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REVIEW
The therapeutic effects and mechanisms of action of
resveratrol on polycystic ovary syndrome: A comprehensive
systematic review of clinical, animal and in vitro studies
Arash Karimi
1
| Helda Tutunchi
2
| Fatemeh Naeini
3
| Mahdi Vajdi
4
|
Majid Mobasseri
2
| Farzad Najafipour
2
1
Nutrition Research Center, Department of
Clinical Nutrition, School of Nutrition and
Food Sciences, Tabriz University of Medical
Sciences, Tabriz, Iran
2
Endocrine Research Center, Tabriz University
of Medical Sciences, Tabriz, Iran
3
Department of Clinical Nutrition, School of
Nutritional Sciences and Dietetics, Tehran
University of Medical Science, Tehran, Iran
4
Student Research Committee, Department of
Clinical Nutrition, School of Nutrition and
Food Science, Isfahan University of Medical
Sciences, Isfahan, Iran
Correspondence
Farzad Najafipour, Associate Professor of
Endocrinology and Metabolism, Endocrine
Research Center, Tabriz University of Medical
Sciences, Tabriz, Iran.
Email: farzadnajafipour@gmail.com
Funding information
Tabriz University of Medical Sciences
Abstract
Polycystic ovary syndrome (PCOS) is one of the most important and common poly-
genic endocrine disorders among women of reproductive age. Resveratrol, a natural
phenol, is involved in various biological activities, including antioxidant, antiseptic, anti-
inflammatory, anti-ageing and anti-cancer effects. This systematic review aimed to
investigate the therapeutic effects and mechanisms of actions of resveratrol in PCOS.
The present study was conducted according to the guidelines of the Preferred Report-
ing Items for Systematic Review and Meta-Analysis statements. We searched PubMed,
Science Direct, Google Scholar, Scopus, ISI Web of Science, ProQuest and Embase
databases up to August 2021 by using the relative keywords. Original studies published
in the English language that assessed the effects of resveratrol on PCOS and its associ-
ated complications were considered. Out of 417 records screened, only 24 articles met
the inclusion criteria: 10 in vitro, 10 animal and 4 human studies. The results obtained
in the present study showed that resveratrol supplementation might be effective in
improving PCOS-related symptoms by reducing insulin resistance, alleviating dyslipi-
daemia, improving ovarian morphology and anthropometric indices, regulating the
reproductive hormones and reducing inflammation and oxidative stress by affecting
biological pathways. According to the available evidence, resveratrol may reduce the
complications of PCOS. However, further studies are recommended for a comprehen-
sive conclusion on the exact mechanism of resveratrol in PCOS patients.
KEYWORDS
polycystic ovary syndrome (PCOS), resveratrol, systematic review
1|BACKGROUND
Polycystic ovary syndrome (PCOS) is one of the most important poly-
genic endocrine disorders that affects premenopausal women.
1
It is
also estimated that the disease affects about 6%–18% of women of
childbearing age.
2
The prevalent physiological manifestations of this
syndrome include hyperandrogenism, ovarian enlargement androgenic
alopecia, hirsutism, acne, oligo-amenorrhea or anovulation, abortion
and infertility.
3
Women with PCOS show an increase in the occur-
rence of various chronic diseases including hyperlipidaemia, hyperten-
sion, obesity, type 2 diabetes (T2DM) and heart disease.
4,5
Recent
studies have shown that reactive oxygen species (ROS) are one of the
factors contributing to the development of PCOS.
6,7
Oxidative stress
can occur in PCOS due to autophagy dysfunction associated with the
Received: 5 April 2022 Revised: 14 June 2022 Accepted: 26 June 2022
DOI: 10.1111/1440-1681.13698
Clin Exp Pharmacol Physiol. 2022;1–15. wileyonlinelibrary.com/journal/cep © 2022 John Wiley & Sons Australia, Ltd. 1
overproduction of ROS.
8
Due to the involvement of visceral adipose
tissue in the inflammatory process by producing inflammatory cyto-
kines, and according to the bidirectional association between PCOS
and abdominal obesity, this tissue plays a key role in the development
of PCOS-related inflammation.
9
Moreover, hyperglycaemia can induce
an inflammatory process in PCOS through the activation of the
nuclear factor kappa B (NF-κB) signalling pathway, which in turn leads
to the release of pro-inflammatory cytokines including interleukin-1
alpha (IL-1α), interleukin-6 (IL-6) and tumour necrosis factor-alpha
(TNF-α).
