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review
Arch Endocrinol Metab. 2018;62/4
1 Departamento de Fisiologia,
Universidade Federal de São Paulo
(Unifesp), São Paulo, SP, Brasil
2 Departamento de Fisiologia e
Biofísica, Instituto de Ciências
Biomédicas, Universidade de São
Paulo (USP), São Paulo, SP, Brasil
Correspondence to:
José Cipolla-Neto
Department of Physiology and
Biophysics, Neurobiology Lab,
Institute of Biomedical Sciences,
Bldg 1, University of São Paulo
Av. Lineu Prestes, 1524
05508-000 – São Paulo, SP, Brazil
cipolla@icb.usp.br
Received on Ago/31/2018
Accepted on Ago/31/2018
DOI: 10.20945/2359-3997000000066
A brief review about melatonin,
a pineal hormone
Fernanda Gaspar do Amaral1, José Cipolla-Neto2
ABSTRACT
Melatonin is a ubiquitous molecule in nature, being locally synthesized in several cells and tissues,
besides being a hormone that is centrally produced in the pineal gland of vertebrates, particularly
in mammals. Its pineal synthesis is timed by the suprachiasmatic nucleus, that is synchronized to
the light-dark cycle via the retinohypothalamic tract, placing melatonin synthesis at night, provided
its dark. This unique trait turns melatonin into an internal synchronizer that adequately times the
organism’s physiology to the daily and seasonal demands. Besides being amphiphilic, melatonin
presents specic mechanisms and ways of action devoted to its role as a time-giving agent, being
widely spread in the organism. The present review aims to focus on melatonin as a pineal hormone
with specic mechanisms and ways of action, besides presenting the clinical syndromes related to its
synthesis and/or function disruptions.
Arch Endocrinol Metab. 2018;62(4):472-9
Keywords
Melatonin; pineal; hypermelatoninemia; hypomelatoninemia
MELATONIN
Melatonin, N-acetyl-5-methoxytryptamine, is a
ubiquitous molecule in nature, being found in almost
all living organisms. It is an indolamine present in
any compartment of the organism for its amphiphilic
characteristics of diffusion (Figure 1). In vertebrates,
mammals in particular, in addition of local production
in several tissues, melatonin is centrally produced by the
pineal gland and directly released in the blood, acting as
a hormone. The pineal gland is an unpaired epithalamic
neuroendocrine gland originating from the roof of the
third ventricle containing, in mammals, melatonin-
producing cells called pinealocytes, in addition to
astrocytes and other cell types (1).
Melatonin synthesis by the pinealocytes in the
pineal gland is under the control of a neural system
originating in the hypothalamic paraventricular nuclei,
projecting directly and indirectly to the preganglionic
sympathetic neurons of the rst thoracic segments of
the spinal cord. Following, through a projection of the
postganglionary sympathetic neuron of the superior
cervical ganglia, nerve bers forming the conary nerves
reach the pineal gland (Figure 2).
Norepinephrine released by the sympathetic
terminals interacts with the classical beta and alpha
noradrenergic receptors in the membrane of pinealocytes
and activates cAMP-PKA-CREB and PLC-Ca++-PKC
pathways to trigger melatonin synthesis (2).
Melatonin synthesis initiates with tryptophan
that, under the action of tryptophan hydroxylase, is
transformed in 5-hydroxytryptophan that, in turn,
is converted to serotonin, which is acetylated, by
arylalkylamine N-acetyltransferase (AANAT) to
N-acetylserotonin (NAS) that is converted to melatonin
by acetylserotonin O-methyltransferase (ASMT) former
called hydroxy-indole-O-methyltransferase (HIOMT).
The three enzymes above are under the control of neural
and endocrine systems that regulate time, duration and
amount of produced melatonin (3) (Figure 3).
The major control is exerted by the circadian timing
system, mainly the hypothalamic suprachiasmatic
nuclei, that times melatonin synthesis so that it is daily
produced in synchrony to the light/dark cycle, being
tightly restricted to the night, provided it is dark. Light
stimulus (mainly in the blue range) activates melanopsin
breakdown in retinal photoreceptive ganglion cells that
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Melatonin hormonal ways of action
Arch Endocrinol Metab. 2018;62/4
project, via the retinohypothalamic pathway, to the
hypothalamus, inhibiting melatonin synthesis (4).
