Melatonin and prostate cancer risk: what the research says

In brief

• An initial study on Icelandic men reported higher levels of urinary melatonin (6‑sulfatoxymelatonin) associated with a lower risk of advanced prostate disease.
• Subsequent studies, including those in larger or multi-ethnic populations, have not always replicated a net effect on the overall incidence of prostate cancer.
• There are plausible biological mechanisms — from its antioxidant effect to its influence on cellular metabolism — that explain why melatonin might affect tumor progression.
• Current evidence is primarily observational and does not allow for causal or therapeutic conclusions; additional rigorous experimental studies are needed.

Abstract: what does science say?

Melatonin is a hormone primarily produced by the small brain organ called the pineal gland; it regulates the sleep-wake rhythm and is measured in epidemiology mainly through its primary urinary metabolite, 6-sulfatoxymelatonin. Some observational studies have suggested that higher levels of this marker may be associated with a lower risk of advanced prostate disease, while larger, multi-ethnic studies have not confirmed a consistent association with overall prostate cancer risk. In the laboratory, melatonin shows antioxidant actions, modulation of cellular metabolism, and potential anti-tumor effects; however, the evidence that endogenous melatonin levels prevent cancer in humans remains incomplete. For now, the data support biological plausibility and epidemiological signals that warrant further investigation, but do not justify clinical changes or therapeutic recommendations based solely on melatonin or its measurements.

Epidemiological Evidence and Biomarker Use

Most studies have used the concentration of the main urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), measured in the first morning sample as an integrated indicator of nocturnal melatonin production. This approach is considered valid for assessing endogenous melatonin exposure in the population and allows for prospective studies based on pre-diagnostic samples. The initial signal that attracted clinical attention came from a study on an Icelandic cohort (AGES-Reykjavik), which reported a marked reduction in the risk of advanced prostate disease in subjects with aMT6s levels above the median. This result stimulated subsequent studies and analyses in different populations, with partially discordant results: some research did not observe a significant association with the overall risk of prostate cancer, emphasizing that the effect might be limited to advanced forms or depend on the clinical and demographic context [1][2][3].

The AGES-Reykjavik Study and the Initial Signal

In a prospective cohort of elderly men included in the AGES-Reykjavik project, researchers measured 6-sulfatoxymelatonin in the first urine sample and recorded future cases of prostate cancer. Compared to advanced cases, the analysis showed a significant inverse association for high levels of the marker compared to lower ones. These results, also presented in conference settings, highlighted a possible role of nocturnal melatonin secretion in the progression to more aggressive forms of the disease, although they require independent confirmation and analysis in larger populations [1].

Replications and Multi-ethnic Populations: Inconsistent Results

Subsequent studies on larger and more diverse samples (including the Multiethnic Cohort) did not find a significant association between aMT6s levels and prostate cancer risk in the overall population, nor clear differences between ethnic subgroups. These outcomes indicate that the signal observed in the initial cohorts might not be generalizable or could be influenced by confounding factors not fully controlled (e.g., screening, comorbidities, medications, or sample collection time) [2][3].

Plausible biological mechanisms

From a biological perspective, there are multiple mechanisms by which melatonin could influence tumor development or progression: direct antioxidant action, modulation of apoptotic pathways, regulation of cellular metabolism, and interaction with MT1/MT2 receptors that can alter proliferation signals. In cellular and animal models, melatonin has been shown to slow tumor growth, modulate angiogenesis, and enhance the effect of some anti-cancer therapies. These experimental evidences are consistent with the hypothesis that melatonin can influence the biology of prostate cells, but their translation to human risk remains complex and conditioned by doses, exposure times, and biological context [5][6][7].

Effects observed in cellular and preclinical models

Laboratory studies on prostate cell lines have shown that melatonin can reduce glucose uptake, slow glycolysis, and decrease the production of key metabolites used for cell growth, suggesting a direct metabolic effect on androgen-sensitive tumors. Other experiments indicate inhibition of proliferation and increased apoptosis after melatonin exposure. These biological effects support mechanistic plausibility, but the concentrations and experimental conditions are often very different from physiological ones in humans [6][5].

Circadian rhythm, night light, and pineal regulation

Melatonin production is regulated by the circadian rhythm and light-dark signals; factors such as shift work, exposure to night light, or sleep disorders can reduce its synthesis. Some genetic and observational studies have investigated variants in circadian genes or the presence of sleep disorders in relation to the risk of oncological outcomes, showing fragmented results that require further confirmation. Individual variability in the structure and function of the pineal gland can also influence melatonin secretion [4][3].

What this means in practice

For the general public, current evidence indicates that there is biological plausibility and epidemiological signals—particularly for advanced prostate disease—but there is not enough certainty to recommend specific preventive measures based on melatonin or its supplementation. Measuring the urinary metabolite (aMT6s) is a useful tool for research and for understanding how sleep, light exposure, and medications affect nocturnal secretion. However, conflicting data across populations and the observational nature of the studies prevent inferring that modifying melatonin levels directly reduces cancer risk.

