Urinary 6-sulfatoxymelatonin Excretion Research Articles

Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome.

BackgroundDeletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene–dosage effects on language development at 7q11.23 have been hypothesized.MethodsMolecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined.ResultsThe two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production.ConclusionsOur observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype–phenotype correlations, possible gene–environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.

Positive Effect of Daylight Exposure on Nocturnal Urinary Melatonin Excretion in the Elderly: A Cross-Sectional Analysis of the HEIJO-KYO Study

Melatonin is involved in a variety of diseases, including cancer, insomnia, depression, dementia, hypertension, and diabetes; its secretion is influenced by environmental light. Although daylight exposure increases nocturnal melatonin secretion in a controlled laboratory setting, whether it increases nocturnal melatonin secretion in an uncontrolled daily life setting remains unclear. We aimed to determine the association between daylight exposure in an uncontrolled daily life setting and urinary 6-sulfatoxymelatonin excretion. A cross-sectional study was conducted in 192 elderly individuals (mean age, 69.9 yr). We measured ambulatory daylight exposure using a wrist light meter in two 48-h sessions; furthermore, we measured overnight urinary 6-sulfatoxymelatonin excretion, an index of melatonin secretion, on the second night of each session. The median duration of daylight exposure of at least 1000 lux was 72 min (interquartile range, 37-124). Univariate linear regression analysis showed marginal to significant associations between log-transformed urinary 6-sulfatoxymelatonin excretion and age, current smoking status, benzodiazepine use, day length, log-transformed duration of daylight exposure of at least 1000 lux, and daytime physical activity. In a multivariate model, log-transformed duration of daylight exposure of at least 1000 lux was significantly associated with log-transformed urinary 6-sulfatoxymelatonin excretion (regression coefficient, 0.101; 95% confidence interval, 0.003-0.199; P = 0.043). Furthermore, an increase in the duration of daylight exposure of at least 1000 lux from 37 to 124 min (25th to 75th percentiles) was associated with a 13.0% increase in urinary 6-sulfatoxymelatonin excretion (6.8 to 7.7 μg). Daylight exposure in an uncontrolled daily life setting is positively associated with urinary 6-sulfatoxymelatonin excretion in the elderly.

Phototherapy and Orange-Tinted Goggles for Night-Shift Adaptation of Police Officers on Patrol

The aim of the present combined field and laboratory study was to assess circadian entrainment in two groups of police officers working seven consecutive 8/8.5-h night shifts as part of a rotating schedule. Eight full-time police officers on patrol (mean age ± SD: 29.8 ± 6.5 yrs) were provided an intervention consisting of intermittent exposure to wide-spectrum bright light at night, orange-tinted goggles at sunrise, and maintenance of a regular sleep/darkness episode in the day. Orange-tinted goggles have been shown to block the melatonin-suppressing effect of light significantly more than neutral gray density goggles. Nine control group police officers (mean age ± SD: 30.3 ± 4.1 yrs) working the same schedule were enrolled. Police officers were studied before, after (in the laboratory), and during (ambulatory) a series of seven consecutive nights. Urine samples were collected at wake time and bedtime throughout the week of night work and during laboratory visits (1 × /3 h) preceding and following the work week to measure urinary 6-sulfatoxymelatonin (UaMT6s) excretion rate. Subjective alertness was assessed at the start, middle, and end of night shifts. A 10-min psychomotor vigilance task was performed at the start and end of each shift. Both laboratory visits consisted of two 8-h sleep episodes based on the prior schedule. Saliva samples were collected 2 × /h during waking episodes to assay their melatonin content. Subjective alertness (3 × /h) and performance (1 × /2 h) were assessed during wake periods in the laboratory. A mixed linear model was used to analyze the progression of UaMt6s excreted during daytime sleep episodes at home, as well as psychomotor performance and subjective alertness during night shifts. Two-way analysis of variance (ANOVA) (factors: laboratory visit and group) were used to compare peak salivary melatonin and UaMT6s excretion rate in the laboratory. In both groups of police officers, the excretion rate of UaMT6s at home was higher during daytime sleep episodes at the end compared to the start of the work week (p < .001). This rate increased significantly more in the intervention than control group (p = .032). A significant phase delay of salivary melatonin was observed in both groups at the end of study (p = .009), although no significant between-group difference was reached. Reaction speed dropped, and subjective alertness decreased throughout the night shift in both groups (p < .001). Reaction speed decreased throughout the work week in the control group (p ≤ .021), whereas no difference was observed in the intervention group. Median reaction time was increased as of the 5th and 6th nights compared to the 2nd night in controls (p ≤ .003), whereas it remained stable in the intervention group. These observations indicate better physiological adaptation in the intervention group compared to the controls. (Author correspondence: diane.boivin@douglas.mcgill.ca)