Due to its amphiphilic nature, melatonin is not
stored inside the pinealocytes, being released as it is
synthetized. The pineal gland is profusely vascularized
and its attachment, dorsal and posterior, to the third
ventricle wall allows melatonin to be released into
the cerebrospinal uid of the central nervous system
during the night, as well as into the blood stream. In
the blood, melatonin is usually bound to albumin,
metabolized to 6-hydroxymelatonin by cytochrome
P450 isoforms (mainly CYP1A2) and conjugated to
6-sulfatoxymelatonin in the liver, for the subsequent
urinary excretion. 6-sulfatoxymelatonin production
perfectly reects the plasma levels of melatonin, so
its urinary measurement is a less intrusive method
to evaluate the pineal function and melatonin
production (Figure 3). In the central nervous system
melatonin is degraded to N-acetyl- N2-formyl-5-
methoxykynuramine (AFMK) that is deformylated to
N-acetyl-5- methoxykynuramine (AMK) (5).
Melatonin, as an ancient chemical messenger,
developed several pleiotropic mechanisms of action
(6). First, there are mechanisms that are not mediated
by cellular receptors and involve the direct interaction
of melatonin and other molecules, as its antioxidant
action. Melatonin is one of the most powerful natural
antioxidants, not only by directly chelating oxygen and
nitrogen reactive species, but also by mobilizing the
intracellular antioxidant enzymatic system. Second, as
any other hormone, melatonin acts through specic
cellular receptors. Membrane melatonin receptors,
in mammals, are of two types, MT1 (MTNR1A, in
humans) and MT2 (MTNR1B in humans). These
membrane melatonin receptors are heterotrimeric Gi/
Go and Gq/11 protein-coupled receptors that interact
with downstream messengers such as adenylyl cyclase,
phospholipase A2 and phospholipase C, generally
decreasing cAMP and cGMP production and/or
increasing diacylglycerol and IP3 formation. MT1 and
MT2 receptors are found in almost all peripheral tissues,
as well as in the central nervous system. In addition to
acting through membrane receptors, melatonin might
interact with ROR/RZR (retinoid orphan receptors/
retinoid Z receptors) nuclear receptors (7) (Figure 4).
As mentioned before, melatonin hormonal pineal
production is restricted to the night and a light
signal, mainly with the characteristics of day-light
(predominance of the blue range), blocks melatonin
Figure 1. Melatonin molecule (232,2 molecular weight).
Figure 2. Neural control of pineal melatonin synthesis. RHT:
retinohypothalamic tract. SCN: suprachiasmatic nucleus. PVH:
paraventricular nucleus. SCG: superior cervical ganglion.
secretion. This complex and very well-organized neural
system control is the product of natural selection that
turned the melatonin nocturnal prole into the internal
representative of the environmental night. In addition,
and as a consequence, the duration of melatonin
nocturnal secretion episode follows the duration of the
night as it varies along the year. Long winter nights
determine long plasma melatonin duration episodes
and the reverse occurs following the short nights of
summer time.
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Melatonin hormonal ways of action
Arch Endocrinol Metab. 2018;62/4
Figure 3. Melatonin synthesis pathway and hepatic metabolization. The
enzymes are written in italic and the derived molecules are underlined.
Melatonin synthesis circadian rhythm synchronized
to day/night cycle, restricted to the night and to
its duration, converts melatonin to the internal
representative of the daily and seasonal photoperiod.
As a consequence of being a representative of the
environmental photoperiod, melatonin has, in some
way, to control the organism physiology during the 24
hours of the day and all through the seasons of the year.
To do that, melatonin, using the classical hormonal
mechanisms of action, developed several especial ways
of action (8).
As any other hormone, melatonin acts through the
classical way in the sense that its effects are seen as a
direct and immediate consequence of its interaction with
molecular effectors. These are called immediate effects
(Figure 5). Depending on the molecular effectors and
the involved mechanisms of action, such are the possible
effects: antioxidant action; reduction of cAMP-PKA-
CREB and cGMP; increased DAG, IP3, PKC activity;
regulation of potassium and calcium channels; etc. As
it would be expected for any hormone, the effects are
dependent on the target tissue and the correspondent
intracellular melatonin signaling pathway.
