Decrease In Melatonin Production Research Articles

Peculiarities of circadian regulation of the thyroid gland

Circadian rhythmicity is an autonomous period of organ cells’ functioning that is controlled by feedback mechanisms and specific genes. The thyroid gland, as a peripheral organ of the endocrine system, is subordinate to the adenohypophysis and pineal gland. Melatonin, as one of the main mediators of circadian influence, is well known for its antitumor and regulatory effects on a number of tissues, but its relationship with the hormone-producing activity of the thyroid gland has not been sufficiently studied. The purpose of the work was to analyze the current data on circadian regulation of the thyroid gland by examining evidence-based scientific publications from open databases over the past five years. Melatonin-producing pineal cells possess the homeotic genes Otx2 and Crx whose deactivation leads to a significant decrease in melatonin production by the pineal gland. In addition to pineal cells, melatonin can be synthesized by adenohypophysis-independent parafollicular cells. The effect of melatonin on thyrocytes is provided by binding to MT1 receptors and affecting the expression of thyroglobulin, RX-8, and TTF-1 (NKX2-1) genes. Under conditions of short photoperiod, melatonin inhibits the production of thyroid-stimulating hormone (TSH) β, which, in turn, acts on hypothalamic tanycytes by regulating the balance of deiodinase (Dio2/Dio3). This leads to a well-regulated seasonal control of the release of the thyroid hormone triiodothyronine. Conclusions. Circadian regulation of thyrocyte activity occurs under the influence of melatonin, which is secreted by pinealocytes and sometimes by parafollicular cells. TSH is secreted with a certain circadian periodicity under the influence of the activation of chronorhythmic genes. Hormone replacement therapy should be aimed not only at restoring the levels of pituitary hormones, but also at restoring the biological rhythm of TSH secretion. Melatonin affects the circadian work of thyrocytes, which is proven by determining the expression of the chronorhythm genes Bmal-1, Dio2, TTF-1. In thyroid pathology, there is a violation of circadian rhythms, a decrease in melatonin levels, and a decrease in the expression of Clock genes.

시뮬레이션 프로그램을 이용한 Melanopic-to-photopic Ratio(α-opic) 및 연색특성 향상에 대한 연구

Invention of artificial lights has extended human activity time, which has greatly contributed to the development of modern civilization. However, continuous exposure of artificial lights has reduced human sleeping time, which causes a decrease in melatonin production resulting in the side effects such as insomnia, depression, and so on. To prevent the reduction of melatonin by the artificial lights, LED packages helping melatonin generation have been developed. While the commercial LED packages have a high melanopic to photopic ratio (M/P ratio) due to their peak wavelength near the melatonic response around 490nm, those cannot accurately express several colors, that is, give a low R<SUB>9</SUB> or R<SUB>12</SUB> value less than 60 resulting from the peak. Since M/P ratio has a similar formula to that of scotopic to photopic ratio (S/P ratio), the former would have a trade-off relation with color rendering properties as the latter. Therefore, those should be optimized to have values above a certain level by adjusting LED package’s spectral compositions. In this study, M/P ratio and color rendering characteristics were simulated by special combination of 4 blue LEDs and 7 types of phosphors. As a result, the M/P ratios were 0.67, 0.72, 0.78, 0.9, 1.04, 1.14, 1.23, and 1.35 or more. Also, the color rendering properties were R<SUB>a</SUB>≥89, R<SUB>9</SUB>≥75, R<SUB>12</SUB>≥80, R<SUB>9-14</SUB>≥83, and Q<SUB>a</SUB>≥79.

Динаміка змін показників математичного аналізу серцевого ритму в умовах адреналінової міокардіодистрофії на тлі різної функціональної активності епіфіза

