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International Journal of Reproductive BioMedicine
Volume 17, Issue no. 12, https://doi.org/10.18502/ijrm.v17i12.5789
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Review Article
The role of melatonin in polycystic ovary
syndrome: A review
Sina Mojaverrostami1D.V.M., Narjes Asghari2M.Sc., Mahsa Khamisabadi3
D.V.M., Heidar Heidari Khoei4, 5 D.V.M.
1Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran,
Iran.
2Department of Molecular Medicine, Faculty of Medical Biotechnology, National Institute of
Genetic Engineering and Biotechnology, Tehran, Iran.
3Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
4Student Research Committee, School of Medicine, Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
5Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti
University of Medical Sciences, Tehran, Iran.
Abstract
Background: Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder,
affecting approximately 20% of women within reproductive age. It is associated
with hyperandrogenism, obesity, menstrual irregularity, and anovulatory infertility.
Melatonin is the main pineal gland hormone involved in the regulation of the circadian
rhythm. In recent years, it has been observed that a reduction in melatonin levels
of follicular uid exists in PCOS patients. Melatonin receptors in the ovary and intra-
follicular uid adjust sex steroid secretion at different phases of ovarian follicular
maturation. Moreover, melatonin is a strong antioxidant and an effective free radical
scavenger, which protects ovarian follicles during follicular maturation.
Objective: In this paper, we conducted a literature review and the summary of the
current research on the role of melatonin in PCOS.
Materials and Methods: Electronic databases including PubMed/MEDLINE, Web of
Science, Scopus, and Reaxys were searched from their inception to October 2018 using
the keywords “Melatonin” AND “Polycystic ovary syndrome” OR “PCOS.”
Results: Based on the data included in our review, it was found that the administration
of melatonin can improve the oocyte and embryo quality in PCOS patients. It may also
have benecial effects in correcting the hormonal alterations in PCOS patients.
Conclusion: Since metabolic dysfunction is the major nding contributing to the
initiation of PCOS, melatonin can hinder this process via its improving effects on
metabolic functions.
Key words: Hyperandrogenism, Infertility, Melatonin, PCOS.
How to cite this article:Mojaverrostami S, Asghari N, Khamisabadi M, Heidari Khoei H. “The role of melatonin in polycystic ovary syndrome:
A review,” Int J Reprod BioMed 2019; 17: 865–882. https://doi.org/10.18502/ijrm.v17i12.5789 Page 865
Corresponding Author:
Sina Mojaverrostami;
Department of Anatomical
Sciences, School of Medicine,
Tehran University of Medical
Sciences, 16 Azar St., Poursina
St., Tehran, Iran.
Postal Code: 1417933791
Tel: (+98) 21 64432348
Email:
sinamojaver@gmail.com
Received 12 February 2019
Revised 16 May 2019
Accepted 20 July 2019
Production and Hosting by
Knowledge E
Mojaverrostami et al. This
article is distributed under the
terms of the Creative
Commons Attribution License,
which permits unrestricted
use and redistribution
provided that the original
author and source are
credited.
Editor-in-Chief:
Aatoonian Abbas M.D.
International Journal of Reproductive BioMedicine Mojaverrostami et al.
1. Introduction
Polycystic ovary syndrome (PCOS) is a complex
disorder arising from the interaction of genetic
and environmental reasons that affects up to 20%
of women at reproductive age (1). According to
the ESHRE/ASRM consensus, at least two of the
following three features should be present for
proper PCOS diagnosis: 1) ovulatory dysfunction
(oligoanovulation and/or anovulation); 2) hyperan-
drogenemia (the biochemical feature of androgen
excess) or hyperandrogenism (the clinical feature
of androgen excess); 3) polycystic appearance of
ovaries in ultrasonography (2), together with the
exclusion of other etiologies (3). In addition to
reproductive and cosmetic sequelae, PCOS syn-
drome is associated with a higher risk of metabolic
disorders including insulin resistance, increased
oxidative stress (4), cardiovascular disease, type 2
diabetes mellitus, liver disease, and endometrial
cancer (5, 6).
Women with PCOS often seek treatment due
to their complaints of infertility and menstrual
cycle irregularities which are the results of chronic
oligo/anovulation (7). Changing lifestyles, such as
nutritional counseling and weight loss are the
necessary step of all treatment plans (8). Despite
the many advances in the understanding of the
Pathobiology and treatment strategies of PCOS
over the past decades, many questions remain to
be answered and the treatment of the syndrome
remains empirical.
Melatonin (N-acetyl-5-methoxytrypamine) is an
indolamine hormone that was rstly recognized
in the 1950s (9). Melatonin levels are regulated
by photoperiod as its production and secretion
are promoted at night in response to darkness
since light can suppress its secretion (9). Melatonin
is also produced in other organs such as the
gastrointestinal tract, skin, retina, bone marrow,
and lymphocytes (10, 11). It seems that mitochondria
are the site of melatonin synthesis within cells.
Moreover, the female reproductive organ, including
the follicular cells, oocytes, and cytotrophoblasts
are also among the melatonin production sites
(12). Several studies have shown the involvement
of melatonin in the pathogenesis of diabetes,
cancer, Alzheimer’s disease, immune and cardiac
diseases (13-15). Melatonin has been identied to
have different pharmacological properties such as
antioxidant, immunomodulatory, anti-angiogenic,
and oncostatic effects (16). Melatonin acts as
an inhibitory factor on the hypothalamic pituitary
gonadal axis (17). Melatonin receptors are trans-
membrane G-protein-coupled receptors including
melatonin receptor 1 (MT1; MTNR1A) and melatonin
receptor 2 (MT2; MTNR1B) (18).
