J. Arendt

FACTORS INFLUENCING URINARY 6-SULPHATOXYMELATONIN, A MAJOR MELATONIN METABOLITE, IN NORMAL HUMAN SUBJECTS

6‐Sulphatoxymelatonin (aMT6) has been measured, by a direct radioimmunoassay, in urine from 130 normal volunteers aged 2–80 years. Its relationship to a number of physiological parameters has been assessed. Total urinary excretion of aMT6s did not vary in a group of 40 children aged 2–20 years (24 boys and 16 girls) except when expressed as a function of body weight. In this case, total aMT6s excretion over 24 h decreased as a function of age. In 90 adult volunteers (44 men and 46 women) aged 20–80 years, there was an age‐related decline in total 24 h aMT6s excretion with significantly lower values in elderly subjects. In this same adult group no relationships were found between total aMT6s excretion and body weight or height. No sex differences were found either in the 2–20 years or the 20–80 years groups. Pineal calcification was assessed by lateral skull X‐ray in 26 adult volunteers (17 men and 9 women) aged 20–50 years. No significant differences in aMT6s excretion were found as a function of pineal calcification. In 16 of these subjects plasma melatonin and aMT6s also showed no relationship to pineal calcification. These studies confirm the usefulness of aMT6s as an index of melatonin secretion in normal volunteers.

REDUCED NOCTURNAL MELATONIN SECRETION IN CHRONIC SCHIZOPHRENIA: RELATIONSHIP TO BODY WEIGHT

Melatonin was estimated by RIA in samples taken at 24.00 h and 08.00 h from twenty‐one male chronic schizophrenics and twelve age‐sex matched controls and subsequently in more frequent nocturnal samples from nine of the chronic schizophrenics. The 24.00 h melatonin level and the 24.00/08.00 h melatonin ratio were significantly reduced in the chronic schizophrenic patients. Similar results, with no evidence of subsidiary peaks of melatonin secretion, were obtained in those patients who were retested. No relationships between melatonin secretion and age or anterior pituitary hormone secretion were demonstrated, but an effect of body weight was noted which accounted, in part, for the difference between schizophrenics and controls. These results suggest that the low levels of melatonin noted in studies on depressed patients may not be specific and that body weight must be controlled in subsequent studies of melatonin secretion in patients with psychiatric disease.

24‐HOUR PROFILES OF MELATONIN, CORTISOL, INSULIN, C‐PEPTIDE AND GIP FOLLOWING A MEAL AND SUBSEQUENT FASTING

Melatonin, free and total cortisol, insulin, C‐peptide and glucose‐dependent insulin‐releasing peptide (GIP) were measured in the plasma of twelve normal volunteers (eight women and four men), at hourly intervals for 24 h following a meal and subsequent fasting. One volunteer was excluded from calculations due to a possible effect of stress on melatonin secretion. Melatonin and cortisol showed the normal 24‐h variation with peak values at 0200–0500 h, and 0900 h respectively. Following post‐prandial stimulation, gut hormones remained basal throughout the sampling period. No significant relationship was found between 24‐h melatonin secretion and basal, or stimulated gut hormone secretion. Melatonin secretion did relate significantly to body weight, suggesting that data concerning pineal effects in endocrine physiology and pathology, and effective disease, should be reviewed in the light of these observations.

Clinical studies of the effect of (+) and (−)-oxaprotiline upon noradrenaline uptake

In six normal male subjects the mydriatic effect of tyramine eye drops was inhibited by 1 days treatment with desipramine and the (+)- but not the (-)-enantiomer of oxaprotiline. In the same experiment, the secretion of melatonin was increased after treatment with (+)- but not with (-)-oxaprotiline. The effects of (+)-oxaprotiline and of desipramine treatment were similar, as were those of (-)-oxaprotiline and placebo.These findings extend to clinical studies the demonstration in animal experiments of stereo-specificity for the effects of (+)- and (-)-oxaprotiline upon noradrenaline uptake. A comparison of the effects of the two enantiomers should provide an ideal strategy for studying effects of noradrenaline uptake blockade in clinical studies.

