Intense solar activity reduces urinary 6-sulfatoxymelatonin in patients with COPD.

BACKGROUND: Little is known about the link between solar activity and variations in melatonin. In this study, we investigated if melatonin's major urinary metabolite, urinary 6-sulfatoxymelatonin (aMT6s), is lowest under periods of intense solar activity. METHODS: We investigated associations between high-energy solar particle events [Coronal Mass Ejection (CME) mass, speed and energy] on creatinine-adjusted aMT6s (aMT6sr) concentrations in 140 patients with chronic obstructive pulmonary disease (COPD) using up to four seasonal urine samples (n = 440). Mixed effect models with a random intercept for each subject were used to estimate associations, including effect modification attributable to diabetes, obesity, and reduced pulmonary function. RESULTS: Higher values of CME were associated with reduced aMT6sr concentrations, with stronger associations in patients with diabetes. An interquartile range (IQR) increase in natural log CMEspeed averaged through two days before urine collection was associated with a reduction of 9.3% aMT6sr (95%CI: - 17.1%, - 0.8%) in aMT6sr. There was a greater reduction in aMT6sr in patients with diabetes (- 24.5%; 95%CI: - 35.9%, - 11.6%). In patients without diabetes there was no meaningful association (- 2.2%; 95%CI: - 12%, 8.4%). There were similar associations with CMEenergy and CMEmass. There was no effect modification attributable to reduced pulmonary function or obesity. CONCLUSIONS: This is the first study in patients with COPD to demonstrate strong detrimental impact of high-energy solar particle events on aMT6sr, with greater associations in patients with diabetes. Since melatonin is an anti-oxidant, it is possible that adverse effects of intense solar activity may be attributable to a reduction in circulating melatonin and that patients with both COPD and diabetes may be more susceptible.

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances.

Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P < .05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r = -.28, P < .05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r = -.31, P < .05) and positively associated with TNF level (r = .42, P < .01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.

Sleep variability, 6-sulfatoxymelatonin, and diabetic retinopathy.

PURPOSE: Recent evidence suggests that diabetic retinopathy (DR) is associated with abnormal melatonin regulation, possibly related to dysfunction of the melanopsin-expressing intrinsically photosensitive retinal ganglion cells. This study explored melatonin regulation in type 2 diabetes (T2D) patients with DR and its relation to sleep and circadian functioning. METHODS: Thirty-five participants (10 non-diabetic controls, 10 T2D without DR, and 15 T2D with DR) were recruited. Overnight urine 6-sulfatoxymelatonin (aMT6s) and objective sleep and wrist activity (7-day actigraphy) were obtained. RESULTS: After adjusting for covariates, having T2D with DR was significantly associated with lower urinary aMT6s (ß = - 1.369, p = 0.004) compared with controls, while having T2D without DR was not (p = 0.418). T2D patients with DR reported poorer sleep quality (p = 0.014) and had greater variability of sleep duration (p = 0.017) than others, while no differences were found in sleep duration, efficiency, and rest-activity rhythm. After adjusting for covariates, lower nocturnal aMT6s was significantly associated with greater sleep variability. CONCLUSION: T2D patients with DR exhibited low overnight production of aMT6s which likely contributed to sleep irregularities possibly due to weak circadian signaling. Whether or not melatonin supplementation could improve health in T2D patients with DR remains to be explored.

Disruption of central and peripheral circadian clocks in police officers working at night.

Working atypical schedules leads to temporal misalignments between a worker's rest-activity cycle and their endogenous circadian system. Several studies have reported disturbed centrally controlled rhythms, but little is known on shift workers' peripheral clocks. Here, we assessed central clock markers, urinary 6-sulfatoxymelatonin and salivary cortisol, and clock gene expression in 2 peripheral clocks, oral mucosa cells and peripheral blood mononuclear cells (PBMCs), in 11 police officers. Before working 7 consecutive nights, officers' centrally controlled rhythms were aligned to a day-oriented schedule. These rhythms were partially realigned to the shifted schedule and dampened after a week working nights. For peripheral clocks at baseline, Period (PER)1-3 and nuclear receptor subfamily 1, group D, member 1 (REV-ERBα) in oral mucosa cells had a significant mRNA peak in the afternoon, whereas in PBMCs, higher PER1-3 expression was observed at 10:00 compared with 19:30. After a week working nights, PER1-3 and REV-ERBα expression in oral mucosa cells lost rhythmicity, and in PBMCs, the morning/evening difference observed at baseline was lost. To our knowledge, this is the first study to demonstrate the disruption of several peripheral clocks in real shift workers. Molecular circadian disturbances are believed to have important clinical implications for the occurrence of shift work-associated medical disorders.-Koshy, A., Cuesta, M., Boudreau, P., Cermakian, N., Boivin, D. B. Disruption of central and peripheral circadian clocks in police officers working at night.

