Melatonin and prostate cancer risk: an update on the evidence

In brief

• There are experimental studies showing anti-proliferative effects of melatonin on prostate cancer cells and animal models.
• Observational studies in humans yield conflicting results: some research reports inverse associations with advanced disease, while others find no significant relationship.
• Proposed mechanisms include modulation of the androgen-receptor axis, antioxidant activity, regulation of circadian rhythm genes, and receptor-dependent and independent actions.
• The evidence does not allow for asserting a causal relationship or recommending the preventive use of melatonin for prostate cancer; larger clinical and prospective studies are needed.

Abstract: what does science say?

Melatonin is the main hormone of the night and a key signal of the circadian rhythm. In the laboratory, melatonin concentrations can slow the growth of prostate cell lines and modify signals related to cell proliferation and survival. Observational studies in humans, measuring the main urinary metabolite (6-sulfatoxymelatonin), have yielded inconsistent results: research in specific populations found an inverse association with advanced disease, while larger, multi-ethnic studies did not confirm a clear protective effect. Multiple biological plausibilities exist, but methodological limitations (single-point biomarker measurement, possible confounding, population diversity) prevent definitive causal conclusions. In summary, the literature suggests potential anti-cancer mechanisms of melatonin, but evidence that higher levels reduce the risk of prostate cancer in humans remains uncertain.

Scientific Evidence: Types of Studies and Results

Experimental Evidence and Biological Mechanisms

In vitro and animal model experiments show that melatonin can limit prostate cell proliferation, induce apoptosis, modify androgen receptor trafficking, and alter metabolic and angiogenic pathways. Studies on LNCaP and PC3 tumor cell lines document an antiproliferative effect and cell differentiation following melatonin treatment [1]. More recent research has described specific molecular mechanisms, including increased HDAC1 SUMOylation and reduced SENP1, which result in decreased transcriptional activity of the androgen receptor in androgen-sensitive cells [5]. Further studies indicate that melatonin can resynchronize clock genes (PER2, CLOCK) altered in prostate tumor cells, offering a plausible pathway of action linked to the circadian rhythm [6].

Observational Evidence in Humans

Studies measuring urinary 6-sulfatoxymelatonin report conflicting results. Some cohorts and hospital studies have observed that higher melatonin levels (or a favorable melatonin/cortisol ratio) are associated with a lower probability of advanced cancer or the presence of the disease [3]. However, a large, multi-ethnic prospective study found no significant associations between urinary melatonin levels and overall or advanced prostate cancer risk [2]. These differences may stem from diverse populations, different measures (early morning vs. 24h), control for confounders, and limited statistical power for advanced forms.

Circadian Genetics and Related Factors

Variants in circadian rhythm genes have been studied as possible indicators of prostate cancer susceptibility and progression; partial results indicate nominal associations, but no solid and repeated evidence at the genome-wide level [4]. This supports the hypothesis that perturbations in biological timing may contribute to risk, but does not prove that melatonin is the primary causal factor.

What this means in practice

For the general public: the data do not justify the use of melatonin as a proven strategy to prevent prostate cancer. Available information shows biological plausibility and promising laboratory results, but high-quality clinical and prospective studies are insufficient for recommendations. Those who use melatonin for sleep problems or on medical advice should discuss it with their doctor, especially if they are undergoing cancer therapies or taking medications that may interact. Improving sleep hygiene, reducing exposure to bright light at night, and following healthy lifestyles remain established strategies for general health; the impact of these behaviors on prostate cancer risk is an active area of research [2][3].

Key takeaways

• Melatonin is a key marker of the circadian rhythm with multiple biological activities.
• In vitro and in animal models, it shows relevant anti-tumor effects, but experimental conditions often use concentrations higher than physiological ones [1][5].
• Human observational studies show conflicting results; a large, multi-ethnic study found no significant associations [2].
• Associating melatonin levels with reduced risk requires caution: association is not causation.
• Always consult a doctor before taking melatonin for preventive or therapeutic purposes.

