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Unlabelled: OBJECTIVES. This work was designed to study melatonin (M) production levels in duodenal ulcer (DU) patients in the exacerbation and remission stages and in DU patients with a different course of DU in the exacerbation and remission stages., Methods: DU patients (15 men aged 20 to 45, mean age 34,2 +/- 1,1 years) were studied. The control group included 11 healthy volunteers (men aged 20-45, mean age 32,5 +/- 1,4 years). M was measured by RIA-method using H(3)-labeled M in daily urine collected at 3-hour intervals (8 portions per day). Mathematical processing was carried out using ANOVA, Student's t-test, and cosinor analysis. Differences at p< or = 0,05 were considered to be significant., Results: A strong disturbance of M secretion in DU patients both in the exacerbation and remission stages and a direct correlation between the degree of M production disturbance and severity of clinical course of DU were revealed., Conclusion: The obtained results suggest that circadian rhythms of M production are altered in DU patients. M was supposed to be involved in the pathogenesis of DU.

Factors other than light may affect variations in melatonin, including disturbances in the geomagnetic field. Such a possibility was tested in Alta, Norway, located at latitude 70 degrees N, where the aurora borealis is a result of large changes in the horizontal component (H) of the geomagnetic field. Geomagnetic disturbances are felt more strongly closer to the pole than at lower latitudes. Also noteworthy in Alta is the fact that the sun does not rise above the horizon for several weeks during the winter. To examine whether changes in geomagnetic activity influence the secretion of melatonin, saliva was collected from 25 healthy subjects in Alta several times during the day-night and at different times of the year. Single cosinor analyses yielded individual estimates of.the circadian amplitude and MESOR of melatonin. A 3-hour mean value for the local geomagnetic activity index, K, was used for approximately the same 24-hour span. A circadian rhythm was found to characterize both melatonin and K, the peak in K (23:24) preceding that of melatonin (06:08). During the span of investigation, a circannual variation also characterized both variables. Correlation analyses suggest that changes in geomagnetic activity had to be of a certain magnitude to affect the circadian amplitude of melatonin. If large enough (> 80 nT/3 h), changes in geomagnetic activity also significantly decreased salivary melatonin concentration.

The objective of this study was to assess melatonin production in patients with acute intermittent porphyria (AIP), with and without known epileptic seizures, as a guide to whether melatonin may have anti-convulsive or pro-convulsive effects in AIP. Melatonin concentration in urine, sampled over eight hours on two consecutive nights, was analysed in eight AIP patients with epileptic seizures and in 14 AIP relatives without epilepsy. The AIP patients with epileptic seizures had a significantly lower urinary excretion of melatonin, compared with their AIP relatives without epilepsy, which may indicate that melatonin has a protective effect on seizures.

The study was made on Wistar rats. A shift in endogenous biological rhythms was simulated by that in the light phase by 12 hours and evaluated by the shift in the rhythm of rectal temperature. Experiments revealed that desynchronization potentiated ulcerative processes in the rat stomach. The study demonstrated the protective effect of intraperitoneally injected melatonin to prevent the formation of ulcerative defects in the rat stomach during artificially simulated desynchronization.

Somatostatin has been found in the pineal gland of several animal species, which suggests that it may be involved in the regulation of melatonin secretion. Whether somatostatin has regulatory influence on melatonin secretion in man has never been unequivocally shown. We studied the nocturnal melatonin secretion in 8 healthy volunteers, and 6 women with untreated primary hypothyroidism, a disease state that is associated with increased nocturnal secretion of melatonin. The participants were given subcutaneous injections at 18:00 h and 23:00 h of either saline or octreotide (Sandostatin; each injection 50 microg). During the nights when the healthy volunteers were given octreotide, melatonin secretion was similar to that recorded during administration of saline. Also the urinary excretion of melatonin was of similar magnitude at these two occasions. By contrast, the GH secretion was significantly lower the nights the healthy controls were given octreotide (GH AUC 22.6+/-5.4 mU/l x h during octreotide and 126.6+/-21.9 mU/l x h during saline; p<0.01). The patients with hypothyroidism also showed similar nocturnal melatonin secretion during octreotide and saline. Urinary excretion of melatonin also remained unchanged, as did GH secretion. The total nocturnal secretion of TSH was, however, significantly reduced by octreotide (TSH AUC 562+/-136 mU/l x h during octreotide and 851+/-185 mU/l x h during saline; p<0.05), thus suggesting that 100 microg of octreotide should be sufficient to inhibit also the pinealocytes if their function were regulated by somatostatin. Since exogenous somatostatin--in the form of octreotide--fails to influence nocturnal secretion and urinary excretion of melatonin in normal subjects and in patients with primary hypothyroidism, it is reasonable to assume that endogenous somatostatin may not be an important regulator of melatonin secretion in man.