Hypogonadotrophic hypogonadism and primary amenorrhoea associated with increased melatonin secretion from a cystic pineal lesion

A 17‐year‐old girl presented with primary amenorrhoea and failure to develop secondary sexual characteristics, although her height was above the 90th centile. Endocrine investigations revealed hypogonadotrophic hypogonadism (basal LH and FSH levels <0.5 U/l; FSH rose to 2.0 U/l and LH to 1.0 U/l after GnRH). ACTH, GH, TSH and PRL secretion were normal. A magnetic resonance scan revealed no abnormality in the pituitary, pituitary stalk or hypothalamus but demonstrated a partly cystic enhancing lesion in the pineal region. Melatonin production (assessed as urinary 6‐sulphatoxymelatonin: aMT6s) at baseline was markedly increased: 459–530 ng/kg/24 h compared with aged‐matched controls: 136±69 (P=0.01). However, melatonin production retained a largely normal rhythm with increased production during the night. Treatment with ethinyloestradiol 100 μg daily had no apparent effect on the production of melatonin. Treatment with atenolol, 100 mg daily at 1600 h, was associated with suppression of nocturnal melatonin secretion but a brisk rebound in the morning and a considerably delayed peak excretion time (10.2 h) compared with controls (3.9 h). It is likely the pineal lesion, which may be hyperplasia or possibly even tumour, was responsible for the increased melatonin secretion. These data support the hypothesis that melatonin may have a causal role in hypogonadotrophic hypogonadism.

Melatonin in humans: it's about time.

Melatonin signals night time by its rhythmic profile of secretion. Its measurement provides the best indicator of internal circadian clock timing. Treatment with melatonin induces sleepiness and lowers body temperature during ‘biological day’ (i.e. when its endogenous secretion is minimal) and it acts as a ‘chronobiotic’ to change the timing of the circadian clock. It has been used successfully to treat disorders of biological rhythms in humans

Rapid decrease in melatonin production during successful treatment of delayed puberty.

true positive (ELISA positive, western blot confirmed) specimens found in any one method divided by the number of true positives, plus the false negatives (total true positives). The positive predictive value is given as the number of true positives divided by the number of true positives plus false positives (p 565 in Griner et al). The values for sensitivity (given in table and n) are for test sensitivity, not for positive predictive value, and are correct as published.

The effect of abolition of the endogenous corticosteroid rhythm on the circadian variation in methotrexate toxicity in the rat

SummaryMonitoring of indices of haematological, renal and hepatic toxicity in rats after a single i.v. bolus of methotrexate has shown that they vary with the time of day at which the drug is administered. Maximum toxicity occurs after administration at 0600 h. Further experimentation has shown that the amount of corticosteroid present in the blood has a profound effect on the toxicity of methotrexate in the rat. If the endogenous production of corticosterone is suppressed by treatment with dexamethasone the toxicity of methotrexate is markedly increased at whatever clock time it is administered. However, if constantly high plasma levels are achieved by giving supplementary corticosterone methotrexate toxicity is diminished regardless of what time it is given.Since the timing of maximum methotrexate toxicity corresponds to the circadian nadir of endogenous plasma corticosterone concentration in the rat the possibility that it might be related to corticosterone production must be considered. Whether this phenomenon occurs in man and has any clinical relevance has yet to be investigated.

Human exposure to ultraviolet radiation at the Antipodes - a comparison between an Antarctic (67°S) and Arctic (75°N) location

Abstract. We used ultraviolet radiation dosimeters to investigate human exposure at two polar latitudes with a 24-h photoperiod: at Rothera Station (UK) (67°S) and at a field camp in the Haughton impact structure in the Canadian High Arctic (75°N). Mean personal UV radiation exposure in the Antarctic location was 4.3 times greater than that in the Arctic location, even in the absence of ozone depletion. More than zenith angle accounted for the higher UV exposure. Widespread snow and ice covers, and probably less atmospheric pollution, caused higher personal exposures. Although the mean exposures were higher in the Antarctic location, the mean exposure ratio in the Antarctic (0.20±0.09) was similar to the value measured in the Arctic (0.27±0.09) on clear days. We use the Antarctic ratio to provide quantitative estimates of UV-radiation exposure for workers at the Geographical South Pole for the winter solstice under a constant 24-h photoperiod. Exposure ratios can be used to translate measurements of UV radiation by horizontally fixed spectroradiometers into estimates of the mean exposures expected in populations at polar latitudes, although variations between individuals are large. The data have implications for determining the UV exposures of indigenous high-latitude populations.

Effects of a phosphodiesterase inhibitor (Rolipram) on the urinary excretion of 6-sulphatoxy melatonin in man.

The urinary excretion of 6-sulphatoxymelatonin (aMT6s) from 2400 to 0600 h was significantly increased following the treatment of ten normal volunteers with a phospho diesterase inhibitor (rolipram 1 mg 8 h for 24 h). The urinary excretion of the metabolite from 0600 to 1200 h was significantly reduced after treatment with rolipram.