Limitations of Evidence

It is crucial to distinguish between observed association and causal proof. Observational studies can suggest correlations but remain susceptible to residual confounding, selection bias, and punctual biomarker measurements that do not reflect long-term exposure [2][3]. Laboratory studies often use doses and experimental conditions that are not comparable to human physiology, limiting clinical generalizability [1][6]. Furthermore, variability among populations, urine collection methods (first morning vs. 24 h), creatinine corrections, and diagnostic timings can explain divergent results. To establish causality, prospective studies with repeated measures, randomized interventions, or intervention studies with relevant endpoints are needed.

Editorial Conclusion

The overall research picture indicates that melatonin has biological effects that can interfere with some tumor mechanisms in the prostate. However, current clinical evidence is not consistent and does not allow melatonin to be considered a proven protective factor against prostate cancer. Science moves forward: larger prospective studies, controlled clinical interventions, and integrated mechanistic analyses are needed to clarify if and how the regulation of the circadian rhythm and melatonin levels can affect the risk and progression of prostate cancer. In the meantime, sleep management and reducing exposure to night light remain reasonable practices for overall health.

Editorial Note

This update was created by integrating experimental studies, observational studies, and systematic reviews to offer a balanced and transparent overview. Therapeutic or preventive decisions should be discussed with a doctor. Complete references are provided in the "Scientific Research" section to allow for verification and further study.

DOIs and links to cited research

1. https://doi.org/10.1002/pros.20155
2. https://doi.org/10.1158/1055-9965.EPI-21-1041
3. https://doi.org/10.1038/srep29606
4. https://doi.org/10.1007/s10552-014-0478-z
5. https://doi.org/10.21037/tau-21-1110
6. https://doi.org/10.1111/j.1600-079X.2010.00767.x
7. https://doi.org/10.1034/j.1600-079x.2000.d01-64.x
8. https://doi.org/10.3390/ijms18040843

Scientific research

1. Sainz RM, Mayo JC, Tan DX, León J, Manchester L, Reiter RJ. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate. 2005;63(1):29–43. https://doi.org/10.1002/pros.20155
2. Vaselkiv JB, Cheng I, Chowdhury‑Paulino IM, Gonzalez‑Feliciano AG, Wilkens LR, Hauksdóttir AM, Eiriksdottir G, Le Marchand L, Haiman CA, Valdimarsdóttir U, Mucci LA, Markt SC. Urinary 6‑sulfatoxymelatonin levels and prostate cancer risk among men in the Multiethnic Cohort. Cancer Epidemiol Biomarkers Prev. 2022;31(3):688–691. https://doi.org/10.1158/1055-9965.EPI-21-1041
3. Tai SY, Huang SP, Bao BY, Wu MT. Urinary melatonin‑sulfate/cortisol ratio and the presence of prostate cancer: A case‑control study. Sci Rep. 2016;6:29606. https://doi.org/10.1038/srep29606
4. Markt SC, Valdimarsdottir UA, Shui IM, et al. Circadian clock genes and risk of fatal prostate cancer. Cancer Causes Control. 2015;26(1):25–33. https://doi.org/10.1007/s10552-014-0478-z
5. Hao L, Dong Y, Zhang JJ, et al. Melatonin decreases androgen‑sensitive prostate cancer growth by suppressing SENP1 expression. Transl Androl Urol. 2022;11(1):91–103. https://doi.org/10.21037/tau-21-1110
6. Jung‑Hynes B, Huang W, Reiter RJ, Ahmad N. Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells. J Pineal Res. 2010;49(1):60–68. https://doi.org/10.1111/j.1600-079X.2010.00767.x
7. Xi SC, Tam PC, Brown GM, Pang SF, Shiu SY. Potential involvement of MT1 receptor and attenuated sex steroid‑induced calcium influx in the direct anti‑proliferative action of melatonin on androgen‑responsive LNCaP human prostate cancer cells. J Pineal Res. 2000;29(3):172–183. https://doi.org/10.1034/j.1600-079x.2000.d01-64.x
8. Fatehi HS, Reiter RJ, et al. Melatonin, a Full Service Anti‑Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci. 2017;18(4):843. https://doi.org/10.3390/ijms18040843