The role of melatonin in the human fetus (review)

Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.     

Liberation of growth hormone and melanocyte-stimulating hormone in natural and melatonin-induced human sleep (author's transl)

As in the early period of night sleep, plasma levels of human growth (HGH) are markedly elevated in afternoon sleep in healthy young males. Melatonin (50 mg i.v.) induces marked secretion of HGH when sleep is prevented. It decreases latencies for sleep onset and deep sleep significantly, and markedly enhances peak secretion of HGH during slow-wave sleep. Plasma melanocyte-stimulating hormone (betal-MSH) levels were influenced neither by melatonin nor by sleep.     

Nucleotide sequences of the proA and proB genes of Treponema pallidum, the syphilis agent

Melatonin has previously been reported to influence cell differentiation and growth in a number of cell culture systems in vitro. In this paper, we describe the effects of high pharmacological and low physiological concentrations of melatonin on cell growth in rat pheochromocytoma cells (PC12 cells). Melatonin produced a biphasic response with respect to cell growth in PC12 cells. At low concentrations (1-10 nM) melatonin suppressed PC12 cell growth whereas at higher concentration (10 microM) it prevented cell death. Cultures treated with high concentrations of melatonin displayed an increase in cell number and a decreased release of lactic acid dehydrogenase (LDH) into the culture media, indicating that melatonin was enhancing cell survival as opposed to stimulating cell proliferation. Inhibition of cell death by high concentrations of melatonin was both time and concentration-dependent and did not require the continued presence of melatonin throughout the entire time of incubation. These studies suggest melatonin is preventing either apoptosis or programmed cell death. In contrast, concentrations of melatonin (1-10 nM) at or near the binding affinity for the nuclear receptor, RZRbeta, suppressed PC12 cell growth. At these concentrations, melatonin failed to inhibit forskolin-induced cAMP formation and process outgrowth as well as prevent forskolin suppression of cell growth. These data indicate that PC12 cells probably lack functionally active cell surface receptors for melatonin and suggest the interaction of melatonin with the nuclear receptor may be responsible for suppression of PC12 cell growth.     

Daytime melatonin administration in elderly good and poor sleepers: effects on core body temperature and sleep latency

Melatonin has been shown to have hypnotic and hypothermic effects in young adults and has been proposed as treatment for insomnia. However, the hypnotic and thermoregulatory effects of melatonin remain to be simultaneously investigated for aged good and poor sleepers. The aim of this study was to explore the short-term effects of exogenous oral daytime melatonin on core body temperature, sleep latency, and subjective vigor and affect in aged women. Twelve sleep maintenance insomniacs and 10 good sleeping postmenopausal female subjects [mean (SD) age = 65.2 (7.4) years] participated in a double-blind, crossover study in which they received a capsule containing either melatonin (5 mg) or a placebo at 1400 hours. Continuous core body temperature and hourly multiple sleep latency tests (MSLT) were collected from 1100-2030 hours. Self-reported estimates of global vigor (sleepiness) and affect were collected prior to each MSLT using visual analog scales. Comparison of good and poor sleepers failed to reveal any significant differences in core body temperature, sleep latency, or subjective vigor and affect. However, for both groups combined, melatonin administration [absolute postadministration mean (SEM) = 36.9 (0.05) degrees C] significantly lowered core body temperature compared with placebo [37.1 (0.05) degrees C]. Similarly, melatonin administration significantly reduced latency to stage 1 (SOL1) and stage 2 (SOL2) [absolute postadministration mean SOL1 = 20.1 (1.7) and SOL2 = 20.7 (1.6) minutes] compared with placebo [SOL1 = 24.3 (1.2) and SOL2 = 25.2 (1.1) minutes]. Treatment had no significant effect on either vigor or affect. Overall, our results suggest that although short-term exogenous oral daytime melatonin has significant hypothermic and hypnotic effects in aged women, the size of the effects is modest.     

