子宫内膜异位症相关性疼痛的发病机制及治疗研究进展

Research progress on the pathogenesis and treatment of endometriosis-associated pain

摘要

子宫内膜异位症是一种常见的慢性、复发性妇科疾病，以异位的子宫内膜组织周期性出血和慢性盆腔疼痛为主要特征，严重影响女性的生殖健康与生活质量。疼痛作为其最常见且最难控制的症状之一，发生机制复杂、表现形式多样且对传统治疗反应有限。该文系统综述了当前关于子宫内膜异位症疼痛机制的研究进展，重点探讨了炎症与免疫异常、神经血管生成、外周敏化、中枢敏化及器官交叉敏化等多个层面的作用机制。在治疗方面，传统药物如非甾体抗炎药、孕激素制剂及促性腺激素释放激素类似物在临床上广泛应用，但疗效和耐受性存在一定局限。近年来，靶向炎症因子及免疫调控的新型药物不断涌现，为改善长期疼痛管理提供了新的思路和潜力。未来结合疼痛机制的深入研究与个体化治疗策略，有望实现更精准的干预，从而提升患者的整体预后和生活质量。

Abstract

Endometriosis is a common chronic and recurrent gynecological disorder characterized by the ectopic implantation of endometrial tissue, which undergoes cyclic bleeding and induces chronic pelvic pain. This condition significantly impairs women's reproductive health and quality of life. Pain is the most prevalent and challenging symptom to manage, with complex underlying mechanisms, diverse clinical presentations, and limited response to conventional therapies. This review systematically summarizes current research advances on the mechanisms of endometriosis⁃associated pain, focusing on multiple contributing factors, including inflammation and immune dysregulation, neuroangiogenesis, peripheral sensitization, central sensitization, and cross⁃organ sensitization. In terms of treatment, conventional pharmacological approaches, such as non⁃steroidal anti⁃inflammatory drugs, progestins, and gonadotropin⁃releasing hormone analogues, remain widely used in clinical practice, but their efficacy and tolerability are limited in long⁃term management. In recent years, novel agents targeting inflammatory mediators and immune regulation have emerged, offering new perspectives and potential for improving chronic pain control. Future research combining in⁃depth exploration of pain mechanisms with individualized treatment strategies holds promise for achieving more precise interventions, thereby enhancing patients' overall prognosis and quality of life.

关键词

子宫内膜异位症 / 疼痛 / 发病机制 / 治疗 / 神经敏化 / 交叉敏化 / 神经血管生成

Key words

Endometriosis / Pain / Pathogenesis / Treatment / Neural Sensitization / Cross⁃Organ Sensitization / Neuroangiogenesis

参考文献

[1] CHOI S, TRAN J P. A review of treatment options for chronic pelvic pain from endometriosis[J]. Pain Manag, 2025, 15(10): 767-777.

[2] MCNAMARA H C, FRAWLEY H C, DONOGHUE J F, et al. Peripheral, central, and cross sensitization in endometriosis—associated pain and comorbid pain syndromes[J]. Front Reprod Health, 2021, 3: 729642.

[3] CHEN Y X, 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.

[4] SONG S Y, JUNG Y W, SHIN W, et al. Endometriosis—related chronic pelvic pain[J]. Biomedicines, 2023, 11(10): 2868.

[5] WERNER F, JASINSKI V, VELHO R V, et al. The role of self—management in endometriosis pain: Insights from a cross—sectional survey in Germany, Austria, and Switzerland[J]. Arch Gynecol Obstet, 2025, 312(2): 425-434.

[6] GOUESBET S, LAMBERT S, AMAZOUZ H, et al. Retrospective assessment of endometriosis pain over the life course: A reliability study within the ComPaRe—endometriosis cohort[J]. Eur J Pain, 2025, 29(6): e70040.

[7] CUFFARO F, RUSSO E, AMEDEI A. Endometriosis, pain, and related psychological disorders: Unveiling the interplay among the microbiome, inflammation, and oxidative stress as a common thread[J]. Int J Mol Sci, 2024, 25(12): 6473.

[8] PICKUP B, COUTTS—BAIN D, TODD J. Fear of progression, depression, and sleep difficulties in people experiencing endometriosis—pain: A cross—sectional study[J]. J Psychosom Res, 2024, 178: 111595.

[9] CASTRO J, MADDERN J, ERICKSON A, et al. Peripheral and central neuroplasticity in a mouse model of endometriosis[J]. J Neurochem, 2024, 168(11): 3777-3800.

[10] PARMAR G, HOWARD A F, NOGA H, et al. Pelvic pain & endometriosis: The development of a patient—centred e—health resource for those affected by endometriosis—associated dyspareunia[J]. BMC Med Inform Decis Mak, 2025, 25(1): 79.