A review of the different publications dealing with melatonin in humans shows that this field has been very active in the last few years. Normative melatonin values have been defined. Various relationships between melatonin and other traits have been studied, such as sleep, circadian rhythm, surgical stress and anaesthesia. Age-related melatonin studies and melatonin during depression and other psychiatric disorders have been reviewed. Finally, some studies have been performed to use melatonin as a medication for sleep disturbance in depression, for jet-lag and as a skin protector for ultraviolet light.

The present study on overnight urinary melatonin was conducted on the most geographically dispersed population to date, over a 1 year period, also covering a broad age range (18-62 years). An inverse relationship between melatonin and age, as well as between melatonin and weight was observed for both genders. Females as a whole, had higher melatonin values than males. Furthermore, the excretion of melatonin exhibited a bimodal distribution, distinguishing two groups of individuals: low and high melatonin excretors. The cut-off point was set at 0.25 nmol/l for ages up to 40 years and at 0.20 nmol/l for subjects above this age. Since melatonin may be involved in several physiological and pathological processes, it could be of importance to detect the type of melatonin excretion that prevails in various conditions, using a simple noninvasive procedure such as the overnight urinary measurement. For that purpose, this large sample could serve as a worldwide reference databank across different ages and locations.

Overnight urines were collected each month for 12-16 months from 321 normal subjects at 19 medical centers in 14 countries distributed on 5 continents at latitudes from 31 01 South to 77 00 North. Mean melatonin concentration was found to negatively correlate with age, weight, and height. When the sexes were considered separately melatonin only correlated with age for female and with age and weight for males. A weak correlation with latitude, but not longitude, was also found.

Plasma concentration of arginine vasopressin (AVP) and melatonin and serum osmolality were measured at noon and at midnight in individuals living in the northern hemisphere on March 22-23, June 13-14, September 26-27, and December 12-13 in 35 healthy volunteers (15 men and 20 women) aged 60-74 years. The nocturnal increase in melatonin was highest in the autumn and lowest in the winter in both sexes. The midnight serum osmolality level was lower in the autumn than in any other time of the year. In both the men and the women the AVP level was higher in winter than in any other season (P < 0.01 and P < 0.0001, respectively). In men, the AVP level was higher at noon than at midnight in 49% of the investigated 24 hr periods, at the same level in 15% and lower in 36% (NS). The corresponding figures for women were 55%, 25%, and 20%, respectively (P < 0.05). This study suggests a possible relationship between melatonin and serum osmolality.

Objective: Most patients with fibromyalgic syndrome (FMS) complain of sleep disturbances, fatigue, and pain. These symptoms might be a consequence of changed melatonin (MT) secretion, since MT is known to have sleep promoting properties. Moreover, serum concentrations of two MT precursors (tryptophan and serotonin)--affecting both sleep and pain perception--appear to be low in patients with FMS. Therefore, the objective of this investigation was to study whether serum MT (s-MT) level is also low in these patients., Design: Eight patients with FMS and 8 healthy sex-, BMI-, and age-matched controls were included in the study. s-MT concentrations were determined every second hour between 1800 and 0800 h. Urine was collected between 2200 and 0700 h for determination of urinary MT excretion. To evaluate total MT secretion between 1800 and 0800 h and MT secretion during the hours of darkness (between 23 and 07 h) individual MT areas under the curve (AUC) were calculated and expressed as group means., Results: The FMS patients had a 31% lower MT secretion than healthy subjects during the hours of darkness (MT AUC 2300-0700 h (mean +/- SEM): 1.70 +/- 0.17 vs 2.48 +/- 0.38 nmol/l; P < 0.05). Also the s-MT peak value was significantly lower in the patient group: 0.28 +/- 0.03 vs 0.44 +/- 0.06 nmol/l; P < 0.05)., Conclusion: Patients with fibromyalgic syndrome have a lower melatonin secretion during the hours of darkness than healthy subjects. This may contribute to impaired sleep at night, fatigue during the day, and changed pain perception.

A multivariate approach using pattern recognition method was applied on a multivariable data set from patients with affective disorders comprising biological and clinical variables. The depressed patients were rated according to 23 items of the comprehensive psychopathological rating scale (CPRS). Variables of importance were selected and clusters of patients were found by combining monoamine oxidase, melatonin and post-dexamethasone cortisol with symptoms of psychomotor retardation and agitation. Patients were distributed with high scores of agitation in the extreme of one direction and with high scores of retardation in the opposite direction. By using the combined clinical and biological variables, a diagnostic subcategory with latent bipolar disorder was identified. Two clusters of unipolar patients, one with low melatonin and low psychomotor retardation scores, and one with high melatonin and high psychomotor retardation scores, were found. Identification of a patient group with latent bipolar disorder may have potential therapeutic value since bipolar patients should be taken care of by a specialist in psychiatry, avoid tricyclic antidepressant therapy and may be candidates for lithium treatment.