Mass spectrometric quantification of urinary 6-sulfatoxymelatonin: age-dependent excretion and biological variation.

Objectives: Regulators of circadian rhythm, including melatonin, influence fundamental biological processes. Measuring the melatonin metabolite 6-sulfatoxymelatonin in urine can estimate melatonin production. 6-sulfatoxymelatonin is mainly analyzed by immunoassays, but these methods are hampered by cross-reactivity and poor reproducibility when used to analyze small molecules. Therefore, we validated a high-throughput liquid chromatography with tandem mass spectrometry (LC-MS/MS) method to quantify 6-sulfatoxymelatonin in urine. We evaluated age-dependent 24-h excretion of 6-sulfatoxymelatonin into urine and the biological variation of urinary excretion in healthy individuals. Methods: The online solid phase extraction method combined with LC-MS/MS was validated according to international guidelines, and used to measure the excretion of 6-sulfatoxymelatonin into urine of 240 healthy individuals. Biological variation of 6-sulfatoxymelatonin excretion was examined in 10 healthy individuals. Results: Urinary 6-sulfatoxymelatonin results were well within the validation criteria (interassay coefficient of variation: <5.4%, quantification limit: 0.2 nmol/L). There was an age-related decrease in 6-sulfatoxymelatonin excretion into 24-h urine [F(5, 234)=13.9; p<0.001]. Within-subject variation of 6-sulfatoxymelatonin was 39.2% in day urine, 15.1% in night urine, and 12.2% in 24-h urine. Between-subject variation was 39.1% in day urine, 37.9% in night urine, and 36.8% in 24-h urine. Conclusions: This MS-based method enables straightforward, reproducible, and sensitive quantification of 6-sulfatoxymelatonin in urine. Urinary 6-sulfatoxymelatonin levels decreased with age. Biological variation of 6-sulfatoxymelatonin excretion into urine was high between subjects and lower within subjects, indicating that repeated measurements of 6-sulfatoxymelatonin in 24-h urine are needed in future studies.

Meta-analysis of melatonin levels in cluster headache-Review of clinical implications.

Cluster headache (CH) has been associated with circadian disturbances. The present systematic review examined available evidence for the utilization of melatonin (MT) in CH prophylaxis. First, case-control studies assessing nocturnal MT or its urine-expelled metabolite 6-sulfatoxymelatonin (aMT6s) in CH individuals and healthy controls (HC) were reviewed and meta-analyzed. Secondly, the results from randomized controlled trials (RCTs) and non-randomized studies evaluating MT's use in the prevention of CH were discussed. Literature search included MEDLINE, EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey. Bouts and remissions were assessed separately. Ten case-control studies (adult participants) were retrieved. Seven evaluated serum MT; meta-analysis involved only three of them (due to deficient reporting, n: bout = 31, remission = 38, HC = 31). Results were compatible with lower nocturnal serum MT levels during bouts [bout-HC; FE-MD = -29.89 pg/mL, 95% CI = (-46.00, -13.78), remission-HC; FE-MD = -2.40 pg/mL, 95% CI = (-16.57, 21.38), bout-remission; RE-MD = -32.10 pg/mL, 95% CI = (-56.78, -7.42)]. Nocturnal urinary melatonin was appraised in two studies, but reporting issues impeded the capitalization of the results. Nocturnal urine aMT6s was evaluated by two studies (n: bout = 29, remission = 22, HC = 20), and pooled results were indicative of lower aMT6s concentration in CH individuals during both active and inactive periods [bout-HC; FE-MD = -9.63 µg/nocturnal urine collection, 95% CI = (-14.40, -4.85), remission-HC; FE-MD = -9.12 µg/nocturnal urine collection, 95% CI = (-14.63,-3.62), bout-remission; FE-MD = -0.58 µg/nocturnal urine collection, 95% CI = (-4.58, 3.42)]. Regarding CH prophylaxis, one RCT and two non-randomized trials were retrieved, involving a total of 41 adult CH individuals (11-episodic, 31-chronic) and rendering the deduction of any conclusions precarious. Overall, available data for the role use of MT in CH are insufficient and inconclusive. Complementary studies evaluating endogenous MT concentrations and MT administration to patients with CH are warranted.

