The pineal gland transduces light–dark cycles into body rhythms by secretion of melatonin, an endogenous indoleamine derived from tryptophan, the concentrations of which in plasma and cerebrospinal fluid are up to 100 times higher at night than in the daytime. This exerts its effects through transmembrane, G-protein coupled receptors (MT1 and MT2) and nuclear receptors in the pituitary gland and hypothalamus.
The natural period of the human circadian system is on average 24.2 to 24.3 h, and the principal resetting agent is light. Exogenous melatonin can shift the timing of the internal clock to earlier and later times, and synchronize a free-running clock that is not properly entrained to the 24-h day, hence it may have a therapeutic role for disorders of sleep rhythm including jet lag, in shift workers, and in blind people.
The mammalian pineal gland is a secretory organ. Whereas in fish and amphibians it is directly photoreceptive, in reptiles and birds it has a mixed photoreceptor and secretory function. Although an endocrine function was considered for many years, this was only given credibility in 1958 by the pioneering work of Lerner, who isolated a small molecule from bovine pineal glands that he named melatonin because it caused blanching of melanophores in amphibian skin. The primary function of the pineal gland in all species studied to date is to transduce information concerning light–dark cycles to body physiology, particularly for the organization of body rhythms, via the secretion of its major hormone melatonin. In some birds and lower vertebrates it serves as a rhythm generating system, or biological clock. In mammals, it is concerned with the coordination of rhythm physiology without having the capacity to act as a rhythm generator. In humans, the gland has been known since antiquity. Many questions remain unanswered about the function of the human pineal gland, but its secretion of the chronobiotic molecule melatonin has prompted enormous interest in the fields of travel medicine, neurophysiology, and endocrine research.
The pineal gland
The pineal gland is less than 1 cm in its longest diameter and weighs less than 0.2 g; it lies above the posterior aspect of the third cerebral ventricle. The major cellular component of the normal mammalian pineal gland, the pinealocyte, is believed to have evolved from truly photoreceptive cells in lower vertebrates and structural remnants of the outer segments of photoreceptor cells are reported in higher vertebrates.
It also contains neuroglial components, principally of astrocytic type, which occasionally become malignant. Human pineal tissue calcifies with age but this does not necessarily diminish its secretory activity. The pineal gland is considered to reside outside the functional blood–brain barrier.
Tumours of the pineal region in children are frequently associated with abnormal pubertal development. Much evidence suggests that precocious puberty in such cases is due to the production of human chorionic gonadotrophin (β-hCG) by germ cell tumours of the pineal gland. Delayed puberty has also been associated with pineal tumours. Pineal tumours are heterogeneous and may arise from germ cells (teratomas, germinomas, choriocarcinomas, endodermal sinus tumours, mixed germ cell tumours), pineal parenchymal cells (pineoblastoma and pineocytoma), and the supporting stroma (gliomas). Classification of pineal parenchymal tumours is complicated by the presence of mixed pineocytoma-pineoblastoma types, some with intermediate differentiation. A new classification has been proposed recently, based on histological features, which is closely related to patient survival.
Treatment of pineal tumours by surgical excision or radiation appears to suppress melatonin secretion leading to sleeping difficulties; melatonin replacement therapy has been reported to benefit such patients with defective melatonin release.
Melatonin, like serotonin, is an endogenous indoleamine derived from tryptophan. The first step in indoleamine synthesis is the 5-hydroxylation of tryptophan by tryptophan hydroxylase—an enzyme with requirements for dioxygen, iron, and tetrahydrobiopterin. The enzyme arylalkylamine N-acetyltransferase, regulated by the sympathetic transmitter noradrenaline, appears to be the rate-limiting step in melatonin synthesis. The enzyme is localized principally in the pineal gland but also in the retina, the skin, within specific cells in the upper gastrointestinal tract, and with minor expression in bone marrow, lymphocytes, and certain epithelia.
Melatonin binds to specific receptors including the seven transmembrane G-protein-coupled MT1 and MT2 receptors, as well as nuclear receptors RZR/ROR orphan receptor family and downstream transcription factors that are associated with melatonin signalling. A third site, named MT3, is the enzyme quinone reductase type 2, which melatonin and its congeners bind and inhibit with high affinity. This action is shared with the natural product reservatrol, and indicates a potential application for melatonin as an antioxidant in pleiotropic detoxification processes, including the treatment and prevention of cancer.