However, in addition to this classical and expected
hormonal way of action, melatonin developed another
one that is not seen during the night when melatonin is
being produced and released but, instead, it is only seen
during the day, being triggered in the absence of plasma
melatonin, provided it was present in the immediate
previous night. These are called prospective effects and
they are of two types (Figure 5). The rst one, called
proximal or consecutive, is seen right at the beginning
of the morning, immediately after the cessation of
melatonin production, when it is maximal and may
extend to several hours. One example is the cAMP/
PKA/CREB pathway super or hypersensitization that is
seen in several peripheral and central systems (9). That
is to say that in consequence of the nocturnal sustained
and prolonged adenylyl cyclase inhibition induced by
melatonin through its Gi-protein coupled receptors,
this signaling pathway shows, following the cessation
of the inhibitory signal, an increased and potentiated
response to any agonists that activates adenylyl cyclase
through any Gs-protein coupled receptors. Depending
on the system (suprachiasmatic nucleus, pancreatic
beta cells, Leydig cells, pars tuberalis, etc.) such is
the magnitude and the duration of the potentiating
prospective consecutive melatonin effect (10-13). That
is to say that melatonin, in spite of being produced
only during the night, determines effects that are best
seen during the day, when melatonin is not present
anymore, and in this case, especially in the morning.
The second type of melatonin prospective effects are
called distal or prolonged effects. These are dependent
on the action of melatonin controlling the transcription
and/or translation of the well-known clock genes (CG)
and the clock-controlled genes (CCG) (14-20). The
clock genes are part of a complex molecular machinery
that includes a cycle of transcription and translation of
several genes and the resulting proteins might either
reinforce the process or inhibit it, so that the cycle
has a duration of approximately 24 hours (21). These
proteins can also control, throughout the 24-hour
cycle, the transcription and translation of other genes,
called clock-controlled genes, that are responsible for
Figure 4. Melatonin mechanisms of action. Classical receptor mediated
and non-mediated pathways and the involvement of nuclear, cytosolic and
membrane receptors.
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Melatonin hormonal ways of action
Arch Endocrinol Metab. 2018;62/4
almost all cell functions. That is to say that melatonin,
through its prospective prolonged effects, controlling
the cycling of the CG and CCG, is able to control cell
and tissue function all over the 24-hours of the day,
even being only produced and released during the
night.
Mediated by these immediate and prospective
effects, melatonin developed others ways of action.
One of them depends on the circadian characteristic
of the melatonin signal and on the contrast between
nocturnal and diurnal values of circulating melatonin.
The precise daily repetition of melatonin signal and
its perfect relation to the dark phase of the day turns
melatonin into the internal synchronizer of circadian
rhythms. This shapes the so-called chronobiotic effect
of melatonin (Figure 5). Melatonin is one of the most
powerful synchronizers of human circadian rhythms and
is used in clinics to adjust circadian rhythmicity in cases
like phase-delayed sleep onset disorder, jet lag, etc. (22-
25) The chronobiotic effect of melatonin depends on
its action at several levels of the circadian timing system,
including the suprachiasmatic nucleus and the clock
genes located in peripheral tissues like, adipose tissue,
muscle, pancreatic beta cells, reproductive organs, etc.
Another important synchronizing ef fect of melatonin
is related to the seasonal rhythms. It is its seasonal effect
(26-28) (Figure 5). The duration of melatonin diurnal
prole and, most importantly, the direction of the daily
change of its duration (towards increasing or decreasing
nights resulting in increasing or decreasing duration of
melatonin production) that is dependent on the typical
relative duration of the day and night along the year,
turns melatonin into the most powerful synchronizer of
seasonal rhythms, being fundamental for the organism
to anticipate and to adapt to the evolving environmental
change along the year. The seasonal synchronizing effect
of melatonin is mediated by its action on the pituitary
pars tuberalis. From there, the signal is transduced to
the hypothalamus, mediated by special glial cells called
tanycytes, and to the distal hypophysis through several
other mediators. In consequence of this functional
system, melatonin is able to control seasonal events like
reproduction, energy metabolism, immune response
and thermogenesis, growth, body weight control, etc.
(29-33).
Finally, another melatonin way of action called
transgenerational effect should be mentioned (Figure 5).
In mammals, in humans in particular, pineal melatonin
production increases as the gestation progress (34).