Breeding in the three-spined stickleback is stimulated by long but not by short photoperiods in many seasons. The aim of the present study was to test the hypothesis that melatonin plays a role in the inhibitory effect of short photoperiod in this species. Adult nonbreeding males were kept either under constant light (Experiment 1) or under a stimulatory long photoperiod (16L 8D, Experiment 2), in water containing 0, 20, or 80 microg/liter melatonin for 16 hr/day for 28 days during the spring. These melatonin treatments were intended to simulate the daily melatonin pattern of a nonstimulatory short photoperiod. In the second experiment, fish were also kept under a nonstimulatory short photoperiod (8L 16D). In the natural breeding season the only germ cells found in the stickleback testes are spermatozoa and spermatogonia, a condition found in many fish under all treatments. In the first experiment, spermatogenesis was not influenced by melatonin. However, testes also containing spermatocytes and spermatids were more common in fish kept under 8L 16D and fish treated with 80 microg/liter melatonin than in 16L 8D controls in Experiment 2. Kidney hypertrophy, an androgen-dependent male secondary sexual characteristic in the stickleback, appeared in most males kept under constant light or 16L 8D and was not influenced by melatonin treatment. In contrast, control males kept under 8L 16D in Experiment 2 did not display kidney hypertrophy. Therefore, the presence of an extended period of elevated melatonin did not prevent the stimulatory effects of long photoperiod on development of this secondary sexual characteristic in the stickleback., (Copyright 1997 Academic Press.)

The effect of bright light on cortisol and the relationship between melatonin and cortisol were studied in 63 depressed patients (42 patients with a seasonal pattern and 21 patients with a non-seasonal pattern). The patients were matched for age, time of treatment and severity of depression. Before and after light treatment the severity of the depression was rated with the Comprehensive Psychopathological Rating Scale (23 items) and the Hamilton Depression Rating scale (18 items), and serum cortisol and melatonin were drawn at nine time-points between 20.00 and 08.00 hours. Two hours of light treatment (350 cd m-2) was given daily for 10 days either in the morning (06.00-08.00 hours) or in the evening (18.00-20.00 hours). As reported earlier, patients with a seasonal pattern improved significantly more than patients with a non-seasonal pattern of depression, and no significant differences were found between the treatment efficacy of morning compared to evening light. A cosinor analysis showed that the cortisol batyphase was significantly advanced by morning light, but was not delayed by evening light. A delay in batyphase cortisol showed a weak significant correlation with a decrease in the absolute and relative sum of scores. The batyphase of cortisol occurred approximately 3 h earlier than the acrophase of melatonin. Of the changes in the melatonin acrophase 43% were reflected in a change of cortisol batyphase, indicating a hierarchical relationship with melatonin as the co-ordinating hormone transducing part of the information of the external light to the phase position of cortisol. No significant differences between patients with a seasonal or a non-seasonal pattern were seen in mesor, amplitude or batyphase of cortisol before treatment, and no significant changes in mesor or amplitude were seen as a result of light treatment.

Melatonin (MT) secretion and excretion were investigated in patients with obstructive sleep apnea syndrome (OSAS). Nine men, mean age 55.1 years, mean body mass index 31.2, with a previously confirmed diagnosis of moderate to severe OSAS, were tested on two occasions: immediately before initiation of continuous positive airway pressure (CPAP) treatment and again after at least 4 weeks of continuous nocturnal use of CPAP. Serum MT concentrations were determined every second hour between 2000 and 0800 hours. Urine was collected between 2200 and 0700 hours for determination of urinary MT excretion. Sleep apnea recordings included ear oximetry, respiration and body movements, body position, and breathing sounds. Nine healthy male controls were tested on one occasion. We found that the MT secretion, as reflected by the area under the curve (AUC), among the OSAS patients did not differ from that found in healthy controls (MT AUC 1.68 vs. 1.92 nmol/l x h). Sleep apnea recordings were normalized during CPAP treatment. Moreover, the excessive daytime sleepiness disappeared in all patients. Neither MT secretion (MT AUC 1.68 vs. 1.56 nmol/l x h) nor urinary excretion of MT (0.122 vs. 0.108 nmol/9 h) changed significantly as a result of the CPAP treatment.

Patients with primary hyperparathyroidism have higher serum melatonin concentrations during active disease than after surgical cure. Whether this is caused by hypercalcaemia per se, increased parathyroid hormone secretion or other mechanisms is unknown. We decided to elucidate whether exogenous hypercalcaemia influences melatonin secretion. For this purpose, eight healthy volunteers were infused with calcium and saline on separate days and in random order (experiment A). Hypercalcaemia inhibited nocturnal melatonin secretion by 20% but left urinary melatonin excretion unaffected. If exogenous hypercalcaemia inhibits melatonin secretion, it is reasonable to assume that calcium channel blockers such as verapamil might have the opposite effect. This was investigated in experiment B, in which eight healthy subjects were treated on separate occasions with oral verapamil and placebo. Verapamil did not affect nocturnal melatonin secretion but increased melatonin excretion by 145%. As 6-sulphatoxy-melatonin is the main melatonin metabolite excreted by the kidneys, it was considered important to find out whether verapamil would also influence the excretion of 6-sulphatoxy-melatonin. This was investigated in experiment C, in which eight healthy volunteers were treated, on separate occasions, with oral verapamil and placebo. In this experiment also, verapamil increased urinary melatonin excretion significantly (by 67%), but left excretion of 6-sulphatoxy-melatonin unaffected. These findings imply that verapamil influences the renal and/or hepatic handling of melatonin.

