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The role of melatonin in polycystic ovary syndrome: A review

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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 fluid exists in PCOS patients. Melatonin receptors in the ovary and intra-follicular fluid 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 beneficial effects in correcting the hormonal alterations in PCOS patients. Conclusion: Since metabolic dysfunction is the major finding contributing to the initiation of PCOS, melatonin can hinder this process via its improving effects on metabolic functions.
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International Journal of Reproductive BioMedicine
Volume 17, Issue no. 12, https://doi.org/10.18502/ijrm.v17i12.5789
Production and Hosting by Knowledge E
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 benecial 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:
Aatoonian 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 identied 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 signicantly 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 specied
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 conrm
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.
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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 signicantly 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 signicantly 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 signicantly 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 signicantly 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
signicantly 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, inammatory
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 signicant
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 signicant 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 signicantly
raised and anti-Mullerian
hormone level signicantly
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 insufcient 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 specic 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
dierent body uids of PCOS patients
Melatonin synthetic enzymes such as arylalky-
lamine N-acetyl-transferase and hydroxyindole-O-
methyltransferase have been identied in most
tissues including ovaries (10). Measurable levels of
melatonin have been identied 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 signicantly
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 signicantly 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 signicant 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 signicantly 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 signicant correlation with the serum LH:FSH
ratio (40). In patients with higher LH:FSH ratios,
melatonin levels were signicantly 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 signicantly 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 conicting
results stating that the total serum melatonin levels
were signicantly 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 signicant 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 signicantly differ-
ent between the PCOS cases and the controls;
the C allele frequency in the PCOS patients was
signicantly higher than the control group which
conrms 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-
nicantly 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 signicant 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 eects 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 proinammatory
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-
inammatory 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 inuence
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 signicant
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 signicantly 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 amplication 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 identied 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 benecial
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 modica-
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 signicant 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 signicantly 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 eects
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-
inammatory 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-inammatory cytokines, TNF-α and IL-1 and the
pro-inammatory enzymes iNOS (83). Similarly, in
different studies, the antioxidant effect of melatonin
along with its inhibitory effects on pro-oxidant
enzymes and pro-inammatory 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 inammatory 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 signicant 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
https://doi.org/10.18502/ijrm.v17i12.5789 Page 877
International Journal of Reproductive BioMedicine Mojaverrostami et al.
safety prole, 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-
nicantly 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 deciency 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 proinammatory state, which underlies the
development of insulin resistance.
Conict of Interest
All authors declare no conicts of interest.
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... Due to the upregulation in monocyte synthesis and the proliferation and maturation of T and B lymphocytes, melatonin also improves the immune response [23,[29][30][31][32]. Figure 1 shows the main effects of melatonin. Many clinical studies have shown that melatonin can work as an adjuvant therapeutic or an option to prevent and treat several human diseases, such as Alzheimer's disease [33][34][35], Parkinson's disease [36], non-alcoholic fatty liver disease [35,37,38], rheumatoid arthritis [39][40][41], multiple sclerosis [42], polycystic ovary syndrome (PCOS) [43,44], dermatitis [45,46], coronavirus disease 2019 (COVID-19) [47], and sepsis [48]. Figure 1 shows the effects of melatonin in humans. ...
... Since melatonin has been extensively studied in sleep-related disorders and other neurodegenerative diseases, this comprehensive review aims to draw on clinical trials to show the effects of this hormone beyond its commonly observed purposes. Many clinical studies have shown that melatonin can work as an adjuvant therapeutic or an option to prevent and treat several human diseases, such as Alzheimer's disease [33][34][35], Parkinson's disease [36], non-alcoholic fatty liver disease [35,37,38], rheumatoid arthritis [39][40][41], multiple sclerosis [42], polycystic ovary syndrome (PCOS) [43,44], dermatitis [45,46], coronavirus disease 2019 (COVID-19) [47], and sepsis [48]. Figure 1 shows the effects of melatonin in humans. ...
