Nocturnal melatonin excretion is decreased in patients with migraine without aura attacks associated with menses

Nocturnal melatonin excretion was studied throughout a complete menstrual cycle in 10 women with migraine without aura attacks associated with menses and 9 women controls. Urine melatonin was determined by radioimmunoassay. The mean nocturnal melatonin excretion throughout the cycle was significantly lower in the migraine patients than in controls. In the control group, melatonin excretion increased significantly from the follicular to the luteal phase, whereas no difference was observed in the migraine group. Results are discussed in view of the role of the pineal gland in the organization of biological rhythms and homeostasis in relation to environmental conditions.     

Urinary 6-hydroxymelatonin sulfate excretion in intellectually disabled subjects with sleep disorders and multiple medications: validation of measurements in urine extracted from diapers

The aim of this study was to examine the applicability of urinary 6-hydroxymelatonin sulfate (MT6s) measurements in the evaluation of melatonin secretion in intellectually disabled patients with sleep disorders. All 17 patients received drugs with potential interactions with melatonin metabolism. Serum melatonin 24-h profiles were determined at hourly intervals. The area under the curve (AUC) value, peak amplitude, half-rise time, and half-decline time were calculated individually. Urinary MT6s excretion was determined from samples collected from disposable diapers during three consecutive days at varying intervals. The average excretion rate for each hour of the day was calculated. The excretion profiles were characterized by total amount of MT6s excretion/24 h/kg body mass, amount of excreted MT6s during 6 h of maximum excretion (MAX 6h), and start time of the maximum excretion (start MAX 6h). There were significant positive correlations between serum melatonin AUC value and total excretion of MT6s/body mass, between serum melatonin amplitude and urinary MAX 6h, and between melatonin half-rise time and start MAX 6h; one patient on phenobarbital medication was out of line. The serum melatonin profiles of the patients were classified by comparing them with those of matched healthy volunteers (low-, normal-, or high secretors, normal or delayed rhythm). Similarly, the parameters of MT6s profiles were compared with those obtained from healthy controls, and the patients were reclassified as normal or aberrant. The classifications based on serum melatonin and urinary MT6s measurements were mostly concordant. The daily pattern of urinary MT6s excretion reliably reflected the phase of the serum melatonin rhythm irrespective of the medications, but in some cases, the total amount of excreted MT6s was lower than expected based on serum melatonin measurements.     

Urinary 6‐hydroxymelatonin sulfate excretion in intellectually disabled subjects with sleep disorders and multiple medications: Validation of measurements in urine extracted from diapers

The aim of this study was to examine the applicability of urinary 6‐hydroxymelatonin sulfate (MT6s) measurements in the evaluation of melatonin secretion in intellectually disabled patients with sleep disorders. All 17 patients received drugs with potential interactions with melatonin metabolism. Serum melatonin 24‐h profiles were determined at hourly intervals. The area under the curve (AUC) value, peak amplitude, half‐rise time, and half‐decline time were calculated individually. Urinary MT6s excretion was determined from samples collected from disposable diapers during three consecutive days at varying intervals. The average excretion rate for each hour of the day was calculated. The excretion profiles were characterized by total amount of MT6s excretion/24?h/kg body mass, amount of excreted MT6s during 6?h of maximum excretion (MAX 6h), and start time of the maximum excretion (start MAX 6h). There were significant positive correlations between serum melatonin AUC value and total excretion of MT6s/body mass, between serum melatonin amplitude and urinary MAX 6h, and between melatonin half‐rise time and start MAX 6h; one patient on phenobarbital medication was out of line. The serum melatonin profiles of the patients were classified by comparing them with those of matched healthy volunteers (low‐, normal‐, or high secretors, normal or delayed rhythm). Similarly, the parameters of MT6s profiles were compared with those obtained from healthy controls, and the patients were reclassified as normal or aberrant. The classifications based on serum melatonin and urinary MT6s measurements were mostly concordant. The daily pattern of urinary MT6s excretion reliably reflected the phase of the serum melatonin rhythm irrespective of the medications, but in some cases, the total amount of excreted MT6s was lower than expected based on serum melatonin measurements.     