The purpose of the study was to examine the features of heart rate variability in experimental hyper- and hypofunction of the pineal gland, complicated by adrenal myocardial dystrophy. Materials and methods. To solve the set tasks, three models of functional states were created: hypo-, hyperfunction of the pineal gland, adrenaline myocardial dystrophy. Hypermelatoninemia was reproduced by administering melatonin. The hypofunction of the pineal gland was simulated by round-the-clock lighting. An experimental model of cardiac pathology, namely adrenaline myocardial dystrophy, was reproduced by administering adrenaline hydrochloride. The degree of tension of regulatory mechanisms and mechanisms of nervous regulation was assessed by mathematical analysis of heart rate variability. Results and discussion. The task of mathematical analysis is to extract “hidden information” and thereby assess the state and degree of tension of the regulatory mechanisms of the whole organism. According to the authors, mathematical analysis allows a differentiated approach to the assessment of regulatory effects, which is done by the nervous autonomic system, subcortical structures and the cerebral cortex. The data obtained by the authors suggest that the introduction of adrenaline in conditions of hypofunction of the pineal gland have cause-and-effect changes. These changes lead to disorders of autonomic regulation and possibly a trigger mechanism for a decrease in melatonin production by the pineal gland. Studies have shown that one of the advantages in conditions of hyperfunction of the pineal gland is the dominant role of parasympathetic processes in the mechanisms of adaptation of the heart to conditions of adrenal myocardial dystrophy. Timely and sufficient activation of melatonin provides a high efficiency of compensatory-adaptive changes and a positive role in increasing myocardial resistance. Conclusion. The results of the study showed that the dynamics of changes in the values of the indicators of the mathematical analysis of the heart rate in adrenal myocardial dystrophy against the background of hypo- and hyperfunction of the pineal gland revealed unidirectional changes. These changes are manifested in a decrease in heart rate, stress index and vegetative balance indicator. Consequently, the results obtained suggest that the introduction of melatonin against the background of adrenal myocardial dystrophy has a general corrective effect on the restoration of the functional state of the heart. Based on the results, the authors consider it appropriate to continue the study of the influence of various stressors on the functional state of the heart in conditions of different physiological activity of the pineal gland

Prolonging photoperiod promotes testosterone synthesis of Leydig cells by directly targeting local melatonin system in rooster testes†.

The study investigated the effects of prolonging photoperiod on the synthesis of testosterone and melatonin in roosters, and the effect of melatonin on testosterone synthesis in rooster Leydig cells as well as its molecular mechanisms. We randomly divided one hundred and twenty 20-week-old roosters into three groups and provided 6, 12.5 and 16h light, respectively. The results showed that prolonging photoperiod promoted testosterone synthesis, decreased melatonin production, and inhibited the expression of melatonin membrane receptors MEL1A, MEL1B, MEL1C, and aralkylamine N-acetyltransferase (AANAT) in rooster testes. Subsequently, rooster Leydig cells were isolated and treated with 0, 0.1, 1, 10, and 100ng/mL melatonin for 36h. The results suggested that melatonin inhibited testosterone synthesis in rooster Leydig cells, and silencing MEL1A and MEL1B relieved the inhibition of melatonin on testosterone synthesis. Additionally, melatonin reduced the intracellular cyclic adenosine monophosphate (cAMP) level and the phosphorylation level of cAMP-response element binding protein (CREB), and CREB overexpression alleviated the inhibition of melatonin on testosterone synthesis. Furthermore, pretreatment with cAMP activator forskolin or protein kinase A (PKA) activator 8-bromo-cAMP blocked the inhibition of melatonin on CREB phosphorylation and testosterone synthesis. These results indicated that prolonging photoperiod promoted testosterone synthesis associated with the decrease in melatonin production and membrane receptors and biosynthetic enzyme of melatonin in rooster testes, and melatonin inhibited testosterone synthesis of rooster Leydig cells by inhibiting the cAMP/PKA/CREB pathway via MEL1A and MEL1B. This may be evidence that prolonging photoperiod could promote testosterone synthesis through the inhibition of the local melatonin pathway in rooster testes.

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.

Daily rhythm of blood melatonin concentrations in sheep of different ages

The aim of the study was to investigate the daily pattern of melatonin during short photoperiods in sheep of different age. Thirty Sarda sheep kept under natural light conditions and divided into three equal groups were used: Group 1 (12–18 months); Group 2 (3–4 years); Group 3 (8–9 years). Blood samples were collected every 2 h for 22 h, starting at 21 December (12:00 h) until 22 December (10:00 h) for plasma melatonin radioimmunoassay determination. Statistical significant effect of time of day and age on melatonin concentration was registered. Mesor and amplitude values were statistically lower in Group 3 than in Groups 1 and 2. This study provides the first characterization of the relationship between age and daily pattern of melatonin in sheep, highlighting a decrease in melatonin production in the older animals.

Is newborn melatonin production influenced by magnetic fields produced by incubators?

