Melatonin As A Hormone New Physiological and Clinical Insights

REVIEW
Melatonin as a Hormone: New Physiological

and Clinical Insights
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José Cipolla-Neto1 and Fernanda Gaspar do Amaral2
1
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, 05508-
000 São Paulo, Brazil; and 2Department of Physiology, Federal University of São Paulo, 04023-900 São Paulo,
Brazil
ORCiD numbers: 0000-0003-3748-3731 (J. Cipolla-Neto); 0000-0003-4492-4822 (F. G. Amaral).
ABSTRACT Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being
produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ,
the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production
and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle,
melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental
geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night
concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive
physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime,
when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/
endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses’ behavior and physiology to cope with the
environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain–acting
molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and
discusses general guidelines to the therapeutic use of melatonin. (Endocrine Reviews 39: 990 – 1028, 2018)
“We wish to report isolation from beef mammalian pineal hormone and focuses on human
pineal glands of the active factor that physiology and pathophysiology.
can lighten skin color and inhibit MSH. It is noteworthy that in spite of the impressive
It is suggested that this substance be amount of data on melatonin and pineal research, a
called ‘melatonin’. ” (1) standard and systematic theoretical framework of
analysis is lacking, among researchers and clinicians,
I t was  and the hard-working team of re-

searchers led by Aaron Lerner finally managed
to isolate the pineal active factor that had been
that would lead to appropriate interpretation of the
obtained data and adequate understanding of the role
played by the hormone melatonin in human physi-
studied for  years and was named for its ability to ology and pathophysiology. To contribute to this
aggregate melanin granules within the melanocytes. discussion, it is the authors’ intention to propose a
ISSN Print: 0163-769X
Sixty years later, those researchers’ work (), along framework of analysis that would help researchers and
ISSN Online: 1945-7189 with more than , other published research health professionals to analyze, understand, and in-
Printed: in USA articles, have shown that melatonin has myriad terpret the effects of melatonin and its putative role in
Copyright © 2018 functions that encompass every live organism in several pathologies. The first point is the proposal of a
Endocrine Society
which its presence was attested. From bacteria to classification of melatonin’s well-known ways of action
Received: 5 March 2018
Accepted: 21 June 2018
humans, this rather simple molecule has proven its and ensuing effects based on the present experimental
First Published Online: skill to be involved in the sustainment of life. This and clinical knowledge. It intends to clarify that the
12 September 2018 review is dedicated to the study of melatonin as a hormonal effects of melatonin cannot be deduced and
990 https://academic.oup.com/edrv doi: 10.1210/er.2018-00084

REVIEW
ESSENTIAL POINTS
· Melatonin is considered a pineal hormone
·· Melatonin is a biological time–domain molecule acting on the circadian, seasonal, and transgenerational timescales
Melatonin developed special ways of action
· The ways of action determine immediate effects expressed during the night and prospective effects expressed during the
following day
· The prospective effects are classified as proximal effects, expressed immediately after melatonin ceases in the early
morning, and distal lengthy effects, expressed throughout the following day

· The following melatonin-related syndromes are described: hypomelatoninemia, hypermelatoninemia, circadian
displacement, and inappropriate melatonin receptor–mediated responses
· General guidelines about therapeutic uses of melatonin are discussed
interpreted exclusively, as is usually done for other clinical syndromes, considering the classic hypo-
classic hormones, as a result of its ongoing immediate production and hyperproduction or function, and
interaction with its molecular effectors. As presented introducing the dysfunctions that directly depend on
here, several of its effects are primed by this interaction melatonin temporal signal organization and melatonin
but will appear only several hours afterward, provided timing action. Finally, as a third point, the authors
melatonin is not present anymore. Additionally, introduce a discussion about the therapeutic use of
several of its hormonal effects directly depend on the melatonin, taking into consideration its characteristic
circadian and seasonal characteristics of pineal mel- ways of action.
atonin synthesis and secretion, which are dependent on The definition of a common intellectual frame-
its daily repetition, daily duration of nocturnal signal, work is essential to guide the planning of experi-
and seasonal direction of changing (increasing or de- mental and clinical research and data interpretation,
creasing period of synthesis), resulting in the timing of allowing the construction of a solid foundation to
the physiological phenomena in the circadian and properly understand the melatonin functional role
annual timescale. The second point, based on the as a hormone in human physiology and conse-
understanding of melatonin’s ways of action, is to quently to interpret and deal with its dysfunction in
propose a classification of melatonin-related putative human pathology.
Melatonin—the Basics synthesizes melatonin to serve as a hormone with

endocrine actions.
Melatonin, chemically characterized in  (), is an Pineal gland melatonin synthesis in mammals is
amphiphilic tryptophan-derived indoleamine (. timed by the hypothalamic suprachiasmatic nucleus
molecular weight) proficient in free radical scavenging (SCN) master clock and synchronized to the light/dark
with noteworthy antioxidant properties due to its cycle by the retinal intrinsic photosensitive ganglion
additional ability to stimulate antioxidant enzymes cells whose projections to the SCN convey the envi-
in different tissues. This ancient role has been pro- ronment photoperiodic information so that melatonin
posed as melatonin’s primary function that is con- production is confined to the dark phase of the night
served throughout evolution, as melatonin has been (). Importantly, note that melatonin synthesis is
found in numerous live organisms from different blocked by light at night, an effect mediated by the
taxa, including cyanobacteria, dinoflagellates, fungi, retinal melanopsinergic system and a complex neural
flatworms, molluscs, starfish, insects, yeast, plants, fish, system (–) that culminates in inhibition of the
amphibians and reptiles, and birds and mammals sympathetic projection to the pineal gland. In humans
(–). this photoinhibition phenomenon is determined by
Melatonin synthesis has been described in all of the light preferably in the blue range ( to  nm) and
above-mentioned organisms, presenting autocrine and in intensities starting at , lux ( to  lux)
paracrine actions. It is also valid for several tissues (–). These two facts (synchronization by the light/
and organs of multicellular organisms that present dark cycle and nocturnal photoinhibition) are im-
local melatonin production with specific intracrine, perative for the role of melatonin as a time domain
autocrine, and paracrine effects, such as retina, molecule that synchronizes the organism’s internal
gastrointestinal tract, bone marrow, lymphocytes, temporal order to the external daily and seasonal light/
and skin (, ). Vertebrates, in addition to that, dark environment, as presented here (see “Chrono-
present a specialized gland, the pineal gland, that biotic effects” and “Seasonal effects”).
doi: 10.1210/er.2018-00084 https://academic.oup.com/edrv 991

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Pineal melatonin synthesis timing by the SCN is of age according to some researchers () and after 
achieved by its projections to the paraventricular years of age according to others (), pineal melatonin
hypothalamic nucleus, which communicates with the production declines to % of the young adult level.
higher thoracic segments of the intermediolateral From there on, there is a continuous decline to values
spinal column, conveying information to the superior as low as % of the young adult level in people $
cervical ganglion from where sympathetic postsynaptic years of age (). Importantly, note that pineal mel-
fibers reach the pineal gland, releasing norepinephrine atonin production is always higher in women at all
exclusively during the dark phase of the night, trig- ages after puberty ().
gering the enzymatic conversion of tryptophan to
melatonin (, ). Tryptophan hydroxylase converts

tryptophan to -hydroxytryptophan, which is converted Melatonin, Mechanisms of Action, Ways of
to serotonin, which, in turn, is acetylated to N- Action, and Effects
acetylserotonin by arylalkylamine N-acetyltransferase
(AANAT), and N-acetylserotonin is converted to mel- Melatonin mechanisms of action
atonin by acetylserotonin O-methyltransferase. Nor- As for its amphiphilicity, melatonin is able to cross the
epinephrine activates b and ab adrenergic receptors cell, organelles, and nuclear membranes and directly
that increase cAMP and protein kinase A (PKA) ac- interact with intracellular molecules in the so-called
tivity, ultimately increasing cAMP response element non–receptor-mediated actions. In addition to that,
binding protein (CREB) phosphorylation and AANAT melatonin also presents receptor-mediated actions
activity, among other mechanisms, leading to melatonin that result from the interaction of this hormone with
synthesis activation (, ). The above-mentioned both membrane and nuclear receptors.
neural control of melatonin production is also seen
in humans, as neurologic patients showing tetraplegia Non–receptor-mediated actions
or lesions on the cervical spinal cord or superior cervical Melatonin is a well-known effective antioxidant, as it is
ganglion and its sympathetic trunks and patients both a proficient direct free radical scavenger [and so are
submitted to surgical sympathectomy or who are under its metabolites ()] and an activator of a series of
treatment with beta-blockers show very low levels of scavenging mechanisms such as stimulation of the
melatonin production, losing the expected nocturnal transcription and activity of antioxidative enzymes (, )
increase and, consequently, its circadian rhythm and binding to transition metals that inhibits the for-
(–). Additionally, note that this particular area of mation of the hydroxyl radical (). Besides that, mela-
sympathetic innervation is not activated by the well- tonin protects lipids, protein, and DNA from oxidative
known characteristic mass mobilization of the sym- damage (, ), being highly concentrated in the mi-
pathetic system, both in humans and in experimental tochondria (). The mechanisms of melatonin antioxi-
animals (). dant actions are extensively reviewed elsewhere (, ).
Pineal melatonin is not stored, being readily re- The antioxidant properties of melatonin are of
leased to the bloodstream (where it is bound to al- crucial importance for the mitochondrial functions, a
bumin) and to the cerebrospinal fluid (CSF), reaching site were free radicals are naturally formed as a result of
several areas of the central nervous system (CNS) and all cellular respiration [reviewed in ()]. Indeed, mela-
peripheral organs, where it will trigger different effects tonin plays critical roles in mitochondrial function
by various mechanisms of action that are pointed out besides the antioxidant protection such as regulation
below. Melatonin half-life in the blood is ~ minutes of respiratory chain complexes I and IV activities ()
in humans, as it is converted to -hydroxymelatonin and protection of mitochondrial DNA from mutations
by cytochrome P isoforms (mainly CYPA) and and deletions (). It was recently demonstrated that
conjugated to -sulfatoxymelatonin in the liver and melatonin is synthetized in mice brain mitochondria
kidneys for subsequent urinary excretion (). In the and acts through the mitochondrial external mem-
CNS, melatonin is metabolized to N-acetyl-N-formyl- brane melatonin receptor  (MT), preventing cyto-
-methoxykynuramine that is deformylated to N-acetyl- chrome c leakage and subsequent apoptosis (an action
-methoxykynuramine (, ). defined as automitocrine) ().
Maternal melatonin is the only source of this Some of the above-mentioned effects are usually a
hormone both to the mammalian fetus (via placental consequence of melatonin–protein direct interaction.
circulation) and to the mammalian newborn (via It is also notable that melatonin plays a role in the
breastfeeding), as their pineal glands do not produce regulation of the ubiquitin–proteasome system that
melatonin until later after birth (–). The ontogeny ultimately controls protein degradation. Melatonin
of human melatonin production was well studied was reported to inhibit Ca+/calmodulin-dependent
(–) and pineal melatonin was found in - to protein kinase II activity and autophosphorylation by a
-month-old full-term infants, reaching its peak in direct interaction with Ca+-activated calmodulin,
prepubertal children, reducing after puberty and acting as an antagonist (). It has also been suggested
reaching the young adult level (, ). After  years that melatonin influences clock genes expression (see
992 Cipolla-Neto and Amaral Melatonin, a Pineal Hormone Endocrine Reviews, December 2018, 39(6):990–1028
REVIEW
“Prospective effects”) by acting as a direct proteasome stimulation of PKC activity in SCN (); () regulation
inhibitor (). of uterus contractility (); and () vasodilatation (). It
Protection against DNA damage is fundamental was recently suggested that MT melatonin receptors in
and melatonin has shown to be efficient in doing so the SCN might correspond to a G protein–coupled
due to its antioxidant properties, once elevated reactive inwardly rectifying potassium channel ().
oxygen species (ROS) levels are a major cause of DNA MT (previously named ML) is a third charac-
damage. Additional mechanisms include the decrease terized mammalian melatonin binding site (not con-
of ATM (a phosphoinositide -kinase–related kinase) sidered a receptor) that is a form of quinone reductase ,
expression and of the histone HAX phosphorylation, a a detoxifying enzyme (, ), and was reported to be
step involved in the DNA damage response, among involved, for example, in the melatonin-derived in-

others [reviewed in ()]. crease of chemotherapeutic-induced cytotoxicity and
apoptosis in tumor cell lines ().
Receptor-mediated actions Melatonin may also interact with nuclear receptors
The discovery, cloning, and characterization of mel- of the retinoic acid–related orphan receptor (ROR)/
atonin membrane receptors were performed in the late retinoid Z receptor group, although that is still con-
s and early s (–). MT and melatonin troversial in the literature (–). Melatonin-induced
receptor  (MT), formerly named Mela and Melb, decrease of -lipoxygenase gene transcription was
are high-affinity specific G protein–coupled receptors shown to involve ROR/retinoid Z receptor melatonin
encoded by the MTNRA (human chromosome q.) signaling ().
and MTNRB (human chromosome q–q) genes.
Human MT is a –amino acid protein, and human Melatonin ways of action and effects
MT is a –amino acid protein with predicted mo- In view of the aforementioned general characteristics
lecular masses of , and , Da, respectively, that of pineal melatonin production and its several specific
were found in several areas of the CNS, including the mechanisms of action, it is noteworthy that to ac-
SCN, mediobasal hypothalamus, thalamus, temporal, complish its physiological role, melatonin presents
parietal, and frontal cortex, hippocampus, the preoptic several ways of action that will determine different
area, basal ganglia, area postrema, retina, cerebellum, and time-allocated effects. It is important to note that
pars tuberalis (PT) [reviewed in (, )]. Peripheral melatonin’s ways of action and ensuing effects might
organs such as adipose tissue (), kidney (), pancreatic vary according to the considered physiological system;
islets (), parotid glands (), adrenal glands (), liver however, they should be broadly taken into account to
(), bone (), skin (), reproductive tract (–), fully understand and interpret melatonin physiology
immune cells (), and cardiovascular system (CVS) and pathophysiology.
[reviewed in ()], among others, also present MT and
MT melatonin receptors. Immediate effects
MT and MT melatonin receptors are hetero- Immediate effects are the consequence of what can
trimetric Gi/Go and Gq/ protein–coupled receptors that be called the classic hormonal way of action and are
interact with downstream messengers such as adenylyl related to melatonin being present in biological
cyclase, phospholipase A, phospholipase C, and calcium fluids and its instant interaction with corresponding
and potassium channels, generally decreasing cAMP and molecular effectors. Therefore, these effects are
cGMP production and/or activating phospholipase C. expressed during the night when melatonin is re-
MT and MT usually dimerize, forming homodimers or leased by the pineal gland and is present in blood
heterodimers that keep both melatonin binding sites and CSF.
functional and with the respective selectivity (). GPR Examples of these immediate effects are described
is another G protein–coupled receptor that may dimerize in the previous section and are mediated or not by
to MT, reducing its affinity to melatonin and to mel- melatonin receptors. The receptor-mediated immedi-
atonin agonists, being a potential regulatory step of this ate effects are expected to be quantitatively and/or
signaling mechanism (, ). qualitatively different depending on the target organs,
MT signaling pathways involve, for example, () local concentration of the hormone, the type of cellular
activation of Kir./. potassium ion channels that receptors and signaling system, the duration of the
mediate the inhibition of neuronal firing in the SCN signal, and the affinity and desensitization of the dif-
(, ); () modulation of protein kinase C (PKC) and ferent receptor types. Therefore, the immediate effects
phospholipase A (); () modulation of specific ion of melatonin depend on, among other factors, the
channels by MT coupling to Gq/ proteins (); () phase of the melatonin circadian production cycle
mitogen-activated protein kinase kinase /–ERK/ (the rising, evening phase; the phase of nocturnal daily
pathway stimulation in nonneuronal cells (, ); and peak; and the dawn falling phase at the end of the
() vasoconstriction (, ). night) that will determine the concentration of ex-
Complementary MT signaling pathways involve, tracellular melatonin and the duration of its interaction
for example, () inhibition of cGMP formation and with its targets and their sensitivity (–).