Melatonin treatment for circadian rhythm sleep disorders

We administered 1-3 mg melatonin to 11 patients (eight men, three women, aged 16-46 years) with circadian rhythm sleep disorders; nine with delayed sleep phase syndrome and two with non-24-hour sleep-wake syndrome. Sleep logs were recorded throughout the study periods and actigraph and rectal temperature were monitored during treatment periods. Melatonin was administered 1-2 h before the desirable bedtime for expected phase-shifting, or 0.5-1 h before habitual bedtime for gradual advance expecting an hypnotic effect of the melatonin. Melatonin treatments were successful in 6/11 patients. Timing and dose of melatonin administration, together with its pharmacological properties for circadian rhythm sleep disorders, should be further studied.     

Transferrin receptor assay and zinc protoporphyrin as markers of iron-deficient erythropoiesis in end-stage renal disease patients

Nine girls with Rett syndrome (mean age, 10.1 years) were monitored 24 hours a day over a period of 10 weeks using wrist actigraphy. Baseline sleep-wake patterns were assessed for 1 week. Subsequently, patients underwent a 4-week melatonin treatment period in a double-blind, placebo-controlled, crossover protocol that employed a 1-week washout between treatment trials. Melatonin doses ranged from 2.5 to 7.5 mg, based upon individual body weight. Baseline sleep quality was poor compared with healthy children. At baseline the group demonstrated a low sleep efficiency (mean [+/- SE], 68.0+/-3.9%), long sleep-onset latency (42.1+/-12.0 minutes), and a short and fragmented total sleep time (7.5+/-0.3 hours; 15+/-2 awakenings per night). Melatonin significantly decreased sleep-onset latency to (mean +/- SE) 19.1+/-5.3 minutes (P<0.05) during the first 3 weeks of treatment. While the variability of individual responsiveness was high, melatonin appeared to improve total sleep time and sleep efficiency in the patients with the worse baseline sleep quality. Finally, a 4-week administration of melatonin appears to be a safe treatment as no adverse side effects were detected, yet long-term effects of chronic melatonin use in pediatric patients are unknown at this time.     

Melatonin: a popular hormone

This contribution makes an attempt to critically reassess the impressive career of melatonin (MEL) from a stepchild of hormone research to a best-seller of drug marketing. Melatonin, the hormone of the pineal gland, provides temporal information on diurnal and seasonal variation to the body and brain and it is involved in the synchronization of many different aspects of circadian systems to the light-dark cycle. In addition to these receptor-mediated functions, MEL may act as a modulator of intracellular signal transduction to enhance or suppress the responses of many different cells to other incoming signals. Melatonin is also a potent scavenger of reactive oxygen species and may thus protect cells and tissues against radical-mediated damages. The production of MEL declines with increasing age, and circulating MEL levels are affected by certain pharmacological or physiological manipulations. Animal and cell culture experiments suggest that MEL may have beneficial effects on certain aspects of aging and age-associated diseases. Of particular interest in this respect are reports on the influence of MEL on the brain and the immune system. The sole sufficiently investigated indication in humans is the treatment of certain sleep disorders from the group of sleep-wake-rhythm disturbances. These manifest themselves by sleep time of the day, i.e. in shift workers, after flights across time zones and in some aged persons. Clinical studies need to be performed in order to identify possible side effects of long-term MEL treatment. Serious concerns are raised about the use of uncontrolled, impure, or partially degraded MEL preparations.     

Melatonin, its receptors, and relationships with biological rhythm disorders

Melatonin is a neurohormone produced during the night by the pineal gland. Its secretion is regulated by circadian and seasonal variations in daylength, transmitted via visual projections to the suprachiasmatic nucleus which functions as a circadian clock in mammals. Melatonin has been proposed to act as an internal synchronizer of circadian rhythms generated at different levels of the organism. The chronobiotic effects of melatonin in humans have been mainly studied in circadian rhythm sleep disorders related to jet lag, shift work, blindness or aging. Alterations of the melatonin profiles have also been reported in other biological rhythm disorders.     

Immunological requirements for a subunit vaccine against tuberculosis

Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free-running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleep-wake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase-shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.     