Maternal melatonin freely crosses the placenta and
reaches the fetus circulation, being its only source of
melatonin (35-37). Considering this, several of the effects
of melatonin that can be seen in the maternal organism
are seen in the fetus, particularly, the chronobiotic
Figure 5. Melatonin ways of action. The upper boxes represent the different ways of action. The second-line boxes explain how melatonin causes the
correspondent effects. The third-line boxes show examples of the correspondent effects. Note that the Prospective effects are further classied in
Proximal ou consecutive and Distal or prolonged effects.
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Melatonin hormonal ways of action
Arch Endocrinol Metab. 2018;62/4
and seasonal effects (38-40). Maternal melatonin is
responsible for the circadian timing and priming of
the fetus organism. Similarly, the seasonal timing is
transferred from the mother to the fetus, preparing its
neuroendocrine system to the future environment to
be dealt with (41,42). In addition, maternal melatonin
is necessary for the adequate neurodevelopment of the
fetus (43).
MELATONIN PHYSIOLOGY, CLINICAL SYNDROMES
AND THERAPEUTICS
Melatonin, due to its phylogenetic history, its pleiotropic
mechanisms of action and its unique ways of action,
as described above, in addition of being delivered to
the blood stream and directly in the CNS, is able to
regulate several, if not all, the physiological and neural
functions. Among them, circadian and seasonal timing
of organism; sleep and wakefulness cycle; endocrine
functions, as energy metabolism, glycemic control,
blood lipid prole and reproduction, gestation and
fetal development and programming; cardiovascular
system; immune system; neural development, neural
protection and neuroplasticity, etc. A detailed discussion
of this subject can be seen in Cipolla-Neto and Amaral,
2018 (8).
As any other hormone, from the clinical point
of view, melatonin hormonal dysfunction can be
classied as hypo (hypomelatoninemia) or hyper
(hypermelatoninemia) production by the pineal gland.
Hypomelatoninemia is dened by decreased
melatonin nocturnal peak value or total production
when compared to what is expected for the age- and
sex-paired population. This syndrome can be classied
as primary, dependent on factors that directly affect
the pineal gland and/or its innervation, and secondary,
developed as a consequence of a primary event, such as a
systemic disease (e.g. hyperglycemia) or environmental
factor (e.g light at night) (44-50).
Hypermelatoninemia is dened as hyperproduction
of pineal melatonin, usually associated to other diseases
like hypogonadotrophic hypogonadism, anorexia
nervosa, polycystic ovarian syndrome, Rabson-
Mendenhall syndrome and spontaneous hypothermia
hyperhidrosis (51-54).
A third syndrome associated to pineal melatonin
dysfunction is due to what can be called inappropriate
melatonin receptor-mediated response. This melatonin-
receptor dysfunction is usually a consequence of
melatonin receptors genetic variations (e.g. single
nucleotide polymorphisms) and affect either MT1 or
MT2 receptors (55,56).
Finally, in addition to these classical hormonal
dysfunctions and due to melatonin specic
characteristics of production and ways of action, it is
possible to dene another syndrome associated to
the time displacement of the nocturnal melatonin
production causing a phase-displacement of its plasma
prole that is called melatonin circadian displacement
syndrome. The result is a misalignment of the organism
to the circadian timing domain, causing sleep/wake,
metabolic and cardiovascular disturbances, among
other symptoms. This syndrome is usually associated
to the Smith-Magenis disease, the phase-delayed
sleep-wake disorder, and as a consequence of indoors
illumination during the evening/night, among others
(57,58).
Melatonin pharmacokinetics will depend on the
way of administration (oral, fast and/or slow-release,
intravenous, nasal spray, anal suppository, skin patches
or cream, etc.) and on the individual absorption and
hepatic metabolization rates (dependent on the activity
of cytochrome P450 complex, mainly CYP1A2).
Each of these aspects might vary depending on age
and sex. Usually, in a young/middle-aged human
patient, pharmacokinetic studies show that plasma
concentration reaches the peak at approximately 45
minutes after orally administered melatonin, resulting
in a low bioavailability due to the rst pass liver
metabolism (59).