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Prospective effects An example of these proximal effects is the hyper-

Prospective effects are dependent on a special mela- sensitivity or supersensitivity of the intracellular adenylyl
tonin’s way of action, as they are primed during the cyclase/cAMP/PKA/CREB transduction pathway that is
night (), through the immediate effects, but are seen after a long-lasting inhibition induced by the in-
expressed only during the following day when mel- teraction of melatonin and its Gi protein–linked re-
atonin is no longer present. In other words, the ceptor, as was demonstrated in several central and
nocturnal action of melatonin triggers cellular and peripheral melatonin-responsive systems of mammalian
molecular mechanisms that will determine effects that species. Depending on the duration of this interaction,
are expressed only after cessation of the melatonin and consequently the duration of a sustained inhibition
signal and, as a rule, the absence of melatonin during of the adenylyl cyclase/cAMP/PKA/CREB transduction

the following day is a necessary condition for their system, a rebound effect is seen immediately after
occurrence. cessation of the melatonin signal. As a consequence, this
Two types of prospective effects should be con- proximal effect is maximal during the first hours of the
sidered (Fig. ), as presently discussed. day, when there is a greater effectiveness of the in-
Proximal or consecutive effects. Proximal or teraction of any agonist of Gsa-linked receptors, in-
consecutive effects are expressed immediately after creasing the adenylyl cyclase intracellular transduction
cessation of melatonin signal. Assuming an adequate pathway activation owing to its supersensitization and
synchronization to the light/dark cycle, these effects determining a larger effect than would be observed if
are seen in the beginning of the following day and melatonin was not present during the preceding night.
might last for hours, given that melatonin is not This melatonin proximal effect was originally
present. demonstrated in cells of the ovine PT where the effects
of different durations of melatonin signal modulated
cAMP intracellular signaling sensitization (, ).
Melatonin ways of action This sensitization effect determined by melatonin,
reflecting basal and forskolin-stimulated responses,
was demonstrated to gradually intensify depending on
Immediate effects Prospective effects the increasing duration of melatonin pre-exposure,
(and priming of being up to % higher at the maximal sensitization
prospective effects)
time as compared with a preparation that was not
preincubated with melatonin. The time-dependent
sensitization process in this particular system is trig-
Distant or lengthy gered after  hours of melatonin pre-exposure, being
(Clock and clock-controlled genes) maximal after  hours; importantly, note that it was
not dependent on melatonin concentration or on de
novo protein synthesis.
Proximal or In the PT of mice and hamsters, another cellular
consecutive phenomenon regulated by melatonin proximal effects is
effects the diurnal rhythm of Per transcription and translation
(sensitization)
(). This was shown to be a consequence of the
Melatonin nocturnal melatonin Gi/-mediated immediate effect
that primes sensitization of the adenylyl cyclase/cAMP
Biological night Biological day signaling system that appears when the melatonin signal
ends at the beginning of the day. At this precise moment
Night Day
© 2018 Illustration Presentation ENDOCRINE SOCIETY
and for a few subsequent hours, pituitary PT cells are
sensitized to the induction of Per gene expression by
Figure 1. Melatonin ways of action. The daily temporal allocation of immediate, prospective, the adenosine Ab receptor–mediated cAMP trans-
distant/lengthy, and proximal/consecutive melatonin effects is shown. Using these two different of duction signal. As a consequence, melatonin, through its
ways of action (immediate and prospective), melatonin can control cell function distribution
proximal effects, is fine-tuning the proper expression of
during night and day. Immediate effects are all measurable effects occurring during the ongoing
melatonin interaction with its effectors. These effects are seen during the night. At the same time the clock genes transcription/translation inhibitory loop
and still dependent on these immediate effects, melatonin primes other effects that will only be that is critical for the circadian function of this system.
seen during the following day, if and when melatonin is not present anymore. These prospective Importantly, note that the same kind of proximal effect
effects are divided into two categories depending on the time of occurrence and the primed controlling clock genes expression during the day
mechanisms. Proximal effects are dependent on the duration of the nocturnal melatonin signal and following a long-lasting melatonin signal is also seen in
depend on the longstanding cAMP synthesis inhibition mediated by Gi/0 protein coupled to the
pancreatic b cells Rev-erb (reverse erythroblastosis
melatonin receptor. The sensitization of adenylyl cyclase/cAMP signaling system will appear
immediately after the ending of the melatonin signal, at the beginning of the day. The distal or lengthy
virus)a and Bmal (brain and muscle ARNT-like )
prospective effects depend on the control of the clock genes expression. These genes are the molecular gene expression ().
substrate of the circadian rhythmicity in every cell, and their effects are spread throughout the 24-h day The same kind of melatonin proximal effect
mediated by CCGs. [© 2018 Illustration Presentation ENDOCRINE SOCIETY] resulting in sensitization of the adenylyl cyclase/cAMP
REVIEW
signal was determined in several other central and new episode of melatonin secretion during the fol-
peripheral systems. In rat Leydig cells, LH-induced lowing night and are, in general, mediated by the
testosterone production was % to % higher after regulation of gene expression and protein translation
 hours of preincubation with melatonin compared and degradation, mainly involving clock genes. The
with non–pre-exposed Leydig cells (, ). In clock genes products regulate expression of the tissue-
Chinese hamster ovary cells expressing human MT specific output of clock-controlled genes (CCGs) to
receptor, the pre-exposure to a physiological con- control the cellular/tissue/organ circadian function.
centration of melatonin for a length of time that Such rhythmic CCG expression is directly responsible
mimics the period of darkness induced supersensitization for the daily oscillation of cell metabolism and organ/
of the cAMP-dependent signaling cascade during the system function. Therefore, ultimately, melatonin is

withdrawal period, as determined by a potentiation of able to regulate several functions expressed for 
forskolin-mediated stimulation of cAMP formation, hours of the day by regulating the dynamic of the clock
activation of PKA, and CREB phosphorylation (). genes–CCGs interaction (Fig. ). In other words, through
This sensitization effect was time-dependent, being these distal lengthy effects melatonin modulates the
maximal at  hours after preincubation with melatonin period, amplitude, and/or phase of daily expression of
for some parameters (e.g., cAMP) and lasting for at least these rhythmic genes, participating as an active de-
 hours after melatonin withdrawal for other param- terminant of the daily functions of central and peripheral
eters (e.g., phosphorylated CREB). systems. In some of them, the absence or amplitude
Among the peripheral systems where the mela- reduction of melatonin (e.g., pinealectomy, light at night,
tonin proximal effect of cAMP signaling sensitization aging) or the absence of receptor-mediated melatonin
is best studied are the pancreatic b cells and pancreatic function (as in single or double MT/MT knockout
isolated islets, with evidence also found in humans. In mice or, eventually, single nucleotide polymorphisms)
this system the melatonin proximal effect is shown to might result in clock genes arrhythmicity. In several cases,
be involved in b cell survival, function, and circadian adequate melatonin replacement therapy reverts the
rhythmicity (, –). observed effects on clock and CCGs expression. In
Melatonin may also play a direct facilitatory role of addition to these in vivo observations, in vitro melatonin
the b cell function by sensitizing the cells to respond to incubation was shown to be able to trigger, block, and/or
glucagon-like peptide  (GLP-) that results in in- modulate clock genes transcription, depending on the cell
creased insulin secretion, as shown in the INS- rat type and experimental design considered.
insulinoma cell line and isolated pancreatic islets (). A detailed description of these melatonin distal
Moreover, there is some evidence that a long-duration effects is given in the next section.
overnight exposure to melatonin might prevent
cAMP-dependent GLP- receptor rapid homologous Chronobiotic effects
desensitization (), allowing the receptors to be fully A chronobiotic agent is defined as an agent that is able
available (if not upregulated) for mobilization the next to synchronize and reset biological oscillations ().
morning. More recently, it was shown that melatonin The first convincing evidence that melatonin was able
preincubation of rat insulinoma cell line INS / to synchronize the behavioral activity/rest circadian
(in a time frame that mimics the typical night ex- rhythm (see Box ) in mammals came from studies in
posure), in addition to significantly enhancing the free-running nocturnal rats that were entrained by
activation of the cAMP-dependent signal transduction  mg/kg melatonin when it was injected at or im-
pathway as previously demonstrated, attenuated mediately before the beginning of the active circadian
proteotoxicity-induced b cell apoptosis, decreased phase (). In addition to showing the chronobiotic
activation of stress-activated protein kinase/c-Jun property of melatonin, exogenous melatonin entrain-
N-terminal kinase, and diminished the oxidative ing action was shown to be critically dependent on the
stress response (). Moreover, activation of this kind phase of the circadian cycle. A complementary study
of melatonin proximal effects ( to  hours of () demonstrated that the entrainment of free-
preincubation) in hyperglycemia chronically exposed running rats under constant light was achieved at
isolated human islets was shown to significantly reduce even lower doses of melatonin (~ mg/kg), pointing to a
the oxidative stress as well as to partially restore the putative participation of the daily physiological pineal
glucose-stimulated and incretin-stimulated insulin melatonin production in activity/rest circadian rhythm
response. Similar proximal effects of melatonin were synchronization and stability. It was even demon-
demonstrated in postmortem islets obtained from strated that melatonin is able to entrain the restored
patients with type  diabetes mellitus, except for the circadian activity rhythms of hamsters bearing fetal
incretin-mediated insulin release (). SCN grafts (). In humans, the chronobiotic way of
Distal or lengthy effects. Distal or lengthy action of melatonin is classically seen in the entrain-
effects are primed during the night and expressed at ment of the non–-hour sleep–wake rhythm disorder
any time or during the following day, in the absence of either in blind or sighted patients, as discussed below
circulating melatonin. These effects will be reset by the (, ).

REVIEW
Owing to these functional characteristics, mela- their phase, amplitude, and period. At the cellular
tonin is properly defined as a chronobiotic or internal level, one basic mechanism of the circadian timing
zeitgeber (, –). As would be expected from a process, present in almost every cell, either central or
zeitgeber (), melatonin must act on oscillators peripheral, is the cellular molecular oscillatory system
according to a well-defined phase-response curve represented by the so-called clock genes.
(PRC) (). A PRC shows the magnitude of response, The clock genes oscillatory system is characterized
in terms of phase advance or phase delay, derived from by interconnected negative, positive, and regulatory
the action of the zeitgeber on the oscillator, being feedback loops (). The core clock genes are part of
directly dependent on the moment (defined as phase) the primary positive/negative transcription/translation
of its incidence along the intrinsic period of oscillation molecular loop. In the positive feedback limb, the

of the internal clock. Figure  shows a classic PRC of protein products of the genes Clock (circadian loco-
circadian activity/rest cycle responses to light pulses. motor output cycles kaput) and Bmal heterodimerize,
Melatonin PRCs were demonstrated for lizards (), and the dimer acts as a transcription factor that
birds, and mammals (), besides being clearly and positively regulates the transcription of two other
completely demonstrated for humans (), as shown groups of core clock genes, Per (from Period; Per,
in Fig. . In this case, a melatonin PRC is characterized, Per, and Per) and Cry (from Cryptochrome; Cry and
as expected, by two opposing regions (phase-advance Cry). In the negative feedback limb of the primary
and phase-delay zones) and a nonresponsive dead molecular loop, the protein products of these genes,
zone. The dead zone occurs during the night when PERs and CRYs, heterodimerize and translocate into
endogenous levels of melatonin are usually high. The the nucleus to inhibit the positive transcriptional
phase-advance zone is usually located early in the activities of CLOCK/BMAL, resulting in inhibition of
evening,  to  hours (maximum effect at  hours) their own transcription, causing the cycle to rerun
before the beginning of the nocturnal episode of from a low level of transcriptional activity (). It
melatonin production that is characterized by the dim- should be taken into account that the inactivation or
light melatonin onset (DLMO) or, as in the blind degradation of the negative limb proteins PER and
patient, the melatonin onset (, ). The phase- CRY is required to terminate the repression phase and
delay zone is located in the late night/early morning restart a new cycle of transcription, setting the period
hours, around (6 hour) the usual endogenous of the clock ().
melatonin offset. This melatonin PRC guides the The second molecular loop, which is regulatory
clinical administration of melatonin as a chronobiotic and stabilizes the circadian period of the first loop
agent or in replacement therapy. Depending on the (), is composed of two families of nuclear receptors,
desired effect (phase advance, phase delay, or no phase REV-ERB a or b and ROR a, b, or g. The CLOCK/
shift), such should be the moment of melatonin ad- BMAL dimer also initiates the transcription of both
ministration to the patients. Rev-erba or b and Ror a or b. The REV-ERB and
The chronobiotic effect of melatonin (see Box ) ROR proteins then compete for ROR response
depends on its putative action in several levels of the element binding sites within the promoter of Bmal
circadian timing system. The circadian timing system is where ROR proteins initiate Bmal transcription and
composed of a number of structures of the CNS, mainly REV-ERB proteins inhibit it. One should consider
the hypothalamic SCNs, defined as the central oscillator, at least a third, more complex transcriptional loop
that times the peripheral oscillators through neural involving several regulatory elements such as DBP
and/or humoral/hormonal mediators, determining (D-box binding protein), PARzip protein (proline
BOX 1. Circadian Rhythms

