Age-related changes in melatonin levels in humans and its potential consequences for sleep disorders

doi:10.1016/S0531-5565(98)00054-0

Experimental Gerontology

Volume 33, Issues 7–8, November–December 1998, Pages 759-772

https://doi.org/10.1016/S0531-5565(98)00054-0 Get rights and content

Abstract

—Prior to three months of age there is little melatonin (MLT) secretion in humans. MLT production then commences, becomes circadian, and reaches its highest nocturnal blood levels between the ages of one to three years. During the remainder of childhood, nocturnal peak levels drop progressively by 80%. In adults, these levels show an additional drop of some 10%, mainly during senescence. The large drop in serum MLT during childhood is probably the result of the increase in size of the human body, despite a constant MLT production after infancy. The additional decline of MLT with higher age may be due to a yet unidentified physiological mechanism accompanying senescence. The biological significance of these MLT alterations remains unknown. Since the discovery of MLT, an immediate sedative action of this hormone has been known. A number of recent studies have demonstrated that MLT indeed exerts a sleep-promoting action by accelerating sleep initiation, improving sleep maintenance, and marginally altering sleep architecture. The potential of MLT in the treatment of insomnia is being explored, and the results are promising. Although in most of these studies pharmacological dosages of MLT have been used, preliminary data suggest that similar effects can also be achieved by physiological hormone concentrations. The latter observation raises the question of whether MLT might be involved in the physiological control of sleep.

Introduction

Although the physiological function of most endocrine glands was determined by the beginning of the century, the function of the pineal gland, however, was not deciphered until a decade ago, and then only for seasonal breeders. In these species the pineal acts as a neuroendocrine transducer, transmitting information about the existing season to an animal’s endocrine zeitgeber (Tamarkin et al., 1985). For humans, a nonseasonal species, the physiological significance of the pineal remains obscure. Nevertheless, much information has been gathered on the natural secretion pattern of melatonin (MLT), the pineal’s principal product, and its alteration under different physiological and pathological conditions. The following article reviews our knowledge on age-related changes in human MLT secretion and on MLT’s potential involvement in the physiological sleeping mechanism.

Section snippets

The secretion pattern of melatonin in humans

It is well established that in humans, as in other species, MLT is secreted in a circadian pattern with low levels during the day and high concentrations at night. However, the amount of MLT secreted and, consequently, the amplitude of its circadian pattern, may vary considerably among adults. Approximately 1–5% of the population have very low MLT levels, with no evidence of circadian release Waldhauser and Dietzel 1985, Arendt 1988. Why some adults produce no MLT and its consequence is

Age-related changes in melatonin secretion

Although there are no data available on intrauterine MLT production by the human fetal pineal gland, evidence from animal studies Yellon and Longo 1988, Mcmillen and Nowak 1989 and histological findings (Blazquez et al., 1989) do not support that such activity exists. However, because of the apparent free transport of MLT between the maternal and fetal compartment (Zemdegs et al., 1988), fetuses are probably exposed to similar circadian MLT variation as their mothers.

Several groups have studied

Possible causes for the age-related changes in melatonin secretion

The MLT decline during childhood can be explained by alterations in body size during development. The human body increases in size 500 to 800% from early childhood to adolescence, but data on pineal size (Schmidt et al., 1995), pineal HIOMT content (Wurtman et al., 1964), and MLT production Tetsuo et al 1980, Penny 1982, Young et al 1988 indicate only small alterations after infancy. Thus, the MLT decline during childhood appears to be the result of a rather constant rate of hormone production

Changing melatonin levels and human sexual maturation

The age-related changes observed in human serum MLT concentrations certainly raise the question as to their physiological significance. For nearly a century the pineal has been implicated in human sexual maturation Waldhauser and Waldhauser 1988, Silman 1991. Primate and human sexual maturation is characterized by a long period of developmental arrest lasting from late infancy until the onset of puberty. During the first months of life gonadotropin and sex steroid levels are high, and the

Early reports

Lerner and Case (1960) first reported on human administration of MLT and stated that “one patient, given 200 mg MLT intravenously, experienced mild sedation. Numerous metabolic tests done before and after the patient received 200 mg MLT daily for five days revealed no change.” Because the sedative action was considered as a side effect, only three groups explored this topic during the subsequent two decades Anton Tay et al 1971, Cramer et al 1974, Vollrath et al 1981. With one exception, when