Oral melatonin therapy was used to treat-severe circadian sleep-wake disturbances in eight children and young adults in an open study. All patients were functionally blind, six of them because of defects in the anterior visual pathway. All were mentally retarded. Baseline sleep diaries kept by the caregivers before treatment showed non-24-hour sleep-wake syndrome. Diurnal variations in serum and urinary melatonin were examined. Melatonin secretion peak time was delayed in seven patients. Body temperature variation was out of phase relative to sleep and melatonin in five patients, and thus they had signs of internal desynchronisation. Melatonin given in the evening dramatically improved the sleep-wake pattern in all patients. The effect was maintained during long-term therapy for between 1 and 6 years in six patients. One patient fell back into the earlier sleep pattern after 6 to 8 months, and another had increasing sleep disturbance because of reflux oesophagitis, although the improvement regarding the circadian component remained. No side effects have been noted during the therapy. Oral melatonin is promising as an efficient and seemingly safe alternative for treatment of severe circadian sleep disturbances.

Melatonin as a marker of circadian rhythm and the effect of bright light on melatonin were studied in 63 depressed patients, 42 with a seasonal pattern and 21 with a nonseasonal pattern. The patients were matched for age, time of treatment and severity of depression. Before light treatment, blood was sampled for melatonin and depression was clinically rated with the Comprehensive Psychopathological Rating Scale and Hamilton Depression Rating Scale. Two hours of light treatment, 350 cd/m2, was given daily for 10 days 0600 to 0800 or 1800 to 2000. Of the 42 patients with seasonal depression, 26 were treated with morning light and, 16 with evening light. The melatonin amplitude was significantly decreased by light, and the melatonin phase position was advanced by morning light and delayed by evening light. All patients except for 3 in each group changed in the expected direction. Although the patients with seasonal pattern had a more favorable outcome than patients with nonseasonal pattern, there was no difference in therapeutic outcome related to the baseline melatonin phase position. The hypothesis that the short term clinical effects of light therapy either in the morning or evening are related to pretreatment melatonin levels or alteration of melatonin amplitude or phase position was not supported in the study. There was also no significant difference between the seasonal and nonseasonal patients related to the degree of light suppression of melatonin and the rebound effect of serum melatonin levels following bright level exposure between 2200 and 2300 before regular light treatment.

Objectives: Melatonin (MT) undergoes circadian changes in response to external light conditions and has been implicated in the control of other circadian hormone variations. Alcohol inhibits MT secretion in healthy subjects. The purpose of the present investigation was to elucidate whether patients with Wernicke-Korsakoff syndrome (WKS) also have impaired MT secretion after a period of prolonged alcohol abstention. If so, it would be of interest to find out whether this affects cortisol rhythmicity., Design: Seven patients with WKS and 8 healthy controls were included in the study. Venous blood was sampled every 2nd h between 18.00 and 08.00 hours, and urine collected between 22.00 and 07.00 hours., Setting: Department of Internal Medicine, Endocrinology Section, Södersjukhuset, Stockholm., Main Outcome Measures: Peak serum MT values during the night, total nocturnal MT secretion (estimated by MT incremental areas), and urinary excretion of MT were determined in each participant. Serum cortisol levels were determined in the patients at 18.00, 02.00 and 08.00 hours., Results: Patients with WKS had a markedly reduced nocturnal secretion of MT compared to healthy volunteers (MT incremental areas 0.33 +/- 0.21 vs. 1.60 +/- 0.29 nmol L-1 h-1, mean +/- SEM; P < 0.005). Amongst the patients, the serum cortisol level was higher in the morning than in the afternoon (331 +/- 46 vs. 240 +/- 52 nmol L-1; P < 0.01), and showed a nadir during the night (138 +/- 45 nmol L-1) as in normal individuals., Conclusion: Patients with WKS have markedly reduced nocturnal secretion of MT. The exact mechanism behind this finding has to be further elucidated. However, it is of interest to note that despite the lack of clearcut circadian MT changes. WKS patients retain normal cortisol secretion, thus suggesting that MT rhythm may not be obligatory for the proper control of circadian cortisol rhythmicity.

Platelet monoamine oxidase activity (MAO), melatonin and cortisol post-dexamethasone suppression test (DST) were examined in 28 patients with major affective disorder and in 20 controls. MAO activity was lower and cortisol post-dexamethasone was higher in depressed patients. Platelet MAO activity and cortisol in depressed and controls yielded high sensitivity (90%) and specificity (89%). The patients were re-examined after 10 years and categorized into affective psychosis or neurotic depression (ICD-9). Multidimensional analysis identified one subgroup coinciding in 92% with affective psychosis and another subgroup coinciding in 87% with neurotic depression. Combination of MAO, melatonin and post-DST cortisol may be useful in the diagnosis of subgroups of depressed patients and in choice of therapy.