Circadian rhythms are endogenously generated ~24-hour biological rhythms. The circadian timing system is organized in
several levels, from the molecular one, represented by the clock genes, to the systemic regulatory timing neuroendocrine
system. This circadian oscillation is directly synchronized by external environmental cycles, mainly the typical light/dark cycle
of the geophysical day and night. These external rhythmic events that are able to synchronize biological rhythms are called
zeitgebers or synchronizers. Synchronization between oscillators is obtained when the phase relationship between them is
kept constant. “Entrainment” is defined as the particular case of synchronization between oscillators (with different but
similar periods) that occurs when one of the oscillators imposes its period on the other. That is the case of the circadian
rhythms. The endogenous period (shown as free-running rhythms in constant conditions) is always slightly different from 24
hours. The day/night light/dark cycle presents a 24-hour period. During the synchronization, the endogenous master
oscillator assumes the 24-hour period of the external zeitgeber, thus being entrained by it. This entrainment process depends
on phase advances and phase delays of the endogenous oscillator that are strictly dependent on the moment of incidence of
the external stimulus, defining what is called the phase-response curve (see Figs. 3 and 4).
Excellent books about circadian rhythmicity are the Handbook of Behavioral Neurobiology, Vol. 4, Biological Rhythms, edited
by Jurgen Aschoff (New York, NY: Plenum Press, 1981), in particular chapters 5 through 7, and the classic The Clocks That
Time Us, by Martin C. Moore-Ede, Frank M. Sulzman, and Charles Fuller (Cambridge, MA: Harvard University Press, 1982).
REVIEW
and acidic amino acid–rich basic leucine zipper), and pathway in the SCN (). In this context, the role played
NAD+-dependent SIRT that add further regulation by the regulator of G protein–signaling protein 
to the main two clock genes transcription/translation (RGS), that functions as a GTPase-accelerating pro-
loops (). tein for Gi (), should be additionally considered, as it
As can be deduced from the above, virtually every promotes GTP hydrolysis and arrests GTP-bound Gi
stage of the aforementioned gene expression should be signaling. It is shown that melatonin might upregulate
considered nodal points for the circadian control of the RGS gene expression () and that RGS
clock genes and CCGs expression. In this context, protein accumulation peaks during daytime (), acting
melatonin, owing to its functional pleiotropic ways of to overcome the melatonin Gi-mediated effect and
action that regulate basic cellular metabolism, chromatin contributing to the putative daytime domain of cAMP

integrity and gene transcription and translation, nuclear signaling sensitization.
export, microRNA regulation, and mRNA and protein In addition to the control of clock genes tran-
degradation, might modulate almost every stage in clock scription and translation in the central circadian
genes and CCGs expression and function (, –). pacemaker, it is noteworthy that melatonin is able to
In the SCN, the central circadian pacemaker, in vivo modulate clock genes expression in several other CNS
experiments and quantitative in situ hybridization analysis structures as other hypothalamic nuclei, hippocampus,
showed that melatonin systemic injection in rats imme- and striatum (–).
diately prior to the light–dark transition is able to modify As far as peripheral oscillator clock genes expression
the mRNA expression of Rorb (preventing the otherwise and circadian function control are concerned, pancreatic
decreasing expression) and Rev-erba (provoking its phase b cells and islets and the metabolically most relevant
advance) and does not modify Rora expression (). tissues (liver, muscle, and adipose tissue) are all targets
Note that although the above-mentioned effects were for melatonin. Mouse pancreatic islets present self-
noticed in the night immediately after melatonin injection sustained clock gene and protein oscillations that are
(melatonin immediate effects), phase shifting of Bmal directly involved with growth, survival, glucose meta-
mRNA expression is only observed in the following night bolism, and insulin synthesis (). Ramelteon®, a
(melatonin distal and lengthy effect). melatonin receptor synthetic agonist that mimics the
In addition to that, melatonin administration to melatonin receptor–mediated cAMP signaling sensiti-
mice at the light–dark transition, in a short-photoperiod zation proximal effect, controls Rev-erba and Bmal
regimen, is able to modulate the amplitude (and not the expressions in rat pancreatic INS- b cells (), il-
phase) of Per, Per, Bmal, and Clock expression in the lustrating the role played by melatonin in the daily
SCN (). The classic in vitro rat’s brain slice prepa- regulation of glucose-stimulated insulin release (). In
ration containing SCNs was used to study the effect of rodents, visceral white adipose tissue core clock gene
melatonin on neuronal electrical activity and clock expression (Clock, Bmal, Per, Per, Cry, and Rev-erba)
genes expression, and the results demonstrated that
melatonin being present at the subjective day-to-night
Distal and lengthy prospective effects dependent on
transition alters the SCN clock phasing via the regu- clock genes and clock-controlled genes
lation of Per and Per clock genes in an immediate
effect mediated by PKC (). Night Day
Additionally, considered that melatonin is able to Melatonin Absence of melatonin
control the circadian timing of the SCN through
prospective proximal effects. The circadian rhythm of
SCN neuronal excitability presents two temporal 24-hour clock genes cycle
domains that are characterized by distinct sensitivity to
specific signal transduction pathways [reviewed in
()]. The nighttime domain is characterized by the
Clock-controlled genes timed expression
predominance of elevated cGMP level and subsequent
activation of protein kinase G, the cGMP-dependent
protein kinase. Alternatively, the daytime domain can
be characterized by its sensitivity to direct activation of Time-dependent differential effects
the pituitary adenylate cyclase-activating polypeptide/ © 2018 Illustration Presentation ENDOCRINE SOCIETY
cAMP/PKA pathway. The presence of MT and/or
MT melatonin receptors in the SCN is undisputed Figure 2. Distal and lengthy prospective effects are dependent on clock genes and CCGs.
(, –), and considering the ability of both Melatonin during the night, by immediate effects, might stimulate and/or inhibit the expression of
the clock genes. During the day, in its absence, the inverse occurs. Either way, the clock machinery
receptors to inhibit adenylyl cyclase, it is conceivable that
will cycle in accordance to melatonin regulation of the expression of genes either from the positive
the long-lasting nocturnal melatonin signal may be or the negative loop. Once the 24-hour cycle of the clock genes is defined, the clock genes will, by
considered one important factor determining, through themselves, control the expression of the CCGs at different phases of the daily cycle. These genes
its proximal effects, the daytime domain predominance are the effector genes of the cell and will trigger different functions according to the time of the
of supersensitivity to the adenylyl cyclase/cAMP/PKA 24-hour cycle. [© 2018 Illustration Presentation ENDOCRINE SOCIETY]

REVIEW
Figure 3. Light PRC. A PRC shows the magnitude of response, in terms of phase advance or phase delay, derived from the action of the
zeitgeber on the oscillator, being directly dependent on the moment (defined as phase) of its incidence along the intrinsic period of
oscillation of the internal clock. The figure shows the PRC (black curve) derived from light stimulation (importantly, note that the PRC
depends on the wavelength, intensity, and duration of the light pulse) of young adults under dim light (with gray bar and yellow stars
representing light pulses). In this free-running condition, the DLMO or the moment of occurrence of minimal core body temperature is
taken as the internal circadian reference time to plan the moment of incidence of the light pulses (measured in units of circadian
time—that is, the free-running period divided by 24). DLMO is usually attributed to circadian time 14. The difference between the
instant of occurrence of the internal marker (beginning of melatonin secretion or moment of minimal temperature) on the control day
and on the day or days after the light pulse defines the phase shift induced by light exposure at that particular circadian time. Despite
a light PRC being derived in an experimental free-running condition, the same effects of light on phase-shifting the internal circadian
clock can be seen in a day-by-day entrained situation represented by the yellow/dark blue bar. Also shown is the light PRC referenced to

the endogenous melatonin rhythm (red dashed curve). As shown, the beginning of the night until about 1 to 2 hours after the DLMO
(stated at 2100 h) defines the time zone (green) when the light pulses provoke the maximum phase delays of the circadian clock.
Alternatively, light pulses given at the end of the night, near the DLMOff (stated at 0600 h), evokes the maximum phase advance
responses (blue). Notably, there is a time zone, usually corresponding to the middle of the day, when light pulses do not phase-shift the
circadian clock, which is defined as the dead zone (purple). [© 2018 Illustration Presentation ENDOCRINE SOCIETY]
Dead zone Phase delay zone Phase-advance Dead zone

zone
2
Advance
1
Phase shift (hours)
-1
Delay
-2
-3
Dim light
DAY NIGHT DAY

18:00 21:00 24:00 06:00
© 2018 Illustration Presentation ENDOCRINE SOCIETY DLMO DLMOff
is under the control of melatonin as well as the daily demonstrated (). Moreover, melatonin importantly
distribution of its functions such as lipolysis, lipogenesis, participates in the daily distribution of liver gluconeo-
leptin production, and adipocyte proliferation (–). genesis (, ).
The same daily organization of functions and clock Reproductive organ circadian rhythms and phys-
genes expression is seen in humans (–) and iological functions are also under the control of
seems to be, as well, under melatonin regulation (). In melatonin. In rat Leydig cells () the absence of
skeletal muscle, melatonin acting through MT seems to pineal melatonin abolishes Per daily rhythm and
control the amplitude of the clock genes and CCGs increases the daily amplitude of Per gene expression.
Reverba and Dbp and to control the phase of Bmal In this case, melatonin replacement was able to revert
expression (). In sheep, liver clock genes ex- the deleterious effects. It was also demonstrated ()
pression is under photoperiodic control. Under short that pinealectomy altered the daily mRNA expression
nights, Per expression peaks at the end of the night, profile of several clock genes in the rat cumulus–
whereas under long nights there is a phase advance of oocyte complex. The absence of melatonin abolished
Per and the peak occurs at the beginning of the the daily rhythm of Clock, Per, Cry, and Rora in
night (). In mice liver, a significant reduction of cumulus cells, altered the amplitude of Clock, Bmal,
Per daily amplitude in MT knockout animals was and Cry in oocytes, and phase shifted Per and Cry
REVIEW
Figure 4. Melatonin PRC. The melatonin PRC is derived from the phase shifts obtained by the difference between the DLMO moment
of occurrence in a control situation and after oral melatonin exposure, usually taken by individuals in the day-by-day entrained
condition. Melatonin PRC (black curve) is characterized by two opposing regions (phase-advance and phase-delay zones) and
a nonresponsive dead zone. Melatonin pulses in the dead zone (purple area) occur during the night when endogenous levels of
melatonin are usually high (red dashed curve). The phase-advance zone (blue area) is usually located late in the afternoon and early in
the evening, 2 to 7 hours (best seen around 3 to 4 hours) before the beginning of the nocturnal episode of melatonin production. The
phase-delay zone (green) is located in the late night/early morning hours, 61 hour around the usual endogenous melatonin offset. The
figure also shows the best (safe zone) and the worst (forbidden zone) times to use melatonin in chronic conditions, depending on
the desired effects (phase advance, phase delays, or no phase shift at all). It is interesting to compare the melatonin PRC to the light PRC
in Fig. 3. At the beginning of the night, light pulses evoke the biggest phase delays; alternatively, melatonin administration would cause
the biggest phase advances. The opposite is seen at the end of the night, when light evokes phase advances and melatonin evokes phase

delays. [© 2018 Illustration Presentation ENDOCRINE SOCIETY]
Forbidden zone for Safe zone for Forbidden zone for

chronic melatonin chronic melatonin chronic melatonin
administration administration administration
2.0
Phase-advance zone Dead zone Phase delay
zone
1.5
1.0
Advance
0.5
Phase shift (hours)
0.0
-0.5
Delay
-1.0
-1.5
-2.0
0
18:00 21:00 06:00
DLMO DLMOff
© 2018 Illustration Presentation ENDOCRINE SOCIETY Time of melatonin administration
in oocytes and Bmal in cumulus cells. Melatonin Even the mammalian fetus is entrainable by the
replacement therapy was able to counteract several of maternal melatonin signal. It was shown () that
the above-mentioned effects. maternal melatonin regulates SCN Bmal and Per clock
The adrenal gland seems to be another pe- genes expression in the primate capuchin monkey fetus.
ripheral target for the chronobiotic role of mela- Corroborating the importance of maternal melatonin
tonin, as it was shown to synchronize and trigger circadian rhythm as a key signal for the generation and/or
circadian clock genes oscillation. In the capuchin synchronization of the circadian rhythms in the mam-
monkey, for example, it regulates the daily adrenal malian fetus, the absence of maternal melatonin from day
function and Bmal and Per circadian expression  to day  of gestation in rats markedly affected the
peak (). mRNA expression level of clock genes and CCGs in the
Also, note that the literature demonstrated that fetus adrenal gland so that Bmal and Per circadian
melatonin controls peripheral clock genes and CCGs oscillations were abolished and, additionally, the fetal
oscillation in several other systems such as retina (, adrenal circadian rhythm of corticosterone synthesis was
), skin fibroblasts (), and the CVS (), particularly also abolished (, ). All of these effects were
in cardiomyocytes (), as well as PT (, ) and overcome in the adrenal glands from fetuses whose
human myometrial smooth muscle cells (). As clock mothers received melatonin replacement therapy.
genes are well demonstrated in several human cells (, Finally, even the organisms that cohabitate the
, –), it is conceivable that melatonin might act human body may be synchronized by the host’s
as one of their synchronizers (, ). melatonin profile, as was shown for the malarial

REVIEW
Plasmodium parasite () and for a commensal organisms and their ecological niche, the seasonal
bacterium from the human gastrointestinal system, the effect mediated by melatonin is fundamentally im-
noncyanobacterial prokaryote Enterobacter aerogenes, portant to synchronize physiological and behavioral
of which the circadian clock and daily activity pattern seasonal adaptations to the expected changes in ex-
are synchronized by the host’s pineal and gastroin- ternal environmental conditions that are typical of the
testinal melatonin profile (, ). seasons of the year. These adaptations include annual
In addition to controlling clock genes/CCGs expres- cycles of reproduction and metabolism, as well as, for
sion, there are at least two other ways that melatonin can example, the consequent growth and body weight
regulate/induce circadian rhythmicity. The first one is control, thermogenesis and brown adipose tissue func-
regulating the cellular redox state either in central or pe- tion, hibernation, migration, and immune responses.

ripheral oscillators because it is well known that that there is The cyclic photoperiodic annual changes in the
an important functional interplay between the cellular duration of day and night are the most important
molecular circadian clock machinery and the cellular redox environmental factor for synchronization of circan-
state (, ). The other way is through the previously nual rhythms. As the nocturnal melatonin profile
defined supersensitization of adenylyl cyclase and cAMP varies according to the duration of the night, it in-
signaling that appears when melatonin levels decline at ternally encodes the photoperiodic annual change in
dawn. As demonstrated in the PT (), this prospective the day and night length. In this manner, melatonin
effect of melatonin might amplify clock gene expression is the internal hormonal mediator that was “sculpted”
rhythms, providing an additional mechanism for rein- by the environmental photoperiodic changes so that
forcing rhythmicity in central and peripheral tissues. any seasonal physiological and behavioral adaptations
The appropriate interpretation of the chronobiotic are dependent on this predictable annual regular var-
effect of melatonin should additionally consider that the iation on the daily duration of melatonin signal
effectiveness of a chronobiotic agent or zeitgeber (and (–), which is also present in humans (see below).
melatonin is not an exception) is directly dependent on As is well known, there is a critical day/night length
two other factors: the regularity of the daily repetition of ratio (critical photoperiod) that most members of a
its signal (, , , ) and its strength (), certain animal population detect as a signal of
which is represented here by the contrast between changing season and switch from one physiological
nocturnal and diurnal melatonin concentration values. state to another, which will be fundamental for future
In summary, given its periodic circadian release adaptation to the upcoming season (, ). As the
driven by the SCN, the great contrast between night duration of the melatonin nocturnal profile encodes
and day circulating concentrations, in addition to the this environmental photoperiod, it is well known that
pleiotropic mechanisms of action controlling central there is a critical duration of the nocturnal episode of
and peripheral oscillators, melatonin acts as a powerful melatonin secretion capable of triggering the seasonal
chronobiotic hormone and ultimately participates as physiological changes (e.g., brown adipose tissue ac-
one of the most important unifying agents that is tivation and recruitment, increasing food intake and
responsible for the synchrony between the multitude body weight, modification of the reproductive axis
of circadian rhythms at several levels (cell, tissue, according to the species reproductive profile) that are
organ, and system). Therefore, pineal melatonin necessary for the proper adaptation to the seasonal
hormone is an important player in the determination fluctuations of the external environment (e.g., tem-
and stabilization of the internal circadian temporal perature changes, food availability, day and night
order, being crucial to the physiological and thera- duration) ().
peutic prevention and treatment of chronodisruption Moreover, another fundamental element in sig-
(, –). Moreover, as stated previously, pineal naling seasonal changes is the direction of the daily
melatonin, due to its SCN-controlled regularly timed change in photoperiod (increasing or decreasing day
synthesis, is mainly linked to the external light/dark length) and, consequently, the direction of the daily
cycle rather than to the activity/rest cycle (as are change in the duration of the nocturnal episode of
cortisol or corticosterone) of the mammalian organ- melatonin production. Therefore, the history of the
ism. Therefore, acting as a photo-neuroendocrine photoperiodic changes and the consequent melatonin
mediator of the light/dark cycle and as an internal nocturnal secretory profile are the major determinants
zeitgeber, its chronobiotic effect guarantees the ade- of the seasonal physiological changes that are fun-
quate daily rhythmic physiological and behavioral damental for the adaptation of the organism to the
fluctuations that are fundamental to the proper cir- expected future seasonal environment. The impor-
cadian temporal relationship between the organism tance of the history of the annual changes to melatonin
and the environmental day/night cyclic changes. secretory nocturnal profile is shown in Fig. . As
depicted, any given duration of the nocturnal mela-
Seasonal effects tonin signal occurs at two different phases of the
As the chronobiotic circadian effect of melatonin is annual cycle, one in the direction of the winter sol-
important for the adequate daily relationship of the stice (increasing night length/increasing duration of
REVIEW
Figure 5. Melatonin seasonal profile. This figure shows the annual seasons and the correspondent photoperiodic change in the
duration of the day and the night. At the same time, it is possible to see the annual historic evolution of the duration of the daily
episode of melatonin production. The first observation is that the classic calendar of four seasons is reduced to the biological point of
view of two seasons, one determined by increasing duration of the melatonin nocturnal episode and the other defined by the increasing
reduction of the nocturnal episode. The second point to be observed is the importance of the historical perception of the annual
evolution of the environmental photoperiod. Any given duration of the nocturnal melatonin signal occurs at two different phases of the
annual cycle, one in the direction of the winter solstice and another in the direction of the summer solstice. However, from the
biological point of view, the first one triggers physiological and behavioral preparation for the following winter and the second one for
the following summer, depending on how the signal is read and translated by the PT/third-ventricle tanycytes. Finally, note that there is
a critical day/night length relationship—the critical photoperiod that is detected as the signal of changing season and switching from
one physiological state to another—that is internally represented by the critical duration of the melatonin nocturnal profile. [© 2018

