10): 11210-22. https://dx.doi.org/10.1096/fj.201900797R.
Maddern J., Grundy L., Castro J., Brierley S.M. Pain in endometriosis. Front. Cell. Neurosci. 2020; 14: 590823. https://dx.doi.org/10.3389/fncel.2020.590823.
Zheng P., Jia S., Guo D., Chen S., Zhang W., Cheng A. et al. Central sensitization-related changes in brain function activity in a rat endometriosis-associated pain model. J. Pain Res. 2020; 13: 95-107. https://dx.doi.org/10.2147/JPR.S232313.
Iyengar S., Ossipov M.H., Johnson K.W. The role of calcitonin generelated peptide in peripheral and central pain mechanisms including migraine. Mol. Pain. 2017; 158: 543-59. https://dx.doi.org/10.1097/j.pain.0000000000000831.
Fuentes I.M., Christianson J.A. The influence of early life experience on visceral pain. Front. Syst. Neurosci. 2018; 12: 2. eCollection 2018.https://dx.doi.org/10.3389/fnsys.2018.00002.
Li J., Yao X., Zhang J. Treatment of pelvic cavity pain caused by endometriosis with excision of invaded sacrospinous ligament. Pak. J. Med. Sci. 2018; 34(5): 1200-3. https://dx.doi.org/12669/pjms.345.14830.
As-Sanie S., Kim J., Schmidt-Wilcke T., Sundgren P.C., Clauw D.J., Napadow V., Harris R.E. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J. Pain. 2016; 17(1): 1-13. https://dx.doi.org/10.1016/j.jpain.2015.09.008.
Matalliotaki C., Matalliotakis M., Zervou M.I., Trivli A., Matalliotakis I., Mavromatidis G. et al. Co-existence of endometriosis with 13 non-gynecological co-morbidities: Mutation analysis by whole exome sequencing. Mol. Med. Rep. 2018; 18(6): 5053-7. https://dx.doi.org/10.3892/mmr.2018.9521.
Fattori V., Franklin N.S., Gonzalez-Cano R., Peterse D., Ghalali A., Madrian E. et al. Nonsurgical mouse model of endometriosis-associated pain that responds to clinically active drugs. Pain. 2020; 161(6): 1321-31. https://dx.doi.org/10.1097/j.pain.0000000000001832.
Jobling P., Graham B.A., Brichta A.M., Callister R.J. Cervix stimulation evokes predominantly subthreshold synaptic responses in mouse thoracolumbar and lumbosacral superficial dorsal horn neurons. J. Sex. Med. 2010; 7(6): 2068-76. https://dx.doi.org/10.1111/j.1743-6109.2010.01768.x.
Broad L.M., Mogg A.J., Beattie R.E., Ogden A.M., Blanco M.J., Bleakman D. TRP channels as emerging targets for pain therapeutics. Expert Opin. Ther. Targets. 2009; 13(1): 69-81. https://dx.doi.org/10.1517/14728220802616620.
Ge P., Ren J., Harrington A.M., Grundy L., Castro J., Brierley S.M. et al. Linaclotide treatment reduces endometriosis-associated vaginal hyperalgesia and mechanical allodynia through viscerovisceral cross-talk. Pain. 2019; 160(11): 2566-79. https://dx.doi.org/10.1097/j.pain.0000000000001657.
Ruszała M., Dłuski D.F., Winkler I., Kotarski J., Rechberger T., Gogacz M. The state of health and the quality of life in women suffering from endometriosis. J. Clin. Med. 2022; 11(7): 2059. https://dx.doi.org/10.3390/jcm11072059.
de Freitas Fonseca M., Aragao L.C., Sessa F.V., Dutra de Resende J.A. Jr, Crispi C.P. Interrelationships among endometriosis-related pain symptoms and their effects on health-related quality of life: a sectional observational study. Obstet. Gynecol. Sci. 2018; 61(5): 605-14. https://dx.doi.org/10.5468/ogs.2018.61.5.605.
Yong P.J., Williams C., Yosef A., Wong F., Bedaiwy M.A., Lisonkova S., Allaire C. Anatomic sites and associated clinical factors for deep dyspareunia. Sex. Med. 2017; 5(3): e184-95. https://dx.doi.org/10.1016/j.esxm.2017.07.001.
Johnson N.P., Hummelshoj L., Adamson G.D., Keckstein J., Taylor H.S., Abrao M.S. et al.; For the World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum. Reprod. 2017; 32(2): 315-24. https://dx.doi.org/10.1093/humrep/dew293.
Тимофеева Ю.С., Волчек А.В., Кулешов В.М., Маринкин И.О., Айдагулова С.В. Анализ проявлений болевого синдрома при наружном генитальном эндометриозе I–III стадий. Акушерство и гинекология. 2019; 11: 129-35. [Timofeeva Yu.S., Volchek A.V., Kuleshov V.M., Marinkin I.O., Aidagulova S.V. Analysis of pain manifestations in extragenital endometriosis stage I–IV. Obstetrics and Gynecology. 2019; 11: 129-35. (in Russian)].https://dx.doi.org/10.18565/aig.2019.11.129-135.
Gruber T.M., Mechsner S. Pathogenesis of endometriosis: The origin of pain and subfertility. Cells. 2021; 10(6): 1381. https://dx.doi.org/10.3390/cells10061381.

Received 11.05.2022

Accepted 15.06.2022

Yulia S. Timofeeva, PhD, Assistant at the Obstetrics and Gynecology Department, NSMU, Ministry of Health of Russia, +7(906)194-77-55, dr.j.timofeeva@yandex.ru,
630091, Russia, Novosibirsk, Krasny prospect, 52.
Igor' O. Marinkin, Dr. Med. Sci., Professor, Head of the Obstetrics and Gynecology Department, Rector, NSMU, Ministry of Health of Russia,
+7(383)222-32-04, rector@ngmu.ru, 630091, Russia, Novosibirsk, Krasny prospect, 52.
Vitaliy M. Kuleshov, Dr. Med. Sci., Professor, Professor at the Obstetrics and Gynecology Department, NSMU, Ministry of Health of Russia,
+7(383)341-04-36, kuleshov_vm@mail.ru, 630091, Russia, Novosibirsk, Krasny prospect, 52
Svetlana V. Aidagulova, Dr. Biol. Sci., Professor, Head of the Laboratory of Cellular Biology and Fundamental Basis of Reproduction, Central scientific laboratory, NSMU, Ministry of Health of Russia, +7(913)909-22-51, asvetvlad@yandex.ru, https://dx.doi.org/0000-0001-7124-1969, 630091, Russia, Novosibirsk, Krasny prospect, 52.

Authors' contributions: Timofeeva Yu.S. – material collection and processing, writing the text; Marinkin I.О. – the concept of the investigation; Кuleshov V.M. – editing; Aidagulovа S.V. – material collection and processing, editing.
Conflicts of interest: The authors declare that there are no possible conflicts of interest.
Funding: The article has been prepared for publication without sponsorship.
For citation: Timofeeva Yu.S., Marinkin I.О., Кuleshov V.M., Aidagulovа S.V.
Pathogenesis of pain in endometriosis.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 9: 12-18 (in Russian)
http://dx.doi.org/10.18565/aig.2022.9.12-18

Pathogenesis of pain in endometriosis

Timofeeva Yu.S., Marinkin I.О., Кuleshov V.M., Aidagulovа S.V.

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