Melatonin: a major regulator of the circadian rhythm of core temperature in humans.

The circadian rhythm of core body temperature (BTc), with maxima during the day and minima at night, is normally coupled with the sleep-wake cycle. Pineal melatonin secretion occurs contemporaneously during the nighttime hours and is mediated by the activation of beta-adrenergic receptors during darkness. The hypothesis that nocturnal melatonin secretion may be involved in the regulation of the human circadian BTc rhythm was examined. The temporal relationship between melatonin and the circadian BTc rhythm was characterized in 12 young women, normally entrained to the light-dark cycle. Melatonin levels were manipulated through the administration of exogenous melatonin (2.5 mg, orally) during the daytime (n = 6) or suppression of endogenous nocturnal melatonin secretion by the beta-adrenergic antagonist atenolol (100 mg; n = 6) in double blind placebo-controlled experiments conducted during 2 consecutive days. Serum melatonin levels and BTc were monitored at 20- and 10-min intervals, respectively. In a nightshift worker the temporal relationship between the circadian rhythm of melatonin and BTc was investigated before and after entrainment to a reversed wake-sleep cycle. Our data show that in normally entrained subjects, the time course and amplitude of nocturnal melatonin secretion were temporally coupled with the decline of BTc (r = 0.97; P less than 0.00001). The same occurred in the nightshift worker, both during the dissociation and after entrainment to the reversed sleep-wake cycle. Compared with placebo, administration of melatonin significantly reduced daytime BTc (P less than 0.01), and the suppression of melatonin (by atenolol) attenuated the nocturnal decline of BTc (P less than 0.01). Cosinor analysis showed that the amplitude of the circadian BTc rhythm was reduced by about 40\% in response to both daytime melatonin administration (P less than 0.05) and nocturnal melatonin suppression (P less than 0.02). In conclusion, circadian rhythms of melatonin and BTc are inversely coupled. The demonstrated hypothermic properties of melatonin are accountable for the generation of at least 40\% of the amplitude of the circadian BTc rhythm. Manipulation of melatonin levels might be clinically useful to resynchronize the BTc rhythm under conditions of BTc rhythm desynchronization.