Illustration Presentation ENDOCRINE SOCIETY]
Increasing nights - Decreasing nights -

increasing melatonin decreasing melatonin
Minimal melatonin Maximal melatonin Minimal melatonin
Critical photoperiod Critical photoperiod

Critical melatonin duration length Critical melatonin duration length
Winter phenotype
Decreasing melatonin
Increasing melatonin
Summer phenotype Summer phenotype
Summer Autumn Winter Spring Summer

solstice equinox solstice equinox solstice
© 2018 Illustration Presentation ENDOCRINE SOCIETY
nocturnal melatonin signal) and another in the di- intermediate -hour light/-hour dark cycle. The
rection of the summer solstice (decreasing night first one (previously adapted to  hours of light and
length/decreasing duration of nocturnal melatonin  hours of dark per day) became reproductively
signal). However, from the biological point of view, the active and the other one (previously adapted to 
first one triggers physiological and behavioral prepa- hours of light and  hours of dark per day) became
ration for the following winter and the second one for reproductively inhibited. In other words, in the first
the following summer, depending on how the signal is group the CNS read the -hour melatonin signal as
read and translated by the PT, transmitted to the “preparation for the winter” (moving from  hours
pituitary pars distalis, and, via the third-ventricle of dark to  hours of dark; longer night length),
tanycytes, transmitted to the hypothalamus (see be- whereas in the second group, the same -hour
low) (–). Accordingly, the different adaptive melatonin signal was read in opposite direction and
effects of melatonin depend on the different phases of was translated as “preparation for the summer”
the year and are ultimately determined by the hy- (moving from  hours of dark to  hours of dark;
pothalamic detection of the history of the melatonin shorter night length).
secretory episode duration, day after day, during the According to the previous discussion, in mammals,
annual photoperiodic cycle. This was exemplified by the annual sequential variation of melatonin profile
analysis of two groups of Suffolk ewes that were duration is the internal representative of the environ-
previously adapted to  or  hours of light per day mental photoperiod (day/night length ratio) that is the
(). These animals are reproductively active during main synchronizer of the circannual rhythmicity but
the winter (long night length). The -hour light/-hour not the only one (). Similar to the circadian chro-
dark cycle–adapted group presented reproductive sys- nobiotic effect, the seasonal effect of melatonin depends
tem inhibition whereas the -hour light/-hour dark on its putative action as an “internal circannual zeit-
cycle–adapted group presented reproductive system geber or synchronizer” acting on several levels of the
stimulation. Both groups were transferred to an circannual timing system that is composed of a number

REVIEW
of structures, mainly the PT, third ventricle tanycytes, able to transport peptides and hormones by trans-
and several hypothalamic nuclei (, , –). cytosis, playing the role of sensors of nutrients, hor-
The mechanism involved with the synchronizing mones, and immune and inflammatory mediators
effect of melatonin that will trigger the physiological (–). Therefore, these cells seem to be the func-
adaptation according to the respective seasonal en- tional link between PT (and, for extension, melatonin-
vironment depends on melatonin interaction with mediated environmental photoperiodic changes), CSF,
MT receptors (through immediate and prospective blood, and hypothalamus, being an important player in
effects as inhibition of cAMP synthesis and its sub- the seasonal regulation of reproduction, energy meta-
sequent supersensitization and clock genes daily bolism (ultimately, body weight), and immune function
transcription/translation cycle) at the PT- specific (, , , ).

thyrotroph cells (, –). These specific PT cells PT-specific thyrotroph TSH released in the ex-
express both the a and b subunits of TSH, but they are tracellular space acts as a paracrine factor on tanycytes
not under the control of the hypothalamic TSH- TSH receptors, inducing an increase in the expression
releasing hormone, as are pars distalis thyrotroph of type  iodothyronine deiodinase (DIO) and re-
cells classically. Instead, PT TSH synthesis and release ducing the expression of type  iodothyronine deio-
do not respond to TSH-releasing hormone (nor to dinase (DIO). DIO converts T in T and DIO
thyroid hormones) and is under strict control of converts T in reverse T, degrading T to diiodo-
melatonin, mainly mediated by its MT membrane thyronine. The coordination of both enzyme activities
receptor and clock genes expression regulation (, will regulate the availability of the active thyroid
–). At night onset, melatonin, through im- hormone in the hypothalamus, modulating several of
mediate effects, induces Cry gene and CRY protein its nuclei and neuroendocrine systems functions and,
expression (, –). Alternatively, PER protein consequently, the interplay between the physiological
is induced immediately after melatonin signal offset and behavioral functions that are necessary for the
depending on its prospective effects (primed during organism to cope with the environmental changes
the previous night) mediated by cAMP super- (, , ). Long days (short duration of daily
sensitization (, –). Therefore, the PER– nocturnal melatonin episode) enhance TSH pro-
CRY phase relationship critically determines the duction in PT-specific thyrotrophs, which increases
amount of PER–CRY dimer—an essential element of DIO expression and suppresses DIO expression,
the inhibitory limb of the clock genes circadian increasing thyroid hormone signaling in the medi-
cycle—being a direct reflex of the seasonal changes in obasal hypothalamus. On the contrary, short days
the duration of the nocturnal melatonin signal (, (long duration of daily nocturnal melatonin episode)
). In this way, the clock genes machinery seems to trigger an opposite effect. As far as seasonal re-
be the link between melatonin and TSH expression by production is concerned, this T hypothalamic
PT-specific thyrotrophs (, ). generating mechanism appears to be the same in
In addition to TSH, melatonin regulates neuromedin both long-day and short-day breeders, and thus it
U (NMU) expression and release in PT-specific thyro- must be complemented by some downstream in-
trophs (). NMU seems to be an important mediator trinsic hypothalamic species-specific mechanisms to
of the seasonal effects of melatonin on energy meta- the proper regulation of the final seasonal breeding
bolism as it is detailed below and elsewhere (). It is status (and, perhaps, all other seasonal adaptations)
interesting to observe that obesity in humans is related to (–).
genetic variants of the NMU encoding gene but not of Accordingly, a restricted seasonal differential
the NMU receptor encoding gene (, ). hypothalamic gene expression following the above-
Physiological and behavioral adaptations to the mentioned hypothalamic thyroid hormone availability
seasonal changing environment are ultimately de- was recently shown to be the final step in the propa-
termined by the hypothalamus. The retrograde gation of the photoperiodic message from PT to the
functional connection between PT (“season sensor or mediobasal hypothalamus ().
decoder”) and the hypothalamus includes another Note that for certain seasonal physiological ad-
fundamental element, the third-ventricle tanycytes. aptations such as reproductive activation and in-
Tanycytes are radial glial cells whose cell somas are activation, in addition to the above-described PT
interposed between the vascular bed of the median retrograde action in the hypothalamus, there is an
eminence and the third-ventricle ependymal cells, anterograde action that regulates prolactin production
whose cellular processes project to the PT and to in the pituitary pars distalis. In this case, the
several hypothalamic nuclei (paraventricular, dorso- melatonin-driven PT mediators are different from
medial, ventromedial, arcuate) (, ). Tanycytes TSH and NMU. There is no consensus about their
seem to be key elements, as they are settled at the characterization, but messengers from PT to pars
interface between blood, CSF, and brain tissue. In fact, distalis include tachykinins, vascular endothelial
tanycytes express cell membrane receptors for TSH, growth factor, and endocannabinoids (). An in-
NMU, GPR, FGFR, IL-, and LPS, and they are trinsic endocannabinoid system was shown to be
REVIEW
important for communication between PT and pars of some placental factors such as the vasoactive in-
distalis, including in the human brain (). testinal polypeptide, progesterone, estradiol, and others
In summary, the melatonin seasonal effect is de- (, ).
pendent on the regular and predictable change of the Alternatively, it is well known that maternal
duration of its synthesis and blood presence across melatonin is freely transferred to the fetus via the
successive nights and how this message is decoded by placenta (–), and this maternal–fetal transfer of
PT through retrograde and anterograde paracrine melatonin is the only fetal source of this hormone.
mediators. These mediators convey the photoperiodic Moreover, melatonin concentration in fetal umbilical
information to the mediobasal hypothalamus and circulation reflects the day–night difference and
pituitary, triggering the adaptive physiological and nocturnal duration as seen in the maternal circulation

behavioral responses that anticipate the predictable (, –).
changes of environmental seasons, guaranteeing health This transplacental melatonin has several effects on
maintenance. fetus physiology, including the coordination of pe-
The question of whether the melatonin circannual/ ripheral organs and tissues development, neural de-
seasonal synchronizing effect is important in human velopment and neural plasticity, and metabolic,
physiology and pathophysiology should be considered. cardiovascular, and immunological programming, an
The evolutionary history of photoperiodism () anticipatory biological response that prepares the
points to a positive response to this question. Its offspring to cope with forthcoming environmental
demonstration, however, is not an easy task. All of the demands. Among these programming effects of ma-
experimental studies described previously depend on ternal melatonin on the developing fetus, one re-
an elaborate protocol, using artificial photoperiod markable effect is the timing of the fetus future
condition and its controlled changes or, alternatively, physiology and behavior, another time domain action
in a more naturalistic study, the observation and of hormonal melatonin. Maternal melatonin sends a
measurements of physiological and behavioral pa- temporal circadian (time of the day) and seasonal
rameters for at least  full year or more. For obvious (photoperiod and its history) signal to the fetus so that “In general, the immediate and
reasons this is not directly applicable to humans. its CNS is able to properly deal with the environmental prospective effects of
Additionally, the human cultural attribute allows the day/night fluctuation after birth. It was particularly melatonin determine the same
artificial control of the environment conditions by the shown for the onset of puberty that takes the pho- events both in nocturnal and
introduction of nocturnal lighting, temperature con- toperiodic history during gestation time into account in diurnal animals, but in
trol, food availability throughout the year, and other to be adequately triggered (, , –). opposite phases of the daily
cycle.”
factors. As a consequence, these social conditions are This phenomenon might be called maternal cir-
expected to reduce the impact of a seasonal changing cadian predictive adaptive programming or maternal
natural environment to putative natural human cir- photoperiodic predictive adaptive programming. This
cannual physiological and behavioral responses (, transgenerational timing programming effect of
). However, using adequately designed epidemio- melatonin is an example of the so-called predictive
logical studies, an adequate choice of communities adaptive responses (–). The only difference to
living in different cultural settings, and proper experi- the general concept of predictive adaptive responses is
mental conditions, it is possible to show that several that, thanks to the earth rhythmic geophysical tem-
parameters of human physiology (e.g., birth, puberty, poral organization, the photoperiod and day/night
metabolism, body weight, eating behavior, glucose cycle of the future environment is almost confi-
homeostasis, hormonal production, thermoregulation, dently predictable and, with a great degree of certainty,
immune responses, sleep duration) show circannual there will be no chance of mismatch between the
rhythms so that humans might be characterized as predicted environment and the real one. Therefore, the
seasonal as any other photoperiodic mammal (, developmental plasticity determined by maternal
–). Moreover, humans show seasonal changes in melatonin is able to generate an almost perfect tem-
melatonin production (, –), and melatonin poral adaptation of the offspring to the future day/
seems to act as a circannual synchronizer in humans, night cycle and the evolving seasons of the year.
despite no direct demonstration (–). In , an elegant paper showed for the first time
the effect of maternal melatonin in timing the circa-
Transgenerational and programming effects dian behavior of hamster pups (). They used SCN-
The daily maternal plasma melatonin rhythm typically lesioned arrhythmic dams (absence of circadian pineal
shows an increase in amplitude from the first to the melatonin rhythm) and injected them with melatonin
second and to the last third of pregnancy, reaching a in antiphase ( hours and  hours, different
maximum at term and returning to basal levels im- groups), using different concentrations, for  to  days
mediately after delivery, including in humans (–). during gestation. The pups wheel-running activity
This physiological regular increase of melatonin con- period and acrophase were measured at weaning, and
centration during pregnancy seems to be dependent, the average acrophases differed between groups by ~
in rats, on the number of fetuses and is under control hours and were correlated to the time of prenatal

