6-sulfatoxymelatonin Levels Research Articles

Features of melatonin cyrcadian secretion in patients with gastroesophageal reflux disease associated with obstructive sleep apnea/hypopnea syndrome

Aim. To evaluate the features of melatonin cyrcadian production in patients with gastroesophageal reflux disease associated with obstructive sleep apnea/hypopnea syndrome.
 Methods. We examines 29 patients with gastroesophageal reflux disease were examined (group 1), 29 patients with gastroesophageal reflux disease associated with obstructive sleep apnea/hypopnea syndrome (group 2), and 22 patients with obstructive sleep apnea/hypopnea syndrome (group 3). The comparison group included 21 people without gastroesophageal reflux disease and obstructive sleep apnea/hypopnea syndrome (group 4). The content of 6-sulfatoxymelatonin was determined in 24-hour urine and separately in its daytime and night portions by enzyme immune assay. The night/day index was calculated. The compared groups were comparable by gender but the patients with obstructive sleep apnea/hypopnea syndrome and gastroesophageal reflux disease associated with this syndrome differed from the patients from comparison group by older age, which is consistent with epidemiology of sleep apnea. The analysis of the data obtained was performed using the program Statistica 10.0. When comparing quantitative indicators between four independent samples, KruskelWallis test was used. In order to study the relationship between the phenomena, the Spearman rank correlation coefficient was calculated.
 Results. A significantly increased level of 6-sulfatoxymelatonin in 24-hour urine was determined in group 2 (p=0.0000), as well as in day (0.0000) and night portions (0.015) compared to group 1, in 24-hour urine (p=0.0007) and its day portion (p=0.0001) compared to group 3, in day portion of urine compared to group 4 (p=0.029). In group 2 compared to group 4 a significant shift in melatonin synthesis peak during daytime hours was observed, which is expressed in a statistically significant decrease in the night/day index (p=0.0003). Correlation analysis revealed statistically significant relations between the level of 6-sulfatoxymelatonin in urine and the severity of sleep apnea (in 24-hour urine: r=0.64, p=0.0000; in daytime portion: r=0.62, p=0.0000; in night portion: r=0.40, p=0.003), as well as respiratory monitoring indicators indicating sleep fragmentation due to apnea (the number of awakenings associated with respiratory events: r=0.58; p=0.00001; activation of the central nervous system associated with respiratory efforts: (r=0.50; p=0.0002).
 Conclusion. The patients with gastroesophageal reflux disease associated with obstructive sleep apnea/hypopnea syndrome have an increased level of 6-sulfatoxymelatonin in urine associated with the shift of its peak synthesis to daytime hours; the identified changes correlate with apnea/hypopnea index reflecting the severity of apnea and sleep disturbance.

Genital endometriosis and melatonin: a role in the pathogenesis and its possible use in the treatment of the disease

Hypothesis/aims of study. Melatonin is found in almost all living organisms, the range of its effects being quite diverse. Effects of this hormone in the human body are realized via two ways, through specific receptors and non-receptor pathways. Melatonin may act through both membrane and nuclear receptors. In the present work, the expression of MTR1 and MTR2 melatonin receptors was studied in the eutopic endometrium and endometrioid heterotopies, and the level of melatonin metabolite, 6-sulfatoxymelatonin, in daily urine in patients with genital endometriosis (GE) was analyzed.
 Study design, materials and methods. The experimental group included 67 patients of reproductive age with a verified diagnosis of GE, and the control group consisted of 18 individuals with an ovulatory menstrual cycle without gynecological pathology. The 6-sulfatoxymelatonin level in daily urine was determined by enzyme immunoassay. The study of MTR1 and MTR2 melatonin receptor expression in the endometrium and endometrioid heterotopies was performed in 24 patients with GE and in 10 women of reproductive age who were examined for infertility who did not have gynecological pathology based on diagnostic laparoscopy. To study the expression of melatonin receptors, the endometrium and endometrial heterotopy sampling was carried out from day 18 to day 22 of the menstrual cycle. Morphological assessment included histological and immunofluorescence studies using confocal laser scanning microscopy.
 Results. In patients with GE, there was found a tendency to a decrease in 6-sulfatoxymelatonin excretion in daily urine compared to the control group. It was also found that the total relative expression area of melatonin receptors in the endometrium of women with GE was significantly lower compared to the endometrium of patients from the control group. Significant differences between the average brightness and optical density were not found. In addition, it was revealed that the relative expression areas of MTR1 and MTR2 melatonin receptors in the eutopic endometrium and in endometrioid heterotopies did not differ significantly. A negative correlation was stated between the relative expression area of melatonin receptors and GE prevalence. Particular attention is paid to the role of melatonin in the development of GE and to the possibilities of working out new treatment regimens with its use.
 Conclusion. The data obtained confirm the undoubted role of melatonin in the pathogenesis of GE, however, the development of new treatment regimens with its use requires further study.

