We found a statistically significant inverse association between first morning urinary 6-sulfatoxymelatonin level and breast cancer risk in this large group of postmenopausal women. Among the 4,661 (25% of 18,643) women in the highest 6-sulfatoxymelatonin quartile, 75 developed breast cancer during follow-up (average follow-up = 2.4 years), compared with 107 of the 4,661 (25%) women in the lowest 6-sulfatoxymelatonin quartile.
While several prior studies evaluated the association between circulating melatonin levels and breast cancer risk in women, their results have been inconsistent; however, these studies are severely hampered by their retrospective design and their small case numbers, making interpretation difficult (30
). Three prospective studies, to date, have been conducted and they also produced inconsistent results. The first study (17
), which used 24-hour urine specimens and comprised 127 cases and 353 control subjects, reported no association between the circulating level of 6-sulfatoxymelatonin and breast cancer risk (OR = 0.99, 95% CI = 0.58 to 1.70, comparing the highest tertile with the lowest tertile of aMT6s concentration). Whether 24-hour urine samples are the right sample to capture the nocturnal melatonin peak has been questioned subsequently (43
). In the Nurses’ Health Study II (14
), first spot morning urine specimens were used. A strong inverse association between levels of 6-sulfatoxymelatonin in first morning urine specimens and breast cancer risk was reported in the 147 premenopausal women with invasive breast cancer and their 291 matched controls (OR = 0.59, 95% CI = 0.36 to 0.97, comparing the highest quartile with the lowest quartile of aMT6s concentration). Most recently, in the Hormones and Diet in the Etiology of Breast Cancer Risk (ORDET) cohort, a similarly strong inverse association between 6-sulfatoxymelatonin output as measured in 12 hour overnight urine specimen and breast cancer risk was observed in their postmenopausal women (OR = 0.56, 95% CI = 0.33 to 0.97 for women in the highest quartile of total overnight 6-sulfatoxymelatonin output vs. the lowest quartile) (16
Our results are in complete agreement with the two more recently published studies using either first morning or overnight urine (14
). Moreover, while based on few cases, our study suggests that circulating melatonin level might be more strongly related to in situ than invasive breast tumors. However, it is not entirely clear how frequently in situ tumors progress to invasive tumors (44
). No prior study has been able to address the association between melatonin and in situ breast tumors. Thus, while plausible, our finding of a stronger effect of endogenous melatonin on in situ tumors, requires replication in a larger data set to rule out a chance finding.
Strengths of our study are that we were able to consider most important breast cancer risk factors, including sleep duration and night work in our analyses. When we adjusted for life-time duration of night work, which was queried in 1988, results remained unchanged. Excluding case patients who were diagnosed within the first 2 years after urine collection did not alter our findings; however, the short follow-up (2.5 years average) in our study limited our ability to address this fully. Our study is further limited by the lack of information on circulating sex steroid levels. Finally, we were unable to correct for laboratory measurement error and within-person variability in our data set; however, because of the random nature of this error, we expect that this correction would have strengthened our observed risks. Moreover, the intra-class correlation over a 3 year period in premenopausal women from the Nurses’ Health Study II cohort was fairly high (0.72), suggesting that melatonin remains fairly stable over time (46
In summary, our findings show that melatonin secretion, as assessed by first morning urinary 6-sulfatoxymelatonin concentration, is associated with the risk of developing breast cancer in postmenopausal women. Studies to confirm our findings should have longer follow-up and should also address the importance of interrelationships with sex steroids in these associations.