[11] SHAFRIR A L, LALIBERTE A, WALLACE B, et al. Pelvic pain symptoms and inflammation among adolescents and adults with and without endometriosis[J]. Int J Mol Sci, 2025, 26(11): 5377.

[12] MADDERN J, GRUNDY L, CASTRO J, et al. Pain in endometriosis[J]. Front Cell Neurosci, 2020, 14: 590823.

[13] PARK W, LIM W, KIM M, et al. Female reproductive disease, endometriosis: From inflammation to infertility[J]. Mol Cells, 2025, 48(1): 100164.

[14] THOMAS V G. Examination of the proposed relationships between cyclic menstruation and human reproduction[J]. Front Glob Womens Health, 2025, 6: 1589736.

[15] LAUX—BIEHLMANN A, D'HOOGHE T, ZOLLNER T M. Menstruation pulls the trigger for inflammation and pain in endometriosis[J]. Trends Pharmacol Sci, 2015, 36(5): 270-276.

[16] MACHAIRIOTIS N, VASILAKAKI S, THOMAKOS N. Inflammatory mediators and pain in endometriosis: A systematic review[J]. Biomedicines, 2021, 9(1): 54.

[17] CLOWER L, FLESHMAN T, GELDENHUYS W J, et al. Targeting oxidative stress involved in endometriosis and its pain[J]. Biomolecules, 2022, 12(8): 1055.

[18] MOSLEH H, HOSSEINI S, HAJIZADEH N, et al. Role of neuropeptides in patients with endometriosis: A literature review[J]. Middle East Fertil Soc J, 2024, 29(1): 49.

[19] BASHIR S T, REDDEN C R, 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.

[20] WILSON T R, KASPER S, BURNS K A. An emerging role for neutrophils in the pathogenesis of endometriosis[J]. NPJ Women's Health, 2025, 3: 9.

[21] 罗喜, 黄紫薇, 张伶俐 . 子宫内膜异位性疼痛的神经新生机制研究进展[J]. 中国优生与遗传杂志, 2023, 31(7): 1512-1516.

[22] LUO X, HUANG Z W, ZHANG L L. Research progress on the neurogenesis mechanism of endometriosis pain[J]. Chin J Birth Health Hered, 2023, 31(7): 1512-1516.

[23] SMOLARZ B, SZAFLIK T, ROMANOWICZ H, et al. Analysis of VEGF, IGF1/2 and the long noncoding RNA (lncRNA) H19 expression in Polish women with endometriosis[J]. Int J Mol Sci, 2024, 25(10): 5271.

[24] LIU D Q, LIU M J, YU P L, et al. Brain—derived neurotrophic factor and nerve growth factor expression in endometriosis: A systematic review and meta—analysis[J]. J Obstet Gynecol, 2023, 62(5): 634-639.

[25] 孙佳星, 李世杰, 罗小婉, 等 . 脑源性神经营养因子在轻型子宫内膜异位症中的表达及意义[J]. 吉林医学, 2024, 45(9): 2063-2066.

[26] SUN J X, LI S J, LUO X W, et al. Expression and significance of brain—derived neurotrophic factor in mild endometriosis[J]. Jilin Med J, 2024, 45(9): 2063-2066.

[27] SREYA M, TUCKER D R, YI J, et al. Nerve bundle density and expression of NGF and IL—1β are intra—individually heterogenous in subtypes of endometriosis[J]. Biomolecules, 2024, 14(5): 583.

[28] 梅珊珊, 丁杰, 倪喆鑫, 等 . 巨噬细胞在子宫内膜异位症神经纤维及血管生成中的作用及机制[J]. 国际妇产科学杂志, 2022, 49(1): 106-110.

[29] MEI S S, DING J, NI Z X, et al. The role of macrophages in neurogenesis and angiogenesis in endometriosis and its mechanism[J]. J Int Obstet Gynecol, 2022, 49(1): 106-110.

[30] MECHSNER S, KAISER A, KOPF A, et al. A pilot study to evaluate the clinical relevance of endometriosis—associated nerve fibers in peritoneal endometriotic lesions[J]. Fertil Steril, 2009, 92(6): 1856-1861.

[31] ZANINELLI T H, FATTORI V, HEINTZ O K, et al. Targeting NGF but not VEGFR1 or BDNF signaling reduces endometriosis—associated pain in mice[J]. J Adv Res, 2025, 73: 593-605.

[32] ZONG C X, SUN L, XU X, et al. Huayu Sanjie enema liquid relieves pain in endometriosis model rats by inhibiting inflammation, peripheral sensitization, and pelvic adhesion[J]. Evid Based Complement Alternat Med, 2022, 2022: 5256578.