Association of functioning and quality of life with objective and subjective measures of sleep and biological rhythms in major depressive and bipolar disorder.

Disruptions in biological rhythms and sleep are a core aspect of mood disorders, with sleep and rhythm changes frequently occurring prior to and during mood episodes. Wrist-worn actigraphs are increasingly utilized to measure ambulatory activity rhythm and sleep patterns. A comprehensive study using subjective and objective measures of sleep and biological rhythms was conducted in 111 participants (40 healthy volunteers [HC], 38 with major depressive disorder [MDD] and 33 with bipolar disorder [BD]). Participants completed 15-day actigraphy and first-morning urine samples to measure 6-sulfatoxymelatonin levels. Sleep and biological rhythm questionnaires were administered: Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), Munich Chronotype Questionnaire (MCTQ), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Actigraph data were analyzed for sleep and daily activity rhythms, light exposure and likelihood of transitioning between rest and activity states. Mood groups had worse subjective sleep quality (PSQI) and biological rhythm disruption (BRIAN) and higher objective mean nighttime activity than controls. Participants with BD had longer total sleep time, higher circadian quotient and lower 6-sulfatoxymelatonin levels than HC group. The MDD group had longer sleep onset latency and higher daytime probability of transitioning from rest to activity than HCs. Mood groups displayed later mean timing of light exposure. Multiple linear regression analysis with BRIAN scores, circadian quotient, mean nighttime activity during rest and daytime probability of transitioning from activity to rest explained 43% of variance in quality-of-life scores. BRIAN scores, total sleep time and probability of transitioning from activity to rest explained 52% of variance in functioning (all p < 0.05). Disruption in biological rhythms is associated with poorer functioning and quality of life in bipolar and MDD. Investigating biological rhythms and sleep using actigraphy variables, urinary 6-sulfatoxymelatonin and subjective measures provide evidence of widespread sleep and circadian system disruptions in mood disorders.

Salt Loading Aggravates the Relationship between Melatonin and Proteinuria in Patients with Chronic Kidney Disease.

Objective Salt loading induces renal damage independently of blood pressure (BP) elevation via reactive oxygen species and sympathetic activity. Melatonin, a hormone that regulates the circadian rhythm, has multiple functions, including anti-oxidant effects and the inhibition of sympathetic activity. We have shown that impaired melatonin secretion is associated with renal damage in chronic kidney disease (CKD) patients. However, the associations between salt loading, melatonin secretion, and urinary albumin and protein have not been clarified. Methods We recruited 32 CKD patients, conducted 24-hour ambulatory BP monitoring and collected daytime and nighttime urine while the patients were consuming a standard salt (10 g/day) or low salt (6 g/day) diet. The excretion levels of albumin, protein and 6-sulfatoxymelatonin (aMT6s), a metabolite of melatonin, in daytime and nighttime urine were investigated in patients consuming standard salt and low salt diets. Results The urinary aMT6s levels in daytime and nighttime of the patients consuming standard salt and low salt diets did not differ to a statistically significant extent. However, the urinary aMT6s levels in patients consuming a standard salt diet-but not patients consuming a low salt diet-were significantly and negatively correlated with the daytime and nighttime urinary albumin and protein levels. Contrarily, no significant correlations were found between the urinary aMT6s levels and the BP levels, renal function, and plasma angiotensin II levels in patients consuming either a standard salt or low salt diet. A multiple regression analysis adjusted for age, sex, and body mass index revealed that the urinary albumin and protein levels were significantly and negatively associated with the urinary aMT6s levels in patients consuming a standard salt diet, but not in patients consuming a low salt diet. Conclusion Salt loading aggravates the relationship between melatonin secretion and albuminuria or proteinuria.