The effects of melatonin on female reproduc-
tive physiology are mediated via its receptors
in hypothalamic, pituitary, and ovarian sites (19).
Melatonin is also a potent free radical scavenger
that exerts protective effects in female reproductive
organs; for instance, it is involved in the protection
of the oocyte against oxidative stress, particularly
at the time of ovulation. It can also be used to
protect the developing fetus from oxidative stress
can be happened by melatonin (20). The levels of
melatonin in follicular uid are higher than its levels
in the blood (21). The concentration of melatonin
in follicular uid signicantly rises as the follicles
become mature (22).
In this paper, we have made an effort to review
the possible roles of melatonin in the pathogen-
esis of PCOS as well as the potential melatonin-
centered therapeutic measures, which can be
recruited herein.
2. Materials and Methods
2.1. Search strategy
Related published articles were searched in the
following electronic databases: PubMed/MEDLINE,
Page 866 https://doi.org/10.18502/ijrm.v17i12.5789
International Journal of Reproductive BioMedicine Melatonin in PCOS
Web of Science, Scopus and Reaxys. All the
sources were searched from their inception to
October 2018 using the keywords “Melatonin” AND
“Polycystic ovary syndrome” OR “PCOS.”
2.2. Study selection
Titles and abstracts from the electronic
databases were scrutinized following the search
for the keywords, and the full-text papers which
were expected to match with our inclusion
criteria were obtained. The following specied
inclusion criteria were used: (1) studies that
used melatonin in context of PCOS or those in
which melatonin was somehow shown to be
related to any of the mechanisms involved in the
pathogenesis of PCOS; (2) papers with available
full texts; (3) Papers in English language only.
There was no limitation regarding the inclusion
of any human or animal models for PCOS or
cell lines researches. Furthermore, the following
exclusion criteria were applied: (1) no report
on the treatment with melatonin; (2) no report
with the PCOS disease; (3) no report on the
use of melatonin for treating PCOS in clinical
or animal models or cell lines researches; (4)
no report on the melatonin level alternation in
the different body biological uids; (5) review
articles; and (6) non-English language articles
(Figure 1).
Figure 1. Flow diagram of the search strategy.
2.3. Data extraction
The papers, meeting all the aforementioned
criteria were reviewed separately to conrm
the reliability of the extracted data. All
characteristics of the articles such as author
name, year, study location, study population,
study period, treatment method, dose of
treatment, and outcomes were extracted
from the papers. The extracted data of
the selected studies are shown in Tables I
and II.
https://doi.org/10.18502/ijrm.v17i12.5789 Page 867
International Journal of Reproductive BioMedicine Mojaverrostami et al.
Table I. Changes in Melatonin levels of PCOS patients
Author, year
(ref) Country Participants Mean age
(year) Sample Melatonin or its metabolite levels
𝛼MT6s in urine (μg/24 h)
Melatonin in saliva, blood, and
follicular uid (pg/ml)
Hormonal levels in serum LH, FSH (mIU/ml)
Testosterone(ng/ml) 8-OHdG (ng/ml)
Result
Patients Control LH/FSH
ratio Patients Control
Luboshitzky
et al., 2003
and 2004
(33, 34)
Israel 12 women
with PCOS 20.3 ±4.8 Urine
αMT6s:
52.6 ±20.3 30.5 ±6.5
LH
FSH
T
13.5 ±2.9
5.3 ±2.1
0.58 ±0.28
4.6 ±2.2
6.5 ±1.4
0.3 ±0.1
The level of LH,
testosterone, and αMT6s
were signicantly higher in
PCOS patients
Luboshitzky
et al., 2001
(35)
Israel 22 women
with PCOS 22.9 ±5.2 Urine
αMT6s:
54.0 ±20.3 30.1 ±6.6 LH/FSH 2.04 ±1.24 0.74 ±0.39
PCOS patients had higher
levels of aMT6s,
testosterone, LH/FSH ratio,
and insulin than control
women. Testosterone was
a good indicator for aMT6s
concentration in PCOS
patients which inversely
related to aMT6s
Shreeve
et al., 2013
(42)
UK 15 women
with PCOS 29.8+3.7 Urine
αMT6s:
60.3 ±30.6 37.7 ±21.5
FSH
LH
T
8-OHdG
6.9 ±0.6
8.1 ±1.2
2.3 ±0.2
120.5 ±42.1
84.0 ±40.8
Night-time melatonin and
8-OHdG concentrations
were signicantly higher in
PCOS women compared
to healthy women
Jain et al.,
2013 (40) India 50 women
with PCOS 24.87 ±4.43 Blood
plasma
Melatonin:
63.27 ±10.9 32.51 ±7.5
FSH
LH
T
LH/FSH
5.43 ±1.53
16.13 ±7.95
1.2.84 ±6.96
3.10 ±1.69
6.60 ±2.86
7.18 ±1.97
0.84 ±12.75
1.15 ±0.25
Melatonin level increase in
all the cases of PCOS
women but testosterone
level rise in 72% of
patients. Melatonin level
positively related to
increased testosterone
concentration
Terzieva
et al.,2013
(49)
Bulgaria 30 women
with PCOS 25.07±1.10 Blood
serum
Melatonin:
49.37 ±3.79 42.91 ±9.38
FSH
LH
T
LH/FSH
6.83 ±1.04
12.43 ±3.83
0.60 ±0.05
1.64 ±0.33
5.57 ±0.32
4.08 ±0.35
0.32 ±0.03
0.73 ±0.03
In PCOS women, serum
melatonin concentration
was signicantly higher
than the healthy women
Zangeneh
et al., 2014
(50)
Iran 77 women
with PCOS 26.6 ±4.7 Blood
serum
Melatonin: 25.48
±24.27 32.45 ±24.27 – – –
Melatonin concentration in
serum of PCOS women
was signicantly lower
than the control women
Kim et al.,
2013 (72)
South
Korea
13 women
with PCOS 31.1 ±0.8 FF
Melatonin:
20.9 ±3.6 136.8 ±26.1 – – –
In women with PCOS,
melatonin concentration in
follicular uid was
signicantly lower than the
control group
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International Journal of Reproductive BioMedicine Melatonin in PCOS
Table II. Protective effects of exogenous Melatonin in PCOS
Author, year
(ref) Country Study
design PCOS model Sample
size Treatment (dosage) Route of
administration Duration Results
Lemos et al.,
2016 (68) Brazil In-vivo
PCOS rats
(induced by
constant light
stimulation)
50
Combination of
melatonin (200
μg/100 g b.w.) and
metformin
hydrochloride (50
mg/100 g b.w.)
