{"paper_id":"2b74a8b0-eb35-438e-88c2-b6ada639fd3c","body_text":"Systemic Inflammation and Psychological Trauma in Endometriosis: A Narrative Review Towards Integrated Management\nDOI:\nhttps://doi.org/10.59493/advpbl/2026.1.7Keywords:\nChronic pelvic pain, Endometriosis, Immune dysregulation, Multidisciplinary pain management, Pro-inflammatory cytokines, Trauma-informed careAbstract\nEndometriosis is increasingly recognized as a systemic inflammatory disease with complex immune and neuroendocrine dysregulation. This narrative review synthesized evidence on the bidirectional relationship between systemic inflammation and psychiatric comorbidities, drawing from 32 peer-reviewed studies (2020–2026). Results indicate that endometriotic lesions release interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) into systemic circulation, driving chronic immune activation and Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation. This leads to significant (p < 0.05) alteration of cortisol secretion, neuroinflammation, and structural changes in the hippocampus and amygdala, which in turn perpetuate hyperalgesia, fatigue, and heightened vulnerability to depression and anxiety. Conversely, psychological trauma and diagnostic delays exacerbate inflammatory profiles, forming a self-perpetuating cycle. To break this neuro-immune cycle, clinicians must transition from isolated surgical management to integrated, multidisciplinary care. This requires operationalizing trauma-informed practices through routine Adverse Childhood Experiences (ACE) screening, validated pelvic pain psychological distress tools, and explicit referral pathways to specialized psychiatric support and pelvic-floor physical therapy. Future research must address a critical gap in the literature by identifying the precise dose-response thresholds linking specific circulating cytokines to localized psychiatric symptom severity; these key gaps regarding optimal screening tools and intervention timing warrant future prospective studies.\nReferences\nLiu F, Yuan S, Yan Q, Yang S, Yan W, Xiang T, Wu Z, Li G, Ren W, Wang W, 2026. Global Trends in Endometriosis Burden, 1990-2021: A Sociodemographic Analysis Using GBD 2021 Data and Projections to 2036. International Journal of Women's Health, 18: 560463. https://doi.org/10.2147/IJWH.S560463\nWorld Health Organization. 2025, Endometriosis. Available at https://www.who.int/news-room/fact-sheets/detail/endometriosis (Accessed 2 July, 2026).\nScarparo IMT, Zanella C, Cardoso MS, Martins AS, Leandro ACF, 2026. Underdiagnosed endometriosis: Repercussions of diagnostic delay on chronic pain, fertility, and quality of life. International Health Sciences Review, 2(3): 93–102. https://doi.org/10.70164/ihsr.v2i3.178\nde Kok L, Boersen Z, Coppus S, van Haaps A, van Hanegem N, Klinkert E, Maas J, Mijatovic V, Smeets M, Steensma A, Teklenburg G, van Vliet H, Braat D, Schers H, Nap A, 2026. Diagnostic delay in endometriosis: is there any progress? Reproductive Biomedicine Online, 53(1): 105405. https://doi.org/10.1016/j.rbmo.2025.105405\nLi W, Feng H, Ye Q, 2025. Factors contributing to the delayed diagnosis of endometriosis-a systematic review and meta-analysis. Frontiers in Medicine, 12: 1576490. https://doi.org/10.3389/fmed.2025.1576490\nBreton Z, Gouesbet S, Indersie E, Gabillet M, Tran VT, Aflak N, Borghese B, Petit E, Roman H, Millepied AC, Nève De Mevergnies M, Kvaskoff M, 2026. Endometriosis Diagnostic Delay and Its