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study

ObjectiveThis prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. MethodsBreast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. ResultsThis cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. ConclusionThe first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

Melatonin and cortisol exhibit different circadian rhythm profiles during septic shock depending on timing of onset: a prospective observational study

BackgroundSeptic shock has been found to disrupt circadian rhythms. Moreover, timing of onset has been associated with different circadian profiles in experimental studies.ResultsIn this prospective study, we enrolled 26 patients divided into two groups: Group A (N = 15) included subjects who had septic shock at the time of ICU admission and Group B (N = 11) included patients who developed septic shock during ICU admission. 6-Sulfatoxymelatonin (aMT6s) and cortisol levels were measured in urine samples every 4 h over a 24-h period. Two sets of samples were taken from Group A (entry/septic shock and exit) and three sets from Group B (entry, septic shock and exit). Mean, amplitude that is the difference between peak and mean values, as well as peak time, were estimated for both aMT6s and cortisol. In Group A, amplitude of aMT6s upon entry (septic shock) was reduced in relation to exit (437.2 ± 309.2 vs. 674.1 ± 657.6 ng/4 h, p < 0.05). Peak time occurred earlier (10:00 p.m. vs. 07:00 a.m, p < 0.05) and correlated with higher APACHE II score and longer ICU stay. In Group B, aMT6s mean values were significantly increased during septic shock (2492.2 ± 1709.1 ng/4 h) compared to both entry (895.4 ± 715.5 ng/4 h) and exit (1308.6 ± 1214.4 ng/4 h, p < 0.05 for all comparisons). Amplitude of aMT6s was also elevated during septic shock (794.8 ± 431.8 ng/4 h) in relation to entry (293.1 ± 275.9 ng/4 h, p < 0.05). Regarding cortisol rhythm in Group A, during septic shock amplitude was increased compared to exit (13.3 ± 31 ng/4 h vs. 8.7 ± 21.2 ng/4 h p < 0.05) and correlated with reduced hospital length of stay. In Group B, cortisol mean values and amplitude during septic shock (10 ± 5.3 and 3 ± 1.8 ng/4 h, respectively) were significantly reduced compared to both entry (30 ± 57.9 and 12.3 ± 27.3 ng/4 h) and exit (14.4 ± 20.7 and 6.6 ± 8.7 ng/4 h, p < 0.05 for all comparisons) and correlated with higher SOFA score and longer ICU and hospital stay.ConclusionsSeptic shock induced inverse changes of aMT6s and cortisol circadian rhythm profiles both within and between different groups of patients, depending on timing of onset. Reduced rhythmicity was correlated with severity of disease and longer ICU stay.

Oral melatonin administration improves the objective and subjective sleep quality, increases 6-sulfatoxymelatonin levels and total antioxidant capacity in patients with fibromyalgia

Background/objectiveChronic pain, sleep disturbances and oxidative stress are implicated in the pathogenesis of fibromyalgia. The aim of this study was to assess the effect of melatonin supplementations on sleep quality, 6-sulfatoxymelatonin (aMT6-s) levels, as well as urinary and serum total antioxidant capacity (TAC) in patients with fibromyalgia. MethodsThirty three patients carried out the full study. A baseline period (10days) was included in the experimental design to collect information about patients’ initial status. Then, patients took different doses of melatonin, during 10 consecutive days each. Placebo was given during 10days either before or between melatonin doses. Objective sleep quality was recorded by actigraphy whereas subjective sleep quality was measured by The Pittsburgh Sleep Quality Index. Quantification of aMT6-s and TAC was achieved by ELISA and colorimetric assay kits, respectively. ResultsSix out of seven sleep parameters evaluated by actigraphy were improved after the intake of melatonin as well as the subjective sleep quality. All the biochemical parameters measured were also elevated after the melatonin administration. ConclusionThe daily intake of melatonin improved the sleep quality, increased the aMT6-s levels and the total antioxidant capacity in patients with fibromyalgia.