Melatonin
(subcutaneous
injections) and
Metformin
hydrochloride
(gavage)
20 days
Reduced the time needed for
pregnancy and reduced
plasma estrogen levels in the
treated group, increased the
plasma progesterone levels
and the number and weight
of offspring, besides
improving fetal development
Kim et al.,
2013 (72)
South
Korea In-vitro PCOS women 13
IVM medium
containing 800 µl
IVM medium with 10
µmol /l melatonin
– 2 days
Addition of melatonin leads to
improve in the cytoplasmic
maturation of immature
oocytes and also implantation
rates and pregnancy rates
were enhanced
Pacchiarotti
et al., 2015
(64)
Italy In-vivo PCOS women 165
Combination of
myo-inositol (4000
mg), folic acid (400
mcg) and melatonin
(3 mg)
Orally
administered 14 days
Increasing the number of
mature oocytes in the treated
group was showed and
intra-follicular concentration
of melatonin was four times
higher than in the control
group
Lemos et al.,
(2014) (83) Brazil In-vivo
PCOS rats
(induced with
constant
Illumination)
15
Combination of
melatonin (200
μg/100 g b.w.) and
metformin
hydrochloride (50
mg/100 g b.w.)
Melatonin
(subcutaneous
injections) and
Metformin
hydrochloride
(gavage)
20 days
Combination of two drugs
was more helpful in the
decline of plasmatic levels of
liver enzyme, nitric oxide, and
total glutathione. Also, in the
treated group, inammatory
response and
histopathological damage
were decreased
Lima et al.,
2004 (79) Brazil In-vivo
PCOS rats
(Induced with
pinealectomy or
continuous light)
113
Melatonin (200
μg/100 g body
weight)
Injected intra-
muscularly 4 months
Melatonin-treated groups
showed a signicant
reduction in the number of
cysts and antigonadotrophic
effects
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International Journal of Reproductive BioMedicine Mojaverrostami et al.
Table II. Continued
Author, year
(ref) Country Study
design PCOS model Sample
size Treatment (dosage) Route of
administration Duration Results
Nikmard
et al., 2016
(73)
Iran In-vivo/In-
vitro
PCOS mice
(induced by the
injection of
dehydro-
epiandroster-
one)
16
10−5, 10−6 , and 10−7
mol/L of melatonin
were added into the
medium culture.
– 24 hours
Addition of melatonin to
medium culture increased
maturation rate and cleavage
rate. Highest maturation rate
was observed at 10−6 mol/L
concentration of melatonin
Pai et al.,
2014 (56) India In-vivo
PCOS rats
(induced by
administration
of testosterone)
16 Melatonin (1 mg/kg
and 2 mg/kg )
Intra-
peritoneally
injected
35 days
Both doses of melatonin
meaningfully reduced the
number of cystic follicles,
neoplastic endometrial
glands and decreased
adipocyte hypertrophy
Ahmadi
et al., 2017
(74)
Iran In-vivo
PCOS mice
(induced by
injections of
DHEA)
12 Melatonin (10 mg/kg
body weight)
Intra-
peritoneally
injected
5 days
Administration of melatonin
leads to a signicant increase
in the thickness of the
granulosa layer but the
reduction in the thickness of
the theca layer
Tagliaferri
et al., 2017
(91)
Italy In-vivo PCOS women 40
Melatonin (Armonia
Fast 1 mg; 2 tablets a
day)
Orally
administrated 6 months
Melatonin treatment
decreased androgens levels,
but FSH level signicantly
raised and anti-Mullerian
hormone level signicantly
dropped
Basheer
et al., 2018
(80)
India In-vivo
PCOS rats
(induced by
Letrozole)
–
Melatonin (200
μg/100 g body
weight)
Intra-
peritoneally
injected
–
Melatonin treatment in PCOS
rats restored the MT1 and
MT2 receptors in the ovarian
tissue
Al-Qadhi,
2018 (60) Iraq In-vivo PCOS women 50 Melatonin 3 mg/day Orally
administrated 2 months
Melatonin treatment
decreased LH level and BMI
in PCOS patients
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International Journal of Reproductive BioMedicine Melatonin in PCOS
3. Results
3.1. Study characteristics
After searching the aforementioned databases
with considered keywords, the papers were
reviewed by two authors. In the rst step, titles
and abstracts were screened and 121 papers
that had enough connectivity with our keywords
were included. In the second step, full texts
were reviewed for the eligibility and relevance
of their ndings, and 99 articles were excluded
due to duplicate data, non-English languages,
review articles, and insufcient relevance. Finally,
22 studies were selected, including studies
that have used melatonin administration for
treating PCOS in clinical and animal models of
PCOS and also the studies that have shown
alternation of melatonin levels involved in the
pathogenesis and diagnosis of PCOS; 22 articles
were included in the current review, including
15 clinical human studies and 7 animal studies.
