Urinary Melatonin Concentration and the Risk of Breast Cancer in Nurses' Health Study II

Susan B. Brown; Susan E. Hankinson; A. Heather Eliassen; Katherine W. Reeves; Jing Qian; Kathleen F. Arcaro; Lani R. Wegrzyn; Walter C. Willett; Eva S. Schernhammer


Am J Epidemiol. 2015;181(3):155-162. 

In This Article

Abstract and Introduction


Experimental and epidemiologic data support a protective role for melatonin in breast cancer etiology, yet studies in premenopausal women are scarce. In a case-control study nested within the Nurses' Health Study II cohort, we measured the concentration of melatonin's major urinary metabolite, 6-sulfatoxymelatonin (aMT6s), in urine samples collected between 1996 and 1999 among 600 breast cancer cases and 786 matched controls. Cases were predominantly premenopausal women who were diagnosed with incident breast cancer after urine collection and before June 1, 2007. Using multivariable conditional logistic regression, we computed odds ratios and 95% confidence intervals. Melatonin levels were not significantly associated with total breast cancer risk (for the fourth (top) quartile (Q4) of aMT6s vs. the first (bottom) quartile (Q1), odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.64, 1.28; P trend = 0.38) or risk of invasive or in situ breast cancer. Findings did not vary by body mass index, smoking status, menopausal status, or time between urine collection and diagnosis (all P interaction values ≥ 0.12). For example, the odds ratio for total breast cancer among women with ≤5 years between urine collection and diagnosis was 0.74 (Q4 vs. Q1; 95% CI: 0.45, 1.20; P trend = 0.09), and it was 1.20 (Q4 vs. Q1; 95% CI: 0.72, 1.98; P trend = 0.70) for women with >5 years. Our data do not support an overall association between urinary melatonin levels and breast cancer risk.


Recent meta-analyses of epidemiologic studies suggest that women who work the night shift have a 19%–51% increased risk of breast cancer.[1–3] Decreased melatonin production due to greater light exposure at night is a potential biological mechanism underlying this relationship. Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring hormone produced primarily by the pineal gland.[4] The synthesis and release of melatonin is stimulated by darkness and suppressed by light, with low circulating levels observed during the day and the highest levels being found at night between 2 AM and 4 AM.[4] Melatonin is metabolized through the liver and excreted in the urine, and 6-sulfatoxymelatonin (aMT6s) is the main metabolite of melatonin measured in urine for estimation of circulating melatonin levels.[4]

Multiple lines of evidence support potential antiestrogenic, antioxidant, and antiproliferative properties of melatonin.[4–6] Melatonin may influence estrogen signaling directly at the tissue level through interaction with estrogen receptor or indirectly via down-regulation of the hypothalamic-pituitary-gonadal axis, resulting in reduced levels of circulating estrogens.[7,8] Further, melatonin has been shown to down-regulate aromatase expression, thereby reducing local estrogen production and suppressing tumor growth.[8]

In addition to the potential estrogen-mediated pathways, the activation of melatonin receptors, which bind melatonin, has been shown to inhibit breast tumor initiation, growth, and cell proliferation.[9] Further, in an in vitro study, melatonin receptor 1 was associated with suppressed breast tumor growth.[10] Finally, the antioxidant properties of melatonin may combat oxidative stress by suppressing tumor initiation and promoting apoptosis.[11]

Eight prospective epidemiologic studies[12–19] have examined this relationship, with conflicting results, due in part to the relatively small sample sizes and short follow-up periods in prior studies, as well as the variation in methods of assessing aMT6s levels. We conducted a prospective nested case-control study of urinary aMT6s levels and breast cancer risk among predominantly premenopausal women in the Nurses' Health Study II (NHS II) cohort. The current analysis was an extension of our previous report,[13] with 6 additional years of follow-up and triple the sample size.