Sleep problems and the association with the levels of 6-sulfatoxymelatonin in children with autism spectrum disorder

Objective: To identify the prevalence of sleep problems in children with autism spectrum disorder (ASD) and to explore the association with the main melatonin metabolite, 6-sulfatoxymelatonin (6-SM). Method: This was a prospective case-control study. Children with ASD were recruited from Child Development and Behavioral Research Center (CDBRC) of the Harbin Medical University and Harbin Special Education School from October 2015 to April 2017 (ASD group) . Healthy controls were selected from five kindergartens and one primary school in Harbin by the stratified cluster random sampling (control group) . The Children's Sleep Habits Questionnaire (CSHQ) was used to investigate the sleep problems of the two groups. The patients were matched in a 1∶1 ratio for the age and sex, and the urine samples of case-control pairs were collected in the morning. The level of 6-SM was measured by the enzyme linked immunosorbent assay (ELISA). The student's t test was used for comparison between the ASD group and control group, and the Pearson correlation analysis was used to determine the correlation difference. Result: A total of 212 ASD children (mean (±SD) age was (6.0±2.7) years, and 181 patients (85.4%) were male), and a total of 334 healthy children(mean (±SD) age was (5.9±2.6) years, and 272 patients (81.4%) were male) were recruited. Among them, 101 matched case-control pairs completed the collection of urine samples. According to the statistical analysis, the scores of total CSHQ, bedtime resistance, sleep onset delay, sleep duration, night waking, parasomnia, sleep disordered breathing and daytime sleepiness in children with ASD were significantly higher than those in the control group (48.2±6.2 vs. 46.6±5.4, 11.4±2.5 vs. 10.7±2.8, 1.7±0.8 vs. 1.5±0.7, 4.1±1.4 vs. 3.7±1.1, 4.2±1.5 vs. 3.8±1.1, 8.5±1.5 vs. 8.3±1.4, 3.7±1.0 vs. 3.4±0.8, 11.7±2.5 vs. 12.4±2.7, t=3.16, 3.00, 3.23, 2.76, 3.19, 1.99, 3.45,-2.72, P=0.002, 0.003, 0.001, 0.006, 0.002, 0.048, 0.001, 0.007), the level of 6-SM was significantly lower in children with ASD than that of healthy controls ((1.24±0.50) vs. (1.68±0.63)μg/h, t=-5.50, P<0.01), and the total CSHQ score was negatively correlated with the level of 6-SM (r=-0.50, P<0.01). Conclusion: The children with ASD were at high risk for sleep problems, and the melatonin metabolite of ASD group was abnormal compared with that of the control group. Moreover, there was a negative correlation between the severity of sleep problems and the level of 6-SM in ASD children. The results of our study indicate that the abnormal melatonin metabolism may be one of the causes of sleep problems in children with ASD.

Clinical Considerations Derived From the Administration of Melatonin to Children With Sleep Disorders

Background and ObjectivesDespite the numerous investigations carried out in relation to melatonin, there is a lack of knowledge about the specific melatonin secretion patterns in the diverse primary sleep disturbances. The objective of this study was to analyze the plasma melatonin concentrations in children with primary sleep disorders and the effects of melatonin therapy on their serum levels and their actigraphic sleep parameters. MethodsFourteen participants (nine girls; seven to 14 years old) diagnosed with diverse primary sleep disorders were recruited. Four different melatonin secretion patterns were identified: low plasma melatonin levels, absence of a circadian rhythm, advanced acrophase, and delayed acrophase. A placebo (one week) was administered followed by three months of melatonin therapy (3 mg/night). Urinary 6-sulfatoxymelatonin levels, 24-hour plasma melatonin concentrations, and a seven-day actigraphic record were collected after both treatments. ResultsAfter melatonin therapy, a significant increase (P < 0.001) of urinary 6-sulfatoxymelatonin excretion with a clear circadian variation was observed. Plasma melatonin concentrations were also significantly higher with a recovery in the circadian rhythm. Actual sleep time was significantly longer, with a substantial reduction in the sleep onset latency and night awakenings. No severe side effects were reported. ConclusionsThe main clinical implication of this study is to demonstrate the efficacy of melatonin in three main circumstances: an insufficient hormone production, a disturbed circadian rhythm, and an advanced or delayed acrophase. As ongoing work, we are exploring the effect of different doses of melatonin on the regulation of its concentrations and of its secretion rhythm.

