Melatonin In Man Research Articles

Renale opruiming van melatonien

Only two publications exist in which actual values for the renal clearance of intact melatonin in man is described. The melatonin clearance values were, however, obtained either after the oral intake of melatonin, or by applying different techniques for the determination of melatonin in urine and plasma. In this study, renal clearance of melatonin was determined during the hours where melatonin concentrations are relatively constant. Melatonin levels in plasma and urine respectively were each deter­mined by three analytical techniques, i.e. the Fraser, NID and WHB methods. The results show renal clearance of melatonin to be under 2 ml/min and that higher values are obtained with analytical techniques which bypass the extraction process.

Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection

The pharmacokinetics of melatonin during the day-time has been studied in 4 healthy subjects after a bolus i.v. injection of 5 or 10 micrograms/person and after a 5 h infusion of 20 micrograms per person in 6 healthy subjects. In addition, a pinealomectomized patient whose nocturnal plasma melatonin had been abolished was investigated after the i.v. infusion--once during the night and once during the day. The clearance of melatonin from blood showed a biexponential decay. The pharmacokinetic parameters in the two studies were similar, except for the disappearance rate constant beta and the apparent volume of distribution at steady-state (Vss). Supplementary peaks or troughs were superimposed on the plateau and the falling part of the profile. They were not due to stimulation of endogenous secretion, because they were also seen in the pinealomectomized patient. During the melatonin infusion, the plasma hormone level reached a steady-state after 60 and 120 min, and when it was equal to the nocturnal level. The infusion regime may be valuable in replacing blunted hormonal secretion in disease states.

Lack of an acute modulatory effect of melatonin on human nocturnal thyrotropin and cortisol secretion.

Using a recently developed model for investigating the neuroendocrine role of melatonin in man, we studied melatonin's effect on the nocturnal secretion of thyrotropin and cortisol in 17 normal male volunteers. The model consists of sleep in the dark and all-night sleep deprivation in conditions of: bright light with and without a melatonin infusion, and dim light. We have improved our infusion paradigm so that levels of melatonin during infusion are now indistinguishable from those occurring during sleep in the dark or dim light sleep deprivation. Sleep deprivation per se raised TSH levels compared to normal sleep. However, the three conditions of sleep deprivation could not be distinguished from each other, which suggests that the suppression of TSH by sleep (or the stimulation of TSH by sleep deprivation) is not mediated by melatonin. Cortisol secretion was unaffected by sleep deprivation regardless of melatonin's presence or absence. However, a difference in the pattern of secretion of cortisol in the sleep condition in the early morning (compared to the sleep deprivation conditions) was noted. These data do not implicate melatonin in the acute regulation of TSH or cortisol in normal man. These data also provide a method of melatonin infusion that replicates the pattern and levels seen in sleep.

A model for the study of the acute effects of melatonin in man.

The role of the pineal hormone melatonin in human physiology is uncertain. Previous studies correlated plasma melatonin levels with several physiological parameters or determined the responses to pharmacological doses of melatonin during daylight hours. We established an acute model that is more rigorously physiological. Constant nocturnal bright light in sleep-deprived normal men resulted in low plasma melatonin levels throughout the night, in contrast to sleep in the dark and dim light sleep deprivation nights. Subsequently, melatonin was infused during bright light exposure to approximate physiological levels. Plasma GH and PRL measurements in these four conditions revealed an effect of sleep deprivation independent of the presence or absence of melatonin. A subsample of these men had an intermediate level of melatonin suppression with 500 lux light intensity, relative to those during sleep and bright light. The results suggest that melatonin has no acute modulatory effect on the secretion of these two sleep-related hormones.

Chlorpromazine inhibition of melatonin metabolism by normal and induced rat liver microsomes.

Hepatic metabolism of melatonin has been investigated. Melatonin was converted in vitro by rat liver microsomes to 6-hydroxymelatonin and to a lesser extent to N-acetylserotonin. Induction with phenobarbitone caused a fourfold increase in the formation of the minor product with little effect on 6-hydroxymelatonin production or melatonin turnover. In contrast, benzpyrene induction caused a dramatic increase in melatonin turnover but the formation of both metabolites, particularly 6-hydroxymelatonin was significantly reduced. This suggests that an alternative inducible pathway is involved in melatonin catabolism. Chlorpromazine, which elevates plasma melatonin in man and rat, significantly reduced melatonin turnover and reduced the formation of both metabolites in control and phenobarbitone induced microsomes. With benzpyrene induction, chlorpromazine inhibited melatonin turnover but in this group, 6-hydroxymelatonin concentrations were higher than controls. It is thus proposed that the drug preferentially inhibits the alternative benzpyrene inducible isozyme rather than the melatonin hydroxylase.

Pharmacokinetics of melatonin in man: first pass hepatic metabolism.

Hepatic clearance concepts were applied to existing data on iv and oral administration of melatonin to man. A high hepatic extraction ratio was calculated, suggesting prominent first pass hepatic metabolism and reduced bioavailability for orally administered melatonin. Using clearance parameters and previous data, endogenous production rates for melatonin were determined for normal individuals and patients with cirrhosis. Normal melatonin production was 28.8 micrograms/day, while the production rate for cirrhotic patients was 12.3 micrograms/day. Thus, not only do cirrhotic patients have decreased melatonin elimination, as noted in the original report, but they also have decreased daily melatonin production.

