Elsevier

Sleep Medicine Reviews

Volume 9, Issue 1, February 2005, Pages 11-24
Sleep Medicine Reviews

Physiological review
The basic physiology and pathophysiology of melatonin

https://doi.org/10.1016/j.smrv.2004.08.001Get rights and content

Summary

Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite.

The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body physiology. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas in field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlative observations, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions could depend on the melatonin signal, for instance immune, antioxidative defences, hemostasis and glucose regulation.

Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed. The resulting alteration could increase predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder.

Introduction

Melatonin was isolated and characterised from the bovine pineal by the dermatologist Aaron Lerner as early as 1958.1 It is the main hormone secreted by the pineal gland. Secondary sources are retina, gut, skin, platelets, bone marrow and probably other structures, whose systemic contribution is insignificant.2, 3, 4, 5, 6, 7 This compound of indole structure (N-acetyl-5-methoxytryptamine) is synthesized from serotonin. This aspect and the fact that it lightens the frog skin by contracting melanophores led to the naming of this molecule as Melatonin (i.e. melanophore-contracting hormone; greek: μελαs=black; τoυos=tension, in the sense of contraction).

Although melatonin has extensively been detected in the animal kingdom, recently this compound has also been found in different structures of higher plants (leaves, fruits, seeds). The levels are too low, however, to provide a significant melatonin supply. Also, melatonin is present in lower phyla, including bacteria.8 The ubiquitous molecule melatonin is probably one of the first compounds which appeared on earth to coordinate some basic events of life.

The main physiological functions of melatonin are related to hormonal properties, although it may also exhibit autocrine or paracrine properties, for example in the retina or the gut.9 The pineal gland was initially shown to be an active neuroendocrine transducer of environmental information in animals, especially in photoperiodic species. For many years, the data had been extrapolated to humans. Today, some understanding of the role of melatonin in human physiology and disease has emerged, but many functions and effects of melatonin remain unresolved. This review will focus on data about melatonin in humans, as an introduction to the following chapters.

Section snippets

Biosynthesis

Melatonin is synthesized from tryptophan taken up from the circulation and transformed to serotonin; serotonin is converted into melatonin by a two-step process involving the sequential activities of two enzymes, serotonin-N-acetyl transferase (NAT), which is the limiting enzyme for the synthesis of melatonin, and hydroxyindole-O-methyl transferase (HIOMT).10 The mRNAs encoding these enzymes are expressed with a day/night rhythm in the pineal (for review, see Ref. 11). The synthesis of

The regulating system of the melatonin secretion

The melatonin rhythm is generated by an endogenous clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, like other circadian rhythms in mammals (drinking and feeding, sleep–wake cycle, temperature, cortisol or corticosterone, etc.). Results have been reported in animals, mainly in rodents and monkeys, and extended to humans.32, 33 Pathophysiological observations in patients provide confirmation.34

The light/dark cycle is the main Zeitgeber of the regulating system of melatonin

Functions of melatonin

Melatonin secretion is related to the duration of darkness. The main function of melatonin is to mediate dark signals, with possible implications in the control of circadian rhythmicity and seasonality. The melatonin message, which is generated at night, is differently read in nocturnal animals and humans. In that sense, melatonin does not appear as the universal hormone of sleep. The role of melatonin for the seasonal changes in physiology and behaviour of various photoperiodic species has

Sites and mechanisms of action of melatonin

Melatonin displays pleiotropic physiological functions. Although it is accepted that melatonin mainly acts via specific receptors in cell membranes, the interaction of melatonin with nuclear receptors and intracellular proteins, such as calmodulin or tubulin-associated proteins, as well as its direct or indirect antioxidant effects could explain many general functions of this hormone.76

Immunity

Currently accumulated evidence shows that the pineal is able to play an important role in modulating the immune response (for review, see Ref. 87) since functional (constant light condition) and pharmacological inhibition (propranolol administration) of melatonin synthesis in mice is associated with suppressed humoral and cellular immunological responses. Melatonin can interact with specific membrane binding sites in cells from lymphoid organs. The KD value of these binding sites is in the 0.1–1