Sleep duration, nightshift work, and the timing of meals and urinary levels of 8-isoprostane and 6-sulfatoxymelatonin in Japanese women

ABSTRACTIt has been hypothesized that disruption of circadian rhythms affects human health. Shift work and sleep deprivation are thought to disrupt the normal light–dark cycle, although the disruption due to shiftwork may be dependent on sleep deprivation. Both conditions have been suggested to be associated with an increased risk of cardiometabolic disorders. Non-photic environmental factors, such as the timing of eating, are also thought to regulate circadian rhythm and thus, may have effects on health, but the evidence from human studies is scarce. Oxidative stress is a risk factor of cardiometabolic disorders. Some laboratory studies suggest an involvement of circadian clock genes in the regulation of the redox system. The present study aimed to examine the association of sleeping habits, nightshift work, and the timing of meals with urinary levels of 8-isoprostane, a marker of oxidative stress, and 6-sulfatoxymelatonin, the principal metabolite of melatonin. Study subjects were 542 women who had previously attended a breast cancer mass screening in a community in Japan. Information on bedtimes and wake-up times, history of nightshift work, and the timing of meals was obtained by a self-administered questionnaire. The 8-isoprostane and 6-sulfatoxymelatonin were measured using the first morning void of urine and expressed per mg of creatinine. The geometric mean of 8-isoprostane levels was 12.1% higher in women with ≤6 hours of sleep than that in those with >8 hours of sleep on weekdays, and longer sleep duration on weekdays was significantly associated with lower urinary levels of 8-isoprostane after controlling for covariates (p for trend = 0.04). Women who were currently working the nightshift had a 33.3% higher geometric mean of 8-isoprostane levels than those who were not working nightshift (p = 0.03). Urinary 6-sulfatoxymelatonin levels were unrelated to sleep habits or nightshift work. Women who ate breakfast at irregular times had a 19.8% higher geometric mean of 8-isoprostane levels than those who ate breakfast at a regular time or who did not eat (p = 0.02). Women who ate nighttime snacks at irregular times had a 16.2% higher geometric mean of 8-isoprostane levels than those who did not eat nighttime snacks or who ate nighttime snacks at a regular time (p = 0.003). Among women who ate dinner at a regular time, earlier times for dinner were associated with higher 8-isoprostane and 6-sulfatoxymelatonin levels (p values for trends were 0.01 and 0.02, respectively). However, the times of dinner and nighttime snack are overlapping, and the time of last meal of the day was not associated with 8-isoprostane and 6-sulfatoxymelatonin levels. The time of breakfast or lunch was not associated with these biomarkers among women who ate the meal at regular times. Disturbing the rhythmicity of daily life may be associated with oxidative stress.

Urinary 6-sulfatoxymelatonin level and breast cancer risk: systematic review and meta-analysis

6-Sulfatoxymelatonin (aMT6s) is the main metabolite of melatonin in urine, and is a reliable surrogate biomarker reflecting the blood melatonin concentration. This meta-analysis assessed the association between urinary aMT6s level and BC incidence. The electronic databases PubMed, EMBASE, Cochrane Library, and Web of Science were searched. Risk ratios (RRs) were adopted to estimate the relative BC incidence. A total of 7 prospective case-control publications were included, and 6 of them were distinct studies. Pooled analysis of data from the 6 studies involving 1824 women with incident BC and 3954 matched control participants with no overlapping of subjects among studies indicated no significant association between the highest levels of urinary aMT6s and the incidence of BC (RR = 0.97, 95% CI, 0.88–1.08, P = 0.56). Negative associations were observed in postmenopausal women (RR = 0.88, 95% CI, 0.75–1.02, P = 0.10), estrogen receptor positive BC (RR = 0.83, 95% CI, 0.64–1.07, P = 0.15), and studies using 12-hour overnight urine (RR = 0.81, 95% CI, 0.61–1.07, P = 0.13), all with borderline significances. Lag time or invasive degree did not interfere with the results. There was no evident publication bias detected by the Egger’s test and the funnel plot. Conclusively, the current evidence did not support a significant association between urinary aMT6s level and BC risk.

