Neurologic Manifestations of Endometriosis: A Review of Preclinical and Clinical Evidence

Purpose Endometriosis, a chronic inflammatory condition traditionally associated with pelvic pain and infertility, is increasingly recognized as a systemic disorder with significant neurologic implications. This review synthesizes current clinical and preclinical findings that elucidate the neurological manifestations of endometriosis, including nerve infiltration, neuroinflammation, autonomic dysfunction, and structural and functional brain changes. Recent Findings Emerging evidence highlights a complex interplay between ectopic endometrial lesions and the nervous system, involving both peripheral and central mechanisms of pain sensitization, neuroimmune dysregulation, and comorbid neurologic and psychiatric conditions. The discussion also encompasses rare but critical cases of central and peripheral nerve involvement, as well as the frequent co-occurrence of migraines, cognitive impairments, and mood disorders. By integrating insights from neuroscience, immunology, and gynecology, this paper underscores the need for multidisciplinary diagnostic and therapeutic strategies. Summary Recognizing endometriosis as a disorder with neurologic dimensions is essential for improving patient outcomes and guiding future research toward more effective, individualized interventions. Similar content being viewed by others Data Availability No datasets were generated or analysed during the current study.

Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379. Howard FM. Endometriosis and mechanisms of pelvic pain. J Minim Invasive Gynecol. 2009;16(5):540–50. Woolf CJ. Pain amplification—a perspective on the how, why, when, and where of central sensitization. J Appl Biobehavioral Res. 2018;23(2):e12124. Zheng P, Jia S, Guo D, Chen S, Zhang W, Cheng A, Xie W, Sun G, Leng J, Lang J. Central sensitization-related changes in brain function activity in a rat endometriosis-associated pain model. J Pain Res 2020 Jan 13:95–107. Bashir ST, Redden CR, Raj K, Arcanjo RB, Stasiak S, Li Q, Steelman AJ, Nowak RA. Endometriosis leads to central nervous system-wide glial activation in a mouse model of endometriosis. J Neuroinflamm. 2023;20(1):59. Ashmawi HA, Freire GM. Peripheral and central sensitization. Revista Dor. 2016;17:31–4. Castro J, Maddern J, Grundy L, Manavis J, Harrington AM, Schober G, Brierley SM. A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities. FASEB J. 2021;35(4):e21430. Vincent K, Warnaby C, Stagg CJ, Moore J, Kennedy S, Tracey I. Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain. 2011;152(9):1966–75. Tirlapur SA, Kuhrt K, Chaliha C, Ball E, Meads C, Khan KS. The ‘evil twin syndrome’in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg. 2013;11(3):233–7. Castro J, Maddern J, Erickson A, Caldwell A, Grundy L, Harrington AM, Brierley SM. Pharmacological modulation of voltage-gated sodium (NaV) channels alters nociception arising from the female reproductive tract. Pain. 2021;162(1):227–42. Ji J, Huh Y, Ji RR. Inflammatory mediators, nociceptors, and their interactions in pain. In: Neuroimmune interactions in pain: mechanisms and therapeutics 2023 May 6 (pp. 87–119). Cham: Springer International Publishing. Shiraishi T, Ikeda M, Watanabe T, Negishi Y, Ichikawa G, Kaseki H, Akira S, Morita R, Suzuki S. Downregulation of pattern recognition receptors on macrophages involved in aggravation of endometriosis. Am J Reprod Immunol. 2024;91(1):e13812. Sarma D, Iyengar P, Marotta TR, terBrugge KG, Gentili F, Halliday W. Cerebellar endometriosis. Am J Roentgenol. 2004;182(6):1543–6. Elefante C, Brancati GE, Oragvelidze E, Lattanzi L, Maremmani I, Perugi G. Psychiatric symptoms in patients with cerebral endometriosis: A case report and literature review. J Clin Med. 2022;11(23):7212. Possover M. Laparoscopic morphological aspects and tentative explanation of the aetiopathogenesis of isolated endometriosis of the sciatic nerve: a review based on 267 patients. Facts Views Vis Obgyn. 