Cancer

At present, the validity of melatonin as an oncostatic agent seems well established and the antitumor mechanisms of melatonin have been identified: these include its antiproliferative actions, immunostimulatory effects on host anticancer defences and antioxidant activity. Isolated reports of tumor growth stimulation do however exist, especially if melatonin is administered in the morning, indicating a circadian-stage dependency of antitumor action.91 In the recent past, a limited number of

Melatonin rhythm, a marker of the circadian clock

Melatonin can be considered as a reliable output (the hour-hand) of the endogenous clock. There is a close relationship between the plasma melatonin peak and minimum core temperature, including entrained conditions and constant routine protocols. In contrast to the temperature rhythm, the melatonin rhythm is not very sensitive to masking effects, except the one exerted by light. Consequently, Lewy and Sack recommend to evaluate the onset of the plasma melatonin profile under dim light (50 lux,

Pathophysiology of melatonin secretion

Alterations of 24-h melatonin profiles can be associated with a large variety of pathological situations. Some of the changes may have a pathogenetic relationship with a major disease process. Also, since an abnormality at any level of the regulating system unspecifically modifies melatonin secretion, other changes are more a consequence of the existing disorder. In both situations, the resulting alteration of melatonin secretion could favour predisposition to disease, add to the severity of

Cardiovascular diseases

A preliminary study showed a decreased nocturnal plasma melatonin in coronary heart disease;117 this finding based on a one-point blood sample was confirmed by further studies. Whether a decreased melatonin level may be a predisposing factor or whether the occurrence of the disease decreases melatonin synthesis remains to be determined. In addition, a similar observation was reported during acute myocardial infarction.118 The presence of melatonin as an antioxidant could be beneficial to

Concluding remarks

Although melatonin was discovered more than 40 years ago, the data on the physiological role of this hormone in humans are scant. Continuous progress in our knowledge reinforces, however, the idea that melatonin could play the role of a universal endogenous synchronizer, even for physiological functions whose circadian organization does not appear of paramount importance at first sight. The influence of melatonin on hemostasis, glucose homeostasis, phosphocalcic metabolism and blood pressure

References* (123)

  • J. Herrera et al.

    Melatonin prevents oxidative stress resulting from iron and erythropoietin administration

    Am J Kidney Dis

    (2001)
  • S. Deacon et al.

    Posture influences melatonin concentrations in plasma and saliva in humans

    Neurosci Lett

    (1994)
  • Y. Touitou et al.

    Decreased nocturnal plasma melatonin peak in patients with a functional alteration of the retina in relation with uveitis

    Neurosci Lett

    (1986)
  • H. De Leersnyder et al.

    Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome

    J Pediatr

    (2001)
  • A.B. Lerner et al.

    Isolation of melatonin, the pineal gland factor that lightens melanocytes

    J Am Chem Soc

    (1958)
  • C. Liu et al.

    Localization of Aa-nat mRNA in the rat retina by fluorescence in situ hybridization and laser capture microdissection

    Cell Tissue Res

    (2004)
  • G.A. Bubenik

    Gastrointestinal melatonin: localization, function, and clinical relevance

    Dig Dis Sci

    (2002)
  • A. Slominski et al.

    Serotoninergic and melatoninergic systems are fully expressed in human skin

    Fed Am Soc Eur Biol J

    (2002)
  • D.P. Cardinali et al.

    Melatonin effects on bone: experimental facts and clinical perspectives

    J Pineal Res

    (2003)
  • J. Stefulj et al.

    Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat

    J Pineal Res

    (2001)
  • R. Hardeland

    Melatonin and 5 methoxytryptamine in non-metazoans

    Reprod Nutr Dev

    (1999)
  • D.X. Tan et al.

    Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin

    J Pineal Res

    (2003)
  • M. Bernard et al.

    Melatonin synthesis pathway: circadian regulation of the genes encoding the key enzymes in the chicken pineal gland and retina

    Reprod Nutr Dev

    (1999)
  • J.H. Stehle et al.

    Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland

    Nature

    (1993)
  • R.C. Zimmermann et al.

    Effects of acute tryptophan depletion on nocturnal melatonin secretion in humans

    J Clin Endocrinol Metab

    (1993)
  • A. Munoz-Hoyos et al.

    Pineal response after pyridoxine test in children

    J Neural Transm Gen Sect

    (1996)
  • R. Luboshitzky et al.

    The effect of pyridoxine administration on melatonin secretion in normal men

    Neuroendocrinol Lett

    (2002)
  • D.J. Skene et al.

    Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans

    Br J Clin Pharmacol

    (1994)
  • W.M. Pardridge et al.

    Transport of albumin-bound melatonin through the blood-brain barrier

    J Neurochem

    (1980)
  • R.J. Reiter

    Pineal melatonin: cell biology of its synthesis and of its physiological interactions

    Endocr Rev

    (1991)
  • B. Claustrat et al.

    A once-repeated study of nocturnal plasma melatonin patterns and sleep recordings in six normal young men

    J Pineal Res

    (1986)
  • M. Follenius et al.

    Distinct modes of melatonin secretion in normal men

    J Pineal Res

    (1995)
  • I. Trinchard-Lugan et al.

    The short term secretion pattern of human serum melatonin indicates apulsatile hormone release

    J Clin Endocrinol Metab

    (1989)
  • M. Geoffriau et al.

    Estimation of frequently sampled nocturnal melatonin production in humans by deconvolution analysis: evidence for episodic or ultradian secretion

    J Pineal Res

    (1999)
  • D. Morin et al.

    Melatonin high-affinity binding to alpha-1-acid glycoprotein in human serum

    Pharmacology

    (1997)
  • D. Le Bars et al.

    PET and plasma pharmacokinetic studies after bolus intravenous administration of 11C Melatonin in humans

    Nucl Med Biol

    (1991)
  • P.L. Francis et al.

    Gas chromatographic-mass spectrometric assay for 6-hydroxymelatonin sulfate and 6-hydroxymelatonin glucuronide in urine

    Clin Chem

    (1987)
  • J. Arendt et al.

    Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-h rhythm with Atenolol

    J Clin Endocrinol Metab

    (1985)
  • H. Iguchi et al.

    Melatonin serum levels and metabolic clearance rate in patients with liver cirrhosis

    J Clin Endocrinol Metab

    (1982)
  • P. Ludemann et al.

    Clearance of melatonin and 6-sulfatoxymelatonin by hemodialysis in patients with end-stage renal disease

    J Pineal Res

    (2001)
  • D.M. Edgar et al.

    Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation

    J Neurosci

    (1993)
  • R.Y. Moore

    The fourth C.U. Ariens Kappers lecture. The organization of the human circadian timing system

    Prog Brain Res

    (1992)
  • R.A. Cohen et al.

    Disruption of human circadian and cognitive regulation following a discrete hypothalamic lesion: a case study

    Neurology

    (1991)
  • A.J. Lewy et al.

    Light suppresses melatonin secretion in humans

    Science

    (1980)
  • C.J. Bokjowski et al.

    Suppression of nocturnal plasma melatonin and 6-sulphatoxymelatonin by bright and dim light in man

    Horm Metab Res

    (1987)
  • G.C. Brainard et al.

    Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor

    J Neurosci

    (2001)
  • K. Thapan et al.

    An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans

    J Physiol

    (2001)
  • F.L. Ruberg et al.

    Melatonin regulation in humans with color vision deficiencies

    J Clin Endocr Metab

    (1996)
  • D.M. Berson et al.

    Phototransduction by retinal ganglion cells that set the circadian clock

    Science

    (2002)
  • G.R. Warman et al.

    Circadian neuroendocrine physiology and electromagnetic field studies: precautions and complexities

    Radiat Prot Dosimetry

    (2003)
  • Cited by (0)

    *

    The most important references are denoted by an asterisk.

    View full text