REVIEW
melatonin injection to the pregnant dams. Moreover, photoperiodic information by using pinealectomy,
the different peaks of activity of the offspring were programmed nocturnal infusion of melatonin, and
exclusively determined by the time of melatonin in- exposure to different environmental postnatal
jection and were not dependent on the dose ( to  photoperiods (). In a complementary study,
mg) or the number of repeated days of injection ( or using the same experimental model and animal, the
). A similar set of experiments was done in rats to melatonin signal was efficient in transferring pho-
study the effects of maternal pinealectomy or superior toperiodic information dependent on the daily repe-
cervical ganglionectomy, with or without melatonin tition of the maternal melatonin signal (at least 
replacement for  days in late gestation, on the off- consecutive days) and it also showed an intrauterine-
spring circadian drinking behavior evaluated for sensitive window to the melatonin timing effect be-

 weeks immediately after weaning and during free- tween  and  days before birth ().
running condition (constant darkness) (). The The mechanism of this prenatal melatonin-
results show that the maternal melatonin circadian induced photoperiodic programming was recently
rhythm is also the determinant of the drinking be- elucidated () as it was shown that in Siberian
havior circadian rhythm of the offspring, even though hamsters, the maternal organism primes the fetal PT/
it was evaluated nearly  month after weaning. It is hypothalamic tanycytes system so that TSH gene
noteworthy that scattered drinking behavior acrop- expression in the neonatal PT-specific thyrotroph
hases are present both in pups born to pinealectomized regulates tanycytes deiodinase gene expression in
dams and in pups born to ganglionectomized ones. It is accordance with the photoperiodic history experi-
well known that pinealectomized mammals present no enced during pregnancy. As shown, this intrauterine
circulating melatonin and that ganglionectomized ones melatonin programming effect uses the same mech-
present a residual circulating melatonin throughout the anism that is used to regulate the seasonal effect in
-hour cycle of ~% of the amount of intact animals adult animals.
(). This might indicate that the critical factor de-
termining the transplacental circadian timing of mel-
atonin is the maternal pineal melatonin circadian Melatonin and the Conundrum of Diurnal vs
fluctuation. Therefore, as observed for the chronobiotic Nocturnal Species: Similarities and Differences
effect of melatonin, the transgenerational timing effect
depends on the daily repetition and on the contrast The preceding discussion of the ways of action and
between day and night concentrations of maternal effects of melatonin should be taken into account to
melatonin. This transgenerational timing effect of understand the similarities and differences in the
melatonin was explored at molecular levels (), in physiological effects and regulation of melatonin on
different organs and physiological systems and in both diurnal or nocturnal species. When considering this, it
altricial and precocious species, and it is addressed in is reasonable to recognize that some of the immediate
published reviews (, ). and prospective effects of melatonin might be different
The first convincing demonstrations of in utero according to the daily distribution of the activity/rest
transplacental transfer of daylength information cycle of the studied species. In fact, in nocturnal species
came from research articles that studied the growth such as rats, the immediate effects of melatonin, de-
and reproductive development in voles (Microtus duced from melatonin receptor knockdown, pineal-
montanus) (, ). Studies of gonadal develop- ectomy, and/or melatonin replacement experiments,
ment in Djungarian hamsters and the effects of result in increased insulin sensitivity, higher glucose
prepubertal photoperiodic responses showed for the tolerance, and increased activity, temperature, and
first time that maternal transfer of photoperiodic energy expenditure, in addition to resetting the bar-
information influences prepubertal responses to oreflex so that the rising of blood pressure is limited.
postnatal different daylengths (). Additionally, Alternatively, the prospective effects of melatonin in
this maternal–fetal transfer of photoperiodic information nocturnal species include, for example, daytime he-
was so skillful that vole offspring (Microtus penn- patic insulin resistance and gluconeogenesis.
sylvanicus) expressed different postnatal responses Conversely, melatonin immediate effects in diurnal
depending on the night duration experienced by species involve, for example, the induction of sleep,
their mothers: pups born in the autumn (long nights blood pressure and temperature dipping, cortisol se-
of shorter duration) have much thicker coats than cretion blockade, and induction of insulin resistance
do those born in late winter (long nights of longer and glucose intolerance. The prospective effects are the
duration) (). induction of daytime insulin sensitivity, pancreatic
The study of maternal–fetal transfer of photo- higher sensitivity to glucose and incretins-induced
periodic information in Djungarian hamsters insulin secretion, regulation of daytime blood pres-
showed for the first time that the maternal pineal sure, and energy balance.
melatonin daily profile was fundamental for the As can be seen, despite several immediate effects
proper maternal–fetal intrauterine transference of being different and opposite in direction, the biological
REVIEW
role played by melatonin is to trigger at the nocturnal Additionally, in both species, melatonin acts as a
phase, by its immediate effects, the proper adaptive powerful chronobiotic. It means that the consecutive
mechanisms to the considered species for that phase of and repetitive daily nocturnal presence of melatonin
the day and, additionally, to prepare, by its prospective and the contrast between high nocturnal concentra-
effects, the physiology and behavior to be adaptive tion and diurnal absence or very low concentration
when the complementary daytime phase arises. help to properly set the circadian clock so that the
In other words, in general, the immediate and typical circadian physiology and behavior of the
prospective effects of melatonin determine the same considered species is synchronized to the environ-
events both in nocturnal and in diurnal mammals, but mental light/dark cycle of the day and night. So, in
in opposite phases of the daily cycle. addition to considering the immediate and prospective

Unfortunately, the immediate effects of melatonin effects of melatonin, its chronobiotic effects should be
are the only ones usually considered and discussed in accounted for to better understand its physiological
the literature, as is the case with the discussion about action and resulting effects to establish a proper pu-
the role played by melatonin in the regulation of tative therapeutic application.
energy metabolism, particularly in insulin production,
secretion, and action. It is well demonstrated in
nocturnal mammals (e.g., rats, mice, bats) that the Melatonin, Physiology, Pathophysiology, and
immediate effects, caused by the actual presence of Clinical Application
melatonin, are the sensitization of the organism to the
action of insulin, either by potentiating the insulin The accurate understanding of melatonin physiological
receptor transduction pathways or its peripheral ac- and clinical effects is challenging, as several aspects should
tion, mainly increasing GLUT-dependent glucose be taken into consideration and properly perceived so
uptake in muscle and adipose tissues. It is also shown that its functional characteristics will be adequately
that the absence or reduced production of melatonin interpreted in any considered system or function. The
during the night induces insulin resistance and glucose present literature often brings limited highlights of few
intolerance. The same effects were demonstrated in functional aspects of melatonin, for example, mainly
MT and/or MT knockout mice. emphasizing the immediate effects, or the super- “Experimental studies show
that melatonin might affect
Alternatively, in humans, the immediate effect of sentization effect, or only the chronobiotic or seasonal the sleep mechanism itself, in
melatonin is the opposite: insulin resistance and effects. However, one should keep in mind that mela- addition to circadian control.”
glucose intolerance. Moreover, nocturnal reduction of tonin physiology is integrative per se and is dependent on
melatonin production or reduction of its effects due to the ontogenetic, daily, and seasonal history of its secretion
putative single nucleotide polymorphisms of its re- profile, and on its vastness of actions and resulting effects.
ceptors induces daytime defective insulin release in Owing to its special characteristics, pineal mela-
response to an overload of glucose, owing to insulin tonin is a privileged molecule acting through several
resistance and glucose intolerance. mechanisms and in almost all levels of the physiology
In fact, the nocturnal production of melatonin is of the organism. As previously stated, it acts by reg-
one of the major determinants of the physiological ulating basic cell biology phenomena (, , , ,
insulin sensitivity during the day in humans, and –) in almost every cell type. As far as its
during the night in nocturnal rodents. The overall functional integrative action is concerned, melatonin
effect of melatonin is the same in both species. If only acts both centrally and peripherally in almost every
the immediate effects of melatonin were taken into level of several physiological systems: the CNS, every
consideration, melatonin and insulin would be clas- component of the CVS, the energy metabolism system,
sified as having opposite effects, which is not the case the reproductive system, the immune system, the
as far as regulation of carbohydrate metabolism is hydroeletrolytic regulation system, the respiratory
concerned. system, the endocrine system, bone, and others. The
The adequate therapeutic use of melatonin is ways of action and integrative role of melatonin allow
highly dependent on the proper understanding of its the amplification and diversification of its functional
immediate and prospective effects. For rodents, noc- action, mainly in the time domain [time domain
turnal administration of melatonin increases noctur- molecule, “time messenger” ()] so that it enables
nal insulin sensitivity and daytime hepatic insulin the organism’s physiology for dealing with the present
resistance. In humans, nocturnal administration of challenges (immediate effects) and, at the same time, it
melatonin induces nocturnal insulin resistance and prepares the organism to deal with future predictive
diurnal insulin sensitivity. So, in both species the events (prospective effects), in addition to synchronize
accurate replacement of melatonin during the night the organism’s physiology and behavior to the daily
induces insulin sensitivity in the respective activity/ and annual photoperiodical cycles.
feeding circadian phase. Therefore, the adequate Consequently, it should always be taken into
nocturnal presence of melatonin is essential for the consideration, as far as experimental (even in vitro
determination of the daily cycle of insulin action. experiments) or clinical studies and treatment are

REVIEW
concerned, that melatonin effects will depend on the melatonin. Therefore, melatonin acts mainly in humans
time and route of administration, on the concentration as a powerful circadian zeitgeber (, ).
and duration of the signal, on the regularity of the daily Based on the melatonin well-defined PRC, its
repetition, and on the traits of the target organ (presence immediate and prospective effects, and its strategically
or absence of different melatonin receptors and the timed repetitive daily prescription, this hormone has
associated transduction pathways). successfully been clinically used as a chronobiotic
A literature search, early in , showed that there agent. It is used to entrain daily rhythms mainly in
were  to  clinical studies ( in the last  clinical syndromes involving circadian rhythm dis-
years) that used melatonin, among which almost  orders, such as the syndromes involving temporary or
were randomized clinical trials. Additionally, from permanent circadian misalignment as jet lag, the

 to July , there were  systematic and delayed sleep phase disorder, seasonal affective dis-
narrative reviews about the effects of the clinical use of order, and others and in clinical disorders causing
melatonin ( on melatonin and neurologic and circadian free running as it occurs in the non–-hour
psychiatric diseases, including sleep disorders, and  sleep–wake rhythm disorder, either in totally blind or
on melatonin and cancer, among others) (). Ad- sighted patients (, , –).
ditionally, patents and patent applications related to Importantly, note that melatonin prescription as a
the therapeutic applications of melatonin and its chronobiotic agent should rigorously follow the mela-
analogs claimed from  to September  pre- tonin PRC, taking, in every case, the DLMO as the
dominantly focused on CNS effects (including sleep reference phase to decide the time of melatonin ad-
and circadian disorders, neuroprotection), cancer, and ministration in accordance with the desired effect, that is,
immunological applications (). either phase advance or phase delay (). Additionally,
Finally, considering the above-mentioned aspects the duration of the treatment will depend on the case
of experimental and clinical studies and their extent, it being a transient one (as it is the case for jet lag) or a
follows a selective list of melatonin physiological longer one (as for the treatment of delayed sleep-phase
functions and clinical applications that is surely far disorder or non–-hour sleep–wake rhythm disorder).
from being complete. An embracing approach would
require another text exclusively focused on melatonin Melatonin and sleep
physiology, pathophysiology, and clinical application. The association between melatonin and human sleep
Additionally, to the interested reader, there are several started to be studied in the early s (). In the
reviews that can be consulted for more embracing early s low doses of melatonin, generating near
aspects of melatonin clinical applications (–). nocturnal physiological plasma levels, were able to
The discussion that follows, referenced by melatonin reduce sleep-onset latency and oral temperature,
ways of action as described previously, is centered triggering the usual polysomnographic patterns of the
on some specific melatonin functions and dys- nocturnal sleep architecture observed in young people
functions, namely, circadian and seasonal rhythmic (, ). By the end of the s it was suggested
regulation, sleep–wake cycle, energy metabolism, CVS, () that the beginning of nocturnal melatonin
and, owing to pineal melatonin privileged access to the production is phase locked to the end of the “for-
CNS, its neural putative action. Melatonin action on bidden zone” and to the opening of the “sleep gate”
these systems show the most consistent clinical effects () [zones of increased arousal and induced hyp-
to date. nogogic mechanisms, respectively or, as proposed by
Circadian rhythms and sleep are, by far, the most Moruzzi (), the respective appetitive and con-
frequently studied areas for melatonin clinical appli- summatory sleep behavioral stages], thus triggering the
cation, which led to almost all of its pharmaceutical- nocturnal circadian episode of sleep. This conception
developed analogs. Next in line is ischemia/ attributes to the nocturnal production of melatonin
reperfusion either in the CNS or heart; energy the property of switching the organism from the bi-
metabolism and diabetes are probably the next im- ological day (in diurnal species: arousal, energy intake
portant clinical application to be considered; and the and storage, high cortisol, and active interaction with
CVS pathophysiology, including hypertension, is one the external environment) to the biological night (in
of the most promising future areas of melatonin diurnal species: sleep, low temperature, energy con-
clinical application. It is noteworthy that some areas sumption, low cortisol) [as defined in ()], sug-
that show a huge advance in preclinical studies, such as gesting that melatonin might promote sleep by
cancer and reproduction, still lack clinical controlled regulating the activity–wake/rest–sleep circadian
studies to establish, in these cases, a reliable melatonin rhythm probably by its actions on melatonin receptors
clinical application. in the SCN ().
A randomized clinical trial to study disturbed sleep
Melatonin and circadian rhythms in a population of adults with developmental brain
The following discussion is complementary to the disorders suggested that the efficacy of melatonin
above-discussed chronobiotic and seasonal effects of treatment (irrespective of the dose) was dependent on
REVIEW
the beforehand amount of endogenously produced The chances of odd results are higher because a greater
melatonin, being that the exogenous melatonin was number of individuals may be inappropriately re-
more effective as the lower was the individual natural sponsive to the determined dose, differently from what
nocturnal production (). Confirming the hypoth- would be expected for a small sample study. This
esis of melatonin regulating sleep by acting on the would probably reduce the magnitude of the effect of
circadian rhythm, this study showed that melatonin melatonin in the analyzed outcome. However, one
treatment induced an increase in the day-to-night should be cautious, and more adequately planned and
activity ratio (rhythmic amplitude) and a decrease controlled studies that take into consideration mela-
in the fragmentation of the rhythm, increasing its tonin ways of action and effects, the melatonin PRC,
stability, as evaluated by actgraphic records. and, above all, individual differences will surely help to

The importance of physiological levels of pineal better understand the real therapeutic value of mel-
melatonin for human sleep was assessed by studies on atonin on human sleep.
pinealectomized patients. Despite some contradictory
reports (, ), these patients presented a disrupted Melatonin, energy metabolism, body weight,
-hour circadian rhythm, a reduction of total sleep and diabetes
time, more nighttime awakenings, poor sleep quality, Melatonin is an important player in the regulation of
and, in most cases, all symptoms were reverted by energy metabolism, including body weight, insulin
melatonin treatment (–). sensitivity, and glucose tolerance ().
Experimental studies show that melatonin might Melatonin, through its immediate and prospective
affect the sleep mechanism itself, in addition to cir- effects, regulates energy metabolism, acting in every
cadian control. MT and/or MT knockout mice step of the energy balance, including energy intake
studies showed that the MT melatonin receptor (eating), energy flow to and from storages, and energy
seems to be associated with the incidence of rapid eye expenditure. Additionally, melatonin, through its chro-
movement sleep episodes whereas the MT melatonin nobiotic and seasonal effects, synchronizes energy meta-
receptor was associated with the incidence of nonrapid bolism requirements to the daily and annual rhythmic
eye movement episodes (sleep spindles and delta environmental photoperiod.
waves) (, ). The association of MT to nonrapid Energy metabolism seasonal cycles in mammals are “The CNS is a privileged target
eye movement electroencephalographic patterns was characterized by increased food intake and accumu- for melatonin physiological
demonstrated to be dependent on melatonin action on lation of reserves, mainly fat, during spring and action.”
MT receptors present in reticular thalamic neurons. summer, followed by reduced appetite and use of
Recent reviews and meta-analysis studies of mel- stored energy during winter (in addition to, in some
atonin or its analogs effects on sleep disorders points to cases, a hypometabolic state of torpor or hibernation)
its efficacy in reducing sleep latency, increasing total (, ). These circannual metabolic events are
sleep time, and reducing night awakenings, in addition synchronized by the annual change in photoperiod
to improving overall sleep quality (, , –). and the consequent nocturnal variation of melatonin
Melatonin, or its analogs, seems to be effective in profile duration ().
managing primary insomnia in elderly people, sleep Alternatively, the circadian distribution of energy
disorders associated with neurologic disorders and metabolism functions allows the synchronization of
neurodegenerative diseases (autism, attention-deficit typical behaviors associated with energy harvesting
hyperactivity disorder, Parkinson disease, Huntington and eating, which occur during the active/wakefulness
disease, Alzheimer’s disease), patients with hyperten- phase of the day, with metabolic physiological mod-
sion taking beta-blocker, and rapid eye movement ifications that assure energy utilization and storage for
sleep behavior disorder (, –). later use. This daily phase is necessarily associated with
Note that all of the above-mentioned studies are in high central and peripheral sensitivity to insulin and
line with the daily experience in medical practice, high glucose tolerance, elevated insulin secretion, high
where most of the patients report positive results, glucose uptake by the insulin-sensitive tissues, gly-
especially regarding subjective well-being and quality cogen synthesis and glycolysis (hepatic and muscular),
of sleep. Despite that, some guidelines state that the blockade of hepatic gluconeogenesis, increased adi-
effects of melatonin or its analogs (apart from effects pose tissue lipogenesis, and adiponectin production.
on sleep latency and circadian sleep disorders) are The complementary rest/sleep phase of the day is
small, of low strength, or insufficient (–). These characterized by fasting associated with the conse-
guidelines are mainly based on systematic or narrative quent use of stored energy for life maintenance. This
reviews that are based on the few randomized placebo- phase of the energy metabolism daily cycle exhibits
controlled clinical trials. Additionaly, as shown below, reduced glucose and incretins-induced pancreatic
the dosage of melatonin should be individually ad- insulin release, insulin resistance, accentuated hepatic
justed and would vary among patients. In randomized gluconeogenesis and glycogenolysis, adipose tissue
clinical trials, a fixed and determined dose is usually lipolysis, and leptin secretion. Melatonin is responsible
prescribed to everyone in a relatively large population. for this daily distribution of energy metabolism