Article
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Melatonin is indispensable for the homeostasis of plants and animals. In humans, it can help prevent or be an adjuvant treatment for several diseases mainly related to the immune system, inflammation, and oxidative stress. Moreover, a melatonin-rich diet is linked to several health benefits, such as regulation of circadian rhythm, regulation of the immunological system, epilepsy control, delaying the aging process, and diminishing hormones related to cancer. This review aimed to show the effects of melatonin in diseases beyond its traditional use. The results showed it can present scavenging of free radicals, reducing inflammatory cytokines, and modulating the immune system. Moreover, it can improve insulin resistance, blood pressure, LDL-c, adipose tissue mass, adhesion molecules, endothelial impairment, and plaque formation. These effects result in neuro- and cardioprotection, improvement of liver diseases, rheumatoid arthritis, dermatitis, COVID-19, polycystic ovaries, and sepsis. We conclude that plant melatonin can benefit patients with many diseases besides sleep problems and neurodegeneration. Plant melatonin may be more cost-effective and present fewer adverse events than synthetic. However, more clinical trials should be performed to show adequate doses, formulation, and treatment time.
... The levels are typically ten times higher at night than during the day [12]. One melatonin molecule can scavenge up to 10 reactive oxygen spies (ROS) and nitrogen species (RNS) with its metabolites, compared to most antioxidants [13]- [15]. Several studies have found that melatonin levels in the serum are greater in PCOS patients, suggesting that melatonin may be a useful diagnostic for PCOS [14]. ...
... From this, it could be concluded that the addition of nanomaterial has an inhibition effect on the level of Oxidative stress concentration in patients [26]. Melatonin is represented by molecules characterized by the ability to rapidly inactivate radicals and oxidants [13], [27]. Melatonin can modulate redox homeostasis in PCOS by reducing oxidative stress, promoting ovulation, modulating the inflammation process, and reducing androgen production [14]. ...
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Full-text available
Background: The association between polycystic ovary syndrome (PCOS) and oxidative stress in women, the possible causes of PCOS, insulin resistance (IR), obesity, and oxidative stress. Oxidants are chemical elements that tend to gain electrons, losing positive charge. The Oxidative Stress (OS) is defined as an imbalance between the formation and synthesis of free radicals and the antioxidant defense system, which results in oxidative damage. Objective: The purpose of this research is to investigate the effect of nano-melatonin on oxidative stress in the sera of patients with polycystic syndrome. Methods: The study includes 120 Iraqi women, divided into two groups: 60 PCOS patients and 60 healthy control patients. Sample Analysis Biochemistry analyses the hormonal profile and determines the hormonal levels (LH, FSH, Testosterone, and Prolactin) that were identified for all controls and patients. Hormones analysis was performed using the enzyme-linked fluorescent assay (ELFA) technique. Synthesized ML nanoparticles by ultrasonic sonication. Results: The results indicate that the mean of serum LH significantly increased (P<0.02) in PCOS BMI ≥ 25 patients G1 (6.19±3.13) mIU/mL compared with controls C1 (4.504±1.591) mIU/mL, while a nonsignificant difference (P>0.05) when compared the BMI<25 kg/m2 for G2 (5.55±1.93) with control group C2 (6.31±2.58) of luteinizing hormone in G1 and G2. Conclusions: An increased ratio of LH to FSH was shown to be characteristic of PCOS. For PCOS, high LH values are crucial. For the purpose of diagnosing PCOS, high LH values are crucial release of gonadotropin hormones (LH, FSH) from the pituitary. To higher the production of androgen in ovarian theca cells, The LH receptor is activated by the luteinizing hormone (LH). The nano Mel was higher in the inhibition of Oxidative stress two causes nano-melatonin high surface area and small size.
... In females with PCOS, the level of melatonin in follicular fluid was significantly lower than that in healthy women. Thus, the increased oxidative stress and follicular damage depicted in PCOS conditions led to follicular atresia [98,99]. Melatonin supplementation was also shown to improve the oocyte and embryo quality by altering the ovarian microenvironment to reduce insulin resistance in a randomized double-blind trial of PCOS patients using melatonin and inositol combination [100]. ...
