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Melatonin: A "Higgs boson" in human reproduction

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DOI: 10.3109/09513590.2014.978851 · Source: PubMed

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Gynecol Endocrinol, 2015; 31(2): 92–101

! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.978851

MELATONIN AND REPRODUCTION

Melatonin: a ‘‘Higgs boson’’ in human reproduction

Svetlana Dragojevic Dikic1,2, Ana Mitrovic Jovanovic1,2, Srdjan Dikic2,3, Tomislav Jovanovic2,4, Aleksandar Jurisic1,2,
and Aleksandar Dobrosavljevic1
1
Department of Obstetrics and Gynecology ‘‘Narodni front’’, 2Medical Faculty, University of Belgrade, Belgrade, Serbia, 3University Medical Center
‘‘Bezanijska kosa’’, Belgrade, Serbia, and 4Institute of Physiology, Clinical Center of Serbia, Belgrade, Serbia

Abstract Keywords
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As the Higgs boson could be a key to unlocking mysteries regarding our Universe, melatonin, Cancer, immune function, melatonin,
a somewhat mysterious substance secreted by the pineal gland primarily at night, might be reproductive function, reproductive health
a crucial factor in regulating numerous processes in human reproduction. Melatonin is a
powerful antioxidant which has an essential role in controlling several physiological reactions, History
as well as biological rhythms throughout human reproductive life. Melatonin, which is referred
to as a hormone, but also as an autocoid, a chronobiotic, a hypnotic, an immunomodulator Received 27 September 2014
and a biological modifier, plays a crucial part in establishing homeostatic, neurohumoral Accepted 16 October 2014
balance and circadian rhythm in the body through synergic actions with other hormones Published online 7 November 2014
and neuropeptides. This paper aims to analyze the effects of melatonin on the reproductive
function, as well as to shed light on immunological and oncostatic properties of one of the
most powerful hormones.
For personal use only.

Introduction produced in different tissues and organs, functions as a paracoid

or autocoid that has a significant influence on the regulation of
In 2012, the physicists of the European Organization for Nuclear
homeostatic and neurohumoral balance [10].
Research (CERN), Switzerland, publicized the discovery of the
Having been recognized as a pineal hormone possessing skin
Higgs boson, ‘‘the world’s most wanted particle’’. Almost
lightening properties and conveying information about environ-
50 years after the Higgs boson was first mentioned, this
ment to different parts of the body, melatonin was later also
advancement has brought about the completion of the standard
identified as a significant regulator of seasonal and circadian
model of particle physics, which describes all the existing
rhythm with the ability to entrain biological rhythms and control
particles and the forces acting upon them. This unique subatomic
reproductive functions in a wide variety of species. It is a
particle provides mass to all elementary particles, and it is owing
pleiotropic compound generated in different tissues which has
to it that matter exists. The particle is the basic unit, or quantum,
multiple and various effects on several physiological processes.
of the Higgs field, an entity that all particles pass through [1]
Melatonin has a crucial role in a number of significant physio-
(Figure 1). As the Higgs boson could be a key to unlocking
logical processes, such as circadian rhythms, sleep regulation and
mysteries of our Universe, melatonin, a somewhat mysterious
reproductive, neuroendocrine, cardiovascular, neuroimmunologi-
substance secreted by the pineal gland primarily at night, might be
cal and oncostatic actions [11–16]. As numerous studies have
the crucial factor in regulating numerous processes in human
shown that melatonin is a potent and immediate free-radical
reproduction.
scavenger, it appears to be a multifunctional and unique
Lerner et al. [2] first isolated melatonin as a pineal gland
antioxidant [17]. Scientific evidence of melatonin’s important
product and pioneered a new research field in reproductive
role in follicle and corpus luteal function, pregnancy, puberty, and
physiology. Now, melatonin [indoleamine (N-acetyl-5-methoxy-
parturition time has been provided, indicating melatonin’s crucial
tryptamine)] is considered to be a hormone with a universal
role in reproductive functions [18–20].
photoperiodic signal, and a molecule with diverse physiological
Melatonin has a significant impact on the female reproductive
functions [3]. Apart from being synthesized and released at night
system; the hormone is considered essential for both folliculogen-
by the pineal gland, the hormone is also produced in small
esis and spertmatogenesis, influencing steroid production and
quantities by other extrapineal organs – the retinas, the skin, the
activity and modifying cellular signals on target tissues. It has been
alimentary canal, bone marrow cells, ovaries and many other
implied that melatonin takes part in the control of pubertal onset,
tissues [4–8]. Further studies have also revealed that this
timing of ovulation, sexual maturation and pregnancy protection
indoleamine is ubiquitous and can be synthesized by virtually
and that it has potential utilities in menopausal medicine as well.
all the cells containing a nucleus [9]. Melatonin, which is locally
[21]. Melatonin is a natural antioxidant with immunoenhancing
and oncostatic properties. Also, melatonin is an important free-
Address for correspondence: Svetlana Dragojevic Dikic, Department of
radical scavenger, protecting body and brain cells against genetic
Obstetrics and Gynecology ‘‘Narodni front’’, Medical Faculty, University damage, which is thought to be a precursor to cancer. According to
of Belgrade, Radoja Domanovica 19, 11050 Belgrade, Serbia. Tel/Fax: these data, melatonin is a master regulator of reproductive and
+381 11 380 6238. E-mail: stefand@eunet.rs; s_dikic@yahoo.com general health throughout the life course [21,22].
