Journal of Shandong University (Health Sciences) ›› 2025, Vol. 63 ›› Issue (10): 1-7.doi: 10.6040/j.issn.1671-7554.0.2024.0943

• Special Topic on EndometriosisAssociated Pain •    

Mechanisms of pain in endometriosis

XU Ping, ZHANG Xinmei   

  1. Department of General Gynecology, Womens Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang, China
  • Published:2025-10-17

PDF (PC)

57

Abstract: Endometriosis is a chronic inflammatory disease commonly found in women of reproductive age, affecting multiple organ systems and being estrogen dependent. About 70%-80% of the patients present with pain as the main symptom. Depending on the location of the lesion, the pain is manifested as dysmenorrhea, dyspareunia, dysphasia, non-menstrual chronic pelvic pain, and so on. The mechanism of pain in endometriosis is complex and involves multiple interactive pathways, which has always been a research hotspot. Currently, the interaction between the hypothalamic-pituitary-gonadal axis, the autoimmune inflammatory system, and the peripheral/central nervous system is mainly considered, leading to sustained exacerbation of pain and hyperalgesia. Firstly, the hypothalamic-pituitary-gonadal axis releases estrogen to promote the growth of endometriosis lesions, which stimulates peripheral nociceptors to activate sensory nerve fibers. Then, the lesion triggers the secretion of inflammatory and pain inducing factors by macrophages and mast cells in the autoimmune system, leading to sensitization of the peripheral and central nervous systems. Finally, after activation of the nervous system, it releases factors such as substance P and calcitonin gene-related peptide to continuously activate the immune system, resulting in sustained sensitization, cross sensitization and increased pain.

Key words: Endometriosis, Pain, Estrogen, Inflammatory factors, Peripheral sensitization, Central nervous system sensitization

CLC Number: 