BackgroundDuring permanence in most incubators, newborns are very close to the electric engine, which represents a source of electromagnetic fields (EMF). Previous studies demonstrated a decrease in melatonin production in adults and animals exposed to EMF. AimsTo assess melatonin production in a group of newborns exposed to EMF, and to evaluate whether removing the babies from the source of MF can affect melatonin production. Study design and subjectsWe have recruited 28 babies (study group), who had spent at least 48h in incubator where we had previously assessed the presence of significant EMF. We have measured their mean 6-hydroxy-melatonin-sulfate (6OHMS) urine excretion at the end of their permanence in the incubators, and compared it with their mean 6OHMS excretion after having been put in cribs, where EMF are below the detectable limit (<0.1mG). We have also measured urine 6OHMS twice, with an interval of 48h, in a control group of 27 babies who were not exposed to EMF during both samples. ResultsMean 6OHMS/cr values were respectively 5.34±4.6 and 7.68±5.1ng/mg (p=0.026) when babies were exposed to EMF in incubators, and after having been put in the crib. In the control group, mean 6OHMS/cr values in the first and in the second sample were respectively 5.91±5.41 vs 6.17±3.94ng/mg (p=0.679). ConclusionsThe transitory increase in melatonin production soon after removing newborns from incubators demonstrates a possible influence of EMF on melatonin production in newborns. Further studies are needed to confirm these data.

Effect of exogenous melatonin on viability, ingestion capacity, and free-radical scavenging in heterophils from young and old ringdoves (Streptopelia risoria)

The decrease of melatonin production with aging contributes to the decline in immune function as organisms age. Treatment with the exogenously administered indoleamine restores the reduced immunological functions. Therefore, we investigated the effect of melatonin on viability, phagocyte ingestion capacity, and free radical generation levels of heterophils from young and old ringdove (Streptopelia risoria) aged 3-4 and 11-13 years, respectively. Animals received a single oral dose of melatonin 1 h before lights off for three consecutive days. Experiments were performed at the acrophases and nadirs of melatonin. Melatonin treatment significantly increased serum melatonin levels at the acrophases, but not at the nadirs of the two age groups. In both young and old animals there was increased heterophil viability at acrophases with respect to nadirs, and also increased cell resistance to oxidative stress in the old animals after the melatonin treatment. At acrophases, the index, percentage and efficiency of phagocytosis all increased significantly, and superoxide anion levels decreased significantly with respect to the nadir values of vehicle and melatonin-treated animals, the effect being greater in young than in old ringdoves. At the nadirs, no change was observed in any parameter analyzed. In both young and old animals, phagocytosis and melatonin were positively correlated, while superoxide anion levels and melatonin were negatively correlated. In conclusion, exogenous melatonin enhanced heterophil viability in old animals as well as increasing phagocytosis and free-radical scavenging in both age groups during the nocturnal period, accompanied by an increase in the levels of the indoleamine.

A New Concept for Melatonin Deficit: On Pineal Calcification and Melatonin Excretion

Even though exogenous melatonin has proven to influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin replacement therapy. In this manuscript, we present a new concept towards a definition of a melatonin deficit. The purpose of the study was to introduce a marker for an intra-individual decrease in melatonin production. Therefore, we developed a method to quantify the degree of pineal calcification (DOC) using cranial computed tomography. Combining pineal DOC with the organs's size, we estimated the uncalcified pineal gland volume. This estimation was positively and significantly associated with 6-sulfatoxymelatonin (aMT6s), collected over 24 hours in urine, in 26 subjects. Data yielded evidence that the decline in aMT6s excretion with age can be sufficiently explained by an increased pineal calcification. These results suggest that DOC might be useful as an indicator of an intra-individual, decreased capability of the pineal gland to produce melatonin. DOC might prove to be a response-marker for melatonin replacement therapy and a vulnerability marker of the circadian timing system.

Presence and effects of melatonin in Trypanosoma cruzi.

The unicellular organism Trypanosoma cruzi is an eukaryote whose cell cycle mainly occurs under darkness in the insect gut. The unique external phase corresponds to the metacyclic forms, the forms that are able to infect humans, which appear within the insect deyections. Thus, light may be a powerful stressor in this unicell. Epimastigote forms (the parasite forms that grow and transform to metacyclic forms in the insect gut) of Trypanosoma cruzi grow normally when cultured in a LD cycle of 0:24 hr, reaching exponential growth by the 7th day. A pulse of 2 hr of light (LD 2:22) was enough to block the growth of the epimastigotes, an effect that was correlated with the expression of heat-shock proteins during the first 120 min of light exposure. Thereafter, protein synthesis decreased. Light exposure of metacyclic forms also inhibits the parasitization ability. It is known that light regulates the production of melatonin in most animal species studied, including other unicells such as dinoflagellates. T. cruzi contains and synthesizes melatonin and, thus, light-mediated events on the parasite biological cycle could be mediated by light-induced changes in melatonin produced by this unicell. Epimastigotes cultured under continuous darkness produce melatonin over the 24 hr period in a biphasic manner. Coinciding with the melatonin peaks, there was high melatonin efflux from the parasite into the medium. Epimastigotes cultured for 7 days under a LD cycle of 2:22 hr showed a 55% reduction in melatonin content, although this reduction seems not to be related with the growth delay. In fact, incubation of epimastigotes with exogenous melatonin (1 pM) did not affect parasite growth, but significantly reduced their transformation into metacyclic forms by the 7-8th day of treatment. Thus, the light-dependent decrease in melatonin production by the unicell may be responsible, at least partially, for the light-induce parasitization inhibition. Moreover, melatonin production is highest in the metacyclic forms. These data support a link between light, melatonin production and parasitization ability of T. cruzi and suggest the participation of the indoleamine in its biological cycle.