 DOI: 10.3109/09513590.2014.978851
Figure 1. Higgs boson image: Thomas McCauley/Lucas Taylor/CERN/
CMS Collaboration. A reconstructed event in the CMS detector. The
event shows the possible decay oh the Higgs boson to a pair of photons.
Gynecol Endocrinol Downloaded from informahealthcare.com by 195.178.58.1 on 01/23/15
CERN: The European Organization for Nuclear Research, CMS:
Compact Muon Detector.
Melatonin: synthesis, secretion, and receptors
Melatonin, a universal photoperiodic hormone, is a small
lipophilic indoleamine with a molecular weight of 232; it is
synthesized from tryptophan, an essential amino acid, via
serotonin [3,21]. After being hydroxylated to 5 hydroxy-trypto-
phan, tryptophan is converted into serotonin. Serotonin is
For personal use only.
acetylated to form N-acetylserotonin by the rate-limiting
enzyme alkylamine N-acetyltransferase (NAT). N-acetylserotonin
is then converted into melatonin by acetylserotonin O-methyl-
transferase (ASMT). Pineal generation of melatonin follows a
circadian rhythm characterized by low production levels during
the day and high production levels at night; the circadian pattern
of melatonin generation is by controlled by the suprachiasmatic
nucleus (SCN), the main circadian oscilator. Light information
received by the retina passes primarily through the retino-
hypothalamic pathway and is transmitted to the SCN, where a
circadian clock exists. This transmission enables the synchron-
ization of circadian clock phases with the light–dark cycle over 24
hours. SCN fibers pass through the paraventricular hypothalamic
nucleus, medial forebrain bundle, and reticular formation
influencing the intermediolateral horn cells of the spinal cord
which contains preganglionic sympathetic neurons. The post-
ganglionic sympathetic fibers of the superior cervical ganglion
terminate on the pinealocytes and regulate melatonin synthesis by
secreting norepinephrine. Norepinephrine, secreted by the nerve
terminals derived from the superior cervical ganglion, stimulates
the pineal cells, primarily via b-adrenergic receptors, thereby
accelerating the synthesis of cyclic AMP, the second messenger,
to induce NAT activity during melatonin biosynthesis [23–25].
This pathway is actually activated at night, as the nervous
activities of the superior cervical ganglion are inhibited by light
stimulation (Figure 2). Therefore, darkness is the only condition
for the synthesis of melatonin, whereas sleep is not a precondition
for it. Exposure to light during the night inhibits the synthesis of
melatonin and its secretion, which leads to circadian desynchron-
ization and it could result in various diseases and cell aging [26].
In human beings, melatonin secretion is at its highest level
from the age of 3 to the age of 5 and it starts to decrease from
puberty onwards. Its values are rather invariable until the age of
35–40 and the final decrease in amplitude occurs when low levels
are observed in old age. However, there are huge differences in
the amplitude of the melatonin rhythm among individuals and it
Melatonin and human reproduction 93
has not been proven yet whether these differences have an impact
on human health [26,27].
The circadian rhythm of melatonin secretion is noted not only
in blood but also in most body fluids, including saliva, cerebro-
spinal fluid and follicular fluid, as well as in breast milk, due to
extrapineal melatonin production. Melatonin’s activity is mostly
performed through membrane-bound receptors MT1 and MT2
[28]. There are intramembrane areas in these membrane receptors
and they are members of the superfamily of G-protein coupled
receptors. The third binding site, first identified as MT3, was later
defined as the enzyme quinone reductase [29]. Melatonin’s
activity also includes binding to nuclear receptors, such as retinoid
Z receptor (RZR) and retinoid orphan receptor (ROR), or
cytoplasmic proteins, such as the calcium-binding proteins
calmodulin or tubulin [30]. Certain studies have implied that
modulation in the expression and function of nuclear receptors is
a mechanism for expressing melatonin’s biological effects. By
binding to nuclear receptors, melatonin changes the transcription
of a number of genes that take part in cellular proliferation (e.g.
5-lipoxygenase, p21, or bone sialoprotein) [31,32]. Melatonin
receptors are distributed over a variety of tissues and organs; as a
result, time information based on melatonin concentration is
transmitted to tissues throughout the body enabling a proper
regulation of many physiological functions. Up to now, it has been
confirmed that melatonin receptors can be found in the brain,
spinal cord, pituitary gland, retina, spleen, thymus, adrenal gland,
liver, kidney, heart, lungs, testes, ovaries, blood vessels, lympho-
cytes, as well as in osteoblasts [21,33].
Melatonin: reproductive functions
There is scientific evidence for the huge role melatonin plays in
human reproduction. It plays a part in controlling and regulating
various reproductive functions and it has a significant influence
on the female genital system. Several studies have shown there is
a clear correlation between melatonin and gonadotropins and/or
steroids, which suggests that melatonin may be involved in sexual
maturation, control of pubertal onset, folliculogenesis, oocyte
maturation, ovulation, pregnancy and menopause [21,34–37].