Table I is related to the studies that indicate
the alternation of melatonin levels in different
biological uids such as blood, serum, urine,
saliva, and follicular uid in PCOS patients. Table II
is related to the studies that have used exogenous
melatonin as a drug for curing PCOS in sick
women, animal models, or cell lines researches.
And, the remaining studies are related to the
melatonin receptor gene polymorphisms in PCOS
patients.
3.2. PCOS pathogenesis
PCOS may be initiated by some specic abnor-
malities in the hypothalamus-pituitary compart-
ment, ovaries, adrenal gland, and the peripheral
compartment like adipose tissue (23). In PCOS
patients, an increase in gonadotropin-releasing
hormone (GnRH) pulse frequency enhances the
luteinizing hormone (LH) pulse frequency and
amplitude (24). In spite of elevated LH secretion,
follicle-stimulating hormone (FSH) levels remain
in the lower follicular range due to the negative
feedback of enhanced estrogen levels and follic-
ular inhibition (24). As a result of altered LH:FSH
ratio in PCOS women, the androgen production
by the theca cells in the ovaries is increased;
however, due to the low FSH levels, the follic-
ular maturation is dramatically impaired (25). In
addition, ovarian dysregulation of cytochrome-17,
defects in the aromatase activity of the ovarian
granulosa cells (GC), as well as the stimulation
of the ovarian theca cells by high levels of
insulin-like growth factor 1 (IGF-1) are among other
mechanisms involved in androgen overproduction
(26). Excessive adrenocortical secretion of dehy-
droepiandrosterone is observed in approximately
50-70% of PCOS patients (27). Increased peripheral
5 alpha-reductase activity and enhanced periph-
eral aromatization of androgens to estrogens that
induces the reversal of estrone to estradiol ratio
and a chronic hyperestrogenic state are also seen
in PCOS patients (28). There is general agree-
ment that insulin resistance and hyperinsuline-
mia play a major part in the pathogenesis of
PCOS (29). Hyperinsulinemia stimulates ovarian
theca cells and leads to androgen overproduc-
tion. Hyperinsulinemia along with hyperandrogen-
emia and enhanced levels of IGF-1 inhibit sex
hormone-binding globulin secretion, which surges
the levels of bioactive androgens and worsens
the clinical manifestations of androgen excess in
PCOS patients (29). Also, it has been discovered
that insulin resistance and hyperandrogenism can
affect normal function of adipocytes (30). Previous
researchers have found that adipose tissue dys-
function are associated to metabolic and reproduc-
tive dysfunction including insulin resistance and
androgen excess secretion in most PCOS patients
(31) (Figure 2).
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International Journal of Reproductive BioMedicine Mojaverrostami et al.
3.3. Alternation of melatonin levels in
dierent body uids of PCOS patients
Melatonin synthetic enzymes such as arylalky-
lamine N-acetyl-transferase and hydroxyindole-O-
methyltransferase have been identied in most
tissues including ovaries (10). Measurable levels of
melatonin have been identied in most biological
uids, interestingly in the follicular uid. The con-
centration of melatonin in preovulatory follicles is
higher than that of plasma suggesting its possible
direct effects on ovarian function (32).
In several studies, melatonin levels in PCOS
women have been measured to nd its role in
the PCOS pathogenesis (Table I) (33, 34). The
most important metabolite of melatonin, urinary 6-
sulfatoxymelatonin (aMT6s), is considered to be a
good marker for melatonin production in the body
(35). The plasma concentrations of aMT6s in hyper-
androgenic and PCOS women were signicantly
higher than healthy women possibly due to higher
melatonin production (35). It has been demon-
strated that testosterone and estrogen can regu-
late melatonin secretion. Melatonin secretion has
been shown to decrease in castrated rats due to
the reduction of testosterone levels (36). Ovariec-
tomized rats exposed to 17β-estradiol had reduced
numbers of α/β-adrenoreceptors, responsible for
the stimulation of melatonin production, in their
pinealocytes (37). Sex hormones can adjust the
human biological clock by affecting the hypotha-
lamic suprachiasmatic nucleus and pinealocytes
(38). In a study by Luboshitzky and colleagues,
PCOS women had higher levels of αMT6s, LH,
and testosterone than patients with idiopathic
hirsutism or the control groups. The results of
this study showed that αMT6s level inversely
related to testosterone level in PCOS disease.
However, this result seems contradictory because
other studies in PCOS introduced the direct rela-
tionship between αMT6s and testosterone (33).
