THE NEUROBIOLOGICAL AND IMMUNOLOGICAL BASIS OF THE CO-OCCURRENCE OF ENDOMETRIOSIS WITH DEPRESSION AND ANXIETY: A SYSTEMATIC REVIEW

Endometriosis is a chronic, oestrogen-dependent inflammatory condition affecting approximately 10% of women of reproductive age worldwide. In addition to its well-documented gynaecological symptoms, endometriosis is increasingly associated with psychiatric disorders, particularly depression and anxiety disorders. The neurobiological and immunological mechanisms underpinning this comorbidity remain poorly understood.

This systematic review aims to synthesise current data on the neurobiological, neuroendocrine and immunological mechanisms linking endometriosis to depression and anxiety disorders, taking into account additional psychiatric symptoms such as sleep disorders, post-traumatic stress disorder (PTSD) and sexual dysfunction.

A systematic search of the PubMed/MEDLINE database was conducted to identify articles published between January 2008 and March 2026, using predefined search terms relating to endometriosis, mental health, neuroinflammation and immune dysregulation. Study selection was carried out in accordance with the PRISMA 2020 guidelines. Studies analysing the association between endometriosis and psychiatric outcomes, or investigating the underlying biological mechanisms, were included.

Thirty studies met the inclusion criteria. The data consistently indicate elevated rates of depression (prevalence 9.8-98.5 per cent) and anxiety (11.5-87.5 per cent) in women with endometriosis compared with the general population. Key mechanisms identified include: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis; systemic and central neuroinflammation mediated by pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha), oestrogen-induced neurotransmitter imbalances, central sensitisation, oxidative stress and gut-brain axis dysfunction.

The relationship between endometriosis and psychiatric disorders is bidirectional and mediated by combined neuroendocrine-immunological pathways. These findings highlight the need for integrated, multidisciplinary management strategies that take into account both the somatic and psychological dimensions of endometriosis.