Antidiuretic hormone (ADH) and melatonin in plasma were measured every 4 hr during a 24-hr period in 69 elderly volunteers (42 males and 27 females) aged 75.6 +/- 8.8 years (+/- SD) and 73.5 +/- 9.5 years, respectively. The population was divided into three groups, which were examined February 27-28, April 25-26, and November 14-15. For the males, the mean ADH level during 24 hr was lowest in April and highest in November with a level five times higher than in April. The ADH level in February was about three times higher that in April. Females did not show any seasonal variation in the ADH system. The melatonin levels were lowest in November, higher in February, and even higher in April in both male and female volunteers. The ADH increased with age in males (R2 = 0.13; P < 0.05) but not in females (R2 = 0.07; NS). The melatonin concentration decreased with age for the whole group, aged 60-98 years.

The circannual secretion of melatonin in 14 Swedish and 15 Italian patients suffering from episodic cluster headache was compared with 14 Swedish and 15 Italian healthy controls matched for sex and age. Overnight samples of urine were collected once a month from 8 to 14 months and kept at -20 degrees C until analysed with RIA. The melatonin concentrations in nocturnal urine were permanently low in cluster headache and there was no consistent change of the melatonin concentration in relation to cluster periods occurring during the study. There was no definitive circannual or infraannual rhythmicity of melatonin in patients or controls. Multiple analysis of variance with repeated measurements showed a significant effect of disease (p < 0.05), but not of time. Sex, geographical location, age, and smoking also had significant effects (p < 0.001) on the melatonin concentrations. Lower melatonin levels in cluster headache patients than in controls may in part be related to a larger number of smokers in the patient group. The relation between tobacco use and melatonin should be further studied.

To determine whether ethanol inhibits nocturnal melatonin (MT) secretion, three experiments (A, B, and C) were performed in seven normal subjects. In A, ethanol at a dose of 0.34 g/kg was administered orally at 6:00, 8:00, and 10:00 PM. Each dose was increased to 0.52 g/kg in B. In C, water was substituted for ethanol. Blood samples for determination of serum MT levels were drawn every second hour between 6:00 PM and 8:00 AM. Urinary excretion of MT during the night was also determined. In A, serum ethanol reached a maximal level of 13 +/- 1 mmol/L at 12 midnight. In B, the corresponding maximum was 25 +/- 1 mmol/L. The higher alcohol dose inhibited nocturnal MT secretion by 20% +/- 5% (P < .01), whereas the lower dose lacked such effect. Urinary excretion of MT was left unaffected by alcohol at both doses. Five additional normal subjects were given alcohol as described above at a dose of 0.52 g/kg (experiment D). This induced mild nocturnal hypoglycemia as evidenced by a glucose decremental area (5.9 +/- 1.8 mmol/L.h) that differed significantly from zero (P < .05). To determine whether a reduced glucose delivery to pinealocytes might contribute to the decreased MT secretion in alcohol-intoxicated subjects, two experiments (E and F) were performed in eight healthy individuals. In E, ethanol was given orally as in B; three small oral doses of glucose were also given at 8:00 PM, 10:00 PM, and 12 midnight. In F, water was substituted for ethanol and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Two normal control populations, separated by 8,000 miles and 24 degrees of latitude, had similar six-month mean values for overnight urinary melatonin concentrations. These values were significantly higher than six-month values for depressed subjects and abstinent alcoholic subjects, while the means for the two clinical populations were similar. Age and urinary melatonin concentration in the control and clinical populations were inversely related, but the slopes of the linear regression equations were ten times steeper for the control populations than for the clinical populations. Differences in age and sex distributions accounted for some of the differences in values between controls and the clinical populations, although controls still differed from the clinical populations, even after sex and age were factored out. The disparate slopes for age and melatonin concentrations may contribute to some of the conflicting findings of studies comparing populations of different ages. The total melatonin content in the samples from alcoholic subjects, but not the depressed subjects, was lower than that for controls. The difference in the urinary melatonin concentration between the controls and the two patient groups was not accounted for by difference in duration of urine collection period, hours of sleep or body weight.

