{"paper_id":"dd533d2f-721a-413b-a5e3-762cae57e153","body_text":"MELATONIN AS A THERAPEUTIC OPTION FOR ENDOMETRIOSIS: A NARRATIVE REVIEW\nDOI:\nhttps://doi.org/10.31435/ijitss.4(52).2026.6316Keywords:\nMelatonin, Endometriosis, Oxidative Stress, Chronic Pelvic Pain, Anti-inflammatory AgentsAbstract\nEndometriosis is a chronic condition in which conventional hormonal suppression and surgical excision are frequently accompanied by high recurrence and risks to ovarian reserve (Q. Li et al., 2024; Y. Li et al., 2024). Melatonin, a pleiotropic neuroendocrine hormone with antioxidant, anti-inflammatory, and antinociceptive properties, has emerged as an adjunctive candidate that targets the oxidative-inflammatory-angiogenic axis without suppressing reproductive function (Li et al., 2022; Mosher et al., 2019). This narrative review synthesizes the available preclinical and clinical evidence, retrieved through a structured search of PubMed, Scopus, and Web of Science (January 2005–May 2025), examining melatonin's therapeutic role across seven mechanistic domains: lesion size, histological characteristics, oxidative stress, inflammatory modulation, matrix metalloproteinase regulation, angiogenesis, and chronic pelvic pain. Across more than a dozen rodent studies at 10–50 mg/kg/day, melatonin consistently reduced lesion volume and weight, restored superoxide dismutase and catalase activity while lowering malondialdehyde and COX-2, downregulated proMMP-9 and elevated TIMP-1/TIMP-2, and suppressed VEGF/VEGFR-2 signaling (Mosher et al., 2019; Yılmaz et al., 2014). Clinically, two randomized controlled trials — Schwertner et al. (n = 40, 10 mg nightly, 8 weeks) (Schwertner et al., 2013) and Esmaeilzadeh et al. (n = 80) (Esmaeilzadeh et al., 2025) — documented analgesic benefit, with the former reducing daily pain by 39.80% and the latter yielding a VAS change of −1.56 (P < 0.001). Melatonin is therefore a mechanistically distinctive, fertility-preserving adjunctive candidate for endometriosis. However, the evidence base remains weighted toward preclinical rodent models and rests on a small number of short-duration randomized trials. Larger Phase III studies with imaging-based endpoints, dose-finding designs, active-comparator arms, and extended follow-up are required before its clinical role can be considered definitive.\nReferences\nAnderson, G. (2019). Endometriosis Pathoetiology and Pathophysiology: Roles of Vitamin A, Estrogen, Immunity, Adipocytes, Gut Microbiome and Melatonergic Pathway on Mitochondria Regulation. BioMolecular Concepts, 10(1), 133–149. https://doi.org/10.1515/bmc-2019-0017\nÇetinkaya, N., Attar, R., Yıldırım, G., Fıçıcıoğlu, C., Özkan, F., Yılmaz, B., & Yeşildağlar, N. (2014). The effects of different doses of melatonin treatment on endometrial implants in an oophorectomized rat endometriosis model. https://doi.org/10.1007/s00404-014-3466-3\nChuffa, L. G. de A., Lupi, L. A., Cucielo, M. S., Silveira, H. S., Reiter, R. J., & Seiva, F. R. F. (2019). Melatonin Promotes Uterine and Placental Health: Potential Molecular Mechanisms. International Journal of Molecular Sciences, 21(1), 300–300. https://doi.org/10.3390/ijms21010300\nDymanowska-Dyjak, I., Frankowska, K., Abramiuk, M., & Polak, G. (2024). Oxidative Imbalance in Endometriosis-Related Infertility—The Therapeutic Role of Antioxidants. 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Pleiotropic roles of melatonin in endometriosis, recurrent spontaneous abortion, and polycystic ovary syndrome. https://doi.org/10.1111/aji.12839\nYeşildağlar, N., Yıldırım, G., YILDIRIM, Ö., Attar, R., Özkan, F., Akkaya, H., & Yılmaz, B. (2016). The effects of melatonin on endometriotic lesions induced by implanting human endometriotic cells in the first SCID-mouse endometriosis-model developed in Turkey. https://doi.org/10.12891/ceog2035.2016\nYıldırım, G., Attar, R., Özkan, F., Kumbak, B., Fıçıcıoğlu, C., & Yeşildağlar, N. (2009). The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. https://doi.org/10.1016/j.fertnstert.2009.09.021\nYılmaz, B., Kılıç, S., Aksakal, O., Ertaş, İ. E., Tanrisever, G. G., Aksoy, Y., Lortlar, N., Kelekçi, S., & Gungor, T. (2014). Melatonin causes regression of endometriotic implants in rats by modulating angiogenesis, tissue levels of antioxidants and matrix metalloproteinases. https://doi.org/10.1007/s00404-014-3599-4\nZhong, Y., Qiao, X., Huang, X., Li, Y., Wang, R., Liang, J., Liu, T., Bo, W., Lai, H., & Huang, W. (2025). The effects of antioxidant supplementation on pain, oxidative stress markers, and clinical pregnancy rate in women with endometriosis: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Medicine, 12, 1694281–1694281. https://doi.org/10.3389/fmed.2025.1694281\nDownloads\nPublished\nIssue\nSection\nLicense\nCopyright (c) 2026 Rafał Marciniak, Anna Bociąg, Łukasz Ptach, Konrad Kowalski, Aleksandra Milewska\nThis work is licensed under a Creative Commons Attribution 4.0 International License.\nAll articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.\nCC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.","source_license":"CC0","license_restricted":false}