Treatment with estradiol-cyproterone acetate nor-
malized the αMT6s levels in PCOS patients by
inhibiting androgens and gonadotropins (33). In
another study by the same group, women with
PCOS had higher aMT6s, testosterone, LH/FSH
ratio, and insulin values than women in the control
groups. Higher aMT6s levels were due to the ampli-
cation of melatonin production. In some studies,
testosterone was introduced as a determinant of
aMT6s level in PCOS patients (35). Melatonin has
been found to increase the secretion of proges-
terone and androgen in pre-antral follicles after
incubation for two weeks and in antral follicles
after a 30-hr incubation (39). In other studies,
the elevated melatonin levels in serum of PCOS
patients was found to be positively associated
with testosterone levels (40). Results from studies
show that melatonin levels in blood and saliva
along with the level of 6-sulfatoxymelatonin in
urine were signicantly higher in PCOS patients
compared to the healthy women (41). The levels
of 6-sulfatoximelatonin in urine, nocturnal mela-
tonin levels in saliva (at 3:00 am), and melatonin
in the blood had a signicant correlation with
the degree of sleep disorders (41). 8-hydroxy-2’-
deoxyguanosine (8-OHdG) is a marker of oxidative
damage to DNA that can be detected in urine
(42). In one study, the daytime urinary aMT6s
and 8-OHdG levels were similar in PCOS patients
and the control group, while the night-time levels
of these molecules were signicantly higher in
PCOS patients than those of the control group
(42). During the night, PCOS women with raised
oxidative stress markers had higher levels of
8-OHdG and aMT6s. The production of higher
amounts of melatonin was probably for neutralizing
reactive oxygen species (ROS) at the night time.
Melatonin level in PCOS cases was shown to have
a signicant correlation with the serum LH:FSH
ratio (40). In patients with higher LH:FSH ratios,
melatonin levels were signicantly lower than the
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International Journal of Reproductive BioMedicine Melatonin in PCOS
patients with lower ratios, indicating the inverse
correlation of LH:FSH ratio and melatonin secretion
(40).
Different studies have indicated that PCOS
patients have higher serum levels of melatonin
(35, 40), therefore melatonin could be used as
a valuable marker for the prediction of PCOS.
It was suggested that the elevation of serum
melatonin in PCOS patients is due to the reduction
in its follicular uid concentration (32) The role
of melatonin in oocyte maturation has been also
approved. Concentration of melatonin in the pre-
ovulatory follicles is higher than smaller immature
follicles, resulting in higher antioxidant capacity of
larger follicles (43). In PCOS patients, the decline
in the follicular concentration of melatonin is due
to the reduction in the uptake of melatonin from
circulation and an increase in the numbers of atretic
follicles (32). Follicular atresia could be seen in
PCOS patients due to increased oxidative stress
and follicular damage which occurs as a result
of the reduction in intra-follicular melatonin levels
(32). A great deal of research has shown that ROS
generation and lipid peroxidation are meaning-
fully higher in PCOS cases (44, 45). Along with
these changes, levels of superoxide dismutase,
catalase, and glutathione peroxidase are reduced,
which causes intense oxidative stress in ovarian
follicles (46). Melatonin is shown to be capable
of regulating the gene expression of antioxidant
enzymes, in addition to preventing apoptosis by
increasing Bcl2 and reducing Caspase 3 (47,
48). Terzieva and colleagues reported that mela-
tonin levels in women with PCOS in the morning
were signicantly higher than at night time, and
the night-day difference of melatonin levels in
PCOS cases was lower than that of the healthy
group (49). However, a study reported conicting
results stating that the total serum melatonin levels
were signicantly lower in women with PCOS
(50).
3.4. Association of melatonin receptor
gene polymorphisms in PCOS patients
The positive effects of melatonin on different
tissues of the body are mediated by the melatonin
receptors 1A and 1B (18). The earliest study on the
association between common genetic variations of
melatonin receptors and the prevalence of PCOS
was conducted by Wang and colleagues (51). In
this study, four single nucleotide polymorphisms
(SNPs) (rs4753426, rs10830963, rs1562444, and
rs1279265) in MTNR1B gene were determined
and no differences in genotype and allelotype
frequencies for these SNPs were found neither
in the PCOS nor in the healthy women. In addi-
tion, they found a signicant association between
the rs10830963 SNP and the concentration of
testosterone in PCOS patients. The amount of
testosterone, glucose, and insulin in the serums of
women with cytosine/guanine allele (CG) and gua-
nine/guanine allele (GG) genotypes were consider-
ably higher than the cytosine/cytosine allele (CC)
genotypes, which describes the possible effects
of DNA sequence variations of melatonin receptor
genes on the occurrence of PCOS. In subsequent
research that was performed on Chinese women,
the relationship between the pathogenesis of
PCOS and rs2119882 SNP, which is located in the
MTNR1A gene was evaluated. Genotype and allele
frequencies of rs2119882 were signicantly differ-
ent between the PCOS cases and the controls;
the C allele frequency in the PCOS patients was
signicantly higher than the control group which
conrms the association of SNP rs2119882 with
PCOS (52). In another study, an association of
two SNPs, rs10830963 and rs10830962 located
at the MTNR1B gene with PCOS, was examined.
Both genotypes and allelotypes occurrences of
the rs10830963 SNP in PCOS women were sig-
nicantly different compared to healthy women.