REVIEW
functions (, , , ). Pinealectomized rats cell sensitization to cAMP agonists insulin-secreting
show disturbed energy metabolism daily cycles and agents. Additionally, nocturnal melatonin secretion is
metabolic disorders resulting in increased body weight responsible for human b cell survival, contributing to
associated with increased food intake and reduced the preservation of b cell mass and function, including
energy expenditure (). Melatonin replacement to in patients with type  diabetes ().
pinealectomized rats or supplementation to young, The importance of regular melatonin daily secre-
middle-aged, or old rats induces body weight tion determining daytime high insulin sensitivity is
reduction, a decrease in food intake, and an increment well demonstrated by several clinical and epidemio-
in brown adipose tissue energy expenditure (–). logical studies showing an association between low
This energy imbalance toward reducing body weight is producers of melatonin and insulin resistance, so that

likely due to melatonin action on hypothalamic food the magnitude of nocturnal melatonin secretion was
intake circuits, intensifying the anorexigenic signals independently and inversely associated with insulin
and decreasing the orexigenic signals (, ). resistance () and lower melatonin secretion was
In postmenopausal overweight women there is a independently associated with a higher risk of de-
negative correlation between the levels of melatonin veloping type  diabetes (). Moreover, there are
urinary metabolite (-sulfatoxymelatonin) and body several research articles showing an association be-
mass index (). Moreover, in a randomized placebo- tween melatonin receptor dysfunction, resulting from
controlled trial, chronic daily melatonin administra- single nucleotide polymorphisms, and type  diabetes,
tion to postmenopausal women induced a reduction gestational diabetes, and insulin resistance associated
in fat mass and increased lean mass (). In other with polycystic ovary syndrome (–).
randomized clinical trials, melatonin treatment was Additionally, in rats, melatonin participates as an
able to counteract the usual metabolic effects of important epigenetic factor regulating fetal and/or
second-generation antipsychotic drugs such as olan- neonatal programming of adult energy metabolism
zapine and clozapine, including attenuating body ().
weight gain and reducing body fat mass, triglycerides, Given the above discussion, several points are
and total cholesterol levels (–). Also note that a stressed as far as melatonin and insulin sensitivity in
reduction in diastolic blood pressure was also dem- humans is concerned. First, differently from what
onstrated in some of these studies. might be suggested by the title of some recent papers
Melatonin regulates the flux of nutrients to and (), nocturnal melatonin seems to be an important
from storages, regulating insulin secretion and insulin and necessary determinant of daytime insulin sensi-
action. In nocturnal mammals, such as rats, pineal- tivity provided its signal is restricted to the night and
ectomy induces a diabetogenic syndrome that includes the individual has a normal response to melatonin
glucose intolerance as well as peripheral (hepatic, adi- (e.g., no melatonin receptors genetic variants). Thus, at
pose, and skeletal muscle) and central (hypothalamus) the very beginning of the day, melatonin production
insulin resistance. Melatonin replacement therapy is should be interrupted to induce daytime insulin
able to revert all the above-mentioned symptoms [see sensitivity and high b cell sensitivity to incretins-
() for a review]. The absence of melatonin results induced insulin secretion. When that does not oc-
in a reduced total amount of GLUT in all of the cur for any reason, as when there is a misalignment
insulin-sensitive tissues (white and brown adipose tis- between the sleep duration and the phase of the
sue, skeletal and cardiac muscle) and impaired central waking time and melatonin secretion, it causes an
and peripheral insulin signaling (). Additionally, in episode of early morning insulin resistance and hy-
rats, nocturnal activation of melatonin immediate ef- perglycemia, as it is seen in short sleepers, especially
fects regulates diurnal insulin sensitivity (, ). in a population showing an MTNRB (MT) gene
In humans (diurnal mammals), acute adminis- variant (, ). Another observation is related to
tration of melatonin induces glucose intolerance both the clinical use of melatonin supplementation.
in the morning (decreasing insulin release) and in the Depending on the melatonin metabolizing charac-
evening (decreasing insulin sensitivity) (). Alter- teristics of the individual (see below) and its re-
natively, reduction of nocturnal melatonin by pho- sponsiveness to melatonin, and owing to the nocturnal
toinhibition induces diurnal whole-body insulin dose and formulation, the pharmacological-induced
resistance calculated by Matsuda’s composite index, melatonin profile (therefore, not amenable to the
and light at night disrupts the expected circadian daytime photoinhibition phenomenon) might extend
response to morning GLP-–induced insulin release to the early hours of the morning, resulting in an
(, ). These data indicate that even for humans, iatrogenic insulin resistance and hyperglycemia in the
the nocturnal melatonin profile, despite inducing morning.
immediate insulin resistance (what is physiologically
expected to occur during the nighttime rest phase of a Melatonin and the cardiovascular system
daytime active species), prepares, through its pro- The effects of melatonin on the CVS are well known.
spective effects, the daytime insulin sensitivity and b Since the s melatonin was shown to be important
REVIEW
in the regulation of the CVS (, ) and in par- on the CSF due to the particular anatomy of the pineal
ticular of blood pressure. Removal of circulating epithalamic insertion, its vasculature, and the intimate
melatonin by pinealectomy, in rats, causes hyperten- interaction with the third-ventricle pineal recess (,
sion, and melatonin replacement either prevents or ). Additionally, the circulating melatonin might, as
obviates this effect. well, go to the CSF, increasing the CNS melatonin
In addition to blood pressure, melatonin plays an concentration (, ). Melatonin concentration is
important role in the regulation of several others highest in the third ventricle [where it seems to be
parameters of the CVS, including heart rate and directly released by the pineal gland, probably medi-
vascular resistance (, ). Melatonin regulates the ated by the tanycytes, as previously suggested ()],
CVS using receptor- and non–receptor-mediated ef- reduces in the lateral ventricle and cisterna magna, and

fects, immediate, prospective, and chronobiotic ways at the lumbar level it is almost equal to the blood, even
of action. Among the non–receptor-mediated effects in humans (–). For being present in the CSF,
the most important are the antioxidant mecha- melatonin has a privileged and rapid access to neurons
nisms and melatonin action regulating mitochon- and glia, including the ones located far from the
drial function (, ). Melatonin receptors are ventricular system and subarachnoid space, mainly by
present throughout the CVS, including the heart the Virchow–Robin perivascular and extracellular
(cardiomyocytes, left ventricle, and coronary arteries), spaces (, ). Despite the previously mentioned
blood vessels, and CNS structures involved in CVS difference in CSF melatonin concentration, the CSF
regulation (–). As far as blood pressure regu- melatonin profile follows the same circadian pineal
lation is concerned, in addition to its critical impor- production and blood concentration profiles and it is
tance in the regulation of blood pressure circadian subjected to the same general rule of photoinhibition,
rhythms (high during the active phase of the day and free running, and disappearance after peripheral
low during the rest phase of the day) (, , ), sympathectomy, as is the circadian pineal production
melatonin acts centrally, in the hypothalamic para- (, ). Additionally, the CSF melatonin profile/
ventricular nucleus, probably reducing the sympa- concentration might be correlated with several neu-
thetic and the hypothalamic–pituitary–adrenal axis rologic disorders such as traumatic brain injury,
outputs (, , ), in the area postrema (), movement disorders, delirium, and major depressive “Melatonin is considered one
of the most promising
regulating the baroreflex set point, reducing the sym- and bipolar disorders (, –). neuroprotective agents to be
pathetic tone, and increasing the parasympathetic tone, As a complementary factor indicating the impor- tested in large clinical trials.”
in the caudal ventrolateral medulla and/or the rostral tance of melatonin action in the CNS, its receptors are
ventrolateral medulla regulating heart rate (), and, widely distributed in several CNS structures, including
peripherally, acting in the heart, kidney, and directly in neurons and glial cells (–).
the blood vessels, mediating vasoconstriction and va- Considering the privileged access of melatonin
sodilation (, , ). Another additional mecha- directly to the CNS, there is much evidence that it
nism to be considered is the well-known functional might regulate neural functions in two different ways.
interplay between melatonin and the renin–angiotensin In one way, melatonin acts on the general aspects of
system, particularly involved in the regulation of the the neural function, such as neurotransmission and
blood pressure circadian rhythm (–). Moreover, synapse plasticity, neurotrophism, neuroprotection
melatonin participates as an important epigenetic factor (antioxidant, anti-inflammatory, DNA stability and
regulating fetal and/or neonatal programming of adult repair, neurogenesis), and neuroplasticity (neural de-
blood pressure (, ). velopment, neural stem cell proliferation, neuron
In humans, in addition to regulating the daily maturation, dendritogenesis and axogenesis, and basic
rhythm of blood pressure, melatonin is directly in- mechanisms of long-term potentiation and long-term
volved, by immediate effects, in the control of the depression). In the second way, melatonin acts by
expected blood pressure dipping that occurs during regulating specific functions, including circadian and
the night (–). Despite the need for larger-scale seasonal rhythms, reproduction, energy metabolism,
randomized control trials and the existence of some sleep, blood pressure, and others.
contradictory results, the accumulated experimental The following discussion is centered on the general
and clinical evidence points to the importance of mechanism of melatonin action on neural function
melatonin in human cardiovascular events such as regulation.
ischemia/reperfusion injury, myocardial chronic in- The role played by melatonin in neurotransmission
termittent hypoxia injury, pulmonary hypertension, regulation and synaptic plasticity has been known for a
hypertension, valvular heart diseases, and vascular long time (–). The cellular basis of this action
diseases (–). has been recently revealed (, ). Through pro-
teomic and genetic approaches defining protein
Melatonin and the CNS interactome, in addition to functional studies, the
The CNS is a privileged target for melatonin physi- MT melatonin receptor was found at the pre-
ological action. There is a direct release of melatonin synaptic membrane in all studied areas of the CNS

REVIEW
(hypothalamus, striatum, hippocampus, and cerebral concentrations of polyunsaturated fatty acids that
cortex), together with the major components of the importantly contribute to the oxidative processes.
active zone, as the voltage-gated calcium channel Additionally, it is well known that the CNS is a ready
Cav., that, by itself, might connect the melatonin target for oxidative stress because the brain represents
receptor to other synaptic proteins such as SNAP, only % of the body weight, receives % of the cardiac
Munc-, and synapsin (). Moreover, patch-clamp output, and consumes % of the total body oxygen
experiments demonstrated that MT receptors interact (), producing more ROS than any other organ and
with voltage-gated Cav. channel and inhibit pre- tissue. Therefore, scavenging ROS is a prominent
synaptic Ca+ entry, providing a molecular and elec- matter because neuronal cells might be injured by
trophysiological basis for the explanation of a putative oxidative or nitrosative stress, affecting several phys-

general mechanism used by melatonin to regulate iological and behavioral functions and eventually
neurotransmitter release and, in consequence, to contributing to the origin of neurodegenerative diseases
modulate neural function. Moreover, MT receptor such as Parkinson disease, Alzheimer’s disease, and
interactomes include the presence of several ion others (). Melatonin seems to own the most critical
transporters and channels, such as the electroneutral importance to accomplish this antioxidant function,
potassium chloride cotransporter  (SLCA), the most probably contributing to the prevention of neural
zinc transporters SLCA and SLCA, and the and consequent systemic disorders ().
electroneutral Na/HCO cotransporter SLCA. In Melatonin is a potent, endogenously produced
support of this finding, a putative functional association direct free radical scavenger and broad-spectrum
between the MT melatonin receptor and G protein– antioxidant. Additionally, mediated by its melatonin
coupled inwardly rectifying potassium channels was receptor–dependent action, melatonin expresses an
shown to mediate the inhibitory firing rate and the indirect antioxidant effect upregulating and activating
phase-shifting effect of melatonin in the SCN (, ). the classical antioxidant enzymes (, ). In the
More recently, extending the putative effect of mela- antioxidant action of melatonin, it should be considered
tonin to synaptic function and plasticity, studies in mice that one of the main CNS melatonin metabolization
showed that melatonin is directly associated to the process is via N-acetyl-N-formyl--methoxykynuramine
hippocampal and striatal daily variation of postsynaptic and N-acetyl--methoxykynuramine, both potent scav-
density of SHANK protein (SH and multiple ankyrin engers of oxygen and nitrogen free radicals (). This
repeat domains, or proline-rich synapse-associated cascade reaction makes melatonin highly effective, even at
protein) (). SHANK is a postsynaptic protein low concentrations, in protecting the brain from oxidative
associated with dendritic spine growth and maturation, damage ().
synapse formation and maturation, and, ultimately, An important tentative application of the CNS
brain plasticity (, ). Its dysfunction is usually melatonin neuroprotective antioxidant effect is in
associated with a number of neurologic disorders such hypoxic ischemic encephalopathy (HIE), one of the
as schizophrenia, autism spectrum disorder, and Alz- most important reasons for morbidity and mortality
heimer’s disease (). of newborns all over the world (). In HIE, thera-
In addition to this general action on synaptic ac- peutic hypothermia became a standard treatment of
tivity regulation, melatonin regulates neurotrophic newborns $ weeks of gestation, with neonatal
factors expression (glial cell line–derived neurotrophic encephalopathy related to an intrapartum hypoxic
factor, brain-derived neurotrophic factor, conserved event (). In a recent prospective trial (), in-
dopamine neurotrophic factor, nerve growth factor, volving  term newborns,  with HIE and  healthy
persephin, and mesencephalic astrocyte-derived neu- controls, half of the patients were only treated with
rotrophic factor) [see () for a review] and/or po- hypothermia and the other half were treated with
tentiates their neuronal signaling pathway, as for hypothermia and melatonin ( mg/kg daily for five
insulin and IGF- (, ). enteral doses). They found that the melatonin/
Perhaps one of the most important general actions hypothermia group had better results on the follow-
of melatonin in the CNS is neuroprotection. Using up as far as seizures measured by electroencepha-
several cellular and systemic mechanisms, melatonin lography and white matter abnormalities evaluated by
protects neuron and glial cells from degenerative ac- MRI are concerned. This group also improved survival
tions induced by internal or external insults. Mela- with better neurodevelopmental outcome according to
tonin antioxidant action is an example. Melatonin is Denver Developmental Screening Test II. In this way,
highly present in the CNS, as seen before, and due to melatonin is considered one of the most promising
its special permeability, it might permeate several neuroprotective agents to be tested in large clinical
cellular compartments, in particular the cell mem- trials (–). A more extensive review about
brane and brain mitochondria (–) where melatonin effects on brain ischemia can be read
melatonin is also synthesized (). The neural tissue of elsewhere (, ).
the CNS contains relatively low antioxidant enzyme Other general aspects of melatonin actions on the
levels compared with other tissues and contains high CNS are anti-inflammatory action (–), DNA
REVIEW
stabilization and repair (, ), neurogenesis, neural internal circadian phase determination. That is why
development, and neural stem cell protection (–), saliva is usually collected at the beginning of the
dendritogenesis and axogenesis (–), and learning, evening and should not be collected during the night.
memory, and long-term potentiation and long-term Alternatively, urinary -sulfatoxymelatonin excretion
depression (, , –). is directly proportional to the total amount of mela-
Apart from the regulation of specific functions, tonin produced in a given night, provided that the
melatonin seems to play an essential role in keeping patient rests under a low level of environmental il-
the cellular and systemic integrity of the CNS and lumination. Urine collection from dusk to the first
preventing neural damage and eventually contributing urine excretion in the following morning (e.g., the
to prevent the development of neurodegenerative patient should discard the urine excretion at 