Urinary 5-HIAA in migraine: Evidence of lowered excretion in young adult females

Urinary 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in 44 young adult migraine patients (35 women, 9 men) between attacks and in 33 healthy controls (23 women, 10 men). HVA excretion was equivalent in all groups. 5-HIAA was unaltered in men but was significantly decreased in female migraine patients when compared with their sex-matched controls (-31%, p less than 0.01). No relationship was found between 5-HIAA excretion and the various characteristics of migraine, such as the time that had elapsed since the last attack and the presence or absence of oral contraception. The relatively marked decrease in 5-HIAA excretion in female migraine patients can hardly be accounted for by a reduction in either neuronal or platelet serotonin metabolism alone. A reduction in the intestinal contribution to urinary 5-HIAA might be the crucial factor.     

Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache

The typical cyclic occurrence of cluster headache suggests the involvement of hypothalamic rhythm regulating centers in the pathogenesis of this primary headache. In previous studies, reduced 24-h plasma melatonin levels during the cluster period, loss of circadian melatonin secretion in remission, as well as permanently reduced excretion of urinary melatonin in both illness phases have been reported, supporting the hypothesis of a hypothalamic derangement. In this study, the 24-h urinary excretion of the main melatonin metabolite, 6-sulphatoxymelatonin, was evaluated in 20 cluster period cluster headache patients. Thirteen were retested 12 months later, in the same period of the year, during remission. Fourteen age- and sex-matched healthy subjects were the controls. As expected, significantly higher levels of 6-sulphatoxymelatonin were present in nocturnal urine than in day-time urine in controls, while in both cluster headache groups urinary levels of this metabolite did not differ between day and night. Nocturnal levels of 6-sulphatoxymelatonin were significantly lower in both cluster headache groups than controls. Day-time levels did not differ significantly between the groups. Altered excretion of urinary 6-sulphatoxymelatonin even during remission indicates that at least some of these anomalies are independent of the pain, and provides further evidence of involvement of the hypothalamic rhythm regulating centers in cluster headache.     

Does hypercalcaemia or calcium antagonism affect human melatonin secretion or renal excretion?

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.     

Low urinary 6-sulphatoxymelatonin concentrations in acute migraine

Substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms, sleep, and headache disorders. The objective of the study was to assess 6-sulphatoxymelatonin (aMT6s) levels in a large consecutive series of patients with migraine, comparing with controls. A total of 220 subjects were evaluated-146 had migraine and 74 were control subjects. Urinary samples were collected into the same plastic container since 8:00 p.m. to 8:00 a.m. of the next day (12-h period) and aMT6s was measured with quantitative ELISA technique. Among patients with migraine, 53% presented pain on the day of the urine samples collection. Their urinary aMT6s concentration was significantly lower than in the urine of patients without pain [14.0 +/- 7.3 vs. 49.4 +/- 19.0; t(143) = -15.1; 95% CI = -40.0 to -30.8; P < 0.001]. There was no significant difference in the aMT6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [49.4 +/- 19.0 vs. 42.5 +/- 27.9; t(140) = 1.7; 95% CI = -1.2 to 14.8; P = 0.094]. To our knowledge, this is the first study to demonstrate reduction in melatonin levels during attacks in episodic and chronic migraine.     

Melatonin production in thrombocytes and their functional activity in patients with aspirin asthma

The aim of the investigation was to study melatonin production in thrombocytes and their functional activity in correlation with 6-sulfatoximelatonin (6-SOM) urinary excretion in patients with aspirin-induced bronchial asthma (AIBA). Forty-three patients with bronchial asthma (BA) were examined. The main group consisted of 26 AIBA patients; the comparison group consisted of 17 BA patients with no intolerance to aspirin or other non-steroidal anti-inflammatory drugs; 30 practically healthy individuals constituted the control group. The study found no melatonin production in thrombocytes of AIBA patients: only 13.0 +/- 1.3% of platelets expressed melatonin, while in healthy people 97.7 +/- 0.6% of the cells did. Besides, daytime urinary excretion of 6-SOM, the main melatonin metabolite, was lower in AIBA patients. Lower daytime and higher nighttime melatonin production in AIBA patients correlated with the acceleration of the 1st phase and increased intensity of thrombocyte aggregation, which evidences high thrombocyte reactivity to the inducing agent. The presence of a pathologic reaction of thrombocytes to exogenous melatonin, manifesting by changes in the 1st stage of aggregation, suggests the presence of pathology in thrombocyte membrane-receptor complex and the calcium homeostasis of the cell, which determines constant activation and the participation of thrombocytes in the development of asthmatic syndrome.     