To investigate whether the function of pinealocytes is altered in obesity, nocturnal melatonin (MT) secretion was determined in nine healthy subjects and compared with that of eight obese individuals. Serum MT levels were measured every second hour between 6:00 PM and 8:00 AM, and total nocturnal MT secretion (as reflected by the MT incremental area), MT peak time, and nocturnal urinary MT excretion were determined. None of these parameters differed significantly in the two groups. The obese subjects were reinvestigated after 2 days of complete fasting. This caused a decrease in body weight and basal blood glucose levels of 2.6 +/- 0.2 kg (mean +/- SEM, P less than .001) and 1.5 +/- 0.2 mmol/L (P less than .001), respectively, whereas serum cortisol levels remained unchanged. Short-term fasting reduced nocturnal MT secretion, as evidenced by MT incremental areas, which were reduced from 2.01 +/- 0.26 before fasting to 1.64 +/- 0.26 nmol/L.h after fasting (P less than .02). MT secretion peaks were reached simultaneously, and urinary MT excretion values did not change significantly in fasting. To see whether glucose supplementation during short-term fasting would normalize nocturnal MT secretion, we gave an additional seven obese subjects eight small oral doses of glucose (each dose, 0.5 g/kg body weight) at regular intervals during a 2-day fast. Their body weight decreased by 2.8 +/- 0.4 kg (P less than .001), but blood glucose and cortisol concentrations were similar before and after the glucose-supplemented fast, as was the nocturnal MT secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood levels of melatonin, serotonin, cortisol, prolactin, and serotonin uptake by platelets were measured at 08:00, 14:00, 20:00, 02:00, and 08:00 hours in 10 healthy men who ranged in age from 27 to 35 years. The Km values of serotonin active transport by platelets were significantly correlated with melatonin blood levels. There were no other significant correlations. The secretion of steroid hormones and prolactin showed an increase at 02:00 hours; levels of prolactin decreased at 08:00 hours, but steroid levels continued to rise. This finding suggests either a direct effect of melatonin on serotonin active transport or the influence of the suprachiasmatic nucleus on serotonin uptake by platelets. It is also possible that there is a simultaneous decrease in serotonin uptake and decline from peak levels of melatonin due to the rise in steroid secretion.

A potentially confounding variable inherent in studies designed to examine the effect of melatonin administration in humans is the presence of an endogenous melatonin rhythm in the experimental subjects. The effects of exogenous melatonin administration on serum hormone rhythms was recently examined in a male patient who lacked detectable circulating levels of endogenous melatonin. The patient's pineal gland had been destroyed five years previously in the course of treatment for a pineal astrocytoma. On three separate occasions, over approximately a one-year period, the patient was given daily oral melatonin replacement (2 mg/day, 1 mg/day and 0.5 mg/day). These experiments were designed to assess the effects of exogenous melatonin on serum growth hormone, prolactin, cortisol and testosterone rhythms. Analysis of blood samples collected every 2-4 hours periods both before and during melatonin replacement revealed that the exogenous melatonin rhythm was associated with improvements in self-reported sleep and mood ratings. Melatonin administration produced robust nocturnal peaks in serum growth hormone and prolactin levels immediately following ingestion of the hormone, while serum cortisol and testosterone rhythms were not influenced. These results suggest that melatonin may modulate the coordination and enhancement of selected biological rhythms in man.

Objective: The purpose was to investigate whether the function of the pinealocytes is changed in patients with disturbed metabolic rate or in subjects with marked obesity., Design: Venous blood was sampled every second hour between 1800 and 0800 h, and urine collected between 2200 and 0700 h., Patients: Eight patients with thyrotoxicosis, six with primary hypothyroidism, eight with maturity-onset obesity, and 12 healthy controls were included in the study., Measurements: Peak serum melatonin values during the night, total nocturnal melatonin secretion (estimated by melatonin incremental areas), and urinary excretion of melatonin were determined in each participant., Results: Patients with hypothyroidism were found to have higher peak serum melatonin values, total nocturnal melatonin secretion, and urinary excretion of melatonin than normal individuals (Peak melatonin values: 0.55 +/- 0.13 vs 0.27 +/- 0.04 nmol/l, respectively; P less than 0.05. Melatonin incremental areas: 3.38 +/- 0.80 vs 1.45 +/- 0.26 nmol/l h; P less than 0.05. Melatonin excretion: 0.140 +/- 0.023 vs 0.081 +/- 0.013 nmol/9 h; P less than 0.05). Neither of these values differed significantly from the normal in patients with thyrotoxicosis or obesity. Although thyrotoxic patients thus released a normal amount of melatonin during the night, their melatonin secretion peak was phase advanced (melatonin secretion peak appearing at 1.1 +/- 0.5 h in thyrotoxic, and at 3.4 +/- 0.5 h in normal participants; P less than 0.01). No such phase shifts were seen in patients with obesity or hypothyroidism., Conclusions: These findings imply that both hypothyroid and thyrotoxic patients have disturbed pineal function, which is not the case in patients with obesity. The mechanism underlying these observations remains to be elucidated.

A 9-year-old, blind boy with severe mental retardation with a chronic sleep/wake disturbance had a circadian rhythm of 24.75 hours and an internal desynchronization of the endogenous rhythms. Treatment with oral melatonin given at 6 PM induced a regular sleep/wake pattern. Melatonin, in this patient, convincingly entrained the endogenous rhythm to the appropriate chronological 24-hour day.