diseases. hours or  hours and start collecting all of the
Importantly, note that several neurologic disorders produced urine until  hours or  hours the next
(delirium, major depressive and bipolar disorders, morning) is an excellent index of the total nocturnal
autism, attention deficit and hyperactivity disorder, production of melatonin. The amount of melatonin
migraines), including the neurodegenerative diseases produced during the night is directly proportional to the
such as Parkinson disease, Huntington disease, and -sulfatoxymelatonin excreted load that is calculated as
Alzheimer’s disease, present a concomitant and drastic concentration times the total nocturnal urine volume.
reduction in pineal melatonin production, supporting The ratio between -sulfatoxymelatonin and urinary
the routine guidelines to use melatonin as a thera- creatinine is usually calculated for the normalization by
peutic adjuvant in these neurologic disorders (, the patient’s renal function.
–, –). The values of nocturnal melatonin or -sulfa-
toxymelatonin vary individually and according to
sex and age. In any case, despite the great variability
Description and Characterization of Clinical of the values, comparison with a control population
Syndromes Involving Melatonin Dysfunction is feasible, provided it was sampled in accordance
with the desired clinical design, always paired by sex
Unhealthy low or high hormonal synthesis and actions and age.
are classically described in human pathophysiology.
Considering melatonin as a hormone, the present Hypomelatoninemia
section aims to define the syndromes characterized by Hypomelatoninemia is defined by decreased melato-
hypohormonal or hyperhormonal production and by nin nocturnal peak value or total production when
impaired receptor signaling. compared with what is expected for the age- and sex-
However, as the time domain is one major de- paired population. Putatively, several symptoms may
terminant of melatonin action (duration, daily repe- derive from this syndrome that will vary according
tition, immediate and prospective effects, chronobiotic to the basal underlying pathology: circadian and
effects, seasonal effects), there are some putative sleep disorders (insomnia, chronic daytime fatigue
melatonin-related syndromes that are characterized or somnolence, delayed sleep onset, non–-hour
not by hyperproduction or hypoproduction but by the sleep–wake syndrome); hypertension; insulin re-
temporal displacement or extension of melatonin’s sistance and glucose intolerance; dyslipidemia; obesity;
daily profile. Adequate melatonin measurement is a metabolic syndrome; higher risk of type  diabetes;
crucial point, and several observations should be made higher risk of cancer, mainly breast and prostate
relative to this point. cancer; low-quality aging process, such as frailty
First, it is possible to measure blood levels of syndrome, and others. However, differently from
melatonin, saliva melatonin, and -sulfatoxymelatonin other classical hormonal hypofunction syndromes,
in the urine (Fig. ). Differently from any other hypomelatoninemia is usually not found in isolation,
hormone measurement, where the biological samples as it can be seen below, being either a participant of a
are usually collected during the morning hours, either complex genetic disease syndrome or associated with
for blood or saliva melatonin, samples should be several other diseases, the aging process or environ-
collected during the evening and the night, at very low mental disruptors. As a result, the full picture of the
level of illumination, preferably avoiding the blue putative hypomelatoninemia syndrome is rarely seen.
spectrum of light. Ideally, the patient will be in a dark More frequently, fragments of it such as sleep dis-
room or under red light of very low intensity (, lux) turbances and circadian rhythms disorders are the
and have the sample collected every  minutes or more prominent clinical hallmarks, and those should
hour during the evening for DLMO determination not be seen as modest abnormalities but rather as very
(), one of the best indexes of the internal circadian serious ones with systemic repercussions that interfere
timing, or, even during the entire evening/night for with every other aspect of human physiology and
other purposes. Also note that blood collection should behavior, jeopardizing health, quality of life, and even
not affect the patients’ sleep, as it may lead to flawed longevity.

REVIEW
Sleep deprivation is a well-known cause of meta- resistance/diabetes, hypertension, obesity, immuno-

bolic disorders such as obesity, insulin resistance, deficiency, and a higher incidence of tumors. Some of
diabetes, and metabolic syndrome in both children these signals and symptoms could be obviated by
and adults (–). A subtle daily decrease of  melatonin replacement therapy, probably indicating
minutes in the night sleep episode, for example, may the pathophysiological role played by the natural re-
not be perceived by the patient or by the physician, but duction in melatonin production in aging.
it increases insulin resistance and body weight in early
diagnosed patients with type  diabetes, worsening the Primary hypomelatoninemia
metabolic picture (). Primary hypomelatoninemia is dependent on factors
Sleep disturbances derived from melatonin re- that directly affect the pineal or its innervation, em-

duction are clearly seen in pinealectomized patients bryonic formation, or pineal melatonin synthesis as a
(pineal surgical removal usually as a consequence of result of a genetic or innate disease. It might be de-
pineal tumors or cysts) (see “Melatonin and sleep”). pendent on pineal agenesis or hypoplasia, sympathetic
However, in the case of these patients who pres- pineal innervation agenesis, and biochemical defects in
ent a clinical situation where the unique hypo- pineal melatonin synthesis, as is the case in gene
melatoninemia syndrome is represented, there are no polymorphisms linked to the enzymes involved in the
complete, prospective, and embracing studies so far, melatonin synthesis pathway (tryptophan hydroxylase,
and the only available ones are restricted to certain AANAT, or acetylserotonin O-methyltransferase)
aspects of the expected syndrome such as sleep, cir- (–). The absence of circulating melatonin that
cadian rhythms, and eventually some hormonal se- follows surgical pinealectomy should be considered
cretion such as GH, cortisol, prolactin, and ACTH primary hypomelatoninemia as well ().
disturbances (, –).
Alternatively, in aging, some of the typical clinical Secondary hypomelatoninemia
aspects of the expected hypomelatoninemia syndrome Secondary hypomelatoninemia develops as a conse-
are seen, such as sleep and circadian disorders, insulin quence of a primary event, such as another disease, or
as a consequence of environmental factors, including
medications (iatrogenic). Examples of diseases and
situations causing secondary hypomelatoninemia are:
18:00 – 23:00 23:00 – 07:00 7:00–11:00
spinal cord cervical transection, resulting in tetraplegia;
100 cervicothoracic sympathectomy, aging, neurodegen-
erative diseases (Parkinson disease, Huntington dis-
ease, Alzheimer’s disease, depression), genetic diseases
not directly linked to the origin of the pineal gland and
Melatonin (pg/ml)
its innervation (e.g., sepiapterin reductase deficiency

2500
leading to reduced serotonin synthesis and drastic
50 melatonin synthesis reduction without daily rhythm;
6-Sulfatoxymelatonin
fatal familial insomnia and Morvan syndrome); hy-

(ng/hour)
perglycemia associated with diabetes; obesity; exposure

0
to light at night; use of drugs that reduce melatonin
production (e.g., beta-blockers, calcium channel
blockers, inhibitors of angiotensin synthesis and ac-
0
500
tion) and shiftwork (, , , , , –,
–).
21:00 02:00 06:00
DLMO DLMOff Hypermelatoninemia
© 2018 Illustration Presentation ENDOCRINE SOCIETY Medical syndromes associated with hyperproduction
of melatonin are rare, and there are five clinical sit-
Figure 6. Daily curves of blood and saliva melatonin and urinary 6-sulfatoxymelatonin. Any of
uations described so far: spontaneous hypothermia
these parameters can be measured to show the daily profile of melatonin production. This figure
shows the curves deduced from values typical for young adults. The DLMO is best obtained by hyperhidrosis, hypogonadotrophic hypogonadism,
plasma melatonin (red curve and red axis) analysis, followed by saliva (blue curve and blue axis) anorexia nervosa, polycystic ovarian syndrome, and
assay. 6-Sulfatoxymelatonin (green dashed curve and green axis) is frequently assayed for urine Rabson-Mendenhall syndrome (which is a rare ge-
sampling, being the least invasive procedure for sample collection. Blood and saliva samples show netic disorder that shows pineal hyperplasia associ-
melatonin concentrations of the precise time of sampling, whereas urine measurements show the ated with a high level of plasma melatonin and
accumulated amount of 6-sulfatoxymelatonin during an interval of time, being usually expressed as
urinary -sulfatoxymelatonin) (–). Finally, the
the excreted amount of 6-sulfatoxymelatonin per time unit, as shown. Additionally, it is possible
to estimate the entire nocturnal melatonin production by measuring the concentration of 6-
iatrogenic hypermelatoninemia is characterized by
sulfatoxymelatonin in the evening/night accumulated urine collected in the early morning. It is high nocturnal values usually associated with ex-
advisable to refer the 6-sulfatoxymelatonin excretion rate to the renal function evaluated by the tended duration resulting in high morning levels of
concomitant assay of urinary creatinine. [© 2018 Illustration Presentation ENDOCRINE SOCIETY] circulating melatonin, which are determined by
REVIEW
inadequate control of prescribed melatonin. The inadequate receptor response may render the physi-
reported symptoms in hypermelatoninemia are di- ological system nonresponsive to the regulatory role
urnal sleepiness, sleep episodes, low body tempera- exerted by melatonin and, in consequence, it will
ture, dizziness, and hypotonia (). In the express a nonadaptive response to the daily and annual
spontaneous hypothermia hyperhidrosis syndrome, rhythmic behavioral and physiological demands. The
associated with high levels of circulating melatonin immediate consequence is chronodisruption, with the
also during the day (. pg/mL), it is described by symptoms described previously. The proposed pa-
an altered level of consciousness, even complete loss, thologies associated with melatonin receptor variants
and syncopal attacks with sweating and hypothermia are type  diabetes, gestational diabetes, sleep and
(body temperature  to °C). These symptoms as- circadian disorders, Graves disease, impaired meta-

sociated with a high level of melatonin ameliorate with bolic response to a hypocaloric diet, metastasis,
phototherapy and the patients are successfully treated polycystic ovarian syndrome, and others (–,
with beta-blockers (). ).
Circadian displacement
In this putative syndrome, the magnitude of the daily Therapeutic Use of Melatonin, Its
melatonin peak is usually not altered but the blood Pharmacokinetics and Toxicology
melatonin nocturnal curve is displaced in time. It
might be completely displaced to daytime as in the This section addresses general criteria to be considered
Smith-Magenis syndrome, delayed as in attention- when medical doctors intend to prescribe melatonin to
deficit/hyperactivity disorder, or it is extended to the their patients. It is more a series of questions to be
morning, surpassing the nocturnal sleep episode. It considered rather than the determination of specific
also may not be synchronized to the light/dark cycle at dose values, formulation, and time of administration
all, and it would rather be free running, as observed in [see (–) for a thoughtful review]. Moreover, in
some circadian rhythms disorders (e.g., totally blind spite of the several available melatonin receptors ago-
people). Depending on the case and the phase-shifting nists [e.g., Ramelteon® (RozeremÔ, Takeda Pharma-
desired effect, patients should be adequately treated ceuticals America, Inc., Deerfield, IL), Agomelatine®
with melatonin given at the right phase and dosage as (ValdoxanÔ, Servier Laboratories, Paris, France),
discussed elsewhere (). The symptoms associated Tasimelteon® (HetliozÔ, Vanda Pharmaceuticals Inc.,
with a circadian melatonin displacement are a result of Washington DC)], the present discussion is restricted to
the consequent chronodisruption and include sleep melatonin, the natural biological product [note that
and awake states assigned to unusual times, daytime Circadin® (Neurim Pharmaceuticals Inc., Tel-Aviv, Is-
somnolence or even sleep episodes, low diurnal per- rael) is pure melatonin in a slow-release formulation].
formance, nocturnal insomnia, chronologically mis- The time domain is a critical factor to be con-
placed eating behavior, insulin resistance or sensitivity sidered in chronic melatonin treatments, as this
not temporally related to the sleep–wake cycle, and molecule has a unique characteristic of being a hor-
others (, , ). mone that regulates the timing of the organism
physiology and behavior.
Inappropriate melatonin receptor– Melatonin physiological production is precisely
mediated response timed every day, and the beginning of its synthesis
In the case of inappropriate melatonin receptor– helps to set the circadian time to the central clock,
mediated response, pineal melatonin production is concomitantly with the triggering of the biological
adequate, temporally restricted to the night, and night for the CNS and the peripheral targets. The early
controlled by the circadian clock and the annual morning shutting down of its production, timed by the
photoperiod. However, mainly due to genetic varia- central clock and reinforced by the early morning
tions of melatonin receptors (either MT or MT), lights, ceases the biological night and triggers the
usually single nucleotide polymorphisms, the central biological day. The history of the duration of the
and peripheral responses of the target organs to biological nights throughout the year times the annual
melatonin are impaired. The symptoms will be defined calendar of the organism. In addition to this daily and
based on the affected tissues and can virtually include seasonal time domain variation of melatonin signal,
any of the above-mentioned ones. every organism has a particular ontogenetic history of
The first point to be emphasized is that melatonin the magnitude of the daily peak of melatonin pro-
receptor polymorphisms do not necessarily generate duction, as seen previously. Moreover, it should be
nonresponsive receptors. There is evidence in the considered that the melatonin profile is unique for
literature pointing to the fact that single-nucleotide each person (), showing very large interindividual
polymorphism–bearing receptors may inappropriately variation. However, for each individual, “the timing,
respond to the melatonin signal, either as a hypo- amplitude, and even the details of the profile are highly
sensitive system or a hypersensitive system. This reproducible from day to day and week to week rather