SLEEP DISORDERS IN THE EARLY RECOVERY PERIOD OF CEREBRAL STROKE AND THE POSSIBILITY OF CHRONOTHERAPEUTICAL CORRECTION

Sleep disorders in patients in the early rehabilitation period of stroke were studied. It was shown the effectiveness of the chronotherapy (phototherapy and drug Melaxen®) on the dynamics of sleep disturbance, cognitive, emotional and movement disorders, quality of life in the rehabilitation of stroke patients. The concentration of brain-derived neurotrophic factor (BDNF) in blood serum and the level of 6-SOMT in the urine were assessed. The purpose of research was to study the effectiveness of chronotherapy (phototherapy and Melaxen®) on the dynamics of sleep disturbances, cognitive and emotional disorders, BDNF and the level of secretion of melatonin (6-SOMT) in patients after cerebral stroke in the early recovery periods. Materials and methods. We examined 112 patients in the early rehabilitation period of stroke (mean age of 58.0 ± 9.74 years). The main groups of patients along with standard treatment received phototherapy and Melaxen® 3мг/day for 3 months. Sleep quality, cognitive and emotional status, concentration of BDNF in blood serum and night urinary level of 6-sulfatoxymelatonin were assessed. The results and conclusion. The study demonstrated the high efficacy of chronotherapy with Melaxen® in the rehabilitation of patients in early recovery period of stroke. Chronotherapy significantly increased the concentration of BDNF and 6-SOMT, improved cognitive function and sleep parameters, reduced the level of anxiety and depression in the early recovery period of stroke.

Pineal Gland Volume Assessed by MRI and Its Correlation with 6-Sulfatoxymelatonin Levels among Older Men.

The pineal gland produces the hormone melatonin, and its volume may influence melatonin levels. We describe an innovative method for estimating pineal volume in humans and present the association of pineal parenchyma volume with levels of the primary melatonin metabolite, 6-sulfatoxymelatonin. We selected a random sample of 122 older Icelandic men nested within the AGES-Reykjavik cohort and measured their total pineal volume, their parenchyma volume, and the extent of calcification and cysts. For volume estimations we used manual segmentation of magnetic resonance images in the axial plane with simultaneous side-by-side view of the sagittal and coronal plane. We used multivariable adjusted linear regression models to estimate the association of pineal parenchyma volume and baseline characteristics, including 6-sulfatoxymelatonin levels. We used logistic regression to test for differences in first morning urinary 6-sulfatoxymelatonin levels among men with or without cystic or calcified glands. The pineal glands varied in volume, shape, and composition. Cysts were present in 59% of the glands and calcifications in 21%. The mean total pineal volume measured 207 mm(3) (range 65-536 mm(3)) and parenchyma volume 178 mm(3) (range 65-503 mm(3)). In multivariable-adjusted models, pineal parenchyma volume was positively correlated with 6-sulfatoxymelatonin levels (β = 0.52, p < 0.001). Levels of 6-sulfatoxymelatonin did not differ significantly by presence of cysts or calcification. By using an innovative method for pineal assessment, we found pineal parenchyma volume to be positively correlated with 6-sulfatoxymelatonin levels, in line with other recent studies.

Association of Urinary 6-Sulfatoxymelatonin (aMT6s) Levels and Objective and Subjective Sleep Measures in Older Men: The MrOS Sleep Study.