Gender differences in the association between melatonin secretion and diabetes in elderly: The HEIJO-KYO cohort.

OBJECTIVE: Reportedly, melatonin protects the pancreatic islets and decreases insulin resistance; thus, it may contribute to preventing diabetes. Epidemiological data suggested that lower melatonin secretion is associated with higher incidence of diabetes in female nurses. Such associations are unknown in the general population. We evaluated the association between melatonin secretion and diabetes in a general population, including both genders. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 1096 community-based elderly males (n = 519) and females (n = 577) (mean age, 71.8 years) were enrolled. MEASUREMENTS: Overnight urinary 6-sulfatoxymelatonin excretion (UME) and diabetes prevalence were measured. RESULTS: The median UME was 6.7 µg (interquartile range, 4.0-10.5); the prevalence of diabetes was 17.5% in males and 10.7% in females. The prevalence of diabetes decreased with increasing UME quartiles among males (P for trend = 0.009) but not among females (P for trend = 0.96). In a multivariable logistic regression analysis adjusting for potential confounding factors, such as age, smoking and drinking habits, economic status, caloric intake, and physical activity, the odds ratio (OR) for diabetes was significantly lower in the highest UME quartile group compared with the lowest quartile group among males (OR, 0.35; 95% CI, 0.17-0.70; P = 0.003) but not females (OR, 0.94; 95% CI, 0.45-1.95; P = 0.87). Consistent results were observed in the analysis after adjusting for clinical parameters or using continuous UME data. CONCLUSIONS: Melatonin secretion was significantly and inversely associated with diabetes in males but not in females. This association was independent of several important confounding factors.

A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics.

A biophysical model of the key aspects of melatonin synthesis and excretion has been developed, which is able to predict experimental dynamics of melatonin in plasma and saliva, and of its urinary metabolite 6-sulfatoxymelatonin (aMT6s). This new model is coupled to an established model of arousal dynamics, which predicts sleep and circadian dynamics based on light exposure and times of wakefulness. The combined model thus predicts melatonin levels over the sleep-wake/dark-light cycle and enables prediction of melatonin-based circadian phase markers, such as dim light melatonin onset (DLMO) and aMT6s acrophase under conditions of normal sleep and circadian misalignment. The model is calibrated and tested against group average data from 10 published experimental studies and is found to reproduce quantitatively the key dynamics of melatonin and aMT6s, including the timing of release and amplitude, as well as response to controlled lighting and shift work.

[Melatonin and man aging in the European part of the Arctic zone of the Russian Federation.]

The analysis of 6-sulfatoxymelatonin (6-SMT) levels in working-age men (aged 19-69) who live in the European part of the Arctic zone of the Russian Federation is presented. Their urine 6-SMT levels were similar to those of comparison group (residents of Western Siberia). The level of 6-SMT decreased with age and was the lowest in 40-49-year group. Age group 60-69 tended to demonstrate increasing 6-SMT levels. Thus, they were insignificantly different (p>0,05) compared to those of people under 29. We showed that alcohol influenced 6-SMT level. The level was lower in alcohol-consuming north men compared to non-consumers. Free testosterone level in plasma of northerners decreased with age. In 60-69-year group, the level was 50% of that in under-29-year group. Compared to controls, we observed the activation of lipid peroxidation that was not compensated by increased activity of glutathione reductase and plasma SH groups. Age-related decrease in the melatonin metabolite, as an endogenous antioxidant, was accompanied by a gradual accumulation of lipid peroxidation products and lower antioxidative protection mediated by SH groups.

[Interrelation between the melatonin level and indicators of aging and fibrosis in men in the European part of the Arctic zone of Russian Federation.]