Melatonin is a key to regulating seasonal variation in gonadal
activity, i.e. circadian variation is present in ovulation, as in
summer it typically occurs in the morning, whereas in winter it
commonly occurs in the evening. Melatonin may influence
gonadal function indirectly via its effect on gonadotropin-
releasing hormone (GnRH) and gonadotropin secretion or directly
via local melatonin synthesis in gonads, which influences steroid
production and action, and modification of cellular signals for
target tissues. In mammals, it has been proven that melatonin
influences their reproductive function by activating melatonin
receptor sites within the hypothalamo–pituitary–gonadal axis.
The activation of MT1 and MT2 subtype receptors by melatonin
results in a decline in cyclic AMP production and protein kinase
A activity and attenuation of GnRH-induced gonadotropin
secretion.
A decrease in gonadotropin discharge is caused by melatonin-
activated suppression of GnRH-stimulated calcium signaling [34].
Both calcium influx through voltage-dependent calcium channels
and calcium mobilization from intracellular stores are hindered by
melatonin. Inhibition of calcium influx, most likely in a cyclic
AMP/protein kinase C-dependent manner, and the accompanying
calcium-induced calcium release from ryanodine-sensitive intra-
cellular pools by melatonin, brings about delayed GnRH-induced
calcium signaling [38–40]. This tonic inhibitory effect melatonin
has on GnRH activity gradually declined during evolution due to a
reduction in functional melatonin receptor expression. Recent
studies have pointed at the potential effect melatonin may have on
 94 S. Dragojevic-Dikic et al.
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For personal use only.
Figure 2. Pathway of melatonin synthesis in the human pineal gland. This pathway is actually activated during the night without light stimuli, as the
nervous activities of the superior cervical ganglion are inhibited by light stimulation. At night, the postganglionic sympathetic neurons ending in the
pineal gland release norepinephrine, which activates primarily b-adrenergic receptors to stimulate a cascade of molecular events that culminate in
melatonin production and release. Additional details related to these events are summarized in the text. ASMT: acetylserotonin O-methyltransferase,
NAT: N-acetyltransferase.
gonadotropin-inhibitory hormone (GnIH), a multifunctional
neuropeptide. GnIH expression and synthesis increase on short
days, and they seem to be immediately controlled by melatonin by
means of the Mel 1c receptor expressed on GnIH neurons [34,41].
Melatonin and puberty
The precise mechanisms controlling puberty onset are not fully
known. Ovaries and/or testes maturation is triggered by secretion
of follicle-stimulating hormone (FSH) and luteinizing hormone
(LH) under the impact of pulsative GnRH secretion. What
triggers the function of the hypothalamus is still controversial, the
central control unit of the brain and melatonin’s influence being
one of the possible explanations. Reactivation of the hypothal-
amic–pituitary axis starts approximately at the age of 10 due to a
progressive rise in the amplitude and frequency of GnRH pulses
and accordingly the pulsatile secretion of FSH and LH. It is
thought that melatonin’s nocturnal secretory pattern exerts an
inhibiting effect on hypothalamic GnRH secretion in humans [42].
It has been assumed that before puberty, the concentrations of
melatonin are too high for hypothalamic activation to occur.
However, at the age of 9 or 10, the drop in the level of serum
melatonin below the threshold value (500 pmol/l ¼ 115 pg/ml) is
a trigger for GnRH, after which pubertal changes start occurring.
The high level of nocturnal melatonin secretion has been found in
children with delayed puberty whereas low melatonin levels have
been noticed in children with precocious puberty. According to
these findings, melatonin may be a part of the event cascade
preceding the hypothalamic–pituitary–gonadal axis awakening at
Gynecol Endocrinol, 2015; 31(2): 92–101
puberty [43,44]. In some instances and in some species, melatonin
is called progonadotrophic. Surely, melatonin is neither anti-
gonadotrophic nor progonadotrophic per se. More precisely, the
changing duration of the nocturnal melatonin message is a passive
signal for the hypothalamo–pituitary–gonadal axis regarding the
time of year [45,46]. Melatonin has an important role in the
pubertal onset, but it is hard to separate melatonin’s effect from
the complicated interplay of neuropeptides, neurotransmitters and
neurosteroids.
Melatonin: follicular maturation, oocyte quality and
embryo development
Melatonin’s roles in reproduction are concentrated on its direct
activity in ovaries [34]. The ovary is a ‘‘master’’ gland in the
female reproductive system. It influences the balanced and highly
orchestrated function of almost all the organs and glands through
the production of numerous hormones, primarily steroids and
paracrine/autocrine factors, including melatonin. Recent studies
have pointed to the prospect of expanding ovarian function from
purely reproductive purposes to diminishing the effects of
menopausal diseases, heart disease and some types of cancer [47].
Although it has long been generally accepted that melatonin
inhibits reproductive functions in animals, recent reports sug-
gested that melatonin actually promotes these functions [21,48].