Use of nocturnal melatonin concentration and urinary 6-sulfatoxymelatonin excretion to evaluate melatonin status in children with severe sepsis

The aim of this study was to evaluate whether nocturnal melatonin concentration (NMC) and urinary 6-sulphatoxymelatonin (aMT6s) excretion can predict melatonin status in patients with severe sepsis in the pediatric intensive care unit (PICU). Blood samples for the determination of NMC were obtained from each patient at 3 a.m. Urine samples for the determination of aMT6s excretion were obtained from each patient at 12 h intervals. We obtained 89 blood and 178 urine samples from 23 septic patients, and 52 blood and 104 urine samples from 13 non-septic patients. The NMC of septic patients in a state of septic shock was significantly higher than that of septic patients not in septic shock (p = 0.017) and those of non-septic patients (p = 0.019). In contrast, there was no significant difference for nocturnal (NaMT6s) and total aMT6s (TaMT6s) excretion between septic patients with and without septic shock and non-septic patients (p > 0.05). The NMC was significantly higher in septic patients in shock with and without hepatic dysfunction (HD) than in non-septic patients (p = 0.004 and p = 0.024, respectively). NaMT6s and TaMT6s excretion was significantly lower in septic patients with HD than in septic patient without HD (p = 0.040 and p = 0.029, for NaMT6s and TaMT6s, respectively). Our results showed that an elevated NMC may not reflect an increased MT production in septic patients in septic shock. It seems that, to evaluate the melatonin status of septic PICU patients, it is necessary to collect both serum and urine samples.

Prolonged-release melatonin for insomnia &amp;ndash; an open-label long-term study of efficacy, safety, and withdrawal

BackgroundProlonged-release melatonin (PRM) 2 mg is indicated for insomnia in patients aged 55 years and older. A recent double-blind placebo-controlled study demonstrated 6-month efficacy and safety of PRM in insomnia patients aged 18–80 and lack of withdrawal and rebound symptoms upon discontinuation.ObjectiveTo investigate the efficacy, safety, and withdrawal phenomena associated with 6–12 months PRM treatment.MethodsData from a prospective 6–12-month open-label study of 244 community dwelling adults with primary insomnia, who had participated in a placebo-controlled, double-blind dose-ranging trial of PRM. Patients received PRM nightly, followed by a 2-week withdrawal period. Main outcome measures were patient-reported sleep quality ratings (diary), adverse events, vital signs, and laboratory tests recorded at each visit, and withdrawal symptoms (CHESS-84 [Check-list Evaluation of Somatic Symptoms]). Nocturnal urinary 6-sulfatoxymelatonin excretion, a measure of the endogenous melatonin production, was assessed upon discontinuing long-term PRM.ResultsOf the 244 patients, 36 dropped out, 112 completed 6 months of treatment, and the other 96 completed 12 months of treatment. The mean number of nights by which patients reported sleep quality as “good” or “very good” was significantly higher during PRM than before treatment. There was no evidence of tolerance to PRM. Discontinuation of PRM was not associated with rebound insomnia or withdrawal symptoms; on the contrary, residual benefit was observed. PRM was well tolerated, and there was no suppression of endogenous melatonin production.ConclusionResults support the efficacy and safety of PRM in primary insomnia patients aged 20–80 throughout 6–12 months of continuous therapy. PRM discontinuation even after 12 months was not associated with adverse events, withdrawal symptoms, or suppression of endogenous melatonin production.