The results of the correlation analysis between the metabolite melatonin - 6-sulfatoxymelatonin (6-SMT) in the urine and the indicators of aging, interstitial fibrosis, the system of antioxidant protection in men in the Arctic are presented. Negative correlation of medium strength between 6-SMT with calendar age, biological age and molecular marker of aging p16INK4a in leukocytes was noted. A relationship of 6-SMT to fibrosis indices was found. It manifested itself in a negative correlation with sulfated glycosaminoglycans in the urine, with collagen markers: free hydroxyproline, peptide-linked hydroxyproline, and total hydroxyproline. Age-related decrease in the level of 6-SMT may be associated with an age-related increase in interstitial fibrosis in northerners. A positive correlation of medium strength between 6-SMT and hormones: free testosterone level (r=0,53, p=0,0002), total testosterone (r=0,43, p=0,003) and cortisol (r=0,33, p=0,007) was shown. Negative correlations of 6-SMT with the content of ceruloplasmin (r=-0,63, p=0,001) and SCORE scale (r=-0,52, p=0,001) indicate the relationship between melatonin and the antioxidant defense system and the risk of cardiovascular pathology.The results of the correlation analysis between the metabolite melatonin - 6-sulfatoxymelatonin (6-SMT) in the urine and the indicators of aging, interstitial fibrosis, the system of antioxidant protection in men in the Arctic are presented. Negative correlation of medium strength between 6-SMT with calendar age, biological age and molecular marker of aging p16INK4a in leukocytes was noted. A relationship of 6-SMT to fibrosis indices was found. It manifested itself in a negative correlation with sulfated glycosaminoglycans in the urine, with collagen markers: free hydroxyproline, peptide-linked hydroxyproline, and total hydroxyproline. Age-related decrease in the level of 6-SMT may be associated with an age-related increase in interstitial fibrosis in northerners. A positive correlation of medium strength between 6-SMT and hormones: free testosterone level (r=0,53, p=0,0002), total testosterone (r=0,43, p=0,003) and cortisol (r=0,33, p=0,007) was shown. Negative correlations of 6-SMT with the content of ceruloplasmin (r=-0,63, p=0,001) and SCORE scale (r=-0,52, p=0,001) indicate the relationship between melatonin and the antioxidant defense system and the risk of cardiovascular pathology.

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria.

BACKGROUND: Deficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF). METHODS: Subjects with PKU consumed a low-Phe diet combined with AA-MF or GMP-MF for 3weeks each in a randomized, controlled, crossover study. Metabolomic analysis was conducted by Metabolon, Inc. on plasma (n=18) and urine (n=9) samples. Catecholamines and 6-sulfatoxymelatonin were measured in 24-h urine samples. RESULTS: Intake of Tyr and Trp was ~50% higher with AA-MF, and AA-MF were consumed in larger quantities, less frequently during the day compared with GMP-MF. Performance on neuropsychological tests and concentrations of neurotransmitters derived from Tyr and Trp were not significantly different with AA-MF or GMP-MF. Plasma serotonin levels of gut origin were higher in subjects with variant compared with classical PKU, and with GMP-MF compared with AA-MF in subjects with variant PKU. Metabolomics analysis identified higher levels of microbiome-derived compounds synthesized from Tyr, such as phenol sulfate, and higher levels of compounds synthesized from Trp in the kynurenine pathway, such as quinolinic acid, with ingestion of AA-MF compared with GMP-MF. CONCLUSIONS: The Tyr from AA-MF is less bioavailable due, in part, to greater degradation by intestinal microbes compared with the Tyr from prebiotic GMP-MF. Research is needed to understand how metabolism of Trp via the kynurenine pathway and changes in the intestinal microbiota affect health for individuals with PKU. This trial is registered at www.clinicaltrials.gov as NCT01428258.

[Pineamin increased pineal melatonin synthesis in elderly people].

It was investigated the influence of polypeptide complex Pineamin on the 6-sulfatoxymelatonin (aMT6S) excretion in urine by ELISA test of 55 elderly patients with diminished melatoninsynthesis pineal gland function. Pineamin in course dose 100 mg has increased night level of aMT6S urine excretion in 1,9 times in comparison with relevant value untreated. Similar effect was obtained early for medical drug Epithalamin. Epithalamin also restored melatonin level in human and animals during aging. Thus, Pineamin and Epithalamin have similar stimulate effect on melatonin synthesis in elderly people pineal gland.

Urinary melatonin concentration and the risk of breast cancer in Nurses' Health Study II.

Experimental and epidemiologic data support a protective role for melatonin in breast cancer etiology, yet studies in premenopausal women are scarce. In a case-control study nested within the Nurses' Health Study II cohort, we measured the concentration of melatonin's major urinary metabolite, 6-sulfatoxymelatonin (aMT6s), in urine samples collected between 1996 and 1999 among 600 breast cancer cases and 786 matched controls. Cases were predominantly premenopausal women who were diagnosed with incident breast cancer after urine collection and before June 1, 2007. Using multivariable conditional logistic regression, we computed odds ratios and 95% confidence intervals. Melatonin levels were not significantly associated with total breast cancer risk (for the fourth (top) quartile (Q4) of aMT6s vs. the first (bottom) quartile (Q1), odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.64, 1.28; Ptrend = 0.38) or risk of invasive or in situ breast cancer. Findings did not vary by body mass index, smoking status, menopausal status, or time between urine collection and diagnosis (all Pinteraction values ≥ 0.12). For example, the odds ratio for total breast cancer among women with ≤5 years between urine collection and diagnosis was 0.74 (Q4 vs. Q1; 95% CI: 0.45, 1.20; Ptrend = 0.09), and it was 1.20 (Q4 vs. Q1; 95% CI: 0.72, 1.98; Ptrend = 0.70) for women with >5 years. Our data do not support an overall association between urinary melatonin levels and breast cancer risk.

Effects of Melatonin-Aided Therapy on the Glutathione Antioxidant System Activity and Liver Protection.

Acute hepatitis results from oxidative stress triggered by hepatotoxic drugs causing liver injury and the activation of caspases cascade. The glutathione antioxidant system protects against reactive oxygen species and mitigates development of these processes. The effectiveness of silymarin, a polyphenolic flavonoid, essenthiale, composed of phosphatidyl choline, and melaxen, a melatonin-correcting drug, as hepatoprotectors has been investigated. The variation of 6-sulfatoxymelatonin (aMT6s), resulting from the biotransformation of melatonin, and GSH has been measured. The activities of caspase-1 and caspase-3, glutathione antioxidant system, and NADPH-generating enzymes were determined. The aMT6s decreases in patients with drug hepatitis and recovers with administration of mexalen. GSH increased in the presence of the studied hepatoprotectors. Pathologically activated caspase-1 and caspase-3 decreased their activities in the presence of hepatoprotectors with melaxen showing the highest effect. The positive effect of melatonin appears to be related to the suppression of decompensation of the glutathione antioxidant system functions, recovery of liver redox status, and the attenuation of inhibition of the NADPH supply.

[Melatonin in a woman's life: from birth to menopause].

We did a review of the literature data of main Russian publications and databases PubMed/Medline for the last 7 years. In the present article we examine the physiology of secretion of pineal hormone melatonin and its role in the vital processes of the body. The study was focused on the influence of melatonin on the female reproductive system, participation in the aging process and the formation of pathological menopause. The article presents research data on the effectiveness of the drug melatonin in the climacteric syndrome. It is revealed that up to the present time according to the literature data there is no information about the standards of secretion of melatonin for women of different age groups, and the lack of secretion of melatonin can be judged by clinical manifestations, and also when compared with groups of healthy women. Remain unclear issues in the application of drugs melatonin at various complications of pregnancy and gynecological diseases. Long-term use of melatonin is still open in climacteric syndrome.

First-morning urinary melatonin and breast cancer risk in the Guernsey Study.

It has been hypothesized that suppressed nocturnal melatonin production is associated with an increased risk of breast cancer, but results from several small prospective studies of the association have been inconclusive. We examined the association between nocturnal melatonin and breast cancer risk in a case-control study nested within the Guernsey III Study, a British prospective cohort study (1977-2009). Concentrations of 6-sulfatoxymelatonin were measured in prediagnostic first-morning urine samples from 251 breast cancer cases and 727 matched controls. Conditional logistic regression models were used to calculate odds ratios for breast cancer in relation to 6-sulfatoxymelatonin level. No significant association was found between 6-sulfatoxymelatonin level and breast cancer risk, either overall (for highest third vs. lowest, multivariable-adjusted odds ratio = 0.90, 95% confidence interval: 0.61, 1.33) or by menopausal status. However, in a meta-analysis of all published prospective data, including 1,113 cases from 5 studies, higher 6-sulfatoxymelatonin levels were associated with lower breast cancer risk (for highest fourth vs. lowest, odds ratio = 0.81, 95% confidence interval: 0.66, 0.99). In summary, we found no evidence that 6-sulfatoxymelatonin level in a first-morning urine sample was associated with breast cancer risk among British women. However, overall the published data suggest a modest inverse association between melatonin levels and breast cancer risk. Further data are needed to confirm this association.

