Case-control study of melatonin metabolite excretion and colorectal adenoma formation

Introduction: The Study of Sleep and Adenoma Risk (aka SPARK) is a case-control study examining disturbances in sleep and circadian rhythms as risk factors for adenoma formation among screening colonoscopy patients with average colorectal cancer (CRC) risk. The circadian-related hormone, melatonin, has antiproliferative, immune-enhancing, antioxidant, and anti-inflammatory properties. It is elevated in the gut relative to circulating levels, but little is known of its potential protective role in colorectal adenoma formation. This study tested the hypothesis that patients with ≥1 histologically confirmed adenoma had lower melatonin levels relative to polyp-free controls. Methods. Participants frequency matched on age, race, and sex were identified for analysis. Overnight urine samples (first morning void plus any nocturnal voids) were analyzed for the major urinary melatonin metabolite, 6-sulfatoxymelatonin (aMT6s) using a sensitive and specific enzyme-linked immunosorbent assay (ELISA). Creatinine levels were quantified spectrophotometrically using a kinetic modification of the Jaffe procedure. The creatinine-adjusted nocturnal aMT6s concentration (aMT6s-cr) and total overnight aMT6s excretion (overnight urine volume*nocturnal urinary aMT6s concentration) were computed for analysis. Multiple logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for melatonin metabolite excretion in the upper and middle tertile (referent: low tertile) among adenoma cases (n=68) relative to controls (n=81), after adjustment for selected confounders. Results. Adenoma case status was associated with lower melatonin metabolite excretion. For aMT6S-cr, adenoma cases had a lower odds of being in the upper melatonin metabolite tertile (OR: 0.33, CI: 0.13-0.78, p=0.01; middle tertile OR: 0.49, CI: 0.20-1.13, p=0.10, adjusted for race, environmental justice index), and for total overnight aMT6s excretion, adenoma cases also had lower odds of being in the upper tertile (OR: 0.37, CI: 0.14-0.93, p=0.04; middle tertile OR: 0.57, 0.24-1.37, p=0.21, adjusted for race, environmental justice index, smoking, ambient light exposure). Discussion. Screening colonoscopy patients with adenomatous polyps had lower melatonin metabolite excretion than polyp-free controls after screening and adjusting for sociodemographic, environmental, and behavioral risk factors, including melatonin consumption. These findings suggest a potential role of melatonin supplementation for adenoma chemoprevention. Behavioral practices that promote circadian hygiene by improving or stabilizing disrupted melatonin production may also represent novel targets for reducing adenoma and CRC risk.