2021;13(4):369. Posover M. Laparoscopic neuropelveology: laparoscopic management of isolated endometriosis of the sciatic nerve. J Minim Invasive Gynecol. 2021;28(2):168–9. Zamurovic M, Tomic A, Djordjevic K, et al. Isolated deep infiltrating endometriosis of the sciatic nerve: a case report and overview of the literature. Medicina. 2023;59(12):2161. Nair A, Yang JT, Xu D, Zhu QT. Endometriosis of the sciatic nerve masquerading as lumbar spondylosis in a 40-year-old Chinese woman. BMJ Case Rep CP. 2021;14(8):e244584. Di Donna MC, Cucinella G, Sozzi G, et al. Surgical neuropelveology: lateral femoral cutaneous nerve endometriosis. Laparoscopic resection and nerve transplantation. J Minim Invasive Gynecol. 2021;28(12):1978–9. Kale A, Baydili KN, Keles E, et al. Comparison of isolated sciatic nerve and sacral nerve root endometriosis: a review of the literature. J Minim Invasive Gynecol. 2022;29(8):943–51. Carranco RC, Zomer MT, Berg CF, et al. Peritoneal Retraction pocket defects and their important relationship with pelvic pain and endometriosis. J Minim Invasive Gynecol. 2021;28(2):168–9. Yeung PP Jr, Logan I, Gavard JA. Deep Retraction pockets, endometriosis, and quality of life. Front Public Health. 2016;4:85. Selntigia A, Exacoustos C, Ortoleva C, Russo C, Monaco G, Martire FG, Rizzo G, Della-Morte D, Mercuri NB, Albanese M. Correlation between endometriosis and migraine features: results from a prospective case-control study. Cephalalgia. 2024;44(3):03331024241235210. Coxon L, Wiech K, Vincent K. Is there a neuropathic-like component to endometriosis-associated pain? Results from a large cohort questionnaire study. Front Pain Res. 2021;2:743812. Kigloo HN, Itani R, Montreuil T, Feferkorn I, Raina J, Tulandi T, Mansour F, Krishnamurthy S, Suarthana E. Endometriosis, chronic pain, anxiety, and depression: a retrospective study among 12 million women. J Affect Disord. 2024;346:260–5. Davenport AJ, Neagoe I, Bräuer N, Koch M, Rotgeri A, Nagel J, Laux-Biehlmann A, Machet F, Coelho AM, Boyce S, Carty N. Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers. Sci Rep. 2021;11(1):19877. Liu Y, Chen X, Zhang L, et al. Sulforaphane alleviates sciatic nerve endometriosis in a rat model. Biomed Pharmacother. 2024;160:114349. Wang X, Maddern J, Grundy L, et al. Cannabinoid modulation of endometriosis-induced hypersensitivity. Pain. 2023;164(3):503–12. Roman H, Seyer-Hansen M, Dennis T, Merlot B. Excision of deep endometriosis nodules of the sciatic nerve in 10 steps. J Minim Invasive Gynecol. 2021;28(10):1685–6. D’Ancona G, Merlot B, Verrelli L, et al. Robotic management of isolated endometriosis of sciatic nerve: a reproducible approach that can guide through the labyrinth of pelvic neuroanatomy. Fertil Steril. 2023;120(3):703–5. Roman H, Dehan L, Merlot B, et al. Postoperative outcomes after surgery for deep endometriosis of the sacral plexus and sciatic nerve: a 52-patient consecutive series. J Minim Invasive Gynecol. 2021;28(7):1375–83. Allahqoli L, Hakimi S, Momenimovahed Z, et al. Neuropelveology for endometriosis management: a systematic review and multilevel meta-analysis. J Clin Med. 2024;13(16):4676. Funding This study has received no financial support. Author information Authors and Affiliations Contributions R.A. performed literature review. J.P. wrote the main manuscript text. H.H. performed conceptualization, revisions, and supervision of manuscript preparation. All authors reviewed the manuscript. Corresponding author Ethics declarations Human and Animal Rights This article does not contain any studies with human or animal subjects performed by any of the authors. Competing Interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Prakash, J., Akerman, R. & Haber, H. Neurologic Manifestations of Endometriosis: A Review of Preclinical and Clinical Evidence. Curr Obstet Gynecol Rep 14, 27 (2025). https://doi.org/10.1007/s13669-025-00433-1 Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s13669-025-00433-1