In practice: paying attention to sleep quality and the regularity of the sleep-wake rhythm is a good general health strategy; but the use of melatonin as a specific preventive measure against prostate cancer is not supported by current evidence. Any therapeutic changes or the use of supplements should be evaluated with your doctor, especially in the presence of other health conditions or ongoing therapies [2][5].

Key points to remember

• Urinary 6-sulfatoxymelatonin (aMT6s) is the main biomarker used in epidemiological studies to estimate nocturnal melatonin production.
• A study in the Icelandic population observed an inverse association with advanced prostate disease, but not all subsequent research has replicated a similar effect in large cohorts.
• In the laboratory, melatonin shows potentially anti-tumor effects; the clinical translation of these results is still uncertain.
• The evidence is predominantly observational: it does not establish causality nor justify routine therapeutic interventions based on melatonin to prevent prostate cancer.

Limitations of the Evidence

Difference between observational studies and causal evidence: most studies on the association between melatonin and prostate cancer are prospective observational studies. These can identify associations but do not prove a cause-and-effect relationship, because they are vulnerable to residual confounding and bias (e.g., differences in screening, comorbidities, or use of drugs that affect melatonin metabolism) [2][1].

Methodological limitations: measuring aMT6s in a single morning sample is practical but may not capture intra-individual variations over time; furthermore, sample collection, management, and control for creatinine or other factors influence comparability between studies [3][8].

Context variability: factors such as age, ethnicity, nocturnal light exposure, medications (e.g., beta-blockers), and general health status modify melatonin secretion and may explain discordant results among different cohorts [3].

Need for cautious interpretation: replication studies in independent cohorts, analyses with repeated measures over time, and, when possible, controlled experimental trials are needed to clarify if and how melatonin can influence the risk or progression of prostate cancer [2][5][7].

Editorial Conclusion

Research on melatonin and prostate cancer is an active and interesting field because it brings together epidemiology, circadian biology, and molecular mechanisms. There are signals that warrant further study — particularly regarding progression to advanced forms — and solid experimental bases that support biological plausibility. However, at present, the evidence is not sufficient to draw definitive conclusions or to adopt targeted clinical interventions. Scientific communication must therefore remain cautious: inform the public about the results, limitations, and future prospects, without transforming initial suggestions into unvalidated recommendations.

Editorial Note

This update was prepared following criteria of transparency and verifiability of scientific sources, with accessible language and attention to the distinction between observational association and causal proof. The content is for informational purposes only and does not replace personalized medical advice. For clinical questions, consult your trusted doctor.

Scientific Research

The following publications have been selected as direct references to the claims and topics discussed in the article. For each, the clickable DOI is provided for verification.

1. Sigurdardottir LG, Markt SC, Sigurdsson S, Aspelund T, Fall K, Schernhammer E, et al. Pineal gland volume assessed by MRI and its correlation with 6‑sulfatoxymelatonin levels among older men. Journal of Biological Rhythms. 2016;31(5):(see article). https://doi.org/10.1177/0748730416656948. [Used to discuss pineal volume and aMT6s correlation]
2. Sigurdardottir L, Markt S, et al. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. European Urology. (AGES‑Reykjavik study). https://doi.org/10.1016/j.eururo.2014.07.008. [AGES‑Reykjavik study: association with advanced prostate disease]
3. Vaselkiv JB, Cheng I, Chowdhury‑Paulino IM, Gonzalez‑Feliciano AG, Wilkens LR, Hauksdóttir AM, et al. Urinary 6‑sulfatoxymelatonin levels and prostate cancer risk among men in the Multiethnic Cohort. Cancer Epidemiology, Biomarkers & Prevention. 2022;31(3):688–691. https://doi.org/10.1158/1055-9965.EPI-21-1041. [Multi-ethnic population; null results on overall risk]
4. Markt SC, Valdimarsdottir U, Shui IM, et al. Circadian clock genes and risk of fatal prostate cancer. Cancer Causes & Control. 2014;26(1):(see article). https://doi.org/10.1007/s10552-014-0478-z. [Genetic analysis of circadian rhythms and weak associations]
5. Li Y, Li S, Zhou Y, et al. Melatonin for the prevention and treatment of cancer: mechanisms and evidence. Oncotarget. 2017;8:39896–39921. https://doi.org/10.18632/oncotarget.16379. [Mechanistic review and preclinical evidence]
6. Hevia D, Torres M, et al. Melatonin decreases glucose metabolism in prostate cancer cells: a 13C stable isotope‑resolved metabolomic study. International Journal of Molecular Sciences. 2017;18(8):1620. https://doi.org/10.3390/ijms18081620. [Experimental study on tumor metabolism]
7. Mehrzadi S, Pourhanifeh MH, Mirzaei A, et al. An updated review of mechanistic potentials of melatonin against cancer. Cancer Cell International. 2021;21:188. https://doi.org/10.1186/s12935-021-01892-1. [Updated review on biological pathways]
8. Wu AH, Zeleniuch‑Jacquotte A, et al. Urinary 6‑sulfatoxymelatonin level and breast cancer risk: systematic review and meta‑analysis (example of biomarker validation). Scientific Reports. 2017. https://doi.org/10.1038/s41598-017-05752-9. [Used for comparison and methodological validation of aMT6s]