As-Sanie, S., Mackenzie, S. C., Morrison, L., Schrepf, A., Zondervan, K. T., Horne, A. W., & Missmer, S. A. (2025). Endometriosis: A review. JAMA, 334(1), 64–78. https://doi.org/10.1001/jama.2025.2975 Masciullo, L., Viscardi, M. F., Piacenti, I., Scaramuzzino, S., Cavalli, A., Piccioni, M. G., & Porpora, M. G. (2021). A deep insight into pelvic pain and endometriosis: A review of the literature from pathophysiology to clinical manifestations. Minerva Obstetrics and Gynaecology, 73(5), 511–522. https://doi.org/10.23736/S2724-606X.21.04779-1 van Barneveld, E., Manders, J., van Osch, F. H. M., van Poll, M., Visser, L., van Hanegem, N., Lim, A. C., Bongers, M. Y., & Leue, C. (2022). Depression, anxiety, and correlating factors in endometriosis: A systematic review and meta-analysis. Journal of Women’s Health, 31(2), 219–230. https://doi.org/10.1089/jwh.2021.0021 Delanerolle, G., Ramakrishnan, R., Hapangama, D., Zeng, Y., Shetty, A., Elneil, S., Chong, S., Hirsch, M., Oyewole, M., Phiri, P., Elliot, K., Kothari, T., Rogers, B., Sandle, N., Haque, N., Pluchino, N., Silem, M., O’Hara, R., Hull, M. L., … Raymont, V. (2021). A systematic review and meta-analysis of the endometriosis and mental-health sequelae: The ELEMI project. Women’s Health, 17, 17455065211019717. https://doi.org/10.1177/17455065211019717 Gambadauro, P., Carli, V., & Hadlaczky, G. (2019). Depressive symptoms among women with endometriosis: A systematic review and meta-analysis. American Journal of Obstetrics and Gynaecology, 220(3), 230–241. https://doi.org/10.1016/j.ajog.2018.11.123 Ortiz, R., Gemmill, J. A. L., Sinaii, N., Stegmann, B., Khachikyan, I., Chrousos, G., Segars, J., & Stratton, P. (2020). Hypothalamic-pituitary-adrenal axis responses in women with endometriosis-related chronic pelvic pain. Reproductive Sciences, 27(10), 1839–1847. https://doi.org/10.1007/s43032-020-00201-x Petrelluzzi, K. F. S., Garcia, M. C., Petta, C. A., Grassi-Kassisse, D. M., & Spadari-Bratfisch, R. C. (2008). Salivary cortisol concentrations, stress and quality of life in women with endometriosis and chronic pelvic pain. Stress, 11(5), 390–397. https://doi.org/10.1080/10253890701840610 Sherwani, S., Khan, M. W. A., Rajendrasozhan, S., Al-Motair, K., Husain, Q., & Khan, W. A. (2024). The vicious cycle of chronic endometriosis and depression—An immunological and physiological perspective. Frontiers in Medicine, 11, 1425691. https://doi.org/10.3389/fmed.2024.1425691 Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biological Psychiatry, 65(9), 732–741. https://doi.org/10.1016/j.biopsych.2008.11.029 Chang, L., Shan, J., Li, D., & Wang, X. (2025). The neuroendocrine-immune axis in endometriosis: A review on how the nervous system goes beyond pain perception. Biomolecules, 15(11), 1536. https://doi.org/10.3390/biom15111536 Appleyard, C. B., Flores, I., & Torres-Reveron, A. (2020). The link between stress and endometriosis: From animal models to the clinical scenario. Reproductive Sciences, 27(9), 1675–1686. https://doi.org/10.1007/s43032-020-00205-7 Szyplowska, M., Tarkowski, R., & Kulak, 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 Wang, Y., Li, B., Zhou, Y., Wang, Y., Han, X., Zhang, S., He, Z., & Ouyang, L. (2021). Does endometriosis affect mental health and quality of life? A systematic review and meta-analysis. Gynecological and Obstetrical Investigation, 86(4), 315–335. https://doi.org/10.1159/000516517 Brasil, D. L., Montagna, E., Trevisan, C. M., La Rosa, V. L., Lagana, A. S., Barbosa, C. P., Bianco, B., & Zaia, V. (2020). Psychological stress levels in women with endometriosis: Systematic review and meta-analysis of observational studies. Minerva Medica, 111(1), 90–102. https://doi.org/10.23736/S0026-4806.19.06350-X Davenport, R. A., Krug, I., Dang, P. L., Rickerby, N., & Kiropoulos, L. (2024). Neuroticism and cognitive correlates of depression and anxiety in endometriosis: A meta-analytic review, evidence appraisal, and future recommendations. Journal of Psychosomatic Research, 187, 111906. https://doi.org/10.1016/j.jpsychores.2024.111906 Quinones, M., Urrutia, R., Torres-Reveron, A., Vincent, K., & Flores, I. (2015). Anxiety, coping skills and the hypothalamic-pituitary-adrenal (HPA) axis in patients with endometriosis. Journal of Reproductive Biology and Health, 3, 2. https://doi.org/10.7243/2054-0841-3-2 Ahn, S. H., Monsanto, S. P., Miller, C., Singh, S. S., Thomas, R., & Tayade, C. (2015). Pathophysiology and immune dysfunction in endometriosis. BioMed Research International, 2015, 795976. https://doi.org/10.1155/2015/795976 Bjork, E., Vinnars, M.