Membrane G-protein receptors for melatonin are principally expressed in the nervous system but they have been found in numerous other locations. The nuclear transcription factor appears to be expressed in the periphery. There is emerging evidence that a nuclear signalling pathway with ligand-induced control of target gene transcription, mediates some functions of melatonin. The MT2 melatonin receptors have been implicated in mediating learning and memory in experimental mice, and there is also evidence that their activation alters electrophysiological phenomena associated with memory, such as long-term potentiation in neurones; loss of these receptors also decreases hippocampal synaptic plasticity. Melatonin has been reported to control expression of the 5-lipoxygenase gene; the cognate enzyme is not implicated in circadian rhythms but is expressed in myeloid cells and participates in allergic and inflammatory reactions.
Melatonin (formal chemical name, N-acetyl-5-methoxytryptamine) has been found within membrane-bound bodies in pinealocytes. In experimental animals these show light-dependent morphological changes associated with melatonin secretion under altered environmental light conditions. The pineal gland is the principal source of circulating melatonin in mammals, indeed pinealectomy leads to undetectable melatonin concentrations in blood. Synthesis elsewhere, e.g. in the retina, seems to change local concentrations only. Melatonin appears to exert its main effects through MT1 receptors in the infundibular part of the pituitary gland, through MT1 and MT2 receptors in the central biological rhythm generating system of the brain (the suprachiasmatic nuclei of the hypothalamus) and other regions of the hypothalamus that modulate the secretion of pituitary hormones, and that influence core body temperature and other functions.
The role of melatonin and the pineal gland in photoperiodism
In all species studied to date, melatonin is normally synthesized and secreted at night. This rhythm is circadian in nature, i.e. it is endogenously driven by the activity of the suprachiasmatic nuclei. Exposure to light influences the secretion of melatonin, and melatonin release is suppressed particularly by blue light (wavelength 460 to 480 nm) in a manner that increases with length of exposure and intensity of luminance. The length of the day (photoperiod) strongly influences melatonin secretion: the longer the night, the longer the duration of secretion. The long-standing tendency of humans to alter their light environment since the discovery of fire renders this relationship hard to show, except under conditions in which the duration of total darkness is altered. However, the seasonal physiology of many animals is regulated by the photoperiod and changing duration of melatonin secretion is critical for inducing several specific seasonal responses (e.g. reproduction, coat growth). Exogenous melatonin can be used as the photoperiodic signal and has been commercialized to permit regulation of the breeding season in useful domesticated species such as sheep, goats, and mink. In animals and humans there is evidence that an alternative photoreceptive system, which is independent of retinal rods or cones, utilizes a distinct photopigment (melanopsin), and serves to mediate the physiological (but nonvisual) effects of light. This photoreceptive apparatus also appears to respond preferentially to short-wavelength light.
Melatonin and circadian rhythms
Rhythmic melatonin secretion leads to concentrations in the plasma or cerebrospinal fluid that are up to 100 times greater at night than in the daytime, with very large inter-individual but consistent intra-individual variation. These fluctuations are used to assess the timing of the human biological clock: the secretion profile of melatonin provides, in the periphery, the most accurate and sensitive index of the activity of the suprachiasmatic nuclei. In the diagnosis of circadian rhythm disorders, blood and salivary determinations of melatonin are useful, and may be combined with measures of the principal metabolite, 6-sulphatoxymelatonin (aMT6s), in urine. Maximum concentrations are observed in childhood and melatonin concentrations decline thereafter with age. The role of endogenous melatonin in humans is unclear. Peak night-time concentrations in the plasma are closely associated with the nadirs of core temperature, alertness, performance, and metabolism. The profile of secretion is strongly associated with increasing sleep propensity, and sleep is longer and of better quality when taken in phase with peak melatonin secretion (and with the nadir in core temperature). Melatonin is able to reinforce night-time physiology, e.g. in contributing to the propensity to sleep and the decreased nocturnal core temperature. Melatonin appears to play a supporting role in the influence of the light–dark cycle for synchronizing the circadian rhythms to the 24-h day. In the absence of time cures (free-running) the natural period of the human circadian system is on average 24.2 to 24.3 h and the principal resetting agent is light.
Exogenous melatonin clearly shifts the timing of the internal clock to earlier and later times and synchronizes a free-running clock that is incompletely entrained to the 24-h day. Several syndromes associated with long-term insomnia in humans appear to result from slower, faster, or free-running sleep–wake cycles. These include the non-24-h sleep–wake cycle of blind people (with no light perception at all), delayed sleep-phase syndrome, advanced sleep-phase syndrome, and irregular sleep–wake cycles. In addition, abrupt shifts of time cues such as are found in shift work and jet lag lead to circadian asynchrony with resultant difficulties affecting sleep, fatigue, and alertness, and with possible long-term health consequences. In these circumstances, melatonin has actual and potential therapeutic benefit as a result of its chronobiotic activity. Timed exposure to light at high luminance may improve disorders of the circadian rhythm that affect sleep. However, in many circumstances, the correct timing and intensity of light exposure (and avoidance) is hard to achieve. Notably, blind people cannot have access to light treatment and for the non 24-h sleep–wake disorder of the blind, melatonin, correctly timed, is the treatment of choice.