On pineal calcification and its relation to subjective sleep perception: a hypothesis-driven pilot study

We classified the degree of pineal calcification (DOC) into seven groups using cranial Computer Tomography (cCT) and then correlated pineal DOC to chronic subjective sleep-related disturbances as measured by a sleep questionnaire in 36 patients. Analysed by logistic regression models, age and sex were not, but higher pineal DOC was significantly associated with the presence of daytime tiredness (OR=4.15, 95% CI: 1.63, 10.54) and sleep disturbance (OR=1.74, 95% CI: 1.10, 2.74). This study provides initial confirmation of the hypothesis that the increasing degree of pineal calcification (DOC) might indicate a decrease of melatonin production, which consecutively might lead to a disturbed circadian rhythmicity in the sleep-wake cycle, with the principal symptom being daytime tiredness.

Autumnal timing of photoperiodic manipulation critical via melatonin to winter pelage development in mink

AbstractQuantitive collection of night-time urine every 2nd week was used to elucidate the temporal relationship between changes in melatonin production, weight gain, and priming of the winter pelage under natural light conditions and under a long photoperiod (18L: 6D) imposed at different times in four groups of female mink during autumn. In mink maintained outdoors under the natural photoperiod (group 1), melatonin excretion was 1·80 (s.d. 0·80) ng per night (no. = 3) at the beginning of September, thereafter it began to decrease slowly until November when it was only 0·62 (s.d. 0·32) ng per night. These mink had a normal autumn moult during the first half of October and the winter pelage was mature at the end of November. When mink maintained outdoors were transferred to 18L: 6D on 7 September (group 2), excretion of melatonin decreased promptly, autumn moult was disrupted and winter fur priming delayed. Long photoperiod after mid October (group 3), did not interfere with pelage maturation despite the decrease in melatonin production. Mink implanted with melatonin on 14 July (group 4) showed very high melatonin excretion in early September. In these animals the winter pelage growth was unaffected by the long-day conditions; the pelage matured in mid October. Body weight increased in mink of all groups during autumn. This increase levelled off or a weight loss (group 2) was seen along with the final hair maturation. Activation of hair follicles occurred during a 4 to 6 week period. According to these results, melatonin is the photoperiodic signal to autumnal weight increase and autumn moult but seems not to be necessary for later pelage growth and maturation.

Effects of pinealectomy and aging on the serum corticosterone circadian rhythm in rats.

Male Sprague-Dawley rats were housed in alternate light/dark conditions (light on, 7:00 AM, light off, 7:00 PM). Corticosterone was determined by radioimmunoassay from blood samples that were obtained by tail clip at 4-h intervals. Pinealectomized animals have shown significant increase of corticosterone levels at 7:00 AM, 11:00 AM and 7:00 PM in comparison with 2-month-old intact rats. There were no differences in serum corticosterone rhythm between 24-month-old and pinealectomized animals. Twelve-month-old rats have shown significant increase of corticosterone levels at 7:00 and 11:00 AM in comparison with 2-month-old animals. The age-associated increase of serum corticosterone and the similarity between serum corticosterone circadian rhythm in aged and pinealectomized animals suggest that an age-related decrease in melatonin production [Reiter et al., 1981] may contribute to age related changes of hypothalamic-pituitary adrenal axis regulation.

Pineal hydroxyindole-O-methyl transferase activity in the growing rat.

Pineal hydroxyindole-O-methyl transferase activity was measured in growing rats as an estimate of melatonin production during maturation. No significant HIOMT was found at 10 days or earlier. At 14 days HIOMT/gland was 40% of the 8- to 10-week value. Sympathetic innervation, changes in vascularization and metabolite concentrations were discussed as possible mechanisms initiating production of the enzyme. If total HIOMT activity was compared to body weight, a dramatic decrease in relative activity was observed to develop after a peak at 21 days. This was interpreted to suggest a relative decrease in melatonin production occurs after 21 days which might permit previously inhibited sexual maturation to develop. (Endocrinology 84: 1523, 1969)