Correlates: Results from the ComPaRe-Endometriosis Cohort. Journal of Women's Health (2002), 35(2): 172–188. https://doi.org/10.1177/15409996251380129\nDe Corte P, Klinghardt M, von Stockum S, Heinemann K, 2025. Time to Diagnose Endometriosis: Current Status, Challenges and Regional Characteristics—A Systematic Literature Review. BJOG: An International Journal of Obstetrics & Gynaecology, 132: 118-130. https://doi.org/10.1111/1471-0528.17973\nCromeens MG, Carey ET, Robinson WR, Knafl K, Thoyre S, 2021. Timing, delays and pathways to diagnosis of endometriosis: a scoping review protocol. BMJ Open, 11(5): e049390. https://doi.org/10.1136/bmjopen-2021-049390\nNishimata N, Satomi S, 2025. Diagnostic Delays and Economic Burden in Japanese Women with Endometriosis: A Cross-Sectional Analysis. International Journal of Environmental Research and Public Health, 22(11): 1623. https://doi.org/10.3390/ijerph22111623\nAs-Sanie S, Mackenzie SC, Morrison L, Schrepf A, Zondervan K T, Horne AW, Missmer SA, 2025. Endometriosis: A Review. JAMA, 334(1): 64–78. https://doi.org/10.1001/jama.2025.2975\nGriffiths MJ, Horne AW, Gibson DA, Roberts N, Saunders PTK, 2024. Endometriosis: recent advances that could accelerate diagnosis and improve care. Trends in Molecular Medicine, 30(9): 875-889. https://doi.org/10.1016/j.molmed.2024.06.008\nCuffaro F, Russo E, Amedei A, 2024. Endometriosis, Pain, and Related Psychological Disorders: Unveiling the Interplay among the Microbiome, Inflammation, and Oxidative Stress as a Common Thread. International journal of molecular sciences, 25(12): 6473. https://doi.org/10.3390/ijms25126473\nServidoni ACP, Surmann H, Canis M, Taylor HS, Crippa JA, Abrao MS, 2026. The mental health burden of endometriosis: a narrative review. F&S Reviews, 7(2): 100109. https://doi.org/10.1016/j.xfnr.2026.100109\nMerola M, Cosma S, Melotti C, Aral E, Berchialla P, Zanaga G, Cacciato G, Tancredi A, Ostacoli L, Benedetto C, Carletto S, 2026. Psychological factors mediate the relationship between trauma exposure and pain intensity in women with endometriosis: a cross-sectional study. Psychology, health & medicine, 31(6): 1596–1612. https://doi.org/10.1080/13548506.2025.2564309\nDipankar SP, Kushram B, Unnikrishnan P, Gowda JR, Shrivastava R, Daitkar AR, Jaiswal V, 2025. Psychological Distress and Quality of Life in Women with Endometriosis: A Narrative Review of Therapeutic Approaches and Challenges. Cureus, 17(3): e80180. https://doi.org/10.7759/cureus.80180\nMarano G, d’Abate C, Ianes I, Costantini E, Lisci FM, Traversi G, Gaetani E, Napolitano D, Mazza M, 2026. When the Body Hurts, the Mind Suffers: Endometriosis and Mental Health. Psychiatry International, 7(1): 9. https://doi.org/10.3390/psychiatryint7010009\nvan Stein K, Schubert K, Ditzen B, Weise C, 2023. Understanding Psychological Symptoms of Endometriosis from a Research Domain Criteria Perspective. Journal of Clinical Medicine, 12(12): 4056. https://doi.org/10.3390/jcm12124056\nThiel PS, Bougie O, Pudwell J, Shellenberger J, Velez MP, Murji A, 2024. Endometriosis and mental health: a population-based cohort study. American journal of obstetrics and gynecology, 230(6): 649.e1–649.e19. https://doi.org/10.1016/j.ajog.2024.01.023\nZippl AL, Reiser E, Seeber B, 2024. Endometriosis and mental health disorders: identification and treatment as part of a multimodal approach. Fertility and Sterility, 121(3): 370-378. https://doi.org/10.1016/j.fertnstert.2023.12.033\nLi W, Feng H, Ye