  • R711.71
[1] McNamara HC, Frawley HC, Donoghue JF, et al. Peripheral, central, and cross sensitization in endometriosis-associated pain and comorbid pain syndromes[J]. Front Reprod Health, 2021, 3: 729642. doi: 10.3389/frph.2021.729642
[2] Gruber TM, Mechsner S. Pathogenesis of endometriosis: the origin of pain and subfertility[J]. Cells, 2021, 10(6): 1381. doi: 10.3390/cells10061381
[3] Mechsner S. Endometriosis: an often unrecognized pain disorder[J]. Schmerz, 2016, 30(5): 477-490.
[4] Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion[J]. Fertil Steril, 2014, 101(4): 927-935.
[5] Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist[J]. N Engl J Med, 2017, 377(1): 28-40.
[6] Chen YX, Li T. Unveiling the mechanisms of pain in endometriosis: comprehensive analysis of inflammatory sensitization and therapeutic potential[J]. Int J Mol Sci, 2025, 26(4): 1770.
[7] Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications[J]. Hum Reprod Update, 2005, 11(6): 595-606.
[8] Zigmond RE, Echevarria FD. Macrophage biology in the peripheral nervous system after injury[J]. Prog Neurobiol, 2019, 173: 102-121. doi: 10.1016/j.pneurobio.2018.12.001
[9] Gheorghe RO, Grosu AV, Bica-Popi M, et al. The Yin/Yang balance of communication between sensory neurons and macrophages in traumatic peripheral neuropathic pain[J]. Int J Mol Sci, 2022, 23(20): 12389. doi: 10.3390/ijms232012389
[10] Lamceva J, Uljanovs R, Strumfa I. The main theories on the pathogenesis of endometriosis[J]. Int J Mol Sci, 2023, 24(5): 4254.
[11] Yao CC, Narumiya S. Prostaglandin-cytokine crosstalk in chronic inflammation[J]. Br J Pharmacol, 2019, 176(3): 337-354.
[12] Wei YJ, Liang YC, Lin HS, et al. Autonomic nervous system and inflammation interaction in endometriosis-associated pain[J]. J Neuroinflammation, 2020, 17(1): 80. doi: 10.1186/s12974-020-01752-1
[13] Machairiotis N, Vasilakaki S, Thomakos N. Inflammatory mediators and pain in endometriosis: a systematic review[J]. Biomedicines, 2021, 9(1): 54. doi: 10.3390/biomedicines9010054
[14] Binda MM, Donnez J, Dolmans MM. Targeting mast cells: a new way to treat endometriosis[J]. Expert Opin Ther Targets, 2017, 21(1): 67-75.
[15] Yu J, Francisco AMC, Patel BG, et al. IL-1β stimulates brain-derived neurotrophic factor production in eutopic endometriosis stromal cell cultures: a model for cytokine regulation of neuroangiogenesis[J]. Am J Pathol, 2018, 188(10): 2281-2292.
[16] Volpato LK, Horewicz VV, Bobinski F, et al. Annexin A1, FPR2/ALX, and inflammatory cytokine expression in peritoneal endometriosis[J]. J Reprod Immunol, 2018, 129: 30-35. doi: 10.1016/j.jri.2018.08.002
[17] Song SY, Jung YW, Shin W, et al. Endometriosis-related chronic pelvic pain[J]. Biomedicines, 2023, 11(10): 2868.
[18] Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain[J]. Annu Rev Neurosci, 2006, 29: 507-538. doi: 10.1146/annurev.neuro.29.051605.112929
[19] Clower L, Fleshman T, Geldenhuys WJ, et al. Targeting oxidative stress involved in endometriosis and its pain[J]. Biomolecules, 2022, 12(8): 1055. doi: 10.3390/biom12081055
[20] Zubrzycka A, Migdalska-Sk M, Jdrzejczyk S, et al. The expression of TGF-β1, SMAD3, ILK and miRNA-21 in the ectopic and eutopic endometrium of women with endometriosis[J]. Int J Mol Sci, 2023, 24(3): 2453.
[21] Arnold J, Barcena de Arellano ML, Rüster C, et al. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis[J]. Brain Behav Immun, 2012, 26(1): 132-141.
[22] Liang YC, Liu D, Yang F, et al. Perineural invasion in endometriotic lesions contributes to endometriosis-associated pain[J]. J Pain Res, 2018, 11: 1999-2009.
[23] Kaelberer MM, Buchanan KL, Klein ME, et al. A gut-brain neural circuit for nutrient sensory transduction[J]. Science, 2018, 361(6408): eaat5236. doi: 10.1126/science.aat5236
[24] Anaf V, Simon P, El Nakadi I, et al. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis[J]. Hum Reprod, 2002, 17(7): 1895-1900.
[25] Yu J, Berga SL, Zou E, et al. Neurotrophins and their receptors, novel therapeutic targets for pelvic pain in endometriosis, are coordinately regulated by IL-1β via the JNK signaling pathway[J]. Am J Pathol, 2023, 193(8): 1046-1058.