[33] 殷婷, 丛慧芳 . 子宫内膜异位症与痛觉敏化的免疫学研究进展[J]. 国际妇产科学杂志, 2025, 52(2): 206-210.

[34] YIN T, CONG H F. Progress in immunological of endometriosis and pain sensitization[J]. J Int Obstet Gynecol, 2025, 52(2): 206-210.

[35] FAN P Y, LI T. Unveil the pain of endometriosis: From the perspective of the nervous system[J]. Expert Rev Mol Med, 2022, 24: e36.

[36] 毛心齐, 张信美 . 肥大细胞参与子宫内膜异位症疼痛机制的研究进展[J]. 海军军医大学学报, 2024, 45(9): 1089-1096.

[37] MAO X Q, ZHANG X M. Role of mast cells in development of endometriosis pain: Research progress[J]. Acad J Nav Med Univ, 2024, 45(9): 1089-1096.

[38] TUCKER D R, NOGA H L, LEE C, et al. Pelvic pain comorbidities associated with quality of life after endometriosis surgery[J]. Am J Obstet Gynecol, 2023, 229(2): 147.e1-147.e20.

[39] 郑萍 . 基于脑功能活动分析的子宫内膜异位症相关性疼痛大鼠模型中枢敏化机制的研究[D].北京: 中国医学科学院北京协和医学院, 2025.

[40] ZHENG P. Central sensitization, mechanisms in a rat model of endometriosis—related pain based on analysis of brain functional activity[D]. Beijing:Chinese Academy of Medical Sciences & Peking Union Medical College, 2025.

[41] WOOLF C J. Central sensitization: Implications for the diagnosis and treatment of pain[J]. PAIN, 2011, 152(3): S2-S15.

[42] AREDO J V, HEYRANA K J, KARP B I, et al. Relating chronic pelvic pain and endometriosis to signs of sensitization and myofascial pain and dysfunction[J]. Semin Reprod Med, 2017, 35(1): 88-97.

[43] 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.

[44] 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.

[45] GIUDICE L C. Clinical practice. Endometriosis[J]. N Engl J Med, 2010, 362(25): 2389-2398.

[46] CHUNG M K, CHUNG R R, GORDON D, et al. The evil twins of chronic pelvic pain syndrome: Endometriosis and interstitial cystitis[J]. JSLS, 2002, 6(4): 311-314.

[47] WESSELMANN U. Neurogenic inflammation and chronic pelvic pain[J]. World J Urol, 2001, 19(3): 180-185.

[48] GRUNDY L, BRIERLEY S M. Cross—organ sensitization between the colon and bladder: To pee or not to pee?[J]. Am J Physiol Gastrointest Liver Physiol, 2018, 314(3): G301-G308.

[49] QIN C, MALYKHINA A P, AKBARALI H I, et al. Cross—organ sensitization of lumbosacral spinal neurons receiving urinary bladder input in rats with inflamed colon[J]. Gastroenterology, 2005, 129(6): 1967-1978.

[50] MALYKHINA A P. Neural mechanisms of pelvic organ cross—sensitization[J]. Neuroscience, 2007, 149(3): 660-672.

[51] WINNARD K P, DMITRIEVA N, BERKLEY K J. Cross—organ interactions between reproductive, gastrointestinal, and urinary tracts: Modulation by estrous stage and involvement of the hypogastric nerve[J]. Am J Physiol Regul Integr Comp Physiol, 2006, 291(6): R1592-R1601.

[52] LEI L, XU X X, GONG C C, et al. Integrated analysis of genome—wide gene expression and DNA methylation profiles reveals candidate genes in ovary endometriosis[J]. Front Endocrinol, 2023, 14: 1093683.

[53] MORTLOCK S, HOUSHDARAN S, KOSTI I, et al. Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function[J]. Commun Biol, 2023, 6(1): 780.

[54] HAN Q Y, KONO T J Y, KNUTSON C G, et al. Multi—omics characterization of inflammatory bowel disease—induced hyperplasia/dysplasia in the Rag2^—/—/Il10^—/— mouse model[J]. Int J Mol Sci, 2020, 22(1): 364.

[55] LI X, LIU D Z, DAI Z S, et al. Intraperitoneal 5—azacytidine alleviates nerve injury—induced pain in rats by modulating DNA methylation[J]. Mol Neurobiol, 2023, 60(4): 2186-2199.

[56] YAKHNITSA V, THOMPSON J, PONOMAREVA O, et al. Dysfunction of small—conductance Ca²⁺—activated potassium (SK) channels drives amygdala hyperexcitability and neuropathic pain behaviors: Involvement of epigenetic mechanisms[J]. Cells, 2024, 13(12): 1055.