Q, 2025. Relationship between endometriosis and mental health: a systematic review and meta-analysis. Archives of Medical Science, 21(5): 1985–1996. https://doi.org/10.5114/aoms/208502\nAkano OP, Oladapo OJ, Obileke OI, Ezenwafor JC, Jacobs-Aje A, AdeoyeBO, Adeoye AD, Adetunji OA, Ademoye AK, Akinyo AS, 2025. Exploring the Impact of Psychological Stress on Endometriosis.Fertility, Gynecology and Andrology, 5(1): e151749. https://doi.org/10.5812/fga-151749\nSzypłowska M, Tarkowski R, Kułak K, 2023. The impact of endometriosis on depressive and anxiety symptoms and quality of life: a systematic review. Frontiers in Public Health, 11: 1230303. https://doi.org/10.3389/fpubh.2023.1230303\nKori A, Singh A, Caroicar Y, Thomas PE, Chandra A, 2025. The Intersection of Psychology and Gynecology: A Comprehensive Review of Pain Management Strategies in Women's Health. Cureus, 17(6): e86344. https://doi.org/10.7759/cureus.86344\nWatkins E, Orlando M, Weikel K, 2025. Female chronic pelvic pain: From trauma-informed assessment to evidence-based treatment. JAAPA, 39(2): 18–24. https://doi.org/10.1097/01.JAA.0000000000000309\nDuncan JM, Delara R, Ranieri G, Wasson M, 2024. Management of endometriosis: a call to multidisciplinary approach. Journal of Osteopathic Medicine, 125(6): 305–313. https://doi.org/10.1515/jom-2024-0105\nIrshad NUN, Atif MM, Talha M, Jaber AMH, 2025. Linking childhood trauma to endometriosis: evidence and implications for reproductive health screening. Annals of medicine and surgery (2012), 88(1): 7–8. https://doi.org/10.1097/MS9.0000000000004321\nMick I, Freger SM, van Keizerswaard J, Gholiof M, Leonardi M, 2024. Comprehensive endometriosis care: a modern multimodal approach for the treatment of pelvic pain and endometriosis. Therapeutic advances in reproductive health, 18, 26334941241277759. https://doi.org/10.1177/26334941241277759\nSrianand A, Devi PR, Saumya, Pragati S, Khanorkar NA, Das SS, 2026. Medical and Surgical Management of Endometriosis: A Narrative Review of Clinical Outcomes. Cureus, 18(4): e107137. https://doi.org/10.7759/cureus.107137\nDi Spiezio Sardo A, Becker CM, Renner, SP, Suvitie PA, Tarriel JE, Vannuccini S, Garcia Velasco JA, Verguts J, Mercorio A, 2025. Management of women with endometriosis in the 21st century. Current opinion in obstetrics & gynecology, 37(3): 149–157. https://doi.org/10.1097/GCO.0000000000001027\nCarbone MG, Campo G, Papaleo E, Marazziti D, Maremmani I, 2021. The Importance of a Multi-Disciplinary Approach to the Endometriotic Patients: The Relationship between Endometriosis and Psychic Vulnerability. Journal of Clinical Medicine, 10(8): 1616. https://doi.org/10.3390/jcm10081616\nDel Pino-Sedeño T, Cabrera-Maroto M, Abrante-Luis A, González-Hernández Y, Ortiz-Herrera MC, 2024. Effectiveness of psychological interventions in endometriosis: a systematic review with meta-analysis. Frontiers in Psychology, 15: 1457842. https://doi.org/10.3389/fpsyg.2024.1457842\nAl Hussaini HAD, Alatawi ESE, Shabani JAJ, Edhrabooh MIH, Alhawaj SAA, Almahfoodh MS, Alsamiri HY, AlMaatoug AR, Hayderali MIM, Almousa MR, 2024. Management of Endometriosis-Related Pain: Comparing the Effectiveness of Hormonal Therapy, Surgical Interventions, and Complementary Therapies. Cureus, 16(12): e75590. https://doi.org/10.7759/cureus.75590\nAppleyard CB, Flores I, Torres-Reverón A, 2020. The Link Between Stress and Endometriosis: from Animal Models to the Clinical Scenario. Reprod Sci, 27(9): 