Urinary 6‐Sulphatoxymelatonin Levels Are Depressed in Chronic Migraine and Several Comorbidities

(Headache 2010;50:413‐419) Objective.— To assess urinary 6‐sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. Background.— Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. Methods.— Urine samples were collected into a single plastic container over a 12‐hour period from 8:00 pm to 8:00 am of the next day, and 6‐sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State‐Trait Anxiety Inventory, and the Beck Depression Inventory. Results.— A total of 220 subjects were evaluated – 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6‐sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6‐sulphatoxymelatonin levels and depression, anxiety, and fatigue. Conclusions.— To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.     

Aluminium mobilization following renal transplantation and the possible effect on susceptibility to bacterial sepsis

We monitored urinary aluminium excretion in 60 renal allograft recipients for the first 6 months following transplantation. Plasma and urinary aluminium values steadily decreased during the study period. Patients who suffered two or more bacterial infections during this period excreted more urinary aluminium than those with only one or no infections. Twenty patients experienced a two-fold or greater sudden unexpected increase in urinary aluminium excretion: 14 of these patients (60 per cent) had evidence of infection (10 bacterial and four viral), at this time. Both urinary aluminium and fractional aluminium excretion were greater in the 10 patients with bacterial infection than in the other 10 patients. Thus, patients who suffered bacterial infections had higher base-line urinary aluminium excretion, suggesting a higher body burden of aluminium. In addition, bacterial sepsis was associated with aluminium release from tissue stores with an associated increase in urinary aluminium excretion. This implies that patients with an increased body burden of aluminium are more prone to bacterial sepsis, and that aluminium excretion is increased during sepsis.     

Urinary nitric oxide metabolites and lipid peroxidation by-products in migraine

Enhanced endothelium nitric oxide (NO) and superoxide anion release may cause migraine through related cerebral blood flow changes. Thirty subjects suffering from migraine with and without aura and 20 healthy controls were investigated. Urine samples collected for 24 h during and after the migraine attack, and during the headache-free period, were assayed for urinary NO stable metabolites (NOx) and thiobarbituric acid reactive substances (TBARS). During the headache-free period urinary NOx and TBARS levels were higher in migraine sufferers than in controls (NOx 0.77 +/- 0.14 vs. 0.28 +/- 0.15 mmol/mmol creatinine, P < 0.05; TBARS 0.40 +/- 0.19 vs. 0.26 +/- 0.13 micro mol/mol creatinine, P < 0.05). Also, NOx excretion was higher during the headache-free period than during or after the migraine attack (P < 0.05). Urinary TBARS were increased during the attack with respect to the headache-free period (P < 0.05). No differences were observed in the same parameters between sufferers of migraine with and without aura. Urinary NOx and TBARS might be promising as markers of their systemic levels to evaluate the increased vulnerability to oxidative stress in migraine sufferers.     

Aluminium Mobilization Following Renal Transplantation and the Possible Effect on Susceptibility to Bacterial Sepsis

We monitored urinary aluminium excretion in 60 renal allograftrecipients for the first 6 months following transplantation.Plasma and urinary aluminium values steadily decreased duringthe study period. Patients who suffered two or more bacterialinfections during this period excreted more urinary aluminiumthan those with only one or no infections. Twenty patients experienced a two-fold or greater sudden unexpectedincrease in urinary aluminium excretion; 14 of these patients(60 per cent) had evidence of infection (10 bacterial and fourviral), at this time. Both urinary aluminium and fractionalaluminium excretion were greater in the 10 patients with bacterialinfection than in the other 10 patients. Thus, patients who suffered bacterial infections had higherbase-line urinary aluminium excretion, suggesting a higher bodyburden of aluminium. In addition, bacterial sepsis was associatedwith aluminium release from tissue stores with an associatedincrease in urinary aluminium excretion. This implies that patientswith an increased body burden of aluminium are more prone tobacterial sepsis, and that aluminium excretion is increasedduring sepsis.     

Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus

The plasma melatonin profile was significantly disturbed (phase-shift of the maximum melatonin level) in four out of six female sufferers from status migrainosus, compared with nine healthy controls. The number of secretion peaks was similar in both groups. A nocturnal 20 μg melatonin infusion (from 21.00 to 01.00 h) evoked plasma melatonin levels slightly higher than a physiological secretion peak. During infusion, the episodes of secretion were reinforced and the endogenous plasma profile was phase-advanced in two patients displaying a phase-delay. These data suggest impaired pineal function in migraine. In the absence of side effects of melatonin infusion, the relief of certain migraine symptoms described by our patients might support a controlled trial of melatonin in migraine.     

Nocturnal Plasma Melatonin Levels in Migraine: A Preliminary Report

We determined by radioimmunoassay plasma melatonin levels on blood samples drawn at 11 p.m. in migraine patients and control subjects. Ninety-three cephalalgic outpatients (75 females, 18 males) were compared to a control group (24 females, 22 males) matched according to age. Patients were divided into subgroups presenting common migraine (n = 38); ophthalmic migraine (n = 12); and tension headache associated with ophthalmic or common migraine (n = 24), and associated depressive status (n = 19). Statistical analysis revealed a decrease in plasma melatonin levels for the entire migraine population, compared to the control one, and a heterogeneity in both controls and patients; this heterogeneity was found mainly in the depressive and tension headache subgroups. When the migraine population--from which the depressive patients were excluded--was divided into male and female subgroups, a decrease in plasma melatonin levels was observed only for the female subgroups. Results are discussed with reference to the role of the pineal gland in the synchronization of the organism with the environmental conditions.     

NONPHARMACOLOGIC TREATMENTS

Background: The benefits of meditation are well documented, but the biochemical mechanisms have not been fully identified. One effect mechanism may be via influence on neurotransmitters.
Material and methods: Therefore, plasma melatonin and blood serotonin concentrations were measured before and after 1 hour of meditation in advanced male meditators (n = 27, mean age 46 years). They were compared with a matched reference group (n = 29, mean age 43 years) who rested for 1 hour. In the meditators, melatonin, and serotonin from before and after three consecutive hours of meditation were also compared.
Results: Initially, the median melatonin level was 4.9 pg per milliliter in the meditators and 3.1 pg per milliliter in the reference group ( P < .01). After 1 hour of practice, melatonin had decreased to a median of 3.4 pg per milliliter in the meditators ( P < .0001), but was unchanged in the reference group. After 3 hours of meditation, melatonin had declined further in the meditators. After 1 hour of practice, serotonin concentrations decreased in both the meditators and the reference group ( P < .01).
Conclusions: The findings suggest that advanced meditators have higher melatonin levels than nonmeditators. Melatonin decreases during long meditation, a finding the study does not explain. Serotonin declines after both 1-hour meditation and rest, indicating that serotonin may be a marker of general rest and not meditation-specific relaxation.
Comments: Many small studies have evaluated the effects of melatonin on cluster and migraine. Here the authors summarize a relationship of melatonin, serotonin, meditation, and rest (the latter two variables clearly helpful in migraine). Does this help to explain why migraine tends to remit in sleep? Stewart J. Tepper     

The correlation between human plasma melatonin levels and urinary 6-hydroxymelatonin excretion

A significant correlation (0.76) has been found between nighttime peak plasma melatonin levels and the 24-h urinary excretion totals for conjugated 6-hydroxy-melatonin for a group of 22 women. This study validates the comparison of plasma levels of the hormone or urinary levels of its metabolite to assess pineal gland production of melatonin in humans.     