Monitoring the daily melatonin rhythm during the course of phototherapy for affective disorders may be beneficial in assessing the efficacy of such treatments. It is therefore of interest to study the effects of the timing, duration, and intensity of bright light pulses on melatonin levels in normal subjects. To examine the effects of a single exposure to a brief burst of bright light on serum melatonin, groups of healthy human volunteers of both sexes were treated with a 15 minute pulse of bright light (350 cd/m2) early in the evening during the winter months. Serial blood samples were collected from each person and the effect of the light pulse on serum melatonin and cortisol levels determined. Melatonin levels were significantly but only transiently suppressed by the light pulse, while cortisol levels were not affected. These results demonstrate that short duration bright light treatments can influence the melatonin rhythm generating system in humans.

The metyrapone-test was used to study the influence of pituitary-adrenal activity on the pineal function in man. We recorded in blood the circadian rhythmicity of melatonin, ACTH and cortisol and the excretion of melatonin, cortisol and Porter-Silber chromogens in urine before, during and after the administration of 750 mg metyrapone every 4 h during 24 h in two healthy volunteers and in two patients with asymptomatic, moderate hyperparathyroidism and a prolactin-secreting microadenoma, respectively. The present study confirmed our previous report on an increased excretion of melatonin per 24 h and per mmol creatinine during the administration of metyrapone. The excretory maximum preceded the maximal ACTH-adrenal response. Serum melatonin remained unchanged during the administration of metyrapone. A second finding was depressed serum melatonin the night after the test in the subjects with the most marked ACTH-cortisol response following the metyrapone-test indicating suppression of melatonin secretion when ACTH-cortisol secretions were increased. A third finding was a late increase in diuresis appearing the day after metyrapone-administration while glomerular filtration rates did not show significant alterations. Thus, it is shown that the metyrapone-induced cortisol inhibition stimulates both ACTH and melatonin secretion, while high ACTH and cortisol levels are accompanied by reduced S-melatonin levels.

Serum melatonin levels over a 24 hr period were studied in 30 acutely ill patients with major depressive episode, 24 patients with a history of unipolar or bipolar major affective disorder in remission and 33 healthy subjects. A significant negative correlation (-0.45) between body height and maximum nocturnal serum melatonin level was found. Maximum serum melatonin levels during the night were lower in both patient groups than in the healthy controls. No difference was found between maximum nocturnal serum melatonin levels in 26 patients investigated when ill and again in remission. We thus propose low nocturnal melatonin to be a trait-dependent marker for major depressive disorder. A difference in the morning but not night melatonin levels was found between samples taken during the dark, winter season versus samples taken during the bright, spring-summer season. Melatonin levels were not lower in females than in males, when melatonin levels were adjusted for body height. Similar results were found when the nocturnal areas under the curve for melatonin were analyzed.

In two studies of hypertensive patients the relationship between beta-blocker-induced CNS side-effects and the nightly urinary secretion of melatonin was analysed. In one group (n = 10) placebo, atenolol (mean dose 86 mg/day) or propranolol (mean dose 305 mg/day) were given in a double-blind, randomised design. In the other (n = 13) 100-400 mg metoprolol was given daily (mean dose 197 mg). After 4 weeks of treatment all beta-blockers reduced melatonin excretion, but the effect was significant only for metoprolol. Sleep disturbance records revealed more disturbed nights in the metoprolol group compared with the propranolol and the atenolol groups, even when the difference in age between the groups was controlled for. In the metoprolol group a significant relationship (p less than 0.05) was found between the fall in melatonin and the percentage of disturbed nights. Severe CNS side-effects, such as nightmares, occurred only in patients treated with metoprolol (21%), which in all cases were accompanied by low levels of melatonin. Our data suggest that the CNS side-effects during beta-blockade are related to a reduction of melatonin levels.

Melatonin concentrations in serum and urine were examined following oral administration of melatonin to dogs. Four different doses of melatonin ranging from 10 to 80 mg per kg of body weight were given. Melatonin was rapidly absorbed and reached a maximum serum level after 20--30 min, with a distribution phase of 3.5 hours and elimination half life (t1/2) of 5 hours. The fraction excreted in the urine was 0.25% of the administrated dose during the first 5 hours. These results as well as the diurnal rhythm of serum melatonin in the dogs are similar to corresponding data reported in the human.

Rhythm characteristics in the about-daily (circadian) and about-yearly (circannual) frequency ranges were assessed for urinary melatonin. Clinically healthy women in Minnesota, USA, and Kyushu, Japan, were sampled around the clock once in 1-4 seasons. Possible differences that could reflect the large difference in breast cancer incidence in these two geographic locations were investigated. Each subject's risk of developing breast cancer, cardiovascular diseases resulting from an elevated blood pressure, and emotional conditions was numerically evaluated according to epidemiologic questionnaires. A prominent circadian rhythm characterizes urinary melatonin in both populations, peaking in the middle of the night. The American women exhibit a larger circadian rhythm-adjusted mean (mesor) than do the Japanese women. A circannual rhythm is also apparent in the North American women, but not in the Japanese women. The circadian mesor of urinary melatonin correlates negatively with the risk score of emotional depression and positively with that of developing cardiovascular diseases.

