Delayed melatonin circadian timing, lower melatonin output, and sleep disruptions in myopic, or short-sighted, children.

STUDY OBJECTIVES: This study investigated the differences in melatonin circadian timing and output, sleep characteristics, and cognitive function in myopic and non-myopic (or emmetropic) children, aged 8-15 years. METHODS: Twenty-six myopes (refractive error [mean ±â€…standard error mean] -2.06 ±â€…0.23 diopters) and 19 emmetropes (-0.06 ±â€…0.04 diopters), aged 11.74 ±â€…2.31 years were recruited. Circadian timing was assessed using salivary dim-light melatonin onset (DLMO), collected half-hourly for 7 hours, beginning 5 hours before and finishing 2 hours after individual average sleep onset in a sleep laboratory. Nocturnal melatonin output was assessed via aMT6s levels from urine voids collected from 05:30 pm to 8:00 am the following morning. Actigraphy-derived objective sleep timing were acquired for a week prior to the sleep laboratory visit. Cognitive assessments of sustained attention (using psychomotor vigilance task [PVT]) and working memory (using digit spans) were performed on the night of sleep laboratory. RESULTS: Myopic children (9:07 pm ±â€…14 minutes) exhibited a DLMO phase-delay of 1 hour 8 minutes compared to emmetropes (7:59 pm ±â€…13 minutes), p = 0.002. aMT6s melatonin levels were significantly lower among myopes (18.70 ±â€…2.38) than emmetropes (32.35 ±â€…6.93, p = 0.001). Myopes also exhibited significantly delayed sleep onset, delayed wake-up time, poor and reduced sleep, and more evening-type diurnal preference than emmetropes (all p < 0.05). Finally, myopes showed a slower reaction time in the PVT (p < 0.05), but not digit span tasks at night. CONCLUSIONS: These findings suggest a potential association between circadian rhythm dysfunction and myopia in children.

Measuring Urinary 6-Sulphatoxymelatonin in Humans.

The pineal melatonin rhythm provides a robust reference signal for the timing of the endogenous human circadian system. The rhythm in the major urinary metabolite of melatonin, 6-sulphatoxymelatonin (aMT6s), is highly correlated with plasma melatonin and provides a noninvasive method to measure circadian phase, particularly in field-based studies. In this chapter, we describe the protocol for collecting urinary aMT6s and the method used to calculate the acrophase, or peak, time as a circadian phase marker.

Reference intervals for 6-sulfatoxymelatonin in urine: A meta-analysis.

Despite the essential functions of melatonin in the human body, until now no norms of the amount of melatonin produced overnight have been established. Measuring the amount of the main urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s), corrected for creatinine, in the first morning void is the most simple as well as reliable method to evaluate the total amount of melatonin produced at night. We performed a meta-analysis to provide reference estimates and intervals by consolidating data from multiple studies. A total of 68 studies, representing 17,847 subjects, were retained for the analysis. No gender differences could be found in aMT6s values in this meta-review. aMT6s excretion is very high during the first 5 years of life, flattens out in adolescence with gradual decline continuing to 50-60 years, after which the decline stagnates and a limited increase occurs around about 60 years of age. This late increase may suggest the premature death of individuals with low aMT6s levels, as lower aMT6s levels are found in various disorders, such as cardiovascular diseases, cancer and neurodegenerative disorders. Our aMT6s values can be used to identify individuals with a possible melatonin deficiency.

Endogenous melatonin levels and therapeutic use of exogenous melatonin in tension type headache: A systematic review.

BACKGROUND-PURPOSE: A bidirectional relationship appears to connect tension-type headache (TTH) and circadian dysregulation. The present systematic review examined the published evidence for melatonin (MT) supplementation in the prophylaxis of TTH. Initially, we reviewed case-control studies investigating nocturnal MT or 6-sulphatoxymelatonin (aMT6s, a urine-discarded metabolite) in TTH individuals and healthy controls (HC). Secondly, we reviewed studies appraising the use of MT in the prevention of TTH. METHODS: The search strategy involved MEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar and OpenGrey. Case-control studies were appraised according to the Newcastle-Ottawa-Scale, whereas randomised controlled trials were assessed based on the risk-of-bias Cochrane tool. Infrequent, as well as frequent, episodic, and chronic TTH patients were evaluated separately in children and adults. RESULTS: Our search strategy yielded two case-control studies. One (high-quality) did not reveal any difference in morning salivary MT concentration between children with frequent episodic TTH and HC. The second (moderate-quality) was indicative of a disturbed nocturnal secretion pattern in adults with chronic TTH. For the second part, five uncontrolled studies were retrieved. In total, 94 adults with chronic TTH were assessed and results were suggestive of a beneficial effect of MT on headache frequency, intensity, induced disability, and induced analgesic consumption. However, the uncontrolled-unblinded designs may have induced an important placebo effect. Non-adult populations and frequent TTH were substantially understudied. CONCLUSIONS: There are not enough studies to designate the role of MT in the prevention of TTH. Given the disease's background, additional relevant research is warranted for chronic TTH.