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Background Sleep disturbances are more prevalent among women with infertility. Current research increasingly highlights the significant relationship between sleep disturbances and female infertility, suggesting that sleep may be a key factor in reproductive health. In this review, we aim to delve into the complex interplay between sleep disturbances and female infertility, as well as to assess the underlying mechanisms involved, and seek to illuminate the causes of sleep-related fertility issues. The understanding of these contents may help clinicians enhance clinical strategies for managing sleep disturbances in women facing infertility challenges and provide timely support to those seeking fertility treatments. Methods A comprehensive literature search was conducted in the PubMed and EMBASE databases. Studies that described sleep patterns or any type of sleep disturbance, sleep breathing disorders and their associations with female infertility or female fecundity, published between January 1, 2010, and November 1, 2023, were identified and extracted. The screening, data extraction, and quality assessment processes were independently performed by paired reviewers. The quality of the included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal tools for observational and cohort studies. Results A total of 1,179 articles were initially identified from the search strategy (PubMed, n = 377; EMBASE, n = 802). After removing duplicates (n = 83) and screening for eligibility (n = 75), 19 studies were reviewed and determined to be eligible for inclusion. Infertile women generally report poorer sleep quality and exhibit more evening sleep chronotypes. Sleep disorders are significantly associated with infertility. Poor sleep quality, extreme sleep durations, and certain sleep chronotypes are associated with poorer fertility treatment outcomes, such as a reduced number of retrieved oocytes, decreased embryo quality, and lower fertilization rates. Obstructive sleep apnea (OSA) is also more prevalent in women with fertility issues, especially those with polycystic ovary syndrome (PCOS), and may negatively impact reproductive outcomes. The circadian rhythms of the Clock gene system, melatonin and hormone dysregulation, oxidative stress and immune response are considered to be potential mechanisms explaining how sleep disturbance impairs reproductive function, remain to be fully elucidated, and therefore, require further investigation. Conclusions Sleep disturbances are negatively associated with female infertility and poor fertility treatment outcomes. Longitudinal studies are expected to substantiate these findings and inform more nuanced approaches to prior sleep management and lifestyle advisement for infertile women, especially those undergoing fertility treatments. Trial registration This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO, #CRD42024498443).
... However, there was a marginal trend towards decreasing androgens and increasing endometrial thickness after melatonin intake in women with PCOS. Melatonin is an important hormone that plays a crucial role in regulating the development of follicles in the ovaries [48]. The presence of receptors MT1 and MT2 in the ovarian follicle has been shown by multiple authors, which supports the idea that melatonin has a role in the functioning of the ovaries [49]. ...
Article
Full-text available
Background To investigate whether melatonin supplementation can enhance cardiometabolic risk factors, reduce oxidative stress, and improve hormonal and pregnancy-related factors in patients with PCOS. Methods We conducted a systematic search of PubMed/Medline, Scopus, and the Cochrane Library for articles published in English from inception to March 2023. We included randomized controlled trials (RCTs) on the use of melatonin for patients with polycystic ovary syndrome (PCOS). We performed a meta-analysis using a random-effects model and calculated the standardized mean differences (SMDs) and 95% confidence intervals (CIs). Results Six studies met the inclusion criteria. The result of meta-analysis indicated that melatonin intake significantly increase TAC levels (SMD: 0.87, 95% CI: 0.46, 1.28, I² = 00.00%) and has no effect on FBS, insulin, HOMA-IR, TC, TG, HDL, LDL, MDA, hs-CRP, mFG, SHBG, total testosterone, and pregnancy rate in patients with PCOS compare to controls. The included trials did not report any adverse events. Conclusion Melatonin is a potential antioxidant that may prevent damage from oxidative stress in patients with PCOS. However, the clear effect of melatonin supplementation on cardiometabolic risk factors, hormonal outcomes, and pregnancy-related outcomes needs to be evaluated further in large populations and long-term RCTs.