[26] Rocha AL, Vieira EL, Ferreira MC, et al. Plasma brain-derived neurotrophic factor in women with pelvic pain: a potential biomarker for endometriosis?[J]. Biomark Med, 2017, 11(4): 313-317.
[27] Godin SK, Wagner J, Huang P, et al. The role of peripheral nerve signaling in endometriosis[J]. FASEB Bioadv, 2021, 3(10): 802-813.
[28] Bohonyi N, Pohóczky K, Szalontai B, et al. Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis[J]. Mol Pain, 2017, 13: 1744806917705564. doi: 10.1177/1744806917705564
[29] Kale A, Baydili KNS, Keles E, et al. Comparison of isolated sciatic nerve and sacral nerve root endometriosis: a review of the literature[J]. J Minim Invasive Gynecol, 2022, 29(8): 943-951.
[30] Di Donna MC, Cucinella G, Sozzi G, et al. Surgical neuropelveology: lateral femoral cutaneous nerve endometriosis. laparoscopic resection and nerve transplantation[J]. J Minim Invasive Gynecol, 2021, 28(12): 1978-1979.
[31] Li T, Mamillapalli R, Ding S, et al. Endometriosis alters brain electrophysiology, gene expression and increases pain sensitization, anxiety, and depression in female mice[J]. Biol Reprod, 2018, 99(2): 349-359.
[32] As-Sanie S, Kim J, Schmidt-Wilcke T, et al. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain[J]. J Pain, 2016, 17(1): 1-13.
[33] De Blasio FM, Love S, Barry RJ, et al. Frontocentral delta-beta amplitude coupling in endometriosis-related chronic pelvic pain[J]. Clin Neurophysiol, 2023, 149: 146-156. doi: 10.1016/j.clinph.2023.02.173
[34] As-Sanie S, Harris RE, Napadow V, et al. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study[J]. Pain, 2012, 153(6), 1006-1014.
[35] Coxon L, Horne AW, Vincent K. Pathophysiology of endometriosis-associated pain: a review of pelvic and central nervous system mechanisms[J]. Best Pract Res Clin Obstet Gynaecol, 2018, 51, 53-67. doi: 10.1016/j.bpobgyn.2018.01.014
[36] Bashir ST, Redden CR, Raj K, et al. Endometriosis leads to central nervous system-wide glial activation in a mouse model of endometriosis[J]. J Neuroinflammation, 2023, 20(1): 59. doi: 10.1186/s12974-023-02713-0
[37] Tirlapur SA, Kuhrt K, Chaliha C, et al. The ‘evil twin syndrome’ in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis[J]. Int J Surg, 2013, 11(3): 233-237.
[38] Cheng C, Rosamilia A, Healey M. Diagnosis of interstitial cystitis/bladder pain syndrome in women with chronic pelvic pain: a prospective observational study[J]. Int Urogynecol J, 2012, 23(10): 1361-1366.
[39] Schomacker ML, Hansen KE, Ramlau-Hansen CH, et al. Is endometriosis associated with irritable bowel syndrome? A cross-sectional study[J]. Eur J Obstet Gynecol Reprod Biol, 2018, 231: 65-69. doi: 10.1016/j.ejogrb.2018.10.023
[40] DiVasta AD, Zimmerman LA, Vitonis AF, et al. Overlap between irritable bowel syndrome diagnosis and endometriosis in adolescents[J]. Clin Gastroenterol Hepatol, 2021, 19(3): 528-537.
[41] Smorgick N, Marsh CA, As-Sanie S, et al. Prevalence of pain syndromes, mood conditions, and asthma in adolescents and young women with endometriosis[J]. J Pediatr Adolesc Gynecol, 2013, 26(3): 171-175.
[42] Graziottin A, Murina F, Gambini D, et al. Vulvar pain: the revealing scenario of leading comorbidities in 1183 cases[J]. Eur J Obstet Gynecol Reprod Biol, 2020, 252: 50-55. doi: 10.1016/j.ejogrb.2020.05.052
[43] Ge P, Ren JM, Harrington AM, et al. Linaclotide treatment reduces endometriosis-associated vaginal hyperalgesia and mechanical allodynia through viscerovisceral cross-talk[J]. Pain, 2019, 160(11): 2566-2579.
[44] Jobling P, Graham BA, Brichta AM, et al. Cervix stimu-lation evokes predominantly subthreshold synaptic responses in mouse thoracolumbar and lumbosacral superficial dorsal horn neurons[J]. J Sex Med, 2010, 7(6): 2068-2076.
[45] Chaban VV. Visceral sensory neurons that innervate both uterus and colon express nociceptive TRPv1 and P2X3 receptors in rats[J]. Ethn Dis, 2008, 18(Suppl 2): S2-20-S224.
[46] Christianson JA, Liang RM, Ustinova EE, et al. Convergence of bladder and colon sensory innervation occurs at the primary afferent level[J]. Pain, 2007, 128(3): 235-243.
[47] Berna C, Leknes S, Holmes EA, et al. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness[J]. Biol Psychiatry, 2010, 67(11): 1083-1090.