Urinary Excretion of 5-Hydroxyindoleacetic Acid, Serotonin and 6-Sulphatoxymelatonin in Normoserotonemic and Hyperserotonemic Autistic Individuals

Objective: A substantial proportion of individuals with autism have elevated levels of platelet serotonin (5-HT). We examined whether platelet hyperserotonemia is associated with increased gut 5-HT synthesis, altered 5-HT catabolism or altered melatonin production. Methods: Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT was compared in 10 normoserotonemic and 10 hyperserotonemic age-matched autistic individuals. The relationship of urinary 6-sulfatoxymelatonin (6-SM) excretion to platelet 5-HT, and to urinary 5-HT and 5-HIAA excretion, was also examined. Results: In the hyperserotonemic group, significant increases at trend level in urinary excretion of 5-HIAA (p = 0.061) and 5-HT (p = 0.071) and a significant decrease for 6-SM were found (p = 0.027). The urinary 5-HIAA:5-HT ratio was similar in the normo- versus the hyperserotonemic groups. Conclusions: The catabolism of 5-HT does not differ in the groups, but greater exposure of the platelet to 5-HT cannot be ruled out as a cause of the platelet hyperserotonemia of autism. Although only trend level significant, the data point to a need for larger studies to examine more thoroughly the relationships between platelet hyperserotonemia, gut 5-HT synthesis and melatonin production.

Postoperative elevated cortisol excretion is not associated with suppression of 6‐sulfatoxymelatonin excretion

This study tests the hypothesis that elevated postoperative excretion of cortisol is associated with suppression of the nocturnal excretion of 6-sulfatoxymelatonin, the chief metabolite of the circadian hormone, melatonin. Postoperative patients demonstrate circadian rhythm disturbances and suppression of nocturnal melatonin plasma concentration. Since the nocturnal surge in melatonin concentration in normal volunteers is time-locked to the circadian nadir of cortisol concentration, perhaps the attenuation of the nocturnal melatonin surge in postoperative patients results from prolonged elevation in the plasma cortisol concentration. In this observational study performed in 21 patients having unilateral hip or knee arthroplasty, urine was collected every 4 h for the first 48 h after surgery for measurement of urinary 6-sulfatoxymelatonin (EIA) and free cortisol (RIA) excretion. The total (P < 0.05) and peak (P < 0.02) nocturnal 6-sulfatoxymelatonin excretions were lower on the first than the second postoperative night. The nocturnal cortisol nadir preceded the 6-sulfatoxymelatonin surge in 20% of the subjects on night 1 and in 75% of the subjects on night 2. The lack of a consistent relationship between the magnitude or timing of cortisol excretion and 6-sulfatoxymelatonin excretion suggests that cortisol does not mediate postoperative 6-sulfatoxymelatonin suppression.

Association of morning illumination and window covering with mood and sleep among post-menopausal women.

The antidepressant and sleep-promoting effects of light exposure might be useful for treating age-related mood and sleep disorders. In view of recent evidence suggesting beneficial effects of morning light, this study examined the associations of mood and sleep with morning light exposure, 24 h environmental illumination, and the degree to which the volunteers' bedroom windows were covered in the morning. We examined 459 postmenopausal women participating an ancillary study of the Women's Health Initiative conducted at the University of California, San Diego Clinical Center, San Diego, CA, USA. At baseline, volunteers completed a 4-week sleep-recall questionnaire. Volunteers were then assessed for 5-7 days in their home environments with actigraphic wrist monitors. During home recording, self-reported mood was assessed. Morning illumination during the first 4 h after arising, 24-h illumination mesor (cosine-fitted mean), and illumination acrophase (cosine-fitted peak time) were calculated. Sleep was scored each night using validated wrist actigraphic methods. A sleep diary was completed each morning. During two 24-h periods, urine was collected approximately every 2 h during wakefulness and following any voidings during the sleep period. Cosine-fitting established the acrophase of urinary 6-sulfatoxymelatonin (aMT6s) excretion. Morning illumination and 24-h illumination were modestly associated with better mood and sleep. Associations of light with mood and sleep were consistently greater for subjects whose body clocks were delayed relative to the group median. Less morning window covering in the subjects' bedrooms was associated with more morning light and less depressed mood. The results suggest that both morning and 24-h light exposure may be beneficial for older adults.

Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy

Purpose Melatonin, which is produced by the pineal gland at night, is an endogenous sleep regulator. Both sleep disorders and impaired melatonin production are common among the elderly. We examined the excretion of the major melatonin metabolite 6-sulfatoxymelatonin in insomnia patients aged ≥55 years and its relation with the subsequent response to melatonin therapy. Methods We studied 517 insomnia patients, along with 29 age-matched and 30 younger healthy volunteers. Nocturnal urinary 6-sulfatoxymelatonin excretion was assessed between 10 pm and 10 am. Three hundred and ninety-six of the insomnia patients were treated for 2 weeks with placebo and for 3 weeks with 2 mg per night of controlled-release melatonin, of which 372 provided complete datasets. Clinical response, assessed with the Leeds Sleep Evaluation Questionnaire, was defined as an improvement of 10 mm or more on the visual analog scales. Results Mean (± SD) 6-sulfatoxymelatonin excretion was lower in the insomnia patients (9.0 ± 8.3 μg per night) than in volunteers of the same age (18.1 ± 12.7 μg per night, P <0.05) and in younger volunteers (24.2 ± 11.9 μg per night, P <0.05). About 30% of patients (112/372) excreted ≤3.5 μg of sulfatoxymelatonin per night, which is considered to be lower than normal for this age group. These “low excretors” had a significantly higher response to melatonin replacement therapy (58% [65/112] vs. 47% [122/260], P <0.05). Conclusion Low nocturnal melatonin production is associated with insomnia in patients aged 55 years or older, and identifies patients who are somewhat more likely to respond to melatonin replacement.

Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women with polycystic ovary syndrome: the effect of ethinyl estradiol–cyproterone acetate treatment

The role of melatonin in human reproduction is still unknown. Data obtained in patients with hypogonadism and precocious puberty suggest that melatonin and the reproductive hormones are interrelated.The aim of this study was to determine melatonin production in hyperandrogenic women. We studied 12 women with polycystic ovary syndrome (PCOS) and 10 women with idiopathic hirsutism (IH). Patients were treated with cyproterone acetate–ethinyl estradiol (Diane 35) for 4 months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dehydroepiandrosterone sulfate (DHEAS) and 24-h urine collections for the determination of 6-sulfatoxymelatonin (αMT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. The results were compared with those obtained in 15 control women. At baseline, women with PCOS had significantly higher LH and testosterone levels than those with IH and controls. Their αMT6s values (52.6 ± 20.3 µg/24 h) were significantly higher than the values in women with IH (34.3 ± 7.1) and controls (30.5 ± 6.5) (p < 0.001). Diane 35 treatment significantly decreased LH, FSH, testosterone and αMT6s values in PCOS (28.0 ± 13.9 µg/24 h) (p < 0.0001). These results indicate that women with PCOS have increased melatonin production. The normalization of αMT6s and testosterone values during Diane 35 treatment suggests that sex steroids modulate melatonin secretion in these patients either directly or through the suppression of gonadotropin.

Low urinary 6-sulfatoxymelatonin levels in patients with severe congestive heart failure.