Chromosome bands 3p14.2, 9p21, and 13q14 are frequently deleted in roentgenographically occult bronchogenic squamous cell carcinoma of the lung

This study was undertaken to determine whether melatonin (N-acetyl-5 methoxytryptamine) is effective in helping emergency medical services (EMS) personnel who work rotating night shifts reset their biological clocks and minimize circadian rhythm disruption. A double-blinded, randomized, crossover study was performed using 22 volunteers. Participants were working a span of consecutive night (2300 to 0700 hours) shifts and received either a melatonin capsule (6 mg) or placebo to be taken before each of the consecutive day sleeps. Each participant completed a total of 4 spans of consecutive night shifts (2 melatonin, 2 placebo). Collected data included daily sleep diaries, quantification of alcohol/caffeine consumed, and drug side effects. Assessment of sleep quality, posttreatment mood, and workload ratings were measured daily by 10-cm visual analog scale (VAS). Analysis of sleep diaries found no significant difference (P > .05) between the two treatments with respect to mean sleep latency, duration, and efficiency, and subjectively rated sleep quality. Similarly, no significant benefits were noted between the median VAS scores for daily posttreatment mood or workload ratings. Adverse effects were rare; one patient taking melatonin reported a prolonged sedative effect. Despite recent interest in melatonin for treatment of circadian-based sleep disorders, no clinical benefits were noted in EMS personnel working rotating night shifts.     

The effect of melatonin as anti-convulsant and neuron protector

INTRODUCTION: Melatonin is the principal hormone secreted by the pineal gland. In human beings the pineal gland is found on the posterior aspect of the midbrain. Melatonin is synthesized from tryptophan following a circadian rhythm, with low levels during the day and high levels during the night. It regulates many biological processes in relation to the cycles of light and darkness. DEVELOPMENT: Its first known function was that of inducing sleep. In experimental animals its effect as a depressor of the central nervous system and its anti-convulsive action have been shown. Few studies have been done in human beings, although there is some evidence of its beneficial effect in epileptic patients, improving both the frequency of the crises and the EEG tracing. In our experience we gave melatonin to a girl with severe myoclonic epilepsy which did not respond to usual treatment, obtaining improvement in both the number of crises daily and in psycho-motor development. Several possible modes of action have been described for melatonin; increase in Gabaergic transmission at a cerebral level, where GABA is the main inhibitory neurotransmitter; interaction with benzodiazepinic cerebral receptors; it may owe its effect to the activity of its metabolites, particularly kinurenic and kinurenic acid; it may induce hormone changes in the organism. Recent studies show the marked anti-oxidant activity of melatonin. Its considerable capacity to accept free radicles resulting from biological processes has been shown and it thus acts as a cell protector. CONCLUSIONS: It seems reasonable to assume that melatonin has anticonvulsant and neuroprotector properties. Further study may define its pharmacological usefulness in these disorders.     

The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement

The present investigation used a placebo-controlled, double-blind, crossover design to assess the sleep-promoting effect of three melatonin replacement delivery strategies in a group of patients with age-related sleep-maintenance insomnia. Subjects alternated between treatment and "washout" conditions in 2-week trials. The specific treatment strategies for a high physiological dose (0.5 mg) of melatonin were: (1) EARLY: An immediate-release dose taken 30 minutes before bedtime; (2) CONTINUOUS: A controlled-release dose taken 30 minutes before bedtime; (3) LATE: An immediate-release dose taken 4 hours after bedtime. The EARLY and LATE treatments yielded significant and unambiguous reductions in core body temperature. All three melatonin treatments shortened latencies to persistent sleep, demonstrating that high physiological doses of melatonin can promote sleep in this population. Despite this effect on sleep latency, however, melatonin was not effective in sustaining sleep. No treatment improved total sleep time, sleep efficiency, or wake after sleep onset. Likewise, melatonin did not improve subjective self-reports of nighttime sleep and daytime alertness. Correlational analyses comparing sleep in the placebo condition with melatonin production revealed that melatonin levels were not correlated with sleep. Furthermore, low melatonin producers were not preferentially responsive to melatonin replacement. Total sleep time and sleep efficiency were correlated with the timing of the endogenous melatonin rhythm, and particularly with the phase-relationship between habitual bedtime and the phase of the circadian timing system.     