... MT can be an adjuvant therapeutic option to treat and prevent human diseases, such as rheumatoid arthritis [22], COVID-19 [23], Alzheimer's disease [24], Parkinson's disease (PD) [25], multiple sclerosis [26], polycystic ovary syndrome [27], dermatitis [28], non-alcoholic fatty liver disease [29], and sepsis [30]. In this book chapter, we revise MT biosynthesis in plants, its regulation by the plant kingdom, and its roles in these diseases. ...
Chapter
Melatonin (MT) from plant species has attracted attention in the past decade. It is still the only conserved molecule that is broad spectrum as a regulator of biological functions since it has been identified in the unicellular alga, higher plants, and animals. In plants, MT is produced from tryptophan converted to tryptamine in the chloroplast. Subsequent pathways involve the conversion of tryptamine into serotonin, which can form methoxytryptamine and N-acetyl-serotonin resulting in MT. MT has been documented to play a crucial role in governing various aspects of plant growth and development, including the regulation of circadian rhythms and photoperiodic responses. Moreover, it has been found to contribute significantly to antioxidation and stress resistance in plants. Its use as an anti-inflammatory and immunomodulated drug against human diseases also gained significant attention in humans. There is an increasingly shared agreement that MT is valuable in maintaining body functions and homeostasis, particularly during adulthood, owing to its antioxidant, anti-inflammatory, and immunomodulatory properties. MT can mitigate symptoms such as cough, dyspnea, and fatigue and shorten hospitalization time in COVID patients. Moreover, it could reduce thrombotic and septic processes. In Alzheimer’s patients, it improves sleep quality and cognitive function. In Parkinson’s disease, it can enhance sleep quality and non-motor symptoms and reduce oxidant marker levels. In multiple sclerosis it improves sleep time and lowers fatigue scores and inflammatory and oxidative scenarios. In polycystic ovary syndrome, MT reduced insulin, HOMA, LDL-c, body weight, waist circumference, and TNF-α levels. In dermatitis, it led to fewer signs of dermatitis compared to placebo. It decreased the degree of liver fat compared to the placebo group in non-alcoholic fat liver disease.
... [79] Some studies reported that APLN expression was increased due to progesterone in the bovine granulosa cells. This says that the change in levels of estrogen [68,73] may be accountable for APLN and APLNR expressions in the development and maturation of follicle. [79][80][81] On the other hand, APLN also acts on the glucose and lipid metabolism with regulating insulin secretion in PCOS women. ...
... 70,71 Melatonin, is a hormone synthesized and secreted by the pineal gland with potent antioxidant properties, and seems to have beneficial effects in women experiencing infertility 72,73 and in women with PCOS. 74 Follicular melatonin protects granulosa cells, oocytes, and ovaries from oxidative stress, delaying ovarian aging. In a randomized pilot study carried out in 40 women undergoing IVF, the supplementation with melatonin was seen to improve intrafollicular oxidative balance and oocyte quality, and slightly increasing the rate of pregnancies/ live births. ...
Article
Full-text available
Infertility affects 15% of couples in reproductive age worldwide. In women in particular, infertility can be caused by various abnormalities, with polycystic ovary syndrome (PCOS) being the most common. Currently, there are many assisted reproductive techniques (ART) available to combat the burden of infertility. However, positive results are not guaranteed. The administration of inositol has been shown to increase positive reproductive outcomes in women undergoing ART. Here we present a series of clinical cases in which women with a history of infertility and previously failed ART, supplemented with a specific 3.6:1 MYO:DCI ratio, antioxidants, vitamins, and minerals for a period of 1 to 3 months before undergoing in vitro fertilization (IVF). In this series of case reports, we provide preliminary evidence that supplementation with a specific 3.6:1 MYO to DCI ratio, as well as antioxidants, vitamins, and minerals may contribute positively to female fertility in women undergoing IVF, with a history of primary or secondary infertility and previously failed ART.