To assess urinary 6-sulfatoxymelatonin excretion in patients admitted to the hospital because of congestive heart failure (CHF). Urinary 6-sulfatoxymelatonin was measured by a specific radioimmunoassay in 33 hospitalized patients with CHF and in 146 healthy ambulatory volunteers. Individuals with hepatic or renal failure were excluded from the sample. Data were analyzed by the Mann-Whitney test and regression analysis. 6-Sulfatoxymelatonin levels were significantly lower in CHF patients than controls (median 2.6 vs 6.02 microg, p < 0.0001). This decrease was observed regardless of beta-adrenergic blocker or benzodiazepine medication. A significant decrease in 6-sulfatoxymelatonin excretion occurred with age. There were no significant differences in urinary 6-sulfatoxymelatonin levels between chronic and acute CHF patients. The results suggest that circulating melatonin levels are low in patients with CHF. Such a decrease may precede aggravation of heart failure.

ACTIGRAPHIC SLEEP-WAKE PATTERNS AND URINARY 6-SULFATOXYMELATONIN EXCRETION IN PATIENTS WITH ALZHEIMER'S DISEASE

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513–524, 2001)

The tumor promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats

The hypothesis that light-induced circadian clock suppression exerts a promoting effect on liver carcinogenesis was investigated in rats. Sixty-five male Wistar rats were given diethylnitrosamine (DEN, 10 mg/kg/day p.o.) for 6 weeks and were randomized into 3 groups. Rats from group 1 (N = 20) received DEN only. Rats from group 2 (N = 22) also received phenobarbital (pheno, 30 mg/rat/day p.o.) for 4 weeks as a promoting agent and rats from group 3 (N = 23) were exposed to continuous light. Three months after starting DEN treatment, urinary 6-sulfatoxymelatonin (αMT6s) excretion, a marker of circadian clock function, had lost its circadian rhythmicity in the LL group, with a 4-fold lower 24h mean than that found in the LDpheno and LD groups (8.0 ± 3.2 ng ml , 33.6 ± 3.1 ng ml and 34.3 ± 2.4 ng ml respectively; p from ANOVA < 0.001). Laparotomy was then performed. The proportion of rats with macroscopic nodules on liver surface was 72% (LD group), 89% (LDpheno group) and 95% (LL group) (p from χ 2 = 0.1). Nodules were more numerous and larger both in the LL group and in the LDpheno one as compared to the LD group (p from χ 2 < 0.05). All the rats died with hepatocellular carcinomas, with a median survival of 5 months, similar in all 3 groups. Light-induced circadian clock suppression exerted a promoting effect similar to that caused by phenobarbital in this model, yet through different effects on circadian system function.

Pharmacokinetically guided melatonin scheduling in rats with circadian system suppression

To obtain a pharmacologic effect of melatonin in rats kept under prolonged continuous light exposure, conditions known to produce functional suppression of the circadian system, mimicking of the physiologic 24-h pattern of melatonin secretion, a hormonal signal of darkness exposure may be needed. The delivery scheme for melatonin was established in rats in the present studies. First, the plasma pharmacokinetics of [ 3H]melatonin were determined in rats kept under continuous light and in rats synchronized by exposure to alternating 12 h light and 12 h darkness (LD 12:12) in the early light span. The pharmacokinetics of total radioactivity were similar in both groups. Further quantitation of melatonin by thin-layer chromatography revealed differences dependent on light conditions. The mean plasma clearance and steady-state distribution volume were ∼ twice as low with continuous light as with LD 12:12. Plasma protein binding of melatonin was ∼ 33%, irrespective of group or sampling time. These pharmacokinetic parameters were used to devise a 24-h periodic delivery schedule consisting of a 6-h constant infusion of exogenous melatonin, followed by an 18-h melatonin-free interval. In a second study, the melatonin 24-h pattern was estimated from the measurement of 2-h fractions of urinary 6-sulfatoxymelatonin excretion for 4 days. 6 unrestrained rats kept under continuous light received melatonin for 2 days from 22:00 to 04:00 h through an indwelling jugular catheter, connected to a reservoir from a programmable pump. Only the administration of low doses (0.01 mg/kg/day) resulted in both a circadian pattern for 6-sulfatoxymelatonin excretion and normal physiological values during the infusion-free intervals. The resynchronizing efficacy of this schedule should be tested in rats with functional suppression of the circadian system.