-T., Nagaev, I., Nagaeva, O., Lundin, E., Ottander, U., & Mincheva-Nilsson, L. (2020). Enhanced local and systemic inflammatory cytokine mRNA expression in women with endometriosis evokes a compensatory adaptive regulatory mRNA response that mediates immune suppression and impairs cytotoxicity. American Journal of Reproductive Immunology, 84(4), e13298. https://doi.org/10.1111/aji.13298 Siedentopf, F., Tariverdian, N., Rucke, M., Kentenich, H., & Arck, P. C. (2008). Immune status, psychosocial distress and reduced quality of life in infertile patients with endometriosis. American Journal of Reproductive Immunology, 60(5), 449–461. https://doi.org/10.1111/j.1600-0897.2008.00644.x Felger, J. C., & Lotrich, F. E. (2013). Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience, 246, 199–229. https://doi.org/10.1016/j.neuroscience.2013.04.060 Hearn-Yeates, F., Horne, A. W., O’Mahony, S., & Saunders, P. T. K. (2024). The impact of the microbiota-gut-brain axis on endometriosis-associated symptoms: Mechanisms and opportunities for personalised management strategies. Reproduction and Fertility, 5(2), e230085. https://doi.org/10.1530/RAF-23-0085 Scutiero, G., Iannone, P., Bernardi, G., Bonaccorsi, G., Spadaro, S., Volta, C. A., Greco, P., & Nappi, L. (2017). Oxidative stress and endometriosis: A systematic review of the literature. Oxidative Medicine and Cellular Longevity, 2017, 7265238. https://doi.org/10.1155/2017/7265238 Allen, J., Romay-Tallon, R., Brymer, K. J., Caruncho, H. J., & Kalynchuk, L. E. (2018). Mitochondria and mood: Mitochondrial dysfunction as a key player in the manifestation of depression. Frontiers in Neuroscience, 12, 386. https://pmc.ncbi.nlm.nih.gov/articles/PMC5997778/ Mokhtari, T., Irandoost, E., & Sheikhbahaei, F. (2024). Stress, pain, anxiety, and depression in endometriosis—Targeting glial activation and inflammation. International Immunopharmacology, 132, 111942. https://doi.org/10.1016/j.intimp.2024.111942 Maulitz, L., Stickeler, E., Stickel, S., Habel, U., Tchaikovski, S. N., & Chechko, N. (2022). Endometriosis, psychiatric comorbidities and neuroimaging: Estimating the odds of an endometriosis brain. Frontiers in Neuroendocrinology, 65, 100988. https://pubmed.ncbi.nlm.nih.gov/35202605/ Bendis, P. C., Zimmerman, S., Onisiforou, A., Zanos, P., & Georgiou, P. (2024). The impact of oestradiol on serotonin, glutamate, and dopamine systems. Frontiers in Neuroscience, 18, 1348551. https://doi.org/10.3389/fnins.2024.1348551 Dipankar, S. P., Kushram, B., Unnikrishnan, P., Gowda, J. R., Shrivastava, R., Daitkar, A. R., & 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 Donatti, L., Malvezzi, H., Azevedo, B. C., Baracat, E. C., & Podgaec, S. (2022). Cognitive behavioural therapy in endometriosis: A psychological-based intervention. Revista Brasileira de Ginecologia e Obstetricia, 44(3), 295–303. https://doi.org/10.1055/s-0042-1742406 Facchin, F., Buggio, L., Roncella, E., Somigliana, E., Ottolini, F., Dridi, D., Roberto, A., & Vercellini, P. (2021). Sleep disturbances, fatigue and psychological health in women with endometriosis: A matched pair case-control study. Reproductive Biomedicine Online, 43(6), 1027–1034. https://doi.org/10.1016/j.rbmo.2021.08.011 Moradi, Y., Shams-Beyranvand, M., Khateri, S., Gharahjeh, S., Tehrani, S., Varse, F., Tiyuri, A., & Najmi, Z. (2021). A systematic review on the prevalence of endometriosis in women. Indian Journal of Medical Research, 154(3), 446–454. https://doi.org/10.4103/ijmr.IJMR_817_18 Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hrobjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. International Journal of Surgery, 88, 105906. https://doi.org/10.1016/j.ijsu.2021.105906 Privitera, G., O’Brien, K., Misajon, R., & Lin, C.-Y. (2023). Endometriosis symptomatology, dyspareunia, and sexual distress are related to avoidance of sex and negative impacts on the sex lives of women with endometriosis. International Journal of Environmental Research and Public Health, 20(4), 3362. https://doi.org/10.3390/ijerph20043362 Sumbodo, C. D., Tyson, K., Mooney, S., Lamont, J., McMahon, M., & Holdsworth-Carson, S. J. (2024). The relationship between sleep disturbances and endometriosis: A systematic review. European Journal of Obstetrics & Gynaecology and Reproductive Biology, 293, 1–8. https://doi.org/10.1016/j.ejogrb.2023.12.010 Downloads Published Issue Section License Copyright (c) 2026 Julia Wawerska, Martyna Grzywacz, Bartosz Okliński, Maciej Kisielewski, Mateusz Zugaj, Weronika Wrzosek, Rafał Ejsner, Marta Rząsa, Balbina Tybulczuk, Bartłomiej Markowski This work is licensed under a Creative Commons Attribution 4.0 International License. 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