Melatonin administration should always be done
during the evening/night, mimicking the physiological
production. The moment of administration during the
evening/night will depend on the desired effect that
will be determined by the well-known melatonin phase-
response curve. That is to say that depending on the
moment of administration, melatonin is able to act on
the circadian clock resulting in phase-advance, phase-
delay or even no phase-displacement of the circadian
rhythms. If administered in the late afternoon/
beginning of the evening, melatonin phase-advances
the circadian rhythms (as is the case for the treatment of
the sleep-wake phase-delay disorder); if administered in
the end of the night/early morning, melatonin would
phase-delay the circadian clock; if administered during
the evening, beginning around 1 hour before the usual
bedtime and extending to 2 to 4 hours afterwards,
melatonin does not phase displace the circadian
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Arch Endocrinol Metab. 2018;62/4
rhythms, regulating the circadian clock pace (this is the
time of choice if melatonin is being replaced, as in the
pinealectomized or elder patients).
It should be said that, considering the above
discussed melatonin ways of action, one should always
avoid its chronic administration during the day.
The dosage is always a concern and will depend
on the desired effect. If replacement therapy is the
goal, oral melatonin in the range of 0.1 to 0.5 mg
usually generates a plasma concentration varying from
100 to 500 pg/mL, that is 1 to 5 times the expected
physiological concentration at the nocturnal peak in
young people. In addition, 0.5 to 1.0 mg is usually used
for proper circadian timing, as in jetlag for example.
Melatonin-responsive sleep disorders are usually treated
with 1.0 to 5.0 mg oral melatonin. However, one
should always keep in mind that the dosage must be
individually adjusted by the evaluation of the evolution
of the symptoms and the occurrence of adverse effects
as diurnal somnolence or nocturnal nightmares.
CONCLUSIONS
Nowadays, any quick search in PubMed/NCBI shows
that there are about 33,000 papers about melatonin
or pineal and about 1,200 new articles per year, in
addition to a dedicated journal (Journal of Pineal
Research) showing the 2017 impact factor of 11.613
(6th out of 143 journals in the area of Endocrinology
& Metabolism). In spite of this, melatonin hormonal
action is scarcely targeted in the classical Physiology
or Endocrinology books. In Williams’ textbook of
Endocrinology, for example, the pineal gland was
included for a long time in the circumventricular
organs section and is, nowadays, located in a separate
scanty part just after it. Jameson & De Groot devoted,
for a long time, a full chapter to the pineal gland that
is mostly dedicated to pineal tumors. Melatonin in all
its complexity is barely reported. In addition, in several
medical schools all over the world, pineal gland and/or
melatonin is never systematically taught. So, it is about
time to change this picture, considering melatonin as a
hormone decisively important to the mammalian and
human physiology and pathophysiology.
Concerning the clinical aspects of melatonin
dysfunction some observations should be additionally
done. The most common mistake that we nd in
clinical endocrinology when dealing with melatonin
is to expect, as far as hypo or hyper production is
concerned, exactly the same that we would be expected
to occur with the classical glands syndromes: immediate
effects and immediate health repercussions. It is not
the case with pineal and melatonin as it is a time-
domain acting hormone that organizes physiology and
behavior in the circadian and seasonal time. Its absence
induces an unhealthy state whose clinical pictures
is not so tinted as is expressed in other glands but is
still there and will be reected in the long-term health
status rather then immediately. For example, a subtle
alteration in the sleep organization as little as shorter
30 minutes sleep episode every day will not be even
perceived by the patient and the physician. However,
it will determine, in the medium/long term, several
critical alterations in metabolism (insulin resistance,
overweight, etc.), cardiovascular system (hypertension),
loss of performance, GIT events, reproduction/sexual
repercussions, etc. (60). It should be considered, still,
that the sleep/wake cycle is only one among several
others affected systems in melatonin-decient adults
and children. Extend this to several of the circadian
aspects of physiology and the clinical picture becomes
much more serious, resulting in systemic repercussion
reaching every other aspect of human physiology and
behavior, jeopardizing its health and quality of life and
even longevity.
Funding statement: the present work was funded by São Paulo
Research Foundation – Fapesp (2014/50457-0).
Disclosure: no potential conict of interest relevant to this article
was reported.
REFERENCES
1. Vollrath L. The Pineal Organ. Mollendorff WaB, W., editor. Heild-
berg, Germany: Springer-Verlag; 1981. p. 659
2. Kappers JA. The development, topographical relations and in-
nervation of the epiphysis cerebri in the albino rat. Z Zellforsch
Mikrosk Anat. 1960;52:163-215.
3. Afeche SC, do Amaral FG, Villela DCM, Abrahão MV, Peres R,
Cipolla-Neto J. Melatonin and the Pineal Gland. In: Romano E, De
Luca S, editors. New Research on Neurosecretory Systems. New
York: Nova Biomedical Books; 2008. p. 151-77.
4. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its
physiological interactions. Endocr Rev. 1991;12(2):151-80.
5. Hardeland R. Taxon- and Site-Specic Melatonin Catabolism.
Molecules. 2017; 22(11):pii: E2015.
6. Hardeland R, Balzer I, Poeggeler B, Fuhrberg B, Uria H, Behrmann
G, et al. On the primary functions of melatonin in evolution: me-
diation of photoperiodic signals in a unicell, photooxidation, and
scavenging of free radicals. J Pineal Res. 1995;18(2):104-11.
Copyright© AE&M all rights reserved.
478
Melatonin hormonal ways of action
Arch Endocrinol Metab. 2018;62/4
7. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N,
Tosini G, et al. Update on melatonin receptors: IUPHAR Review
20. Br J Pharmacol. 2016;173(18):2702-25.
8. Cipolla-Neto J, Amaral FG. Melatonin as an hormone: New physi-
ological and clinical insights. Endocrine Reviews. 2018, in press.
DOI 10.1210/er.2018-00084.
9. Hazlerigg DG, Gonzalez-Brito A, Lawson W, Hastings MH, Morgan
PJ. Prolonged exposure to melatonin leads to time-dependent
sensitization of adenylate cyclase and down-regulates melatonin
receptors in pars tuberalis cells from ovine pituitary. Endocrinol-
ogy. 1993;132(1):285-92.
10. von Gall C, Garabette ML, Kell CA, Frenzel S, Dehghani F, Schumm-
Draeger PM, et al. Rhythmic gene expression in pituitary depends
on heterologous sensitization by the neurohormone melatonin.
Nat Neurosci. 2002;5(3):234-8.
11. Valenti S, Guido R, Giusti M, Giordano G. In vitro acute and pro-
longed effects of melatonin on puried rat Leydig cell steroido-
genesis and adenosine 3’,5’-monophosphate production. Endo-
crinology. 1995;136(12):5357-62.
12. Witt-Enderby PA, Masana MI, Dubocovich ML. Physiological
exposure to melatonin supersensitizes the cyclic adenosine
3’,5’-monophosphate-dependent signal transduction cascade in
Chinese hamster ovary cells expressing the human mt1 melato-
nin receptor. Endocrinology. 1998;139(7):3064-71.
13. Kemp DM, Ubeda M, Habener JF. Identication and functional
characterization of melatonin Mel 1a receptors in pancreatic beta
cells: potential role in incretin-mediated cell function by sensitiza-
tion of cAMP signaling. Mol Cell Endocrinol. 2002;191(2):157-66.
14. Nagy AD, Iwamoto A, Kawai M, Goda R, Matsuo H, Otsuka T, et
al. Melatonin adjusts the expression pattern of clock genes in the
suprachiasmatic nucleus and induces antidepressant-like effect
in a mouse model of seasonal affective disorder. Chronobiol Int.
2015;32(4):447-57.
15. Kandalepas PC, Mitchell JW, Gillette MU. Melatonin Signal
Transduction Pathways Require E-Box-Mediated Transcription
of Per1 and Per2 to Reset the SCN Clock at Dusk. PLoS One.
2016;11(6):e0157824.
16. de Farias Tda S, de Oliveira AC, Andreotti S, do Amaral FG, Ch-
imin P, de Proenca AR, et al. Pinealectomy interferes with the cir-
cadian clock genes expression in white adipose tissue. J Pineal
Res. 2015;58(3):251-61.
17. Coelho LA, Peres R, Amaral FG, Reiter RJ, Cipolla-Neto J. Daily
differential expression of melatonin-related genes and clock
genes in rat cumulus-oocyte complex: changes after pinealec-
tomy. J Pineal Res. 2015;58(4):490-9.
18. Valenzuela FJ, Torres-Farfan C, Richter HG, Mendez N, Campino C,
Torrealba F, et al. Clock gene expression in adult primate supra-
chiasmatic nuclei and adrenal: is the adrenal a peripheral clock
responsive to melatonin? Endocrinology. 2008;149(4):1454-61.
19. Hiragaki S, Baba K, Coulson E, Kunst S, Spessert R, Tosini G. Mel-
atonin signaling modulates clock genes expression in the mouse
retina. PLoS One. 2014;9(9):e106819.