A potential role for melatonin in the physiological sleep mechanism

The observations outlined indicate an immediate sedative effect for MLT that is demonstrable 15–40 min after intravenous administration and, according to MLT’s pharmacokinetic properties, some 30 min later after oral application Anton Tay et al 1971, Cramer et al 1974, Cajochen et al 1997b. Until 1995, this action was regarded as a side effect due to pharmacological doses. Wurtman’s group, however, first demonstrated that this effect was also attainable with less than 1 mg MLT per oral dose,

Melatonin and insomnia

Strategies to further elucidate MLT’s potential role in normal sleep certainly include sleep examination of subjects with MLT deficiency and MLT examination in insomniacs.

With regard to the first group, to my knowledge no detailed sleep data are available on the above-outlined 1–5% of the general population with low MLT production or on pinealectomized patients treated for pineal neoplasm.

With regard to the second group, lower serum MLT was reported in chronic primary insomnia than in controls

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This corresponds well to an effect that would be mediated by the master circadian clock (Scheer et al., 2012). Conversely, certain drugs (e.g., β-blockers, naloxone, and nonsteroidal antiinflammatory drugs) that affect the nocturnal production of MLT are also associated with impaired sleep (Waldhauser et al., 1998). There are now many reviews and meta-analyses on the effects of exogenous MLT on pathologies in humans and animal models.
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Original ArticlesAge-related changes in melatonin levels in humans and its potential consequences for sleep disorders

Abstract

Introduction

Section snippets

The secretion pattern of melatonin in humans

Age-related changes in melatonin secretion

Possible causes for the age-related changes in melatonin secretion

Changing melatonin levels and human sexual maturation

Early reports

A potential role for melatonin in the physiological sleep mechanism

Melatonin and insomnia

Life Sci

Fertil. Steril.

Neurosci. Lett.

Lancet

Clin. Chim. Acta

Brain Res

Biol. Psychiatry

Eur. J. Pharmacol.

Neurosci. Lett.

Metabolism

Life Sci

Adv. Biosci.

Lancet

Lancet

Plasma concentrations of melatonin in man following oral absorption of different preparations

Br. J. Clin. Pharmacol.

24-hour profiles of melatonin, cortisol, insulin, C-peptide and GIP following a meal and subsequent fasting

Clin. Endocrinol.

Melatonin

Clin. Endocrinol.

Circadian rhythms in serum melatonin from infancy to adolescence peptide neuroregulatorsThe opioid system as a model

J. Clin. Endocrinol. Metab. Yale J. Biol. Med.

Ontogeny of circadian rhythmicity for melatonin, serotonin, and N-acetylserotonin in humans

J. Pineal Res.

Low dose melatonin improves sleep in healthy middle-aged subjects

Psychopharmacology (Berlin)

Case–control study of evening melatonin concentration in primary insomnia

Br. Med. J.

Biochemical and ultrastructural approaches to the onset of the pineal melatonin rhythm in the rat

Neuroendocrinology

Sleep in normal aging and dementia

Sleep

Factors influencing urinary 6-sulphatoxymelatonin, a major melatonin metabolite, in normal human subjects

Clin. Endocrinol. Oxf.

Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis

Am. J. Physiol.

The acute soporific action of daytime melatonin administrationEffects on the EEG during wakefulness and subjective alertness

J. Biol. Rhythms

Plasma melatonin rhythm in normal pubertyInteractions of age and pubertal stages

Neuroendocrinology

A chronobiological study of melatonin and cortisol secretion in depressed subjectsPlasma melatonin, a biochemical marker in major depression

Biol. Psychiatry

Serum immunoreactive melatonin in boys with delayed puberty

Clin. Endocrinol.

On the effects of melatonin on sleep and behavior in man

Adv. Biochem. Psychopharmacol.

Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG

J. Biol. Rhythms

Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance

Proc. Natl. Acad. Sci. USA

Melatonin and insomnia

J. Sleep. Res.

Effect of melatonin on sleep microstructurePreliminary results in healthy subjects

Sleep

Sleep complaints among elderly personsAn epidemiologic study of three communities

Sleep

The pineal gland in relation to growth and development in children

J. Neural Transm. Suppl.

Original Articles
Age-related changes in melatonin levels in humans and its potential consequences for sleep disorders