1675-1686. https://doi.org/10.1007/s43032-020-00205-7\nde Dios Tapia A, Rueda-Extremera M, Cantero-García M, 2026. Cognitive-behavioral, acceptance-based, and mindfulness-based interventions for psychological and sleep-related symptoms during menopause: a systematic review. Acta Psychologica, 264: 106613. https://doi.org/10.1016/j.actpsy.2026.106613\nXu Y, Deng Z, Fei F, Zhou S, 2024. An overview and comprehensive analysis of interdisciplinary clinical research in endometriosis based on trial registry. iScience, 27(3): 109298. https://doi.org/10.1016/j.isci.2024.109298.\nTulandi T, Vercellini P, 2024. Growing evidence that endometriosis is a systemic disease. Reproductive biomedicine online, 49(3), 104292. https://doi.org/10.1016/j.rbmo.2024.104292\nSabbadin C, Saccardi C, Andrisani A, Vitagliano A, Marin L, Ragazzi E, Bordin L, Ambrosini G, Armanini D, 2022. Role of Renin-Angiotensin-Aldosterone System and Cortisol in Endometriosis: A Preliminary Report. International Journal of Molecular Sciences, 24(1): 310. https://doi.org/10.3390/ijms24010310\nSimancas-Racines D, Jiménez-Flores E, Montalvan M, Horowitz R, Araujo V, Reytor-González C, 2026. Endometriosis as a Systemic and Complex Disease: Toward Phenotype-Based Classification and Personalized Therapy. International journal of molecular sciences, 27(2): 908. https://doi.org/10.3390/ijms27020908\nSaunders PTK, Horne AW, 2025. Endometriosis: new insights and opportunities for relief of symptoms. Biology of Reproduction, 113(5): 1029–1043. https://doi.org/10.1093/biolre/ioaf164\nTaylor HS, Kotlyar AM, Flores VA, 2021. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet (London, England), 397(10276): 839–852. https://doi.org/10.1016/S0140-6736(21)00389-5\nTsamantioti ES, Mahdy H, 2023. Endometriosis. [Updated 2023 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567777/(Accessed 3 July 2026).\nGawarecka K, Gałka K, 2026. Endometriosis as a systemic disease with neuroimmunological and tumor-like features: A review of current pathophysiological mechanisms. Annales Academiae Medicae Silesiensis. https://doi.org/10.18794/aams/222342 (Accepted, in press).\nShifon S, Tyrinova T, Veretelnikova T, Pasman N, Chernykh E, 2025. Endometriosis as an immune-mediated disease: pathogenetic mechanisms and therapeutic strategies. Frontiers in Immunology, 16: 1727183. https://doi.org/10.3389/fimmu.2025.1727183\nDonatti L, Malvezzi H, Azevedo BC, Baracat EC, Podgaec S, 2022. Cognitive Behavioral Therapy in Endometriosis, Psychological-Based Intervention: A Systematic Review. Intervenção psicológica baseada na terapia cognitivo-comportamental na endometriose: Uma revisão sistemática. Revista brasileira de ginecologia e obstetrícia: revista da Federação Brasileira das Sociedades de\nGinecologiae Obstetrícia, 44(3):295–303.\nDownloads\nPublished\nHow to Cite\nIssue\nSection\nLicense\nCopyright (c) 2026 Daniel I. Oraekei, Ogbonnaya Mba, Onyeka C. Obidiegwu, Harrison O. Abone\nThis work is licensed under a Creative Commons Attribution 4.0 International License.\nAll articles published in Advanced Pharmaceutical and Biomedical Letters (AdvPBL) are distributed under an Open Access Creative Commons License BY/4.0. Users are allowed to freely download, read, distribute the materials in any medium or format, remix, reuse the articles or quote the articles, so long as proper attribution is given to the original creators (authors and publishers). 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