In addition, the occurrences of GG and GC were
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International Journal of Reproductive BioMedicine Mojaverrostami et al.
higher among PCOS women. According to the
results of the mentioned study, rs10830963SNP
is associated with the predisposition of women to
PCOS. No suggestive differences were observed
in the genotypes and allele distributions of the
other SNPs (rs10830962) between the PCOS and
the healthy women (53). Recently, Song and col-
leagues reported that there is a signicant asso-
ciation between rs2119882 and the prevalence of
PCOS, although no association was found between
rs10830963 and PCOS (54). They reported that the
clinical and metabolic features of PCOS manifest
largely in CC genotype carriers than the TC and
TT genotypes. They also showed that there exists
a considerable difference in the transmission of
allele C of rs2119882 between obese and non-
obese PCOS patients.
3.5. Protective eects of exogenous
melatonin administration in PCOS
3.5.1. Metabolic function improvement by
melatonin
An improvement of metabolic function in PCOS
patients may enhance ovarian function. There has
been growing evidence suggesting the relation of
melatonin with glucose homeostasis and insulin
secretion. Peschke and colleagues have shown
a negative correlation between melatonin and
insulin levels in patients with type 2 diabetes
(55). Furthermore, several studies have shown
that melatonin administration can improve glucose
hemostasis, exert antihyperglycemic effects, and
improve endothelial vascular function in experi-
mental models of metabolic syndrome and type 2
diabetes (56). Faria and colleagues showed that
melatonin, through melatonin receptors 1 and 2,
activates a brain-liver communication and sup-
presses hepatic gluconeogenesis via peripheral
muscarinic receptors in rats (57). Evidence from
in-vitro studies have shown that glucose uptake
in adipocytes and skeletal muscle cells can be
increased by melatonin (58).
Letrozole is an aromatase inhibitor which is
largely used for treatment of breast cancer (34). In
2001, Letrozole, for the rst time, was described as
an ovulation-inducting agent (35). Letrozole inhibits
androgens-to-estrogens conversion at the GC,
resulting in the reduction of estrogen levels, which
consequently releases the hypothalamus-pituitary
axis from its negative feedback and increases
the FSH secretion by pituitary stimulation (35). In
addition, an inhibition of aromatase activity at the
ovarian level increases intraovarian androgens that
improve follicular sensitivity (36). A meta-analysis
including 26 randomized controlled trials (5,560
women) concluded that letrozole therapy appears
to improve live birth and pregnancy rates in anovu-
latory PCOS patients compared with clomiphene
citrate (37, 38). Chottanapund and colleagues (59)
have evaluated the aromatase suppressive effects
of melatonin on hormonal positive breast cancer
cells and have shown that melatonin was as potent
as letrozole in inhibiting aromatization of androgen
to estrogen. Furthermore, in several studies, it has
been demonstrated that melatonin behaves as a
selective estrogen enzyme modulator (SEEM) and
a selective estrogen receptor modulator (SERM)
(40). Moreover, the aromatase-suppressive effect
of melatonin has been also shown in various cells,
such as breast cancer, glioma, and endothelial
cells (42). Several studies have demonstrated that
melatonin reduces obesity and restores adipokine
patterns and ameliorates the proinammatory
state, which underlies the development of insulin
resistance (60). These ndings all together show
that the use of melatonin due to its aromatase-
modulating activity, as well as its reducing effects
on hepatic gluconeogenesis, ameliorating the pro-
inammatory state present in PCOS, improvement
of glucose uptake by peripheral tissues, and the
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International Journal of Reproductive BioMedicine Melatonin in PCOS
subsequent reduction in insulin levels, may be
effective in the management of PCOS patients
(Table II).
3.6. Melatonin in PCOS patients
undergoing assisted reproductive
technology (ART) treatment
PCOS affects ART outcomes and controlled
ovarian hyperstimulation (COH) with conventional
protocols leads to a higher risk of ovarian hyper-
stimulation syndrome (OHSS) (61). Several studies
have demonstrated that the poor fertilization, low
oocyte, and embryo quality adversely inuence
the clinical outcomes in PCOS patients undergoing
ART treatment (62). Insulin resistance of ovarian
GC and overexpression of vascular endothelial
growth factor (VEGF) due to insulin stimulation
are proposed to be the underlying mechanisms of
poor clinical outcomes (63). Melatonin may affect
ovarian microenvironment by improving insulin
resistance. In a randomized double-blind trial of
PCOS patients, the administration of melatonin
with myo-inositol enhanced the oocyte and embryo
quality (64). The main goal in COH of PCOS
patients is to prevent OHSS. The only way to
prevent all type of OHSS in ART treatment is in-vitro
maturation (IVM) followed by in-vitro fertilization
(IVF) since this approach avoids the activation of
VEGF-mediated processes (65). However, despite
the extensive research conducted so far, IVM is
still a suboptimal procedure and the application
of IVM in infertility treatment remains immature
(66). The IVM involves additional procedures that
increase oxidative stress in oocytes and embryos
and reduce the developmental competence of
oocytes, in comparison to the conventional IVF (67).
The effects of melatonin on oocyte and embryo
quality and ART outcomes are discussed in the
following sections of this review.
3.7. Fertility and pregnancy
Recently, several studies evaluated the effects
of melatonin in the treatment of PCOS to improve
fertility and hormonal alterations. Lemos and col-
leagues have shown that rat models of PCOS
have lower weight gain during pregnancy and
show reduced numbers of implantation sites which
result in a decreased number of offspring. Also,
rat models of PCOS have higher collagen content
in the uterine horns which hinders the blastocyst-
endometrial interactions and reduces the implan-
tation rate (68). Co-treatment of melatonin and
metformin can reverse the reduced weight gain
and the high collagen ber content of uterine horns
in the PCOS group, compared to the control group.
Moreover, the number and weights of the offspring,
the blastocyst-endometrium interactions, and the
fetal development were increased while the time
required for pregnancy was decreased (68). In
some recent studies, it has been reported that
oral administration of melatonin has no signicant
effects on clinical pregnancy rate or oocyte and
embryo qualities (69).
3.8. Oocyte maturation
Follicular uid melatonin produced by the
luteinizing GC in the late folliculogenesis period
has a substantial function in the growth and mat-
uration of mammalian oocytes (47). In the ovary,
melatonin receptors in granulosa-lutein cells can
regulate the function of this organ by controlling
progesterone secretion in addition to LH and
GnRH receptors gene expression via pathways
such as mitogen-activated protein kinase and
activation of Elk-1 (22). Melatonin concentrations
are signicantly higher in larger follicles, particu-
larly in preovulatory follicles, due to participation
in the secretion of progesterone and maturation
of oocyte along with subsequent ovulation and
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International Journal of Reproductive BioMedicine Mojaverrostami et al.
luteinization events (70). Interestingly, intrafollicular
melatonin level is considerably lower in PCOS
women than the healthy women which may be the
reason for the anovulation and low oocyte quality
(32).
The supplementation of culture medium with
different substances can increase oocyte mat-
uration and IVF, as a remedy for reproductive
problems (71). Based on these ndings, a number
of studies were designed, using supplementation
of culture media by melatonin to enhance oocyte
maturation and embryonic development. In a study
by Kim and colleagues, melatonin concentration
gradually increased in the culture media of GC
due to its production by GC. Also, the addition of
melatonin to IVM media improved the cytoplasmic
maturation of immature oocytes and increased
the rates of implantation (72). The amplication of
mRNA expression of the enzymes that participate
in melatonin production in cultured GC including
acetylserotonin O-methyltransferase (ASMT) and
aralkylamine N-acetyltransferase (AANAT) has also
been shown. PCOS results in anovulation and
is considered an important cause of IVF failure.
Melatonin along with other substances such as
myo-inositol was identied as a good predictor for
IVF outcomes, and their high concentrations were
an indicator of appropriate quality of oocytes (32).
Oral administration of melatonin in combination
with myo-inositol in PCOS patients enhanced the
quality of the oocyte and embryo, increased the
number of mature oocytes, and nally resulted
in an increased concentration of follicular uid
melatonin (64). In another study, the benecial
effect of melatonin on the quality of oocytes in
PCOS patients during IVM with different melatonin
concentrations was investigated. Also, melatonin
proved to be effective in the stimulation of nuclear
maturation of oocytes as well as in increasing
the cleavage rate via regulating free radicals to a
certain level requiredfor increasing maturation rate
(73). This effect of melatonin on oocyte maturation
had a dose-dependent pattern in a manner that
lower doses were more effective on maturation
rate.
3.9. Histological changes in the ovary
In one study, the histopathological inspection
of the ovary and uterus showed reductions in
neoplastic endometrial glands and cystic follicles
in PCOS rats following melatonin treatment (56).
In another study, the administration of melatonin
reduced cystic follicles and thickness of the theca
layer and increased the number of corpus luteum
and the granulosa layer thickness (74). The reduc-
tion in the thickness of theca interna is due to the
action of melatonin on the reduction of androgen
production in the ovary (75). Melatonin showed
protective effects on corpus luteum against ROS
via its antioxidant effects (76). The absence of
melatonin in pinealectomized animals causes the
development of ovarian cysts due to the modica-
tion of the synthesis of LH and FSH. Increase in the
LH levels is a major abnormality detected in PCOS
(77). Similarly, constant illumination, an induction
model of PCOS in rats, have shown permanent
estrous condition and polycystic ovaries aspect
(78). In one study, pinealectomy and continuous
light were used separately in female rats to induce
PCOS. In both of these methods, the production
of melatonin was diminished and PCOS condition
was observed. In the group treated with melatonin,
a signicant reduction in the number and size
of cysts were observed, probably as a result of
the antigonadotrophic effects of melatonin (79).
Melatonin has shown protective effects against
metabolic and reproductive abnormalities in animal
models of PCOS (56, 80). Melatonin treatment in
PCOS patients signicantly affects body character-
istics including reduced body weight, body mass
index, and intra-abdominal fat (56).
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International Journal of Reproductive BioMedicine Melatonin in PCOS
3.10. Antioxidant eects
Several studies revealed that oxidative stress is
one of the main reasons for female reproductive
system disorders such as infertility, endometrio-
sis, and PCOS (81). This has been supported by
the fact that PCOS patients have higher levels
of oxidative stress compared to healthy women
(45, 82). It has been demonstrated that PCOS
patients are at risk of cardiovascular diseases due
to their higher exposure to oxidative stress and
the following undesirable effects such as blood
pressure and insulin resistance (45). Lemos and
colleagues showed that animal models of PCOS
induced by constant illumination had higher levels
of lipid peroxidation, which leads to increases in
oxidative stress, pro-oxidant enzymes, and pro-
inammatory cytokines (83). Treatment with a com-
bination of metformin hydrochloride and melatonin
was shown to be advantageous in the PCOS
group by regulating plasmatic variables of oxidative
stress, for example, reduction of nitric oxide and
total glutathione levels. Furthermore, treatment
with melatonin apparently reduced liver toxicity,
pro-inammatory cytokines, TNF-α and IL-1 and the
pro-inammatory enzymes iNOS (83). Similarly, in
different studies, the antioxidant effect of melatonin
along with its inhibitory effects on pro-oxidant
enzymes and pro-inammatory cytokines were
reported (84).
Melatonin supplementation to the culture
medium has been shown to increase the oocyte
maturation rate and reduce ROS production (85).
It can promote the expression of superoxide
dismutase and glutathione peroxidase (86); also,
melatonin is able to quench ROS and reactive
nitrogen species (RNS) (76). Scavenging action of
melatonin plays a valuable role during ovulation,
because ovulation is an inammatory process,
and reactive species are generated and released
in the follicular uid (87). Therefore, melatonin
quenches ROS and RNS and protects GC and
oocyte during ovulation (32). Studies have also
displayed that oxidative stress is detrimental to
oocyte maturation, since the activation of oxidative
stress pathway in follicular and IVM medium is
unavoidable due to cellular metabolism and lack
of antioxidant mechanisms, melatonin is a suitable
candidate to be added to the IVM medium (73,
88).
3.11. Melatonin and menstrual cyclicity
in PCOS
Menstrual cycle irregularities are among the
major complications of PCOS that affect the quality
of life of patients leading to infertility (89). The
altered steroid sex hormones in PCOS patients
affect the hypothalamic-pituitary-ovarian axis and
lead to the failure of follicular maturation and
ovulation (89). Furthermore, hyperinsulinemia and
insulin resistance cause ovarian dysfunction (90).
These events result in anovulation and inadequate
hormonal levels leading to irregularities in men-
strual cycle.
Melatonin seems to promote follicular matu-
ration and ovulation through the protection of
follicles against oxidative stress and their rescue
form atresia (40). After six months of melatonin
therapy in 40 normal-weight PCOS patients, men-
strual irregularities and hyperandrogenism were
improved. The lack of signicant alterations in the
secretion of insulin and insulin sensitivity suggests
that melatonin may act on the ovary through
an independent mechanism (91). However, the
effect of long-term melatonin therapy with the aim
of menstrual cyclicity improvement needs to be
evaluated in large-scale prospective randomized
studies.
Thanks to the highly selective effects of mela-
tonin on its receptors and therefore an excellent
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International Journal of Reproductive BioMedicine Mojaverrostami et al.
safety prole, it is well tolerated (92). However,
more studies are required to be carried out in order
to shed light on the possibility of its application in
the context of PCOS.
Figure 2. The role of melatonin in the pathogenesis of PCOS.
4. Discussion
The current review summarizes the role of mela-
tonin in the pathogenesis of PCOS and the protec-
tive effects of exogenous melatonin administration
in the regulation of reproductive function in the
context of PCOS. Melatonin levels in serum and
follicular uid of PCOS patients are different from
healthy women. In PCOS patients, melatonin level
in serum is usually higher than in healthy women,
which is considered as a sign of diagnosing PCOS
(32). But a reverse condition occurs in melatonin
level of follicular uid. Due to fewer uptakes of
melatonin in ovarian follicle in PCOS patients
against healthy women, follicular uid contains
lesser melatonin level compared to the healthy
condition (32). Melatonin seems to promote follicu-
lar maturation and ovulation through the protection
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International Journal of Reproductive BioMedicine Melatonin in PCOS
of follicles against oxidative stress and their rescue
form atresia (40). Furthermore, melatonin showed
protective effects on corpus luteum against ROS
via its antioxidant effects (76). Melatonin level
in follicular uid of PCOS women is notably
lower than in healthy women, which is related
to the ovulation problems. It has been reported
that melatonin administration can compensate the
reduction of this hormone in follicular uid and
can halt ovulation problems (32). Melatonin treat-
ment indicated protective effects against metabolic
and reproductive abnormalities in PCOS patients.
Melatonin administration in PCOS patients sig-
nicantly affects body characteristics including
reduced body weight, body mass index and intra-
abdominal fat (56). During the ovulatory process,
ROS are produced within the follicles; for this rea-
son, the scavenging activity of melatonin plays an
important role during ovulation. Melatonin reduces
oxidative stress and causes oocyte maturation and
luteinization of GC making it as an effective treat-
ment for PCOS patients. Intra-follicular melatonin
concentration was considerably lower in PCOS
patients giving rise to anovulation and poor oocyte
quality in these patients. The administration of
melatonin alone or in combination with other drugs
in PCOS women has been shown to increase the
intrafollicular melatonin concentration, reduce the
intrafollicular oxidative stress, and also increases
the fertilization and pregnancy rates. Melatonin
also improves the production of progesterone from
corpus luteum in PCOS patients. The deciency of
melatonin alters gonadotrophin secretion, reduces
the synthesis of FSH, and increases the synthesis
of LH, the latter being the major change detected
in PCOS patients (77). Melatonin can adjust the
hypothalamic axis by inhibiting the release of hor-
mones such as FSH, which leads to the reduction
of cystic follicles. Melatonin can also regulate the
synthesis of GnRH through its receptors in the
granulosa-luteal cells via inhibiting GnRH receptor
expression and sustaining the corpus luteum which
maintains progesterone secretion (93).
5. Conclusion
In summary, metabolic dysfunction is the major
nding contributing to the initiation of PCOS, mela-
tonin can hinder this process via its improving
effects on metabolic functions. Melatonin treat-
ment in PCOS patients can enhance the quality
of the oocyte and embryo, increase the number
of mature oocytes, reduce obesity, and ameliorate
the proinammatory state, which underlies the
development of insulin resistance.
Conict of Interest
All authors declare no conicts of interest.
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