[57] AGULLÓ L, MURIEL J, MARGARIT C, et al. Sex differences in opioid response linked to OPRM1 and COMT genes DNA methylation/genotypes changes in patients with chronic pain[J]. J Clin Med, 2023, 12(10): 3449.

[58] XIONG H Y, WYNS A, CAMPENHOUT J V, et al. Epigenetic landscapes of pain: DNA methylation dynamics in chronic pain[J]. Int J Mol Sci, 2024, 25(15): 8324.

[59] ACHENBACH J, RHEIN M, GLAHN A, et al. Leptin promoter methylation in female patients with painful multisomatoform disorder and chronic widespread pain[J]. Clin Epigenetics, 2022, 14(1): 13.

[60] MAIARÙ M, ACTON R J, WOŹNIAK E L, et al. A DNA methylation signature in the stress driver gene Fkbp5 indicates a neuropathic component in chronic pain[J]. Clin Epigenetics, 2023, 15(1): 155.

[61] YANG X H, HUANG X Q, LU W C, et al. Transcriptome profiling of miRNA—mRNA interactions and associated mechanisms in chemotherapy—induced neuropathic pain[J]. Mol Neurobiol, 2023, 60(10): 5672-5690.

[62] JEAN—TOUSSAINT R, LIN Z C, TIAN Y Z, et al. Therapeutic and prophylactic effects of macrophage—derived small extracellular vesicles in the attenuation of inflammatory pain[J]. Brain Behav Immun, 2021, 94: 210-224.

[63] FREGER S, LEONARDI M, FOSTER W. Exosomes and their cargo are important regulators of cell function in endometriosis[J]. Reprod BioMedicine Online, 2021, 43(3): 370-378.

[64] SIMEOLI R, MONTAGUE K, JONES H R, et al. Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma[J]. Nat Commun, 2017, 8(1): 1778.

[65] YIN M C, ZHAI L Y, WANG J Z, et al. Comprehensive analysis of rna—Seq in endometriosis reveals competing endogenous RNA network composed of circRNA, lncRNA and mRNA[J]. Front Genet, 2022, 13: 828238.

[66] XU D R, MA X X, SUN C, et al. Emerging roles of circular RNAs in neuropathic pain[J]. Cell Prolif, 2021, 54(12): e13139.

[67] BROWN J, CRAWFORD T J, ALLEN C, et al. Nonsteroidal anti—inflammatory drugs for pain in women with endometriosis[J]. Cochrane Database Syst Rev, 2017, 1(1): CD004753.

[68] DELLA CORTE L, BARRA F, MERCORIO A, et al. Tolerability considerations for gonadotropin—releasing hormone analogues for endometriosis[J]. Expert Opin Drug Metab Toxicol, 2020, 16(9): 759-768.

[69] TAN G C, YEE KHONG T. Cyclic endometrium and exogenous hormone effect[M]//ZHENG W X, FADARE O, QUICK C M,et al. Gynecologic and Obstetric Pathology, Volume 1. Singapore: Springer, 2019: 383-408.

[70] VERCELLINI P, FACCHIN F, BUGGIO L, et al. Management of endometriosis: toward value—based, cost—effective, affordable care[J]. J Obstet Gynaecol Can, 2018, 40(6): 726-749.e10.

[71] GUAN Q H, VELHO R V, SEHOULI J, et al. Endometriosis and opioid receptors: Are opioids a possible/promising treatment for endometriosis?[J]. Int J Mol Sci, 2023, 24(2): 1633.

[72] LIAN Y L, CHENG M J, ZHANG X X, et al. Elevated expression of transient receptor potential vanilloid type 1 in dorsal root Ganglia of rats with endometriosis[J]. Mol Med Rep, 2017, 16(2): 1920-1926.

[73] XIE Z, DING X, WANG Y L, et al. The rs2275913 polymorphism of the interleukin—17A gene is associated with the risk of ovarian endometriosis[J]. J Obstet Gynaecol, 2023, 43(1): 2199852.

[74] KAPLAN S, KIRICI P, TÜRK A. The effects of adalimumab on the rat autotransplantation endometriosis model: A placebo—controlled randomized study[J]. Adv Clin Exp Med, 2022, 31(4): 417-426.

[75] GOENKA L, GEORGE M, SEN M. A peek into the drug development scenario of endometriosis—A systematic review[J]. Biomed Pharmacother, 2017, 90: 575-585.

基金资助

国家自然科学基金资助项目(82001524)

武汉市医学科研项目面上项目(WX21C12)