20. Zeman M, Herichova I. Melatonin and clock genes expression in
the cardiovascular system. Front Biosci (Schol Ed). 2013;5:743-53.
21. Takahashi JS. Finding new clock components: past and future. J
Biol Rhythms. 2004;19(5):339-47.
22. Arendt J, Broadway J. Light and melatonin as zeitgebers in man.
Chronobiol Int. 1987;4(2):273-82.
23. Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Med Rev.
2005;9(1):25-39.
24. Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human
circadian rhythms according to a phase-response curve. Chrono-
biol Int. 1992;9(5):380-92.
25. Lewy AJ. Clinical applications of melatonin in circadian disor-
ders. Dialogues Clin Neurosci. 2003;5(4):399-413.
26. Robinson JE, Karsch FJ. Photoperiodic history and a changing
melatonin pattern can determine the neuroendocrine response
of the ewe to daylength. J Reprod Fertil. 1987;80(1):159-65.
27. Lewis JE, Ebling FJ. Tanycytes As Regulators of Seasonal Cycles
in Neuroendocrine Function. Front Neurol. 2017;8:79.
28. Ebling FJP, Lewis JE. Tanycytes and hypothalamic control of en-
ergy metabolism. Glia. 2018;66(6):1176-84.
29. Dopico XC, Evangelou M, Ferreira RC, Guo H, Pekalski ML, Smyth
DJ, et al. Widespread seasonal gene expression reveals annual
differences in human immunity and physiology. Nat Commun.
2015;6:7000.
30. Roenneberg T, Aschoff J. Annual rhythm of human reproduction:
II. Environmental correlations. J Biol Rhythms. 1990;5(3):217-39.
31. Sivan Y, Laudon M, Tauman R, Zisapel N. Melatonin production
in healthy infants: evidence for seasonal variations. Pediatr Res.
2001;49(1):63-8.
32. Wehr TA. Photoperiodism in humans and other primates: evi-
dence and implications. J Biol Rhythms. 2001;16(4):348-64.
33. Arendt J, Middleton B. Human seasonal and circadian stud-
ies in Antarctica (Halley, 75 degrees S). Gen Comp Endocrinol.
2018;258:250-8.
34. Tamura H, Nakamura Y, Terron MP, Flores LJ, Manchester LC, Tan
DX, et al. Melatonin and pregnancy in the human. Reprod Toxicol.
2008;25(3):291-303.
35. Klein DC. Evidence for the placental transfer of 3 H-acetyl-melato-
nin. Nat New Biol. 1972;237(73):117-8.
36. Reppert SM, Chez RA, Anderson A, Klein DC. Maternal-fetal
transfer of melatonin in the non-human primate. Pediatr Res.
1979;13(6):788-91.
37. Okatani Y, Okamoto K, Hayashi K, Wakatsuki A, Tamura S, Sagara
Y. Maternal-fetal transfer of melatonin in pregnant women near
term. J Pineal Res. 1998;25(3):129-34.
38. Mendez N, Abarzua-Catalan L, Vilches N, Galdames HA, Spich-
iger C, Richter HG, et al. Timed maternal melatonin treatment re-
verses circadian disruption of the fetal adrenal clock imposed by
exposure to constant light. PLoS One. 2012;7(8):e42713.
39. Seron-Ferre M, Mendez N, Abarzua-Catalan L, Vilches N, Valenzu-
ela FJ, Reynolds HE, et al. Circadian rhythms in the fetus. Mol Cell
Endocrinol. 2012;349(1):68-75.
40. Seron-Ferre M, Valenzuela GJ, Torres-Farfan C. Circadian clocks
during embryonic and fetal development. Birth Defects Res C Em-
bryo Today. 2007;81(3):204-14.
41. Weaver DR, Reppert SM. Maternal melatonin communicates
daylength to the fetus in Djungarian hamsters. Endocrinology.
1986;119(6):2861-3.
42. Weaver DR, Keohan JT, Reppert SM. Denition of a prenatal sen-
sitive period for maternal-fetal communication of day length. Am
J Physiol. 1987;253(6 Pt 1):E701-4.
43. Motta-Teixeira LC, Machado-Nils AV, Battagello DS, Diniz GB,
Andrade-Silva J, Silva-Junior S, et al. The absence of maternal
pineal melatonin rhythm during pregnancy and lactation impairs
offspring physical growth, neurodevelopment, and behavior.