Melatonin secretion is dependent both on the environmental lighting and noradrenergic control and seems to be related to the ACTH-cortisol secretion. The aim of the present study was to further elucidate the relationship between ACTH-cortisol and melatonin. For this purpose we chose the Metyrapone test. The melatonin secretion was studied in 10 patients, and increased significantly in 8/10 during and in one after the Metyrapone administration. These results further support a relationship between melatonin and ACTH-cortisol secretion, possibly through a suprapituitary interaction.

Psychiatric symptoms in primary hyperparathyroidism (PHPT) are usually characterized as depressive. In this study 13 patients with PHPT and six control patients with atoxic nodular goiter underwent psychiatric ratings with the comprehensive psychopathological rating scale (CPRS) the day before surgery. The 21 items in this scale were grouped into clusters. The ratings were repeated after successful removal of a parathyroid adenoma. Diurnal serum concentrations of cortisol, melatonin and prolactin were studied pre- and postoperatively in eight of the patients. Patients with PHPT had significantly higher CPRS total scores, 8.5 +/- 1.3, compared with goiter controls, 1.9 +/- 0.8, and showed a significant improvement of psychiatric symptoms after excision of the parathyroid adenoma, to 3.3 +/- 0.9. The preoperative diurnal and peak levels of cortisol and melatonin were higher (P less than 0.05) than after surgery. Serum melatonin fell to levels lower than those in healthy controls. Correlations were found between some clusters or items and cortisol or melatonin. Serum prolactin levels were normal and unaltered by parathyroid surgery. It is concluded that patients with PHPT show well defined psychiatric symptoms many of which are correlated to alterations in serum cortisol and melatonin accompanying PHPT. The improvement of symptoms seen after successful surgery further suggests that PHPT is associated with a specific psychiatric disorder similar to but distinguishable from major depressive disorder.

Serum melatonin concentration in early morning during the menstrual cycle, studied in five healthy women, showed that melatonin was elevated at the time of menstrual bleeding and had its nadir at the time of the menstrual cycling in humans.

Maximum nocturnal serum melatonin level (MTmax) in relation to some clinical variables was studied in 32 patients with a major depressive episode and in 33 healthy subjects with reference to the outcome of the dexamethasone suppression test (DST). Significant regressions were found between MTmax levels and clinical rating scores in CPRS, interpreted as retardation symptoms. Four healthy subjects with disposition for dysthymic reactions had subnormal MTmax levels, which differed from MTmax levels in subjects without such disposition. Patients but not the healthy subjects, who reported parental loss before 17 years of age, had subnormal MTmax levels and differed from patients with no reported parental loss. Patients with no reported suicidal behaviour in clinical history had significantly lower MTmax levels than patients with reported suicide attempts. No relations were found between low MTmax levels and diagnoses, duration of illness, reported inheritance for depressive illness or sleep disturbances. A hypothetical low melatonin syndrome in depression is proposed: low nocturnal melatonin, abnormal dexamethasone suppression test, disturbed 24-h rhythm of cortisol, less pronounced daily and annual cyclic variation in depressive symptomatology.

Urinary melatonin levels were measured in 10 postmenopausal Indian women suffering from advanced stages of breast cancer and in 9 well-matched women with non-endocrine complaints, mostly uterovaginal prolapse. Urines of each patient were collected over a period of 2-3 days in four 4-hourly intervals from 6 a.m. to 10 p.m. and one 8-hourly interval from 10 p.m. to 6 a.m. Serum LH, FSH, prolactin, estradiol and cortisol levels at 11 a.m. were determined as well as estrogen and progesterone receptors of the breast tumors. It was found that 24 hour urinary melatonin excretion in cancer patients was on the average 31% decreased as compared to the controls. This change was accompanied by a 33% increase in serum cortisol levels in the cancer patients. The melatonin excretion patterns of the cancer patients were not synchronized as compared to synchronized patterns of the controls. The number of tumors tested for steroid receptors does not yet allow to conclude if melatonin is different in patients with or without hormone-dependent tumors. The data suggest that pineal melatonin secretion may be modified in quantity as well as rhythmicity in breast cancer patients.

Melatonin was radioimmunoassayed in extracts from brains of Musca autumnalis De Geer, the face fly, obtained 4h apart during 24h in 3 series pools of over 2 dozen brains at each of 6 or 7 circadian times. A circadian rhythm in the data expressed as percent of mean was demonstrated by the population-mean cosinor method. Face flies thus offer themselves for studies of melatonin-mediated chronomodulation by feedsideward mechanisms.

Day and nighttime melatonin and dopamine-beta-hydroxylase activity were measured in blood from 10 Jewish and 9 non-Jewish dystonics and from 22 nondystonic family members. Groups did not significantly differ on either of these measures. These results do not support a generalized abnormality of noradrenergic release in dystonia.