Myopia, or near-sightedness, is associated with delayed melatonin circadian timing and lower melatonin output in young adult humans.

STUDY OBJECTIVES: Myopia, or near-sightedness, is the most common refractive vision disorder and predisposes the eye to many blinding conditions in adulthood. Recent research has suggested that myopia is associated with increased endogenous melatonin production. Here we investigated the differences in melatonin circadian timing and output in young adult myopes and non-myopes (or emmetropes) as a pathogenesis for myopia. METHODS: A total of 18 myopic (refractive error [mean ± standard deviation] -4.89 ± 2.16 dioptres) and 14 emmetropic participants (-0.09 ± 0.13 dioptres), aged 22.06 ± 2.35 years were recruited. Circadian timing was assessed using salivary dim light melatonin onset (DLMO), collected half-hourly for 7 h, beginning 5 h before and finishing 2 h after individual average sleep onset in a sleep laboratory. Total melatonin production was assessed via aMT6s levels from urine voids collected from 06:00 pm and until wake-up time the following morning. Objective measures of sleep timing were acquired a week prior to the sleep laboratory visit using an actigraphy device. RESULTS: Myopes (22:19 ± 1.8 h) exhibited a DLMO phase-delay of 1 hr 12 min compared with emmetropes (21:07 ± 1.4 h), p = 0.026, d = 0.73. Urinary aMT6s melatonin levels were significantly lower among myopes (29.17 ± 18.67) than emmetropes (42.51 ± 23.97, p = 0.04, d = 0.63). Myopes also had a significant delay in sleep onset, greater sleep onset latency, shorter sleep duration, and more evening-type diurnal preference than emmetropes (all p < 0.05). CONCLUSIONS: These findings suggest a potential association between circadian rhythms and myopia in humans.

Impact of Dim Light at Night on Urinary 6-Sulphatoxymelatonin Concentrations and Sleep in Healthy Humans.

Artificial light at night can have negative effects on human wellbeing and health. It can disrupt circadian rhythms, interfere with sleep, and participate in the progress of civilisation diseases. The aim of the present study was to explore if dim artificial light during the entire night (ALAN) can affect melatonin production and sleep quality in young volunteers. We performed two experiments in real-life home-based conditions. Young volunteers (n = 33) were exposed to four nights of one lux ALAN or two nights of five lux ALAN. Melatonin production, based on 6-sulphatoxymelatonin/creatinine concentrations in urine, and sleep quality, based on actimetry, were evaluated. Exposure to ALAN one lux during the entire night did not suppress aMT6s/creatinine concentrations but did aggravate sleep quality by increasing sleep fragmentation and one-minute immobility. ALAN up to five lux reduced melatonin biosynthesis significantly and interfered with sleep quality, as evidenced by an increased percentage of one-minute immobility and a tendency of increased fragmentation index. Our results show that people are more sensitive to low illuminance during the entire night, as previously expected. ALAN can interfere with melatonin production and sleep quality in young, healthy individuals, and both processes have different sensitivities to light.

The urinary 6-sulfatoxymelatonin level after three different work schedules with 2, 4 and 7 consecutive night shifts among Danish police officers.

Night shift work suppresses excretion of melatonin, but little is known about the needed time for recovery. We aimed to compare levels of 6-sulfatoxy melatonin after three different night shift schedules, including recovery days. In a quasi-experimental, within-subject crossover study, 73 male police officers in Denmark collected morning urine after the last recovery day in three different work schedules with two, four, and seven consecutive night shifts followed by a corresponding number of days for recovery. We found no significant differences for 6-sulphatoxymelatonin concentrations in morning urine between the three different work schedules indicating similar recovery of melatonin suppression in the studied work schedules.

Endogenous Melatonin Levels and Therapeutic Use of Exogenous Melatonin in Migraine: Systematic Review and Meta-Analysis.