Melatonin is engaged in various reproductive events such as
folliculogenesis, follicular atresia, ovulation, oocyte maturation,
corpus luteum (CL) function and early embryo development.
Melatonin receptors are found in ovarian granulosa and theca
 DOI: 10.3109/09513590.2014.978851
cells, both of which occur in mature follicles and CL, and these
cells promote steroid hormone production. It is hypothesized that
melatonin is directly involved in the growth and maturity of
oocytes, as well as in the inhibition of factors which might impair
oocyte quality [21]. Additionally, the data collected by measuring
concentrations of melatonin in human ovarian follicular fluid (FF)
showed significantly higher melatonin concentrations when
compared to plasma levels; moreover, the concentrations of
melatonin in follicular fluids increased depending on follicular
growth. Higher melatonin concentrations in the follicular fluid are
retained by both active melatonin ovarian transport from the
blood stream in the FF and ovarian melatonin synthesis (primarily
by granulosa cells) [49,50]. One of the most significant functions
of melatonin was ascertained by showing that melatonin had
radical scavenger properties; indeed, melatonin was discovered to
reduce concentrations of highly reactive hydroxyl radicals result-
ing from both oxygen- and nitrogen-based reactants in vitro and
in vivo [51,52]. Furthermore, melatonin boosts the expression and
activity of antioxidative enzymes [superoxide dismutase (SOD),
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glutathione peroxidase (GPX)] and it inhibits the activity of the
pro-oxidative enzyme nitric oxide synthase (NOS) [26].
Melatonin has been noted to diminish a damaged DNA product
[8-hydroxy-2-deoxygyanosine (8-OHdG)] and the product result-
ing from lipid oxidation (hexanoyl-lysine adduct) in the FF [46].
The level of oxidatively damaged molecules in the FF is in direct
correlation with ovum quality. Additionally, it has been proven
that melatonin stimulates maturation-inducing hormone [MIH (17
a, 20 b-dihydroxy-4-pregnen-3-one)], which heightens oocyte
maturation [46,50,53] (Figure 3). Melatonin and its metabolites
(cyclic 3-hydroxmelatonin, N1-acetyl-N2-formyl-5-methoxytryp-
For personal use only.
tamine, N1-acetyl-5-methoxykynuramine, and 6-hydroxyl-mela-
tonin) with expanded free-radical scavenging properties are
powerful antioxidants [26,50]. Ovulation includes processes
resembling a local inflammatory response; both reactive oxygen
species (ROS) and reactive nitrogen species (RNS) are generated,
bringing about oocyte oxidative damage [50,54]. Although
surplus ROS can also account for oxidative stress leading to
oocyte and granulosa cell structure damage, locally generated
ROS seem to play a crucial part in follicular rupture, and ROS
also act as second messengers which modulate the expression of
genes governing the physiological processes of oocyte maturation.
ROS have to be constantly deactivated to retain only a small
Figure 3. Some of the proposed function of melatonin in the Graafian follicle. ROS: reactive oxygen speies, RNS: reactive nitrogen species, MIH:
maturation-inducing hormone, NOS: nitric oxide synthase.
Melatonin and human reproduction 95
amount that is required for maintaining the normal cell function
[55–58]. It is well known that endogenous antioxidant enzymes
with non-enzymatic antioxidants, such as melatonin and its
metabolites, are found in the follicles operating to quench or
diminish ROS and RNS. Failure or shortage of these oocyte
defenses may bring about the development of oxidative stress with
oocyte damage [59]. Moreover, ROS could be produced in larger
amounts due to certain conditions, including infections, inflam-
mation, chemotherapy, radiation, and superovulation like in
infertility therapy.
It has already been noted that melatonin is capable of
promoting embryo development in various species. When
inseminated mice embryos were cultured in medium with
melatonin, higher fertilization and blastocyst rates were noticed
[60]. The effect melatonin has on embryo development appears to
be due to its antioxidative activity, at least to a certain degree. A
recent study has proven that melatonin treatment is beneficial for
infertile women who have undergone an assisted reproductive
technique (ART)/in vitro fertilization – embryo transfer (i.e. IVF-
ET) program. Those women were given 3 mg of melatonin a day
from day 5 of the previous menstrual cycle to the day of oocyte
retrieval; the percentage of good embryos (day 2 after insemin-
ation) was substantially higher in comparison with the control
cycle where there was no melatonin treatment [61]. The collected
data suggested melatonin played a part in embryo development
and oocyte maturation. Melatonin treatment for reproductive
function restoration and infertility leads to elevated fertilization
and pregnancy rates due to increased intra-follicular melatonin
concentrations with a consequent reduction in intra-follicular
oxidative damage [62]. Melatonin may become a beneficial
treatment for enhancing ovarian function, oocyte quality and
embryo development in infertile women, particularly those who
fail to get pregnant because of poor oocyte quality and those whose
reproductive life is coming to an end [61]. Additionally, melatonin
could create new opportunities for managing various ovarian
diseases including endometriosis, chronic anovulation, polycystic
ovary syndrome, as well as premature ovarian insufficiency [50].