[48] Ploghaus A, Narain C, Beckmann CF, et al. Exacerbation of pain by anxiety is associated with activity in a hippocampal network[J]. J Neurosci, 2001, 21(24): 9896-9903.
[49] Lorençatto C, Petta CA, Navarro MJ, et al. Depression in women with endometriosis with and without chronic pelvic pain[J]. Acta Obstet Gynecol Scand, 2006, 85(1):88-92.
[50] Sepulcri RD, do Amaral VF. Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis[J]. Eur J Obstet Gynecol Reprod Biol, 2009, 142(1): 53-56.
[51] van Aken MAW, Oosterman JM, van Rijn CM, et al. Pain cognition versus pain intensity in patients with endometriosis: toward personalized treatment[J]. Fertil Steril, 2017, 108(4): 679-686.
[1] ZHANG Shuqi, JIANG Yanjiao, YIN Dan. Connection between reproductive tract microbes and the development of endometriosis [J]. Journal of Shandong University (Health Sciences), 2025, 63(5): 120-126.
[2] WEI Jiacheng, YANG Baozhong, WEI Wei, XUE Yating, CUI Chenlong, FANG Jun. MicroRNA-210-3p inhibits inflammatory pain in rats by regulation ten-eleven translocation 2 expression [J]. Journal of Shandong University (Health Sciences), 2024, 62(6): 17-29.
[3] BAI Xiaoliang, SUN Panpan, WANG Hongli, GONG Shunzhi, SUN Yunqi, SHU Meng, QI Xiaoliang. Animal experiment of medical thoracoscopic splanchnotomy [J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 9-13.
[4] WU Shanshan, WANG Shuren, ZHAO Tonghang, ZHANG Zongwang. Postoperative pain associated with digestive endoscopic therapies: a retrospective cohort study [J]. Journal of Shandong University (Health Sciences), 2024, 62(2): 42-50.
[5] LI Xue, ZHANG Zengzhen, LIU Jisong, LI Deqiang, YANG Shaozhong. Effect of ultrasound-guided genicular nerve block on postoperative pain in patients undergoing total knee arthroplasty [J]. Journal of Shandong University (Health Sciences), 2024, 62(10): 68-75.
[6] CHEN Wenjun, SONG Lijun, WANG Junjuan. Five cases of hiatal hernia complicated with pneumonia during painless gastroscopy and literature review [J]. Journal of Shandong University (Health Sciences), 2024, 62(1): 71-75.
[7] LIU Meng, HOU Congzhe, MA Huanyu, ZHANG Zhen, ZHAO Xinrui, ZHANG Ping, ZHU Lin. Effects of β-estradiol on the proliferation of cervical cancer Hela cells [J]. Journal of Shandong University (Health Sciences), 2023, 61(2): 9-15.
[8] ZHANG Lixia, TIAN Yizheng, LYU Shangge, ZHANG Yanan, YAN Lei. Effects of GnRH-a pretreatment on the pregnancy outcomes of frozen embryo transplantation in patients with endometriosis [J]. Journal of Shandong University (Health Sciences), 2023, 61(10): 63-68.
[9] YAN Lei, YUE Caixin, LIU Yichun. Fertility preservation in patients with endometriosis [J]. Journal of Shandong University (Health Sciences), 2022, 60(9): 31-34.
[10] XU Xiaofen, ZHU Xiao, MA Wei, LI Na. Influencing factors of cancer pain management disorder in 123 cancer patients [J]. Journal of Shandong University (Health Sciences), 2022, 60(9): 119-124.
[11] CHEN Shihong, JIANG Dongqing, ZHUANG Xianghua, LI Xiaobo, PAN Zhe, SUN Aili, LOU Nengjun, WANG Dianhui, DU Jiaojiao, SONG Yuwen. Primary biliary cholangitis with bone pain as the main manifestation: a case report [J]. Journal of Shandong University (Health Sciences), 2022, 60(8): 98-102.
[12] LENG Jinhua, SHI Jinghua. Clinical manifestations of adenomyosis [J]. Journal of Shandong University (Health Sciences), 2022, 60(7): 1-5.
[13] CHEN Zhongshao, CHU Ran, LI Mingbao, ZHANG Xiangning. MRKH syndrome-related abdominal scar endometriosis after inguinal uterine hernia repair: a case report and literature review [J]. Journal of Shandong University (Health Sciences), 2022, 60(5): 114-117.
[14] SUN Jiye, WANG Ziou, SUN Xiaowei, LI Hongtao. Effects of traditional Chinese medicine fumigation combined with extracorporeal shock wave therapy on 72 cases of femoroacetabular impingement syndrome and serum inflammatory factor [J]. Journal of Shandong University (Health Sciences), 2022, 60(4): 76-81.
[15] LIN Xueyan, ZHANG Cancan, TIAN Minle, TIAN Yongjie. Expression and significance of poly(ADP-ribose) polymerase-1 in endometriosis [J]. Journal of Shandong University (Health Sciences), 2022, 60(2): 27-31.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd