Reduced Melatonin Production Research Articles

Exogenous melatonin decreases circadian misalignment and body weight among early types.

Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real-life conditions. We conducted a double-blind, randomized, placebo-controlled, crossover trial where melatonin (3mg) or placebo was administered on non-night shift nights for 12weeks in 27 female nurses (37.1 yo, ±5.9 yo; BMI 29.9kg/m2 , ±3.3kg/m2 ). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days off). Composite Phase Deviations (CPD) of actigraphy-based mid-sleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction in circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants' calorie intake or physical activity levels.

Special peculiarities of clinical course of osteoarthrosis of knee joints depending on 6-hydroxymelatonin-sulfate urinary excretion profile

The study objective was to define the special features of the clinical course of knee joint osteoarthrosis depending on 6-sulfatoxymelatonin urinaryexcretion profile.Materials and methods.We surveyed 141 patients with radiological Stage II-III osteoarthrosis (OA) of the knee joints (18 female subjects). Diagnosis of OA was established on the basis of ACR criteria (1991) and EULAR (2010) recommendations. We determined the AO clinical indexes (Lequesne, WOMAC, KOOS), HAQ functional index, sleep quality and psycho-emotional state indicators. ELISA was used to assess 6-sulfatoxymelatonin urinary excretion profile.Results. It was established that 66% of patients with OA of knee joints had a reduced 6-sulfatoxymelatonin urinary excretion compared to this of practically healthy individuals. AO patients with low 6-SMT urinary excretion profiles had higher incidence of severe insomnia and depressive disorders. Reduction in 6-SMT excretion was associated with a moderate increase in pain syndrome and deterioration of physical functions by Lequesne, WOMAC, KOOS, and HAQ indexes.Conclusion.The reducedmelatonin production in ОА patients is a factor of more severe clinical course of the disease due to deterioration of the psycho-emotional state, the development of pain syndrome, and functional disorders.

Clocks, Behavior, and Cognition

The nerve center responsible for controlling our circadian rhythm is located in a cluster of cells known as the suprachiasmatic nucleus in the hypothalamus. Various physiological functions such as sleep, arousal, blood pressure, body temperature, and hormone secretion are regulated in a 24-hour rhythm by this circuit. Somatic cells of other organs have a peripheral clock gene and by synchronizing the rhythm of the central and peripheral clocks, it is possible to live a healthy life. Due to aging and degenerative disease, circadian rhythm gradually collapses. Factors that can contribute to this include reduced expression of the time gene associated with photo stimulation, a reduction in neurotransmitter levels, and reduced melatonin production. Biological clocks play an important role in our emotions, cognitive function, and behavior. Sleep disorders and metabolic disease related to the circadian rhythm affect metabolic and endocrine activities via the autonomic nervous system and the intestinal bacterial flora. Shift work disorder is associated with insomnia and excessive drowsiness as individuals often work during their sleeping hours. Now time management is placed at the center of our society, and it is important to evaluate the medical risk of engaging in shift work. In frontotemporal dementia (FTD), the stereotypical behaviors may be associated with time. In some patients, multiple timed behaviors occupy a considerable part of the patient's daily life. Stereotypical behaviors in FTD are often considered in contrast to obsessive-compulsive disease (OCD). Studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function.

Progressive decrease of melatonin production over consecutive days of simulated night work

Decreased melatonin production, due to nighttime exposure to light, has been proposed as one of the physiological mechanisms increasing cancer risk in night workers. However, few studies measured melatonin production in night workers, and most of these studies did not measure melatonin over 24 h. One study compared total melatonin production between day and night shifts in rotating night workers and did not find significant differences. However, without baseline measures, it was not possible to exclude that melatonin production was reduced during both day and night work. Here, we used data collected in a simulation study of night work to determine the effect of night work on both nighttime and 24-h melatonin production, during three consecutive days of simulated night work. Thirty-eight healthy subjects (15 men, 23 women; 26.6 ± 4.2 years) participated in a 6-d laboratory study. Circadian phase assessments were made with salivary dim light melatonin onset (DLMO) on the first and last days. Simulated day work (09:00–17:00 h) occurred on the second day, followed by three consecutive days of simulated night work (00:00–08:00 h). Light intensity at eye level was set at 50 lux during both simulated day and night work. The subjects were divided into three matched groups exposed to specific daytime light profiles that produced various degrees of circadian phase delays and phase advances. Melatonin production was estimated with the excretion of urinary 6-sulfatoxymelatonin (aMT6s). For the entire protocol, urine was collected every 2 h, except for the sleep episodes when the interval was 8 h. The aMT6s concentration in each sample was multiplied by the urine volume and then added to obtain total aMT6s excretion during nighttime (00:00–08:00 h) and during each 24-h day (00:00–00:00 h). The results showed that melatonin production progressively decreased over consecutive days of simulated night work, both during nighttime and over the 24 h. This decrease was larger in women using oral contraceptives. There was no difference between the three groups, and the magnitude of the decrease in melatonin production for nighttime and for the 24 h was not associated with the magnitude of the absolute circadian phase shift. As light intensity was relatively low and because the decrease in melatonin production was progressive, direct suppression by nighttime light exposure was probably not a significant factor. However, according to previous experimental observations, the decrease in melatonin production most likely reflects the circadian disruption associated with the process of re-entrainment. It remains to be determined whether reduced melatonin production can be harmful by itself, but long-term and repeated circadian disruption most probably is.

The Influence of Light at Night Exposure on Melatonin Levels among Canadian Rotating Shift Nurses

Shift work has been identified as a risk factor for several cancer sites in recent years, with melatonin as a potential intermediate on the proposed causal pathway. This study examined the influence of nighttime light exposure on melatonin levels among 123 rotating shift nurses. Nurses working a rotating shift schedule (two 12-hour days, two 12-hour nights, and five days off) were recruited and participated on a day and night shift in both the summer and winter seasons. Over each 48-hour study period, nurses wore a light data logger and provided two urine and four saliva samples. Saliva measurements showed that the pattern of melatonin production did not differ between day and night shifts. Mean light exposure was significantly higher (P < 0.0001) when nurses were working at night, although peak melatonin levels (P = 0.65) and the daily change in melatonin levels (P = 0.80) were similar across day/night shifts. Multivariate analysis did not show an association between light exposure and melatonin levels when data from both shifts was combined; however, when data from the night shift was considered alone, a statistically significant inverse relationship between light and change in melatonin was observed (P = 0.04). These results show that light exposure does not seem to be strongly related to reduced melatonin production among nurses on this rapidly rotating shift schedule. Future research considering more extreme shift patterns or brighter lighting conditions could further clarify the relationship between light exposure and melatonin production in observational settings.

Expression of protein gene product 9.5, tyrosine hydroxylase and serotonin in the pineal gland of rats with streptozotocin-induced diabetes

Hyperglycemia is a well-known factor in reducing nocturnal pineal melatonin production. However, the mechanism underlying diabetes-induced insufficiency of pineal melatonin has remained uncertain. This study was undertaken to examine the structure, innervation and functional activity of the pineal gland in streptozotocin (STZ)-induced diabetes in rats by immunohistochemistry, Western blotting and image analysis. The number of the pinealocytes and the volume of pineal were also estimated using stereologic quantification including the optical fractionator and Cavalieri's method. It has also shown a progressive reduction of the total area of the pineal gland and the nuclear size of pinealocytes beginning at 4 weeks of induced diabetes. Surprisingly, the immunoreactive intensities and protein amounts of serotonin (5-HT) and protein gene product (PGP) 9.5 in the pineal gland were progressively increased from 4 weeks of diabetes. Meanwhile, nerve fibers immunoreactive for PGP 9.5 had disappeared. Diabetes-induced neuropathy was observed in nerve fibers containing tyrosine hydroxylase (TH). The affected nerve fibers appeared swollen and smooth in outline but they showed a distribution pattern, packing density and protein levels comparable to those of the age-matched control animals. Ultrastructural observations have revealed diabetes-induced deformity of Schwann cells and basal lamina, accumulation of synaptic vesicles and deprivation of the dense-core vesicles in the axon terminals and varicosities. The increase in immunoreactivities in 5-HT and PGP 9.5 and shrinkage of pineal gland in the diabetic rats suggest an inefficient enzyme activity of the pinealocytes. This coupled with the occurrence of anomalous TH nerve fibers, may lead to an ineffective sympathetic innervation of the pinealocytes resulting in reduced melatonin production in STZ-induced diabetes.

Rhythmic control of AANAT translation by hnRNP Q in circadian melatonin production

The circadian rhythm of pineal melatonin requires the nocturnal increment of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase [AANAT]) protein. To date, only limited information is available in the critical issue of how AANAT protein expression is up-regulated exclusively at night regardless of its species-specific mRNA profiles. Here we show that the circadian timing of AANAT protein expression is regulated by rhythmic translation of AANAT mRNA. This rhythmic control is mediated by both a highly conserved IRES (internal ribosome entry site) element within the AANAT 5' untranslated region and its partner hnRNP Q (heterogeneous nuclear ribonucleoprotein Q) with a peak in the middle of the night. Consistent with the enhancing role of hnRNP Q in AANAT IRES activities, knockdown of the hnRNP Q level elicited a dramatic decrease of peak amplitude in the AANAT protein profile parallel to reduced melatonin production in pinealocytes. This translational regulation of AANAT mRNA provides a novel aspect for achieving the circadian rhythmicity of vertebrate melatonin.

Rhythmic control of AANAT translation by hnRNP Q in circadian melatonin production

The circadian rhythm of pineal melatonin requires the nocturnal increment of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase [AANAT]) protein. To date, only limited information is available in the critical issue of how AANAT protein expression is up-regulated exclusively at night regardless of its species-specific mRNA profiles. Here we show that the circadian timing of AANAT protein expression is regulated by rhythmic translation of AANAT mRNA. This rhythmic control is mediated by both a highly conserved IRES (internal ribosome entry site) element within the AANAT 5' untranslated region and its partner hnRNP Q (heterogeneous nuclear ribonucleoprotein Q) with a peak in the middle of the night. Consistent with the enhancing role of hnRNP Q in AANAT IRES activities, knockdown of the hnRNP Q level elicited a dramatic decrease of peak amplitude in the AANAT protein profile parallel to reduced melatonin production in pinealocytes. This translational regulation of AANAT mRNA provides a novel aspect for achieving the circadian rhythmicity of vertebrate melatonin.

Immune markers and ornithine decarboxylase activity among electric utility workers.

The effects of a 60-Hz magnetic field (MF) exposure on white blood cell ornithine decarboxylase (ODC) activity, natural killer (NK) cell activity, lymphocyte phenotypes, and differential cell counts were studied among 60 electric utility workers. Personal MF exposure monitoring over 3 consecutive workdays was followed by collection of a peripheral blood sample. There were no MF-related changes in NK activity or the number of circulating neutrophils, eosinophils, basophils, or T-lymphocytes (CD4, CD8, CD4:CD8 ratio). MF exposure intensity was associated with decreased ODC activity (P<0.01) and lower NK cell counts (P=0.04). Melatonin production, which stimulates the immune system, was quantified on the night preceding immune marker determinations. Exposure-related reductions in ODC activity, NK and B cells, and monocytes were strongest among workers with reduced melatonin production. The biological significance or long-term health consequences associated with these changes are not known.

Melatonin metabolite excretion among cellular telephone users

Purpose : The relationship between cellular telephone use and excretion of the melatonin metabolite 6-hydroxymelatonin sulfate (6-OHMS) was evaluated in two populations of male electric utility workers (Study 1, n =149; Study 2, n =77). Materials and methods : Participants collected urine samples and recorded cellular telephone use over 3 consecutive workdays. Personal 60-Hz magnetic field (MF) and ambient light exposures were characterized on the same days using EMDEX II meters. A repeated measures analysis was used to assess the effects of cellular telephone use, alone and combined with MF exposures, after adjustment for age, participation month and light exposure. Results : No change in 6-OHMS excretion was observed among those with daily cellular telephone use >25 min in Study 1 (5 worker-days). Study 2 workers with >25 min cellular telephone use per day (13 worker-days) had lower creatinine-adjusted mean nocturnal 6-OHMS concentrations (p =0.05) and overnight 6-OHMS excretion (p =0.03) compared with those without cellular telephone use. There was also a linear trend of decreasing mean nocturnal 6-OHMS/creatinine concentrations (p =0.02) and overnight 6-OHMS excretion (p =0.08) across categories of increasing cellular telephone use. A combined effect of cellular telephone use and occupational 60-Hz MF exposure in reducing 6-OHMS excretion was also observed in Study 2. Conclusions : Exposure-related reductions in 6-OHMS excretion were observed in Study 2, where daily cellular telephone use of >25min was more prevalent. Prolonged use of cellular telephones may lead to reduced melatonin production, and elevated 60-Hz MF exposures may potentiate the effect.

Pineal perifusion with calcium channel blockers inhibits differently daytime and nighttime melatonin production in rat

In a previous study we have shown that the response of perifused pineal glands to calcium was different according to the circadian stage at which the glands were removed. This difference may be explained by circadian changes in calcium channel function. Therefore in the present study we documented the effects of calcium channel blockers in perifused rat pineal glands removed in the middle of the light and dark spans (7 and 19 HALO (hours after light onset), in a L/D 12:12 regimen). Moreover, we have studied the effect of calcium channel blockers on adrenergically stimulated pineal glands removed 7 HALO. Inorganic (Co 2+ and Cd 2+) and organic (nifedipine and diltiazem) calcium channel blockers at 10 −4 mol/1 all significantly reduced melatonin production and this inhibition was more effective with the glands removed 7 HALO. In a concentration of 10 −5 mol/1, only Cd 2+ and diltiazem reduced melatonin production significantly in pineal glands removed 7 HALO. Verapamil at 10 −4 and 10 −5 mol/1 showed no significant effect on melatonin production in glands removed both during the light and dark spans. Mn 2+ at 10 −4 mol/1 (but not at 10 −5 mol/1) appeared to stimulate melatonin production in glands removed both during the light and the dark (significant increase only with glands removed during the dark). Cobalt showed an immediate short inhibitory effect on both isoproterenol and norepinephrine-stimulated melatonin release, whereas nifedipine showed a significant inhibition only on isoproterenol-stimulated melatonin release. These results strongly suggest a circadian stage dependence of the pineal gland response to some calcium channel blockers and the involvement of calcium in the release of melatonin from pinealocytes.

Pineal gland metastases from mammary carcinoma

Breast carcinomas often metastasize into various organs, most commonly into the lung and rather infrequently into the pineal gland. There were only 20 cases of the latter recorded until 1950. Currently, the total number of reported cases, including this report, is 74. At Sunnybrook Health Science Centre, between 1984 and 1992, 27 patients died of disseminated breast cancer; 2 patients had metastases to the pineal gland. Five patients had metastatic deposits in the pituitary and J had metastases in both organs. Average survival time from diagnosis of breast tumor to death was nearly 3 years. In contrast, the 2 patients with pineal metastasis lived for 1 and 7 months, respectively, after diagnosis. The significance of pineal metastases with regard to short survival may be related to the fact that destruction of the pineal parenchyma reduced melatonin production, thereby decreasing the nonspecific oncostatic effect normally exerted by pineal gland secretions.