Melatonin and pregnancy
Pregnancy is a physiological state characterized by elevated
metabolic demands for tissue oxygen. This heightened need for
 96 S. Dragojevic-Dikic et al.
oxygen results in an increased production of reactive oxygen
species (ROS), which can damage cell membranes by lipid
peroxidation. In the course of pregnancy, the placenta is the major
source of peroxidized lipids; the serum concentration of
peroxidized lipids rises in pregnant women. Moreover, pregnancy
has a negative impact on some antioxidant enzymes’ activity (e.g.
superoxide dismutase and glutathione peroxidase) in the liver and
placenta [63,64]. It has been noticed that elevated levels of
oxidative stress and unbalanced levels of some micronutrients in
mother’s blood are the reason for some pregnancy-related
disorders. However, some studies have pointed to the protective
effect melatonin has on both the fetus and the mother during
pregnancy, as well as melatonin’ s responsibility for preserving
the integrity of tissues (placenta, fetus) against nitro-oxidative
stress due to toxic radicals and related reactants primarily
produced in mitochondria [65,66]. A significant number of
experimental and clinical conditions have proven melatonin to be
effective in diminishing molecular damage and tissue loss, and
also in enhancing physiological outcomes in situations when great
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free-radical destruction commonly occurs. In normal pregnant
women, melatonin levels rise during gestation with substantially
higher levels after 32 weeks [67]. Melatonin is transmitted from
maternal circulation to fetal circulation, thus producing a day–
night difference in melatonin concentration in fetal circulation.
Melatonin receptors are expressed in the human fetal SCN and in
several regions of the human fetal brain [68,69]. Melatonin could
also improve progesterone synthesis by the corpus luteum and
later by the placenta to assist maintaining the pregnancy, while
hindering the premature release of oxytocin [46]. In the placenta,
melatonin acts in a similar protective way against nitro-oxidative
For personal use only.
stress; likewise, melatonin diminishes the vasospastic effect of
H2O2 on the human umbilical artery. Melatonin also counteracts
mannitol and catalase, two antioxidants that reduce this suppres-
sive effect [70]. It has been discovered that melatonin protects the
fetus from oxidative stress owing to ROS and RNS [46].
Several pregnancy-related diseases and conditions could
benefit from melatonin treatment. In this context, a special
attention should be paid to preeclampsia, a major disorder which
occurs in approximately 5–7% of all pregnancies worldwide and is
a leading cause of premature delivery and fetal growth retardation
[71]. In spite of the fact that the pathophysiology of preeclampsia
is still unidentified, elevated oxidative stress is thought to be one
of the possible triggers [72,73]. Most important signs are high
systolic and diastolic blood pressure, and proteinuria that occurs
during the second half of pregnancy. Maternal complications
include kidney or liver failure, cerebral edema with seizures,
HELLP syndrome (hemolysis, elevated liver enzymes, and
thrombocytopenia) and (rarely) death. Preeclampsia is specially
connected with increased lipid peroxidation in both maternal
circulation and the placenta. Many studies have proposed
melatonin as a useful treatment for preeclampsia owing to its
antioxidant properties. [34,46,65,74]. It has been discovered that
melatonin is efficient against oxidized low-density lipoprotein
(LDL)-induced inhibition of nitric oxide (NO) generation in the
endothelium of human umbilical arteries. Therefore, by inhibiting
LDL oxidation, melatonin could provide protection against
oxidized LDL-induced impairment of endothelial function in
women with preeclampsia [53]. Placental infarction in pre-
eclamptic women leads to fetal growth retardation. Due to the fact
that the placenta transports melatonin from maternal circulation to
fetal circulation and that a damaged placenta is not likely to
transfer indoleamine as efficiently as a healthy one, the observa-
tion that melatonin maintains the integrity of this tissue may have
important implications for protecting the fetus as well.
Melatonin’s other significant traits have also been reported,
some of them being its antihypertensive and anticonvulsive
Gynecol Endocrinol, 2015; 31(2): 92–101
activity [75,76]. Hence, melatonin may have a beneficial effect on
certain parameters that are changed in preeclampsia, providing
protection to both the fetus and the mother. In addition, melatonin
might reduce the abortion rate and recurrent pregnancy loss due to
its antioxidant properties to suppress placental free-radical
damage [77,78]. It has also been shown that melatonin might
belong to the mechanisms underlying the induction of parturition;
melatonin may stimulate the myometrium via its own receptors or
via synergic action with oxytocin through gap junction activity,
which is crucial in stimulating synchronous myometrial contrac-
tions [79,80]. According to presented data, melatonin could be of
great importance for restoring and maintaining a healthy
pregnancy and fetal development.
Melatonin and menopause
The long list of symptoms/signs/medical problems that affect
postmenopausal women have a negative effect on the quality of
their lives. These problems mostly pertain to hot flushes, night
sweats, sleep deprivation, mood disturbances, vulvovaginal atro-
phy, bone loss and fractures, sexual dysfunction, muscle loss,
cardiovascular diseases, breast cancer, loss of memory, loss of
cognition, and possibly Alzheimer’s disease. The severity of the
symptomatology related to hormone deficiency, oxidative cell
damage and immune deficiency due to aging varies between races
and from person to person. With longer life expectancy and the
increased number of world population, it is expected that there
will have been more than 1.1 billion postmenopausal women by
2025 [81–85]. Improving the quality of life is essential in this
vulnerable period; therefore, promoting education and research in
all aspects of women’s health, including a search for optimal
preventive and therapeutic strategies, is of great importance.
Management of menopausal women should be multidisciplinary
and individualized, including counseling, emotional support,
lifestyle modification, diet, nutritional supplement advice, non-
hormonal therapy and hormonal therapy, which should be
individualized according to type, dose, route and duration of the
therapy and to women’s symptoms, general health, family history
and personal risk factors [86,87]. By using individualized
treatment, benefits will generally outweigh the potential risks.
Melatonin may also be useful for treating women who are near
the end of the reproductive phase of their life and postmenopausal
women due to its beneficial effects on various significant
physiological functions, including circadian rhythms and sleep
regulation and reproductive, neuroendocrine, cardiovascular,
neuroimmunological and oncostatic actions, and considering
that melatonin levels decrease with age [46]. Bellipani et al.
[88] confirmed in their study that melatonin treatment could
reverse hormonal and menopause-related neurovegetative disturb-
ances, as well as menopause-related depression; melatonin
treatment was also shown to restore menstrual cyclicity and
fertility in perimenopausal or menopausal women. Melatonin may
aid prolonging reproductive health for women seeking fertility,
particularly those who are approaching or entering menopause, in
terms of the ability to get pregnant and deliver healthy offspring
[61,88]. The presence of melatonin receptors was also proven
in osteoblasts derived from human jaw bones and ilia, and
melatonin accelerated the proliferative differentiation of osteo-
blasts and increased collagen production [89]. According to such
findings, it is expected that melatonin may prevent osteoporosis
and accelerate fracture healing (bone regeneration), which is
important in the menopausal period [21]. As a powerful
antioxidant with immunoenhancing properties, melatonin may
also have a significant role in preventing cardiovascular diseases;
Reiter [90] suggested that melatonin could be an efficient
treatment for hypertension. Several studies have shown that
 DOI: 10.3109/09513590.2014.978851
melatonin’s antioxidant properties could aid diminishing the
severity of Alzheimer’s disease, which is characterized by
inflammation and brain damage caused by free radicals, by
acting against cellular brain changes found in dementia patients
[91,92]. Breast cancer risk increases with aging; the risk of breast
cancer in association with hormone replacement therapy (HRT) in
menopause has already been recognized, but the risk also depends
on the type, dose, route and duration of HRT, as well as individual
risk factors [87]. In addition, increased light exposure of sufficient
intensity at night possibly diminishes circulating melatonin levels
and resets the circadian pacemaker of the SCN; the reduced
melatonin levels could be a permissive factor in breast cancer cell
growth initiation [93]. In breast cancer cells, melatonin inhibits
the expression of estrogen-responsive, cancer-related genes as
well [94]. Therefore, it is expected that combining melatonin with
a variety of anticancer therapies may bring additional efficacy.
Melatonin is derived from serotonin, which has a role in mood
control, so changes in melatonin levels could be responsible for
the links between chronic fatigue, depression, sleep and mood
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disturbances. Sleep is a thalamic function supported by melatonin
that acts by enhancing spindle formation [95]. Presumably acting
on the major circadian clock, i.e. SCN, melatonin plays an
essential part in regulating bodily rhythms, including synchroniz-
ing sleep with the normal period of darkness. Melatonin has been
successfully used to treat insomnia and circadian sleep disorders,
which could be of great importance in menopausal management
strategies [96]. In connection with using melatonin as a treatment
for sleep disturbance, melatonin might also be used to prevent and
treat ‘‘jet lag’’ disorder [26]. Moreover, as it has been recently
discovered, novel melatonin agonists (ramelteon and agomelatine)
For personal use only.
have been found to have more effect in improving sleep efficiency
in elderly insomniacs [97]. The melatonergic antidepressant
agomelatine, i.e. N-[2-(7-Methoxy-1-naphthyl)ethyl] acetamide,
with both MT1/MT2 receptor agonist properties, without signifi-
cant affinities to muscarinic, adrenergic, dopaminergic, or
histaminergic receptors and with selective antagonism to 5-
HT2c receptors, and ramelteon, i.e., N-{2-[(8S)-1,6,7,8-tetrahy-
dro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide, with high
selectivity for MT1 and MT2 melatonin receptors, have
revolutionized the treatment of insomnia and depressive disorders
with no reports of significant or serious adverse effects [98,99].
As melatonin has both sleep-enhancing and chronobiotic charac-
teristics, the use of melatonergic antidepressants is considered
even more effective in treating elderly patients suffering from
depressive disorders and sleep deprivation [97].
Melatonin: immune function and cancer related to
reproductive health
Melatonin is a natural antioxidant with immunoenhancing
properties. There are numerous natural mechanisms against
carcinognesis; these mechanisms belong to two major categories:
immune and non-immune mechanisms. Immunosurveillance,
which belongs to the first category, is one of the most important
processes which detect and eliminate cancerous cells.