BACKGROUND: Sleep disorders and circadian dysregulation appear to be associated with primary headache disorders. OBJECTIVE: The aim of this study was to review the existing evidence for the deployment of melatonin in migraine prophylaxis. Initially, case-control studies investigating nocturnal melatonin and 6-sulphatoxymelatonin (aMT6s, melatonin metabolite discarded by the urine) levels in patients with migraine and healthy controls (HC) would be reviewed and meta-analyzed. Second, results from randomized controlled trials (RCTs) and non-randomized studies evaluating the use of melatonin in migraine would be synthesized. METHODS: MEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey were comprehensively searched. The quality of studies was assessed according to the Newcastle-Ottawa Scale (case-control studies) and the Risk-of-Bias Cochrane tool (RCTs). Random-effects (RE) or fixed-effects (FE) model was used based on heterogeneity among studies (homogeneity assumed when PQ > 0.1 and I2  < 30%). Publication bias was assessed by funnel plots. RESULTS: Literature search provided 11 case-control studies. Evidence was compatible with lower nocturnal serum [5 of 6 studies were synthesized due to deficient reporting of 1 abstract, migraine n = 197, HC n = 132, RE MD = -12.29 pg/ml, 95%CI = (-21.10, -3.49)] and urinary melatonin [3 studies, migraine n = 30, HC n = 29, RE MD = -0.12 nmol/nocturnal (12 hours) urinary collection, 95%CI = (-0.22, -0.03)], as well as urine aMT6s levels [1 study, migraine n = 146, HC n = 74, MD = -11.90 µg/nocturnal (12 hours) urine collection, 95%CI = (-19.23, -4.57)] in adult migraine patients compared to HC [1 study involving children did not reveal any difference regarding nocturnal urine aMT6s, n = 18 per group, MD = -6.00 µg/nocturnal (12 hours) urine collection, 95%CI = (-21.19, 9.19)]. Regarding the treatment-prevention of migraine, 7 RCTs and 9 non-randomized studies were retrieved. Data synthesis was not feasible for the comparison of melatonin and placebo due to the existing clinical and methodological heterogeneity of the 5 relevant RCTs. Overall, melatonin was more efficacious and equally safe with placebo in the prevention of migraine in adults (3 of 4 RCTs provided superior efficacy results for melatonin, 1 RCT revealed no difference regarding Headache Frequency -HF-), while there are limited data for children (1 RCT revealed no difference against placebo regarding HF). Additionally, no difference was revealed between melatonin and amitriptyline (1 RCT), sodium valproate (1 RCT) or propranolol (1 non-randomized study) with respect to their efficacy in adults with migraine, while melatonin was more effective than pizotifen (1 RCT). In children with migraine, amitriptyline is more efficacious regarding most assessed parameters (2 studies, n = 85 per group, HF: RE MD = 4.03, 95%CI = (2.64, 5.42), Headache Duration: RE MD = 0.72, 95%CI = (0.41, 1.03), Headache Severity: FE MD = 1.57, 95%CI = (1.13, 2.00), Response to Treatment: FE MD = 0.33, 95%CI = (0.16, 0.69), Headache Induced Disability Severity: RE MD = 6.07, 95%CI = (-11.87, 24.01 ), Analgesic Consumption - assessed in 1 study, n = 40 per group - MD = 1.11, 95%CI = (-0.10, 2.32)), although melatonin presents a superior safety profile than amitriptyline both in adults and in children. CONCLUSIONS: Melatonin may be of potential benefit in the treatment-prevention of migraine in adults, but complementary evidence from high-quality RCTs is required.

The effects of indoor ambient temperature at work on physiological adaptation in night shift nurses.

AIM: To examine the effects of indoor ambient temperature on thermal comfort, night work tolerance (fatigue, sleepiness and night adaptation) and urinary melatonin in night shift nurses. BACKGROUND: Night shift induces physical stress and mental stress. Night shift work and ambient temperature are associated with work performance. The working environment must be improved for successful night shift working. However, the effects of indoor ambient temperature on night shift nurses are unclear. METHODS: In this crossover study, 20 participants were divided into two groups of 10 and were assigned to work in one of two thermo-controlled environments (23°C vs. 26°C) during two consecutive night shifts. Thermal and humidity sensation vote, night work tolerance, body temperature and urinary melatonin were assessed. RESULTS: There were significant differences between the two groups in thermal sensation and body temperature. There were no significant differences in humidity sensation vote or night work tolerance. Urinary melatonin levels decreased significantly during the second 23°C night shift. CONCLUSION: A temperature of 23°C may exert a positive effect on night shift adaptation. IMPLICATIONS FOR NURSING MANAGEMENT: Nurses and nursing managers should assess thermal comfort during night shifts, and improved thermal comfort level should be provided to nurses.

Urinary levels of 6-sulphatoxymelatonin and their associations with sleep disorders and behavioural impairments in children with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with sleep disturbances that may result from abnormalities in melatonin production. The correlations of melatonin levels with the severity of sleep disorder and/or severity of ASD were reported. OBJECTIVES: To evaluate urinary levels of the melatonin metabolite, 6-sulphatoxymelatonin (aMT6s), in children with ASD, and their associations with sleep abnormalities and behavioural impairments. METHODS: Study involved 77 children with ASD and 84 controls aged 2.5‒15.5 years. Sleep disorders were assessed by Children's Sleep Habits Questionnaire. Morning and afternoon levels of aMT6s were determined by radioimmunoassay method. Urinary creatinine levels were assessed by an enzymatic method. RESULTS: The urinary aMT6s/creatinine values indicate that the night-time melatonin levels are significantly lower in ASD than in controls, but there are no significant differences in the daytime levels. In the ASD group, on average, a 6.8-fold difference between night-time and daytime values of urinary aMT6s/creatinine was found, whereas for the controls a 12.5-fold difference was observed, indicating a lower night-time increase in melatonin levels. In ASD group, the difference in night-time-daytime aMT6s/creatinine value correlated with some types of sleep problems, but not with the severity of ASD. CONCLUSION: The results indicate that in ASD there are differences in the patterns of melatonin secretion that may be associated with sleep impairment (Tab. 4, Fig. 2, Ref. 28).