REVIEW
like a hormonal fingerprint” (). As a consequence very important point to be observed because the
of this individual variation, the duration of the daily pharmacological melatonin profile is not subjected to
signal and its onset phase (DLMO) vary from person the early morning photoinhibition seen for the
to person, mainly based on the chronotype and sleep physiological melatonin production. Daytime som-
duration type (morning or evening types, long or short nolence is a good clinical criterion to be considered as
sleepers). “Early birds” or morning people start the an indication of morning extension of the melatonin
melatonin daily production earlier than the “night pharmacological profile. The gold standard to check if
owls” or evening people do, and the duration of that is the case would be to measure melatonin either
nocturnal melatonin production in long sleepers is directly in the plasma or saliva or to measure the
more prolonged than in short sleepers. It should also be urinary metabolite -sulfatoxymelatonin early in the

considered that a certain melatonin dosage could result morning (we should remember that there is no other
in different plasma concentrations in different patients plasma hormonal reference to be used as a marker of a
due to interindividual differences in absorption, dis- higher or lower dosage, as is the case for several of the
tribution, metabolism, and elimination of melatonin, hormones dependent on the hypothalamus–pituitary
which are related to age (from premature babies to axis, as melatonin production is not subjected to the
elderly people), clinical condition (relatively healthy to classical feedback phenomenon).
critically ill), pathologies, and functional integrity of Dosage is another crucial point to be discussed, and
some physiological systems such as the gastrointestinal there is no general consensus in the literature. Average
tract, liver, and kidney. These substantial differences, if young people taking ~. to . mg of melatonin will
not adequately taken into account, may potentially present plasma concentration in the range of  to
impact the desired clinical efficacy.  pg/mL that is considered “physiological,” and
All of the above-mentioned statements point to the . mg would result in plasma concentration of ~
fact that a proper chronic melatonin hormonal re- to  pg/mL, far higher than the physiological
placement therapy is only achieved when dosage and concentration (, ). These values should be taken
formulation are carefully chosen and individually tailored into consideration when replacement therapy is in
and controlled to accomplish the desired clinical effect. question. However, depending on the clinical appli-
The first and most important aspect would be to cation (), one can find a large range of used
determine the DLMO of each patient and then pre- dosages, as . mg/d for the central clock synchro-
scribe melatonin according to this reference time nization, . to  mg/d for sleep disorders treatment,
point. As this procedure is not feasible in the everyday  mg/d for amyotrophic lateral sclerosis treatment
clinical practice, another more practical approach is to (), or even  mg as a short-period drug ad-
reference the daily nocturnal time intake of melatonin ministration (). The same is true for pharmaceu-
to the so-called usual time of sleep during the night. tical formulations and routes of administration (oral,
The time each person chooses to go to sleep every nasal spray, skin patch and creams, intravenous and
night is determined, in most cases, by chronobiological suppositories). However, depending on the primary
type (mainly if allowed by social constraints). As most outcome, the pharmaceutical formulation matters
oral melatonin formulations take ~ minutes to  importantly. For example, if the outcome is an acute
hour to be bioavailable, it is advisable to prescribe (for some or a few days) phase displacing, as it is
melatonin to be taken about an hour before the re- desired for jetlag treatment, a fast-release pulse cor-
ported usual bedtime every day. As melatonin is a rectly timed (according to the PRC) is perfectly ade-
powerful timer of the organism physiology, this timed quate. However, if the desired effect is a sustained
everyday intake should be rigorously maintained. The phase displacement as, for example, in non–-hour
second and an important aspect to be considered sleep disorder or circadian dysfunction in totally blind
before melatonin is prescribed is that its nocturnal people, the synchronizing effect requires chronic
pharmacological profile should be restricted to the continuous daily intake of melatonin. In this case, as
natural biological night of each patient. That is to say described previously, the chronobiotic effect requires
that the dose and the pharmaceutical formulation not only the first nocturnal pulse of melatonin but also
(fast, slow, or mixed-release forms) should be wisely an all-night melatonin signal to prime the next day’s
considered. If chronic replacement therapy is in prospective effects. For this purpose, a slow-release or
question, the preferred formulation should generate an dual-release formulation is the most appropriate. When
initial blood concentration high enough to set the time the first primary desired outcome is a hormonal re-
of the circadian clock, and the dynamics of the drug placement therapy, as is the case in aging and several
release, absorption, and metabolism should also diseases that present melatonin production reduction
build a nocturnal profile very close to the one that such as diabetes, autism spectrum disease, neurode-
would be physiologically produced by the patient. generative diseases, and others, or pinealectomy, the
Moreover, and foremost, the duration of the phar- most appropriate formulation would be, as well, a slow
macological nocturnal profile has to be such that it or dual release that would build a pharmacological
will end by the usual wake time of the patient. This is a profile more similar to the natural physiological one.
REVIEW
Another point to be discussed is management of either in the pups or in the rat dams treated with
the melatonin daily profile in the displacement situ-  mg/kg/d ().
ations previously described. The first approach is to Exogenous melatonin pharmacokinetics and bio-
use melatonin and/or phototherapy to try to displace availability are known in experimental animals (,
the circadian rhythms in the case of circadian rhythms ) and in humans (). Human studies considered
disorders. Classically, the use of melatonin and light different routes of administration and patients of
should strictly follow the PRCs for each of them (Figs. various ages, pointing out that the time to reach
 and ). As the respective PRCs are in phase op- maximal plasma concentrations is ~ minutes for
position (light during the day and melatonin during orally administered melatonin, with a generally low
the night), the approach should be amended ac- bioavailability due to the first-pass metabolism in the

cordingly. If the intended goal is to phase advance the liver [reviewed in ()]. Besides that, age, liver
rhythms, melatonin should be given at the end of the metabolic status, and drug interactions may influence
afternoon or at the beginning of the evening, and light plasma melatonin levels.
should be applied at the end of the night or at the Despite the great number of studies about the
beginning of the day. Conversely, light in the evening clinical use of melatonin, few have been designed to be
and melatonin at the end of the night should be used if randomized, double-blinded clinical trials that would
the aim is to phase delay the rhythms. However, in this test for safety and the adverse effects of exogenous
particular case, it should be carefully considered be- melatonin in humans (). By all means, melatonin
cause, as stated before, the daily extension of the administration is shown to be safe, and the adverse
melatonin profile could be a putative chronodisruptive described effects are usually either irrelevant or are also
signal. If the intended clinical outcome is to syn- described in the placebo groups.
chronize free-running rhythms, as in totally blind Several studies (–) performed in newborns
patients, melatonin should be given strictly at the and older children who received different doses (. to
same clock time every day. Finally, for the circadian  mg) of oral or intravenous melatonin for the acute
displacing treatment, as seen in patients with Smith- or chronic management of a number of clinical issues
Magenis syndrome, it is necessary to block daytime (newborn ischemia, respiratory distress, surgery, epi-
melatonin production, which is not subjected to the lepsy, Smith-Magenis syndrome, autism, attention- “The general conclusion is that
melatonin lacks toxic adverse
usual photoinhibition by the melanopsinergic ret- deficit/hyperactivity disorder, and other neurologic effects, being a safe drug for
inal system in these patients (), using regular diseases involving primary or secondary sleep im- clinical treatments.”
b-blocking agents and, additionally, it is necessary to pairment) have proven melatonin safety. It is note-
build a nocturnal pharmacological melatonin profile worthy that the pubertal development of children
that would replace the absent natural nocturnal one. treated with . to  mg/d for an average of  years
As a final observation, melatonin ultimate blood was not different to the observed in nontreated age-
concentration and profile depend on the absorption, matched children ().
transportation, and, most importantly, on the hepatic Melatonin lack of toxicity and clinical safety were
metabolism. In this last case, interaction between also shown in studies (, ) involving adults and
melatonin and other drugs should be considered elder patients who were treated with various doses (.
mainly when the drug is metabolized by liver cyto- to  mg/d) of oral, intravenous, or rectal suppository
chrome P enzymes, particularly CYPA (, melatonin for short or long treatment of sleep dis-
–). Depending on drug interactions, the mel- orders, jet lag, depressive disorders, attention-deficit/
atonin plasma profile might be abnormally extended, hyperactivity disorder, autism, amyotrophic lateral
resulting in adverse morning effects. sclerosis, Huntington disease, diabetes and metabolic
Exogenous melatonin pharmacokinetics, toxicology, syndrome, polycystic ovary syndrome, and frailty,
and safety have been studied in a limited manner, but among others.
the general conclusion is that melatonin lacks toxic Finally, two unresolved questions about melatonin
adverse effects, being a safe drug for clinical treatments. clinical therapy regarding its putative seasonal effect in
Given that the correct timing of administration and the humans and high dosages remain. Given that humans
adequate dose and formulation were followed, the most show, despite the social and cultural aspects of environ-
common tested concentrations vary from . to  mg/ mental modifications, circannual behavioral and physio-
kg, but a report administered up to  mg/kg to rats logical rhythms, and that melatonin might play some role
with no measurable toxic adverse effects (). The in their determination, the question that remains is:
% lethal dose for intraperitoneal melatonin injection Should chronic melatonin treatment, in terms of dosage
was determined for rats ( mg/kg) and mice and formulation, vary according to the annual season?
( mg/kg), but it was not possible to be de- The second question is related to chronic high-
termined for melatonin oral administration (tested dosage treatment as seen for multiple sclerosis ( mg
up to  mg/kg in rats) and for melatonin sub- every night, at bedtime, for up to  years) (), where
cutaneous injection (tested up to  mg/kg in rats the diurnal levels of melatonin were very high, although
and mice) (). Adverse effects were also not found to a lesser extent than the values observed during the

REVIEW
night. In that study, the authors explicitly stated that the general guidelines toward clinical melatonin therapy
treatment was generally well accepted and “no signs of assessment. In addition to the classical hormonal syn-
hangover or increased fatigue during daytime were dromes related to hypomelatonin and hypermelatonin
noted.” Is it possible that the organism chronically production, clinical syndromes related to inappropriate
adapts itself to a new level of melatonin oscillation so melatonin receptor–mediated response and to melato-
that “normal” physiological and chronobiotic responses nin characteristic timing effects should also be consid-
would be stated? The answers to these two questions ered, as they cause the rupture of the internal temporal
will depend on adequately planned clinical and ex- organization of the organism, resulting in several pu-
perimental future scientific work. tative signals and symptoms.
As far as therapy using melatonin is concerned,

several cautions should be taken into consideration:
Concluding Remarks restrict the chronic administration to the night; the
time of administration should be carefully chosen
This review considered melatonin as a pineal hor- according to the desired effect; and the dosage and
mone. As stated, melatonin is a special hormone that formulation should be individually adapted to
acts in the biological time domain. To deal with these build a blood melatonin profile that mimics the
timeline effects, melatonin developed receptor- physiological one and end by the beginning of the
mediated or nonmediated unique ways of action. morning.
The immediate way of action is similar to the classic In addition to that, the present urban society and
and well-known hormone–effector interaction. The the industrial production processes as organized
difference is that, in addition to the immediately should be taken into account, as both depend on the
measurable effects (e.g., inhibition of cAMP synthesis presence of indoor lights during the night and include
and its consequences for the considered system), the profuse use of electronic devices whose screens are
melatonin primes during the night, either by sustained rich in blue wavelength light. Light during the night
action via Gi/o PCR and subsequent supersensitization delays the beginning of the secretory episode of
or by regulating the expression of clock genes and melatonin and blunts its peak, causing chronic
CCGs, effects that will only be seen during the fol- hypomelatoninemia, sleep deprivation and, eventually,
lowing day, after the melatonin signal ceases. More- chronodisruption ().
over, owing to its special mechanisms of synthesis and Finally, after  years of melatonin isolation, it is
synchronization to the environmental light/dark cycle, about time to systematize the present knowledge and
melatonin acts as an internal synchronizer of circadian to introduce a common language in the field. It is also
and circannual rhythms, consequently synchronizing about time for the endocrine and neural sciences to
the organism physiology and behavior to the envi- consider the pineal as a gland and melatonin as a
ronmental day and night and seasons of the year. hormone, including the addition of these subjects to
Additionally, melatonin is crucial to the trans- medical and biological science course programs, and
generational transplacental circadian and seasonal to define clinical syndromes involving alterations in
time transfer. The offspring is prepared in advance to melatonin production, such as described earlier.
deal with the environmental daily and annual phase Concurrently, it is crucial to discuss and establish
after birth, expressing what should be considered a guidelines for the clinical use of melatonin for
typical time domain predictive adaptive response. treatment purposes. The present review aimed to
Considering these particular hormonal physiological shed light on some of these topics, stimulating a
characteristics of melatonin, it is possible to define some broader and clearer way of thinking about and
melatonin-related pathological syndromes and discuss perceiving melatonin.
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REVIEW
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clinical efficacy? Clin Pharmacokinet. 2016;55(9): 554. van Geijlswijk IM, Mol RH, Egberts TC, Smits MG.
1027–1030. Evaluation of sleep, puberty and mental health in Abbreviations
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placebo, of the toxicology of chronic melatonin somnia. Psychopharmacology (Berl). 2011;216(1): circadian locomotor output cycles kaput; CNS, central
treatment. J Pineal Res. 2000;29(4):193–200. 111–120. nervous system; CREB, cAMP response element binding
551. Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea 555. Zetner D, Andersen LP, Rosenberg J. Melatonin as protein; Cry, Cryptochrome; CSF, cerebrospinal fluid; CVS,

S, Chiurazzi P, Cordaro S, Corona G, Trimarchi G, protection against radiation injury: a systematic cardiovascular system; DIO2, type 2 iodothyronine deiodi-
Barberi I. Effects of melatonin treatment in septic review. Drug Res (Stuttg). 2016;66(6):281–296. nase; DIO3, type 3 iodothyronine deiodinase; DLMO, dim-
newborns. Pediatr Res. 2001;50(6):756–760. light melatonin onset; GLP-1, glucagon-like peptide 1; HIE,
552. Gringras P, Gamble C, Jones AP, Wiggs L, Williamson hypoxic ischemic encephalopathy; MT1, melatonin receptor
PR, Sutcliffe A, Montgomery P, Whitehouse WP, Acknowledgments 1; MT2, melatonin receptor 2; NMU, neuromedin U; Per,
Choonara I, Allport T, Edmond A, Appleton R; Financial Support: This work was supported by Fundação Period; PKA, protein kinase A; PKC, protein kinase C; PT, pars
MENDS Study Group. Melatonin for sleep problems de Amparo à Pesquisa do Estado de São Paulo Grant 2014/ tuberalis; PRC, phase-response curve; Rev-erb, reverse eryth-
in children with neurodevelopmental disorders: 50457-0 (to J.C.-N.). roblastosis virus; RGS16, G protein–signaling protein 16; ROR,
randomised double masked placebo controlled Correspondence: José Cipolla-Neto, MD, PhD, De- retinoic acid–related orphan receptor; ROS, reactive oxygen
trial. BMJ. 2012;345:e6664. partment of Physiology and Biophysics, Neurobiology species; SCN, suprachiasmatic nucleus.

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REVIEW

Melatonin as a Hormone: New Physiological

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I t was  and the hard-working team of re-

990 https://academic.oup.com/edrv doi: 10.1210/er.2018-00084

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Melatonin—the Basics synthesizes melatonin to serve as a hormone with

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Prospective eﬀects An example of these proximal eﬀects is the hyper-

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BOX 1. Circadian Rhythms

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Dead zone Phase delay zone Phase-advance Dead zone

DAY NIGHT DAY

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Forbidden zone for Safe zone for Forbidden zone for

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Increasing nights - Decreasing nights -

Critical photoperiod Critical photoperiod

Summer phenotype Summer phenotype

Summer Autumn Winter Spring Summer

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Sleep deprivation is a well-known cause of meta- resistance/diabetes, hypertension, obesity, immuno-

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its innervation (e.g., sepiapterin reductase deﬁciency

fatal familial insomnia and Morvan syndrome); hy-

perglycemia associated with diabetes; obesity; exposure

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