Plasma concentrations of melatonin in man following oral absorption of different preparations.

The plasma concentrations of melatonin in man, fasting and fed, were determined after ingestion of three different oral preparations. A dose of 2 mg was given as either a gelatine capsule, a solution in corn oil or as a slow-release pill. Gelatine capsules and the corn oil preparation gave reproducibly timed peak plasma concentrations, 30 to 60 min after ingestion regardless of nutritional status, and plasma melatonin remained at or above endogenous night-time levels for 3-4 h with mean elimination half-lives of 0.54 to 0.67 h. The slow-release preparation usefully extended high plasma melatonin concentrations for 5-7 h after ingestion but the timing of peak concentrations was very dependent on nutritional status. These preparations should be of use in the study of timed melatonin administration in man.

Circulating Melatonin in Man: Episodic Secretion throughout the Light-Dark Cycle

A sensitive and specific RIA for melatonin has been validated for human plasma. Five young adult men had plasma samples obtained every 20 min during two 24-h periods. One was a normal active period and the other a basal period with complete bed rest. Melatonin was found to be secreted episodically throughout the 24 h in each condition, with secretory episodes clearly present during the waking day in the presence of bright light.

A simplified radioimmunoassay for melatonin and its application to biological fluids. Preliminary observations on the half-life of plasma melatonin in man

A simplified and rapid radioimmunoassay (RIA) for melatonin is presented. Melatonin is extracted from serum, plasma or urine and RIA is performed by using [ 3H] melatonin as the tracer. The standard curve covers the range 0.2–4.3 nmol/l. By increasing the sample volume the range can be extended to 0.06 nmol/l. The intra-assay variability is 7% (relative standard deviation = rsd) and the inter-assay variability is 10% (rsd). The recovery of melatonin added to calf serum is 96%. The long term variability of the assay (43 assays on aliquots of one serum sample during 6 months) is 13.5% (rsd). The serum levels in man after one oral dose of 430 μmol melatonin have been measured. The peak value, 620 nmol/l, was noted after 0.5 h and the melatonin concentration was still above the normal range at 24 h (2.1 nmol/l).

Annual rhythm of serum melatonin in man

Serum melatonin measured by radioimmunoassay in healthy subjects at 8 a.m. was found to undergo bimodal annual variations with peaks in January and July. This annual rhythm may represent changes in total secretion or phase shifts in the circadian rhythm.

Melatonin assays in body fluids.

A variety of methods now exist for the assay of melatonin in body fluids. Their relative merits are compared and the validation of one in particular (RIA) described. Physiological studies of melatonin by RIA have shown probable modulation of its secretion by gonadal steroids. The circadian activity maximum in the dark phase of one of the pineal melatonin synthesizing enzymes, N-acetyltransferase, is reflected in peripheral melatonin levels. Man, like all other species studied so far, has a dark phase rise in circulating melatonin. During the menstrual cycle, melatonin shows a luteal phase rise. Further evidence of pineal rhythmicity is found in seasonal melatonin variations in man. The study of the rhythmic properties of peripheral melatonin in man may provide important information on central nervous function.

Studies of the 24 hour rhythm of melatonin in man.

In a series of four separate studies of the 24-hour pattern of melatonin secretory function in man, the following results were obtained. Sequential measurement of the concentration of melatonin in plasma and urine demonstrated a 24-hour rhythm in which more melatonin is secreted during the sleep-lights off as compared to the waking-lights on period. However, during "free-running" and after an acute phase shift of the sleep-wake cycle, a melatonin rhythm can be dissociated from the sleep-lights out rhythm. A radioimmunoassayable plasma melatonin substance was found in significant amounts throughout the entire 24-hour day using a frequent sampling technique (every 20 min). Melatonin appears to be secreted into the blood in discrete brief episodes superimposed on a maintained "baseline" concentration. The half-life appears to be less than 30 min.

Absolute identification of melatonin in human plasma and cerebrospinal fluid.

MELATONIN, the compound responsible for the lightening of amphibian skin, was extracted from bovine pineal glands and chemically characterised by Lerner et al.1,2. Recent reviews3–5 have suggested that melatonin has an endocrine role, particularly in relation to chronobiology, pituitary function and cerebral physiology. Most of this work has been accomplished by animal experimentation. So far the evidence for the existence of melatonin in man has been indirect. It is formed biosynthetically from tryptophan and the necessary enzyme system is known to be present in the human pineal throughout life7. There is however little evidence to suggest that it circulates in human blood or cerebrospinal fluid (CSF). Attempts to identify melatonin by bioassay8 or radioimmunoassay9 have not been accompanied by the chemical identification of the substance measured. We present here, for the first time, unequivocal evidence based on gas chromatography (GC) and mass spectrometry (MS) of the presence of melatonin in human plasma and CSF.

Growth hormone responses to melatonin in man.

Oral administration of 1 gram of melatonin caused rapid and significant elevations of serum human growth hormone in eight out of nine normal male subjects. The mean (+/- standard error of the mean) of the peak response by growth hormone was 22.9 +/- 4.6 microunits per milliliter. The increased secretion of growth hormone may be due to interaction of melatonin with hypothalamic serotoninergic receptors.