Melatonin has an important immunomodulatory role in
immunocompromised states related to various diseases, particu-
larly during aging, and the activating lymphocytes and mono-
cytes/macrophages by melatonin may prevent tumor development
[100,101]. Daily and seasonal changes in immune function
correspond to biosynthesis and secretion of melatonin [102].
Additionally, the synthesis of melatonin by human lymphocytes
proves the hypothesis that melatonin regulates immune function.
Some other studies have shown that the melatonin synthesized by
human T cells helps the control of interleukin (IL)-2 generation by
acting as an intracrine, autocrine and/or paracrine substance
Melatonin and human reproduction 97
[8,103]. Melatonin receptors can be found in the monocyte/
macrophage lineage [104]. Melatonin distribution boosts the
production of monocytes and natural killer (NK) cells in bone
marrow and spleen within 7–14 days since the beginning of the
treatment [105]. Both these cell types belong to the non-splenic
immune system, so according to the collected data, melatonin can
be effective in stopping neoplastic growth and in devastating
infected cells. Stimulation of monocyte production by melatonin
may be accounted for either by its direct action on melatonin
receptors in monocytes or by its sensitizing action on monocytes
to stimulants (cytokines, such as IL-3, IL-4, or granulocyte
macrophage colony-stimulating factor) [106].
Natural killer cells play a significant part in immunosurveil-
lance against neoplasia and virus-infected cells [107]. The
increase in the number of NK cells caused by melatonin is
associated with a heightened production of cytokines, such asIL-
2, IL-6, IL-12 and interferon (IFN)-g by T helper (Th)-1
lymphocytes and monocytes [105,108]. The fact that melatonin
receptors are found on T lymphocytes accounts for melatonin’s
activity in releasing cytokines that improve NK activity and raise
the number of NK cells. Being members of the immunocompe-
tent-cell family, which take part in the innate immune response,
NK cells are supposed to work together with other T cells, in
particular suppressor T cells, during early phases of the
autoimmune response [109]. Lymphocytes have a significant
role in fighting neoplasia by recruiting immune system cells and
activating antigen-specific effector cells. The importance of
CD4+ Th cell stimulation in cancer chemotherapy has been
recognized. CD4+ lymphocytes discharge IFN-g and tumor
necrosis factor (TNF)-a, which activate and control cytotoxic T
cell responses [110,111]. Th-1 cells directly kill tumor cells by
discharging cytokines that activate ‘‘death’’ receptors on the
surface of a tumor cell. Melatonin also favors Th-2 responses; not
only does it stimulate the secretion of IFN-g and IL-2, it also
stimulates the release of IL-10 [112]. Additionally, melatonin’s
immunoenhancing properties depend not only on its ability to
improve cytokine generation but on its antiapoptotic and antioxi-
dant activities as well [113]. These properties are of great
importance for protection and improving of reproductive health.
There are significant scientific studies about melatonin as an
oncostatic agent against various types of tumor, such as melan-
oma, breast cancer, ovarian and colorectal cancer [114–122];
many reports have focused on melatonin as mammary gland
tumor suppressant [26,34,93,123–125]. It has been shown that
melatonin suppresses tumor development both in vivo and
in vitro. There are several mechanisms through which melatonin
can show its oncostatic activity: (1) its direct pro-apoptotic, gene-
mediated actions on tumor cells; (2) its antioxidant actions; (3)
diminishing the uptake of crucial factors of tumor growth and
tumor growth signaling molecules [e.g. linoleic acid (LA)]; and
(4) improving immune mechanisms in the body, which has been
shown to be a significant oncostatic property [110]. Despite the
fact that melatonin affects the expression of a wide spectrum of
genes, its primary effectors tend to be connected with the genes
regulating the cell cycle, adhesion, and transport. This finding is
in accordance with accepted data on melatonin’s impact on cell
proliferation, apoptosis, and adhesion. Importantly, melatonin has
also shown to have an evident impact on the expression of genes
related to oncogenesis (e.g. Mybl1, Rasa1, Mllt3, Enigma
homolog 2) and calcium metabolism (Kcnn4 and Dcamkl1) [126].
Considering the fact that melatonin considerably limits free
radical-mediated cell damage, the indoleamine reduces cancer
inception. Once tumors are formed, melatonin reduces their
growth and the possibility of metastasis by suppressing the uptake
of growth factors, e.g. LA, and by inhibiting telomerase activity
(26). Telomerase is a specialized ribonucleoprotein polymerase
 98 S. Dragojevic-Dikic et al.
which extends the telomeres of eukaryotic chromosomes [127].