Horm Behav. 2018 Aug 13. DOI: S0018-506X(17)30530-5.
44. Amaral FG, Castrucci AM, Cipolla-Neto J, Poletini MO, Mendez
N, Richter HG, et al. Environmental control of biological rhythms:
effects on development, fertility and metabolism. J Neuroendo-
crinol. 2014;26(9):603-12.
45. Amaral FG, Turati AO, Barone M, Scialfa JH, do Carmo Buon-
glio D, Peres R, et al. Melatonin synthesis impairment as a new
deleterious outcome of diabetes-derived hyperglycemia. J Pineal
Res. 2014;57(1):67-79.
46. Wetterberg L, Bratlid T, von Knorring L, Eberhard G, Yuwiler A. A
multinational study of the relationships between nighttime uri-
nary melatonin production, age, gender, body size, and latitude.
Eur Arch Psychiatry Clin Neurosci. 1999;249(5):256-62.
Copyright© AE&M all rights reserved.
479
Melatonin hormonal ways of action
Arch Endocrinol Metab. 2018;62/4
47. Rommel T, Demisch L. Inuence of chronic beta-adrenoreceptor block-
er treatment on melatonin secretion and sleep quality in patients with
essential hypertension. J Neural Transm Gen Sect. 1994;95(1):39-48.
48. Cox MA, Davis M, Voin V, Shoja M, Oskouian RJ, Loukas M, et
al. Pineal Gland Agenesis: Review and Case Illustration. Cureus.
2017;9(6):e1314.
49. Hanish AE, Butman JA, Thomas F, Yao J, Han JC. Pineal hypopla-
sia, reduced melatonin and sleep disturbance in patients with
PAX6 haploinsufciency. J Sleep Res. 2016;25(1):16-22.
50. Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea
SH, et al. Genetic variation in melatonin pathway enzymes in chil-
dren with autism spectrum disorder and comorbid sleep onset
delay. J Autism Dev Disord. 2015;45(1):100-10.
51. Arendt J, Bhanji S, Franey C, Mattingly D. Plasma melatonin lev-
els in anorexia nervosa. Br J Psychiatry. 1992;161:361-4.
52. Tarquini R, Bruni V, Perfetto F, Bigozzi L, Tapparini L, Tarquini B.
Hypermelatoninemia in women with polycystic ovarian syn-
drome. Eur J Contracept Reprod Health Care. 1996;1(4):349-50.
53. Luboshitzk y R, Shen-Orr Z, Ishai A, Lavie P. Melatonin hyper-
secretion in male patients with adult-onset idiopathic hypo-
gonadotropic hypogonadism. Exp Clin Endocrinol Diabetes.
2000;108(2):142-5.
54. Duman O, Durmaz E, Akcurin S, Serteser M, Haspolat S. Sponta-
neous endogenous hypermelatoninemia: a new disease? Horm
Res Paediatr. 2010;74(6):444-8.
55. Bonnefond A, Froguel P. The case for too little melatonin signal-
ling in increased diabetes risk. Diabetologia. 2017;60(5):823-5.
56. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A.
MTNR1A and MTNR1B gene polymorphisms in women with ges-
tational diabetes. Gynecol Endocrinol. 2017;33(5):395-8.
57. Barboni MTS, Bueno C, Nagy BV, Maia PL, Vidal KSM, Alves RC,
et al. Melanopsin System Dysfunction in Smith-Magenis Syn-
drome Patients. Invest Ophthalmol Vis Sci. 2018;59(1):362-9.
58. Eckel RH, Depner CM, Perreault L, Markwald RR, Smith MR,
McHill AW, et al. Morning Circadian Misalignment during Short
Sleep Duration Impacts Insulin Sensitivity. Curr Biol. 2015;25(22):
3004-10.
59. Harpsoe NG, Andersen LP, Gogenur I, Rosenberg J. Clinical phar-
macokinetics of melatonin: a systematic review. Eur J Clin Phar-
macol. 2015;71(8):901-9.
60. Arora T, Chen MZ, Cooper AR, Andrews RC, Taheri S. The Impact
of Sleep Debt on Excess Adiposity and Insulin Sensitivity in
Patients with Early Type 2 Diabetes Mellitus. J Clin Sleep Med.
2016;12(5):673-80.