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Melatonin, synthesized by the pineal gland, plays a pivotal role in female reproductive physiology. In addition to its established function in regulating circadian rhythms, melatonin influences critical reproductive processes, such as ovulation, menstrual cycle regulation, and fertility. Recent studies underscore melatonin’s regulatory effects on the hypothalamic-pituitary-gonadal axis, influencing the secretion of gonadotropins, including follicle-stimulating hormone and luteinizing hormone. Furthermore, melatonin has been implicated in the pathophysiology of reproductive disorders, such as polycystic ovary syndrome and endometriosis, where its antioxidant and anti-inflammatory properties may enhance ovarian function and fertility. Melatonin also plays a protective role against oxidative stress in granulosa cells, thereby improving oocyte quality and increasing the potential for successful fertilization. These effects position melatonin as a promising therapeutic agent in assisted reproductive technologies, such as in vitro fertilization. Studies demonstrate that melatonin supplementation mitigates the harmful effects of reactive oxygen species on ovarian cells, enhancing embryo development and improving pregnancy outcomes. By counteracting oxidative stress and apoptosis in reproductive tissues, melatonin emerges as a crucial factor in promoting reproductive health.
Article
Background One of the common endocrine disorders is polycystic ovary syndrome (PCOS) with prevalence of about 5%–15% of women within reproductive age. It is related to androgen disturbance, obesity, and irregular menstrual cycle. Pineal gland secretes melatonin hormone, which is involved in the regulation of the circadian rhythm. Melatonin receptors in the ovary adjust sex steroid secretion. Furthermore, it is considered a strong antioxidant, which protects ovarian follicles during follicular maturation. Objectives To evaluate the level of melatonin in patients with PCOS and its relation with reproductive hormones and anthropometric measures. Materials and Methods A case-control study included 200 women in reproductive age (20–40 years), including 100 PCOS patients and 100 controls who appeared to be in generally good health. Anthropometric measurements were evaluated. Reproductive hormones and anti-Müllerian hormone (AMH) were evaluated using the mini VIDAS method. Human MT (Melatonin) ELISA Kit from Elabscience source (USA) was used for measuring melatonin levels. Results Luteinizing hormone/follicle-stimulating hormone (FSH) ratio, AMH, and melatonin were significantly higher in PCOS women, whereas FSH level was significantly lower in PCOS compared with controls. There was an adverse relationship between melatonin levels with thigh circumference, waist circumference, and waist/hip ratio ( P < 0.05). There was a significant adverse correlation between melatonin and testosterone hormone in PCOS patients ( P < 0.05). Melatonin level showed an AUC of 0.755 at a cutoff point of 20 ng/mL and more, giving a sensitivity (78%) and specificity (75%). Conclusions Although PCOS women had higher serum melatonin concentrations, their effect on ovarian hormones is diminished. Melatonin had a connection with androgen, and melatonin supplements may improve metabolic dysfunction in PCOS patients.
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Background and objectives: Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrinological and metabolic disorder in women of reproductive age which leads to infertility/subfertility. The present study was commenced to elucidate the therapeutic efficacy of melatonin in the pathogenesis of letrozole induced polycystic ovary syndrome (PCOS) in Wistar rat. Materials and methods: Letrozole was administered orally (1 mg kg-1) to induce PCOS condition in Wistar female rats for a period of 2-3 weeks followed by a dose of melatonin (200 µg/100 g b.wt.) to PCOS induced rats. On the completion of experimental period the level of cytokines and expression level of different receptors was assessed. Results: The PCOs rats showed down regulation in melatonin (MT1 and MT2), estrogen (ER-α) and cytokine (IL-2R and IL-6R) receptors expression and high circulatory level of IL-6 and TNF-α during PCO condition. These anomalies in expression pattern and circulatory level of cytokines were restored following the treatment. Conclusion: Finding of present study showed the role of melatonin supplementation at receptor level and also suggesting a crosstalk between MT1R / MT2R via cytokine IL-2R and IL-6R resulting in modulation of ER-α receptors.
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