Pharmaceutical use of melatonin
In addition to its use in blind circadian rhythm disorder, melatonin has proved successful in normalizing delayed sleep timing in delayed sleep-phase syndrome, stabilizing irregular sleep–wake cycles in neurologically disabled children, and in treating the symptoms of jet lag. Melatonin treatment has also been suggested as a means to improve sleep in night-shift workers, in older individuals with insomnia (for which a registered preparation is available on prescription), and in patients with pineal tumours.
Many studies have been carried out to investigate the efficacy of melatonin as a chronobiotic agent for the alleviation of symptoms of jet lag. The results of one meta-analysis to assess the effectiveness of oral melatonin, taken in different dosing regimens for alleviating jet lag after travel across several time zones, showed that the agent is effective in preventing or reducing jet lag and that its short-term use appears to be safe on an occasional basis. Side-effect reporting has been low, except in patients with epilepsy or those who are taking warfarin in whom convulsant effects or increased bleeding, respectively, have been reported. Melatonin may theoretically influence reproductive development in children and reduce sexual activity, if overused, in adults. No evidence of these effects has yet been reported and the newly introduced prolonged-release agent has been found to be effective and safe in mitigating the disordered sleep of children with neurodevelopmental diseases. Recent studies of jet lag tend to recommend the use of preflight timed melatonin (0.5 mg) to initiate an advance or delay as required of the circadian system, and to use postflight higher doses (3–5 mg) again timed correctly, to reinforce the shift in timing and to acutely induce sleepiness.
Another meta-analysis was less positive. Melatonin is nevertheless recommended as a treatment for jet lag, delayed sleep-phase syndrome, and irregular sleep–wake cycles by the American Academy of Sleep Medicine. Its use in shift work has proved inconsistent, not all studies have been successful regarding its use in insomnia in older people, and there is insufficient data to evaluate properly its effect in pineal tumours. The timing of treatment with respect to internal circadian timing is very important and judging such timing is often not simple, especially in shift work and jet lag.
Melatonin is freely available in the United States of America, but only recently has a melatonin formulation been registered for use in insomnia in older people in Europe and a melatonin agonist (ramelteon) has been approved by the United States Food and Drug Administration, again for insomnia. Melatonin is available as a prolonged-release prescription drug (Circadin) and is approved by the European Medicines Agency as a single treatment a dose of 2 mg for patients aged at least 55 years, for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor sleep quality. Moreover, the findings of a randomized controlled clinical trial showed that melatonin had beneficial effects on delirium in geriatric patients. Other formulations and derivatives of melatonin are under development and a distinct agonist (agomelatine) is registered for use in major depression; the potential therapeutic effect is postulated to be mediated by an antagonist effect on the serotonin receptor, 5HT2C.
In summary, there is evidence indicating that oral ingestion of melatonin may be beneficial when used occasionally after transmeridian flights that would induce daytime fatigue and sleep disturbance associated with gastrointestinal complaints, weakness, malaise, loss of mental efficiency, and other symptoms that characterize jet lag. Clearly, since the drug is not as yet licensed in all countries, routine pharmaceutical quality control must be established and the use and safety of melatonin in pregnancy has not yet been completely established. Given that prion-related diseases result from the ingestion or injection of material derived from brain or other animal tissues, only pure biosynthetic melatonin should be considered for human use. Melatonin derived from bovine pineal or other biological sources should be avoided.
Recently, partial deficiency of melatonin, induced by excess nocturnal exposure to light, has been suggested to explain an increased risk of cancer in shift workers. It seems more likely that a general disturbance of the circadian system rather than selective suppression of melatonin provides the mechanistic explanation for the increased frequency of cancers in this group. Melatonin also has antioxidant properties and is widely taken in certain communities, particularly in the United States of America, where it is claimed to provide unspecified protection against ageing, degenerative diseases, cancer, and impaired immune function, as well as reproductive and psychiatric illness. Nonetheless, it should be acknowledged that, as in other vertebrates, melatonin has diverse physiological actions in humans, many of which are not fully understood. At present, the principal authenticated indication for exogenous melatonin is for the control of sleep disorders and the treatment of symptoms associated with jet lag, rather than the many conditions for which our scientific understanding of its proposed benefits is as yet incomplete.
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