MELATONIN AS A THERAPEUTIC OPTION FOR ENDOMETRIOSIS: A NARRATIVE REVIEW
DOI:
https://doi.org/10.31435/ijitss.4(52).2026.6316Keywords:
Melatonin, Endometriosis, Oxidative Stress, Chronic Pelvic Pain, Anti-inflammatory AgentsAbstract
Endometriosis 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.
References
Anderson, 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
Çetinkaya, 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
Chuffa, 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
Dymanowska-Dyjak, I., Frankowska, K., Abramiuk, M., & Polak, G. (2024). Oxidative Imbalance in Endometriosis-Related Infertility—The Therapeutic Role of Antioxidants. International Journal of Molecular Sciences, 25(12), 6298–6298. https://doi.org/10.3390/ijms25126298
Esmaeilzadeh, S., Habibolahi, F., Moher, D., Basirat, Z., Gholinia, H., Golsorkhtabaramiri, M., & Mirabi, P. (2025). Melatonin and sleep parameters in infertile women with endometriosis: first results from the triple-blind randomized controlled trial of administration of melatonin in chronic pelvic pain and sleep disturbance. https://doi.org/10.1371/journal.pone.0321635
Esmaeilzadeh, S., Sadrzadeh, A., Moher, D., Sepidarkish, M., Alamolhoda, S. H., & Mirabi, P. (2025). Efficacy of antioxidant supplementation in alleviating endometriosis-related pain: insights from a systematic review and meta-analysis of RCTs. Reproductive Biology and Endocrinology, 23(1), 164–164. https://doi.org/10.1186/s12958-025-01485-x
Ferreira, I. de O., Barbon, M., Rosa, J. T. da, Costella, A. P., Brietzke, A. P., & Laste, G. (2024). Melatonin and Gynecologic Disorders: A Literature Review. Journal of Advances in Medicine and Medical Research, 36(2), 143–159. https://doi.org/10.9734/jammr/2024/v36i25375
Harlev, A., Gupta, S., & Agarwal, A. (2015). Targeting oxidative stress to treat endometriosis. https://doi.org/10.1517/14728222.2015.1077226
Khatun, M. S., Islam, Md. A., Islam, T., Islam, M. A., Ishrat, S., Deeba, F., Jahan, N., & Banu, J. (2025). Efficacy of melatonin and letrozole combination therapy compared to letrozole alone in the treatment of symptomatic endometrioma in infertile women. International Journal of Reproduction Contraception Obstetrics and Gynecology, 14(9), 2853–2858. https://doi.org/10.18203/2320-1770.ijrcog20252709
Koç, Ö., Gündüz, B., Topçuoğlu, A., Buğdaycı, G., Yılmaz, F., & Duran, B. (2010). Effects of pinealectomy and melatonin supplementation on endometrial explants in a rat model. https://doi.org/10.1016/j.ejogrb.2010.06.012
Li, Q., Zheng, T., Chen, J., Li, B., Zhang, Q., Yang, S., Shao, J., Guan, W., & Zhang, S. (2024). Exploring melatonin’s multifaceted role in female reproductive health: From follicular development to lactation and its therapeutic potential in obstetric syndromes. https://doi.org/10.1016/j.jare.2024.04.025
Li, Y., Hung, S. W., Xu, Z., Ding, Y., Zhang, T., Tan, Z., Zhang, R., Lin, Y., Song, Y., Wang, Y., & Wang, C. C. (2024). Melatonin Inhibits Endometriosis Growth via Specific Binding and Inhibition of EGFR Phosphorylation. https://doi.org/10.1111/jpi.70022
Li, Y., Hung, S. W., Zhang, R., Man, G. C. W., Zhang, T., Chung, J. P. W., Fang, L., & Wang, C. C. (2022). Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight. https://doi.org/10.3390/nu14194087
Mosher, A., Tsoulis, M., Lim, J., Tan, C., Agarwal, S. K., Leyland, N., & Foster, W. G. (2019). Melatonin activity and receptor expression in endometrial tissue and endometriosis. https://doi.org/10.1093/humrep/dez082
Ou, Y., Wang, H., Zhou, C., Chen, Y., Lyu, J., Feng, M., & Huang, X. (2025). Endometriosis-associated infertility: Multi-omics insights into pathogenesis and precision therapeutics. Frontiers in Endocrinology, 16, 1613334–1613334. https://doi.org/10.3389/fendo.2025.1613334
Parua, S., Choudhury, G. R., Bhattacharya, S., Hazra, A., Dutta, S., Sengupta, P., & Bhattacharya, K. (2024). Melatonin in Female Fertility: Multifaceted Role From Reproductive Physiology to Therapeutic Potential in Polycystic Ovary Syndrome, Endometriosis, and Ovarian Failure. Chronobiology in Medicine, 6(4), 145–162. https://doi.org/10.33069/cim.2024.0022
Paul, S., Sharma, A. V., Mahapatra, P. D., Bhattacharya, P., Reiter, R. J., & Swarnakar, S. (2008). Role of melatonin in regulating matrix metalloproteinase‐9 via tissue inhibitors of metalloproteinase‐1 during protection against endometriosis. Journal of Pineal Research, 44(4), 439–449. https://doi.org/10.1111/j.1600-079x.2007.00547.x
Schwertner, A., Santos, C. C. C. dos, Costa, G. D., Deitos, A., Souza, A. de, Souza, I. C. C. de, Torres, I. L. da S., Cunha‐Filho, J. S., & Caumo, W. (2013). Efficacy of melatonin in the treatment of endometriosis: A phase II, randomized, double-blind, placebo-controlled trial. https://doi.org/10.1016/j.pain.2013.02.025
Söderman, L., Böttiger, Y., Edlund, M., Järnbert‐Pettersson, H., & Marions, L. (2023). Adjuvant use of melatonin for pain management in endometriosis-associated pelvic pain—A randomized double-blinded, placebo-controlled trial. https://doi.org/10.1371/journal.pone.0286182
Tesařík, J., & Tesarik, R. M. (2025). Melatonin in the Treatment of Female Infertility: Update on Biological and Clinical Findings. Biomedicines, 13(10), 2434–2434. https://doi.org/10.3390/biomedicines13102434
Yang, H., Zhou, W., Gu, C., Meng, Y., Shao, J., Li, D., & Li, M. (2018). Pleiotropic roles of melatonin in endometriosis, recurrent spontaneous abortion, and polycystic ovary syndrome. https://doi.org/10.1111/aji.12839
Yeşildağlar, 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
Yıldırım, 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
Yılmaz, 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
Zhong, 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
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