Studies of intestinal permeability in inflammatory diseases using polyethylene glycol 400

It has been proposed that increased bowel permeability might play a role in the pathogenesis of inflammatory disease. Intestinal permeation was investigated by measuring the 6-hour urinary excretion of polyethylene glycol (PEG) 400 in 40 adult volunteer controls and in patients with inflammatory disease. Of the patients, 15 had Crohn's disease; 7, ulcerative colitis; 2, celiac disease; and 7, rheumatoid arthritis. No significant difference in total urinary excretion over a 6-hour period was found between controls and patients with ulcerative colitis. Patients with Crohn's disease, celiac disease, or with rheumatoid arthritis were found to have significantly decreased urinary excretion of PEG 400. The results of this study indicate that there is no identifiable increase in intestinal permeation as measured by PEG 400 excretion during periods of active inflammatory disease.     

Low melatonin excretion during mechanical ventilation in the intensive care unit

Biochemical markers for the circadian rhythm were studied in patients treated at the ICU (intensive care unit) of two regional hospitals. A normal rhythm is characterized by a relatively higher melatonin and a lower cortisol excretion at night. Disturbances affect sleep, mood and cognitive performance. All urine excreted between 07:00 and 22:00 hours (day) and between 22:00 and 07:00 hours (night) was collected and sampled throughout the entire ICU period (median, 10 days) in 16 patients for the excretion of 6-SMT (6-sulphatoxymelatonin), which is a metabolite of melatonin, and free cortisol. The overall excretion of 6-SMT was slightly lower and the cortisol excretion higher than reported for healthy reference populations. Mechanical ventilation was associated with a markedly lower 6-SMT excretion (median, 198 ng/h) compared with periods without such help (555 ng/h; P<0.0001), whereas infusion of adrenergic drugs increased the 6-SMT excretion (P<0.01). Five patients (31%) showed a virtually absent melatonin excretion for 24 h or more. The diurnal rhythms were consistently or periodically disturbed in 65% and 75% of the patients. These alterations cannot be explained by excessive exposure to light at night. In conclusion, there was hyposecretion of melatonin during mechanical ventilation, an overall high cortisol excretion and a disturbed diurnal rhythm of both of these hormones in most patients treated in two ICU departments.     

The Kallikrein-Kinin System in Bartter''s Syndrome and Its Response to Prostaglandin Synthetase Inhibition

The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartter's syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.     

Urinary noradrenaline excretion and renal function in normal and hypertensive 50-year-old men.

1. Sympathetic nervous system activity, measured by urinary noradrenaline excretion, was determined in a group of untreated hypertensive subjects (n = 35), a reference group (n = 80) and a normotensive group (n = 51), all derived from a random population sample of 50-year-old men. It was compared with casual and resting blood pressure, urinary sodium excretion, urinary cretinine concentration and glomerular filtration rate. Hypertension was defined as systolic pressure greater than 175 or diastolic greater than 115 mmHg on two separate occasions. Normotension was defined as systolic pressure less than 160 and diastolic pressure less than 95 mmHg. 2. There was no difference in the average excretion of noradrenaline during the day or night between the reference, normotensive and hypertensive groups. None of the hypertensive patients had values for urinary noradrenaline excretion during the day above the range found in normotensive subjects, indicating that hypertension with increased sympathetic nervous system activity is uncommon when hypertension in defined as above. 3. No correlation between urinary noradrenaline excretion during the day and blood pressure was found in the reference group or in the normotensive group. In the hypertensive group, there was a negative correlation between urinary noradrenaline excretion and blood pressure after rest. This finding might indicate that factors other than sympathetic nervous system activity determine the level of blood pressure in hypertensive subjects. 4. In the hypertensive group, urinary noradrenaline excretion during the day was positively correlated with both urinary sidium excretion during the day and glomerular filtration rate. Urinary noradrenaline excretion per 24 h was positively correlated with urinary sodium excretion during the same time. High resting blood pressure, low urinary sodium excretion, low glomerular filtration rate and a reversed diurnal rhythm of urinary excretion characterized hypertensive patients with low urinary noradrenaline excretion, indicating more severe hypertension in these hypertensive patients with reduced sympathetic nervous system activity.