Sleep and melatonin have been associated with healthy aging. In this study, we examine the association between melatonin levels and sleep among older men. Cross-sectional study of a community-dwelling cohort of 2,821 men aged 65 years or older recruited from six U.S. centers. First morning void urine samples were collected to measure melatonin's major urinary metabolite, 6-sulfatoxymelatonin (aMT6s). We also assessed objective and subjective sleep parameters. We used logistic regression models to calculate multivariate (MV) odds ratios (ORs), and 95% confidence intervals (CIs) adjusted for important demographic variables and comorbidities. In the overall sample, the only significant finding in fully adjusted models was that aMT6s levels were inversely associated with subjectively measured daytime sleepiness (sleepiness mean score of 5.79 in the top aMT6s quartile, and 6.26 in the bottom aMT6s quartile, MV OR, 1.32; 95% CI, 0.95-1.84; p trend ≤ .02). When restricting to men without β-blocker use (a known melatonin suppressant), aMT6s levels were significantly associated with shorter sleep time, that is, less than 5 hours (MV OR, = 1.90; 95% CI, 1.21-2.99; p trend = .01), and worse sleep efficiency, that is, less than 70% (MV OR, 1.58; 95% CI, 1.28-2.65; p trend < .001). aMT6s were not associated with subjective sleep quality or respiratory disturbance in any of our analyses. Lower nocturnal melatonin levels were associated with worsened daytime sleepiness, sleep efficiency, and shorter sleep time in older men. The role of circadian interventions, and whether melatonin levels are a modifiable risk factor for poor sleep in older men, warrants further study.

The association of body size in early to mid-life with adult urinary 6-sulfatoxymelatonin levels among night shift health care workers.

BackgroundAdult body mass index (BMI) has been associated with urinary melatonin levels in humans; however, whether earlier-life body size is associated with melatonin, particularly among night shift workers, remains unknown.MethodsWe evaluated associations of birth weight, body shape (or somatotype) at ages 5 and 10, BMI at age 18 and adulthood, weight change since age 18, waist circumference, waist to hip ratio, and height with creatinine-adjusted morning urinary melatonin (6-sulfatoxymelatonin, aMT6s) levels among 1,343 healthy women (aged 32–53 at urine collection, 1996–1999) in the Nurses’ Health Study (NHS) II cohort. Using multivariable linear regression, we computed least-square mean aMT6s levels across categories of body size, and evaluated whether these associations were modified by night shift work.ResultsAdult BMI was inversely associated with aMT6s levels (mean aMT6s levels = 34 vs. 50 ng/mg creatinine, comparing adult BMI ≥30 vs. <20 kg/m2; Ptrend <0.0001); however, other measures of body size were not related to aMT6s levels after accounting for adult BMI. Night shifts worked prior to urine collection, whether recent or cumulatively over time, did not modify the association between adult BMI and aMT6s levels (e.g., Pinteraction = 0.72 for night shifts worked within two weeks of urine collection).ConclusionsOur results suggest that adult BMI, but not earlier measures of body size, is associated with urinary aMT6s levels in adulthood. These observations did not vary by night shift work status, and suggest that adult BMI may be an important mechanism by which melatonin levels are altered and subsequently influence chronic disease risk.

The effects of sleep and light at night on melatonin in adolescents.

The circadian hormone melatonin has wide-reaching effects on human physiology. In adolescents, the impact of nighttime light exposure and other modifiable behavioral factors on melatonin levels is poorly understood. We cross-sectionally examined the influence of nighttime behaviors on melatonin levels in 100 adolescents (average age: 15.7; 55 female, 45 male), who completed a self-administered questionnaire and provided a first morning urine sample to assay for urinary 6-sulfatoxymelatonin (aMT6s) levels. We used mixed-effects regression models to test for differences in aMT6s levels by categories of covariates. Self-reported sleep duration, ambient light levels during sleep, and use of electronics after turning off lights did not significantly predict aMT6s levels. Compared to those who reported weekend bedtimes before 11 pm, urinary aMT6s levels were significantly lower among participants reporting weekend bedtimes after midnight (52.5 vs. 38.0 ng/mg creatinine, P trend=0.007). Sleep interruption also appeared to be significantly associated with lower urinary aMT6s levels, but only if lights were turned on during sleep interruption (43.0 ng/mg creatinine for participants with sleep interruption but not turning lights on, vs. 24.6 ng/mg creatinine for participants reporting that they turned on the light when their sleep was interrupted P difference=0.032). Our study suggests that self-reported sleep-related behaviors have little to no effect on adolescent circadian systems, though larger studies are needed to confirm our findings.

Circadian clock genes and risk of fatal prostate cancer.

Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels. We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians' Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes. None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels. We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.