Association between melatonin secretion and nocturia in elderly individuals: a cross-sectional study of the HEIJO-KYO cohort.

PURPOSE: Nocturnal voids are regulated by circadian biological rhythms, including decreased urine production and increased bladder storage capacity at night. A previous experimental study suggested that exogenous melatonin decreases urine production and increases bladder capacity in rats. However, little is known about whether melatonin secretion, which is considerably lower than exogenous melatonin, is associated with nocturia in humans. We evaluated the association between melatonin secretion and nocturia. MATERIALS AND METHODS: In this cross-sectional study we examined 861 community based elderly individuals with a mean age of 72.1 years. We measured nocturnal void frequency and overnight urinary 6-sulfatoxymelatonin excretion as an index of melatonin secretion. Nocturia was defined as 2 or more nocturnal voids. RESULTS: Univariate comparisons between the 261 and 600 study participants with and without nocturia, respectively, showed marginal to significant associations of nocturia with age, gender, body mass index, estimated glomerular filtration rate, calcium channel blockers, benign prostatic hyperplasia, total voided urine volume, urinary 6-sulfatoxymelatonin, duration in bed, day length, and daytime and nighttime physical activity. The multivariate logistic regression model adjusted for the former confounding factors revealed that higher urinary 6-sulfatoxymelatonin was significantly associated with a lower nocturia OR (adjusted OR 0.73, 95% CI 0.56-0.96, p=0.023). After adjustment for age, gender and duration in bed the mean volume of a single voided urine significantly increased with tertiles of increasing urinary 6-sulfatoxymelatonin (p for trend=0.022). CONCLUSIONS: Melatonin secretion is significantly and inversely associated with nocturia in a general elderly population.

Do fluctuations in endogenous melatonin levels predict the occurrence of postoperative cognitive dysfunction (POCD)?

Delirium is a complex neuropsychiatric disorder that has an adverse impact on CNS function. Abnormal fluctuation of melatonin secretion occurs in the postoperative delirium (POD) in elderly patients. POD is strongly associated with early postoperative cognitive dysfunction (POCD). The aim of this study is to test if significant fluctuation of melatonin secretion perioperatively might indicates POCD. A total of 97 patients, ages 65-80 years, scheduled for major orthopedic surgery or abdominal surgery which was expected to last more than 2 h, were consecutively recruited into this study. Neuropsychological evaluation was performed 1 d before and one week after surgery. Morning urine samples were collected on the day of surgery and on days 1, 2 and 7 after surgery. The 6-SMT/creatinine ratio (M/C ratio) was employed to give an objective estimate of urine 6-SMT concentration. Ultimately, 95 patients completed assessments and were included in the analysis. POCD was found in 30 patients (31.6%) at 1 week after operation. There was significant fluctuation in urinary 6-SMT in 39 of the 95 patients (as evidenced by urinary 6-SMT levels increased or decreased by more than twofold compared with their preoperative baseline). Fluctuations in 6-SMT levels occurred on different days and in some patients lasted for more than 1 d. The incidence of POCD in patients with 6-SMT fluctuation was significantly higher (p < 0.01). The results indicate that in the first week after major noncardiac surgery, POCD occurs in a significant proportion of people, and is linked to fluctuations in endogenous melatonin levels. Measurement of urinary 6-SMT during the perioperative period may assist the diagnosis of POCD.

Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis.

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.

Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women.

Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence of insulin resistance based on fasting blood samples collected in a cross-sectional study of 1,075 US women (1997-1999) without diabetes, hypertension, or malignancy. Urinary 6-sulfatoxymelatonin level was standardized to urinary creatinine level; insulin resistance was defined as an insulin sensitivity index value (using the McAuley formula) less than 7.85. Logistic regression models included adjustment for age, body mass index, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes mellitus, blood pressure, plasma total cholesterol, uric acid, and estimated glomerular filtration rate. Higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance. In fully adjusted models, the odds ratio for insulin resistance was 0.45 (95% confidence interval: 0.28, 0.74) among women in the highest quartile of urinary 6-sulfatoxymelatonin:creatinine ratio compared with women in the lowest quartile. Nocturnal melatonin secretion is independently and inversely associated with insulin resistance.