Does histamine stimulate trigeminal nasal afferents?

The pineal hormone melatonin is secreted with a marked circadian rhythm. Normally, maximum production occurs during the dark phase of the day and the duration of secretion reflects the duration of the night. The changing profile of secretion as a function of daylength conveys photoperiodic information for the organization of seasonal rhythms in mammals. The role of melatonin in mammalian circadian physiology is less clear. However, exogenous melatonin can phase shift, and in some cases entrain, circadian rhythms in rodents and humans. It can also lower body temperature and induce transient sleepiness. These properties indicate that melatonin can be used therapeutically in circadian rhythm disorder. Successful outcomes have been reported, for example in jet lag and shift work, and with cyclic sleep disorder of some blind subjects. Melatonin receptors of several subtypes are found in the brain, the retina, the pituitary and elsewhere. They are currently under intense investigation. Melatonin agonists and antagonists are under development.     

Disorders of the sleep-wake cycle in adults

Adults have an intrinsic body clock which regulates a complex series of rhythms including sleep and wakefulness, fatigue and cognitive ability. This endogenous clock naturally runs more slowly than the solar day and is entrained to a 24-h rhythm primarily by the alternation of light and darkness. Jet lag, shift-work sleep disorder, and some of the chronic insomnias are caused by a temporal discrepancy of the body clock relative to the surrounding environment and social network. The underlying mechanisms and general management are described. Both bright light and melatonin therapy have potential in the management of these disorders. Traditionally, bright light therapy has been used to alleviate the depression associated with seasonal affective disorder. Melatonin has received much ill-formed publicity, it being claimed that it is a panacea and an 'antiageing' treatment. Both of these treatment approaches are reviewed.     

Ketoconazole and other imidazole derivatives are potent inhibitors of peroxisomal phytanic acid alpha-oxidation

Twelve young adults were treated with either melatonin, 3 mg or 6 mg, or placebo, at two different times before an early evening nap (18.00-20.00 h) according to a balanced double-blind Latin square design. Polysomnographic monitoring revealed that both dosages of melatonin significantly shortened sleep latency and increased total sleep time in comparison to placebo, irrespective of the time of administration. Subjects also tended to assess their sleep as 'deeper' after melatonin treatment. Based on previous data and the present results, it was concluded that exogenous melatonin exerts hypnotic effects only when circulating levels of endogenous melatonin are low.     

On the antioxidant activity of melatonin

Melatonin has been widely reported to be an effective antioxidant. Studies of its ability to inhibit the autoxidation of lipids in homogeneous solution and in model heterogeneous systems show that melatonin is not a peroxyl radical trapping antioxidant. In contrast, melatonin can inhibit metal ion-catalyzed oxidation processes.     

Melatonin in light treatment of patients with seasonal and nonseasonal depression

Melatonin as a marker of circadian rhythm and the effect of bright light on melatonin were studied in 63 depressed patients, 42 with a seasonal pattern and 21 with a nonseasonal pattern. The patients were matched for age, time of treatment and severity of depression. Before light treatment, blood was sampled for melatonin and depression was clinically rated with the Comprehensive Psychopathological Rating Scale and Hamilton Depression Rating Scale. Two hours of light treatment, 350 cd/m2, was given daily for 10 days 0600 to 0800 or 1800 to 2000. Of the 42 patients with seasonal depression, 26 were treated with morning light and, 16 with evening light. The melatonin amplitude was significantly decreased by light, and the melatonin phase position was advanced by morning light and delayed by evening light. All patients except for 3 in each group changed in the expected direction. Although the patients with seasonal pattern had a more favorable outcome than patients with nonseasonal pattern, there was no difference in therapeutic outcome related to the baseline melatonin phase position. The hypothesis that the short term clinical effects of light therapy either in the morning or evening are related to pretreatment melatonin levels or alteration of melatonin amplitude or phase position was not supported in the study. There was also no significant difference between the seasonal and nonseasonal patients related to the degree of light suppression of melatonin and the rebound effect of serum melatonin levels following bright level exposure between 2200 and 2300 before regular light treatment.