The telomeres have a fundamental role in preserving the integrity
of chromosomal structures; due to the fact that the telomeres
constantly shorten (when cells divide), the chromosomes become
unstable and more vulnerable to fragmentation. Additionally,
melatonin inhibits angiogenesis through endothelin-1 synthesis
attenuation. Endothelin-1 directly stimulates both endothelial and
perivascular cells. Moreover, it indirectly stimulates angiogenesis
by increasing the release of vascular endothelial growth factor
(VEGF), a great pro-angiogenic substance. Finally, fibroblasts
and cancer cells are stimulated by endothelin-1 to produce pro-
angiogenic proteases [128]. Considering the fact that endothelin-1
acts in multiple ways on stimulating tumor angiogenesis, any
agent that limits endothelin-1 synthesis may negatively influence
tumor growth by taking away all the oxygen and nutrients from
the cancer. A recent paper has reported that endothelin-converting
enzyme-1 [129], a zinc-dependent metalloproteinase which splits
inactive endothelin precursors to form mature endothelin-1, is
suppressed by melatonin. If melatonin exerts a similar inhibiting
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effect on the blood vessel invasion in tumors, this activity may
mean a substantial contribution to the suppressing effects
manifested by melatonin in the field of tumor growth inhibition.
This field of research is currently investigated.
Melatonin’s breast cancer risk protection in women is of great
importance. In recent years, low melatonin levels following light-
induced suppression of melatonin synthesis have been blamed for
the elevated risk for breast cancer among women working night
shifts [124,125,130]. Depending on the balance of the circadian
rhythm, generation of melatonin at night could be a ‘‘regulatory
signal’’ for the carcinogenic process, or it could be a ‘‘natural
For personal use only.
restraint’’ on tumor inception, development and/or progression.
Some studies have investigated the protective role melatonin has
in mammary carcinogenesis of postmenopausal women with
advanced breast cancer. Urinary levels of melatonin in these
women are lower than those in the control group [131]. The
suppressing effect melatonin has on mammary carcinogenesis has
been accounted for by melatonin’s impact on immune modulation.
Additionally, it has been reported that in steroid-responsive
tumors, such as breast cancer, melatonin interferes with estrogen
receptor control, transactivation and intracellular signal transduc-
tion cascades, which results in attenuation of steroid stimulatory
actions [132]. There have been suggested three different mech-
anisms for inhibiting the progression of breast cancer by
melatonin: (1) by indirect neuroendocrine mechanism regulation,
which includes melatonin down-regulation of the hypothalamo–
pituitary–gonadal axis and a consequent reduction in estrogen
levels; (2) by acting on receptor sites within the tumor, altering
estrogen receptor function therefore acting as a selective estrogen
receptor modulator (SERM); and (3) by regulating the enzymes
involved in estrogen biosynthesis in peripheral tissues and thus
acting as a selective estrogen enzyme modulator (SEEM) [27].
Considering the fact that melatonin down-regulates the aromatase,
sulfatase and 17 b-hydroxyl steroid-dehydrogenase pathways and
elevates the activity and expression of estrogen-sulfotransferase,
this indoleamine could protect mammary tissue from excessive
estrogen influence. Therefore, melatonin possesses both
SERM and SEEM properties, the crucial properties needed for
possible prevention and treatment of estrogen-dependent mam-
mary tumors [133].
Conclusions
Melatonin, a pineal and extrapineal hormone, represents a key
factor in the regulation of numerous human reproduction
processes. Clearly, melatonin regulates the seasonal and photo-
period-dependent day aspects of reproductive events. The fact that
Gynecol Endocrinol, 2015; 31(2): 92–101
melatonin has been found to be a direct free-radical scavenger and
an indirect, powerful, multifunctional antioxidant has greatly
lengthened the list of mechanisms owing to which indoleamine is
beneficial for reproductive physiology. Depending on its produc-
tion site and the target organ, melatonin can act as a hormone,
autacoid, hypnotic, immunomodulator or a biological modifier.
Melatonin plays a part in different significant physiological
functions, including circadian rhythms and sleep regulation.
Melatonin plays a particularly important role in controlling and
regulating a variety of reproductive functions with a significant
impact on the female genital system. Melatonin is implicated in
the control of pubertal onset, sexual maturation, timing of
ovulation, reproductive life potential, and pregnancy protection,
as well as in alleviation of menopause-related symptoms and
disorders. Melatonin may also be beneficial not only for
preserving reproductive health but also in general health. Due
to its crucial role in regulating circadian, immunological,
reproductive and neurobiological mechanisms, melatonin, with
its chronopsychophysiological properties, has been proven to be
a master regulator of reproductive health. Additionally, with
its immunological and oncostatic properties, melatonin is one of
the best ‘‘intracellular defenders’’ with a potential to act on many
target tissues and organs; melatonin may be considered the
‘‘Higgs boson’’ of human reproduction.
Many uses related to melatonin still remain a mystery and
require further research. The major objective of future research is
to investigate optimal melatonin supplementation in different
pathophysiological conditions and make an optimal selection of
patients who may benefit from antioxidant and immunomodulat-
ing melatonin therapy. This therapy may be used for ovarian
function and fertility recovery and pregnancy protection, as well
as for the prevention and treatment of serious neurodegenerative
and malignant disorders [134]. The time for clinical melatonin use
is obviously approaching; therefore, investigation of its use is
essential not only for reproductive well-being but also for
improving general health and life in humans.
Acknowledgements
The authors thank Professor Russel Reiter (University of Texas Health
Science Center) for useful instructions during the preparation of this
manuscript and for permission to use and adapt figures from his work.
Declaration of interest
The authors report no conflicts of interest.
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