Urinary Melatonin Levels, Sleep Disruption, and Risk of Prostate Cancer in Elderly Men

Melatonin has anticarcinogenic properties in experimental models. We undertook a case–cohort study of 928 Icelandic men without prostate cancer (PCa) nested within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort to investigate the prospective association between first morning-void urinary 6-sulfatoxymelatonin (aMT6s) levels and the subsequent risk for PCa, under the hypothesis that men with lower aMT6s levels have an increased risk for advanced PCa. We used weighted Cox proportional hazards models to assess the association between first morning-void aMT6s levels and PCa risk, adjusting for potential confounders. A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning aMT6s levels compared with those who reported no sleep problems. Men with morning aMT6s levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04; 95% confidence interval, 1.26–12.98). These results require replication in larger prospective studies with longer follow-up. Patient summaryIn this report, we evaluated the prospective association between urinary aMT6s levels and risk of PCa in an Icelandic population. We found that lower levels of aMT6s were associated with an increased risk for advanced PCa.

Atopic dermatitis, melatonin, and sleep disturbance.

Sleep disturbance is common in patients with atopic dermatitis (AD). However, studies have largely been questionnaire-based, and the pathophysiology remains unclear. The aims of this study were to determine objective characteristics of sleep disturbance in children with AD and explore contributing factors and clinical predictors. Sleep parameters were measured by actigraphy and polysomnography in 72 patients with AD and 32 controls ages 1 to 18 years. Urinary 6-sulfatoxymelatonin levels, serum cytokines, and total and allergen-specific immunoglobulin E (IgE) levels were also measured. The patients with AD had significantly reduced sleep efficiency, longer sleep onset latency, more sleep fragmentation, and less nonrapid eye movement sleep. Results from actigraphy correlated well with those from polysomnography. The AD disease severity was associated with sleep disturbance (r = 0.55-0.7), and a Scoring Atopic Dermatitis index of ≥48.7 predicted poor sleep efficiency with a sensitivity of 83.3% and a specificity of 75% (area under the curve = 0.81, P = .001). Lower nocturnal melatonin secretion was significantly associated with sleep disturbance in the patients with AD. Other correlates of sleep disturbance included pruritus, scratching movements, higher total serum IgE levels, and allergic sensitization to dust mite and staphylococcal enterotoxins. Poor sleep efficiency is common in children with AD and can be predicted by the Scoring Atopic Dermatitis index. Melatonin and IgE might play a role in the sleep disturbance. Further studies are required to explore the mechanisms and clinical implications, and actigraphy could serve as a useful evaluating tool.

Highlights of This Issue

Arsenic poses a significant human cancer risk and millions worldwide are exposed to naturally occurring arsenic in grains, vegetables, meats and fish, and through food processed with water containing arsenic. Oberoi and colleagues estimated the global burdens of bladder, lung, and skin cancers due to inorganic arsenic in food using World Health Organization estimates of food consumption and reported arsenic levels in different foods. Worldwide, thousands of additional cases of bladder, lung, and skin cancers are attributable to inorganic arsenic in food. These findings warrant policy changes to help reduce arsenic in food.Exposure to light-at-night has been shown to disrupt melatonin production, but this effect has only partly been confirmed in studies of night shift workers. Papantoniou and colleagues examined the variation of urinary 6-sulfatoxymelatonin levels in day or night shift workers while continuously monitoring light exposure. 6-sulfatoxymelatonin levels were lower in night compared to day workers and the lowest 6-sulfatoxymelatonin levels were observed in night workers. These findings may relate to future cancer risks in these worker populations.Infections in early childhood may protect against pediatric acute lymphoblastic leukemia (ALL). Marcotte and colleagues selected pediatric ALL cases from the California Cancer Registry and investigated markers of exposure to infections, including date of birth, and the timing of influenza and respiratory syncytial virus (RSV) seasons. The authors observed an increased risk of ALL for spring and summer births and for those first exposed to an influenza or RSV season at nine to twelve months compared to those exposed during the first three months of life. These results support the hypothesis that infections in early childhood decrease risk of ALL.Inflammation influences cancer development and progression and an elevated platelet/lymphocyte ratio (PLR) has been linked to poor prognosis in several malignancies. Templeton and colleagues conducted a systematic review to explore the association of blood PLR and overall survival from various solid tumors. A significant association between blood PLR and survival was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma. PLR represents an inexpensive biomarker with prognostic value in solid tumors.