10,11
Current medications are often used to prevent the devel-
opment of the signs and symptoms of the disease, while the drugs are
not completely able to eliminate the complications of the disease.
Therefore, natural products are one of the topics of concern for the
management of PCOS complications.
12
Resveratrol (trans-3,5,40-trihy-
droxystylbene) is a natural polyphenol found in berries and nuts.
13
The bioavailability of resveratrol is close to zero because of its exten-
sive metabolism and excessive degradation. Thus, in the systemic cir-
culation, the plasma levels of the metabolites of resveratrol can reach
only 2 micrograms (μg) after consuming 25 milligram (mg) of resvera-
trol orally.
14
It has been well-documented that both passive diffusion
and the active transport (the active sodium-glucose transporter
1 [SGT1] existing in the membrane of small intestine cells) mecha-
nisms contribute to the resveratrol absorption.
15
In accordance with
studies, after absorption of resveratrol by small intestine cells, albumin
as a carrier is the main plasma protein (98.3% protein binding rate) for
resveratrol and its metabolites.
16
Resveratrol metabolites like sulphate
conjugate and glucuronide conjugate are predominantly present in the
systemic circulation.
17
Glucuronidation is the predominant metabolic
pathway that resveratrol undergoes in low doses (5–50 μg).
18
Due to
resveratrol's important properties such as antioxidant, anti-inflamma-
tory, anti-ageing and anti-cancer, it affects oocyte quality and matura-
tion.
19
Recent studies have also confirmed the effect of resveratrol as
a female hormone modulator.
20
Resveratrol can improve insulin sensi-
tivity by enhancing the proliferation of pancreatic βcells, insulin secre-
tion, and improving glucose metabolism.
21
Given the importance of PCOS and its multifaceted condition,
which leads to hormonal imbalances, insulin resistance and antioxi-
dant and anti-inflammatory imbalances, systematic review studies are
necessary to evaluate the existing findings. Due to the lack of system-
atic reviews on the effects of resveratrol on PCOS, the present sys-
tematic review aimed to comprehensively evaluate the therapeutic
effects of resveratrol on PCOS, emphasizing on its physiological roles
and possible mechanisms of action in this hormonal disorder.
2|RESULTS
2.1 |Selected articles
A total of 417 articles were initially identified from databases
(121 from the Web of Sciences, 33 from PubMed, 83 from Embase,
73 from Science Direct, 61 from Scopus and 45 from Google Scholar).
After eliminating duplicate studies, 136 articles remained for analysis of
the title and abstract. Finally, 48 studies were considered eligible based
on the research topic. After a critical analysis, 24 articles were included in
the present study (10 in vitro, 10 animals and 4 human studies). Tables 1
and 2,andFigure1show the main characteristics of the selected articles.
2.2 |Findings from the quality assessments
The results of the methodological quality assessment of included human,
animal and in vitro studies are presented in Figures 2,3and 4,respec-
tively. The results of the blinded outcome assessment for human studies
showed that three studies were classified as having an unclear risk of bias
(Figure 2). The SYRCLE risk of bias tool was used to evaluate the quality
of animal studies. The qualitative assessment exhibited that most of the
studies were rated as low risk of bias for the group similarities at baseline
category, sequence generation, selective outcome reporting and other
bias category sources. In most of these studies, randomization in animal
housing, random outcome assessment and blinding outcome assessment
was not mentioned clearly. Methods of blinding were properly described
in 20% of the included studies. Moreover, the risk of incomplete outcome
data was identified in 80% of the studies and the risk of allocation con-
cealment was identified in 70% of the animal studies (Figure 3). The
OHAT risk of bias tool was used to evaluate the in vitro studies. The qual-
itative assessment showed that most studies were rated as low risk of
bias for the similarity of experimental conditions, incomplete analysis,
confidence in the exposure characterization, adequate administration of
dose or exposure level and other sources of bias category. In most of
these studies, the outcome assessor was not mentioned clearly. Methods
of allocation of groups were properly described in 63% of the included
studies. The risk of a complete report of outcome was unclear in one
study (10%) and high risk in two studies (20%) (Figure 4). Also, adequate
allocation of groups was high risk in two studies (20%).
2.3 |In vitro studies
Wang et al.
22
investigated the effects of resveratrol on inflammatory
and oxidative stress factors in granulosa and theca cells. The authors
reported that resveratrol inhibited the expression of p66Shc and the
production of ROS (p< 0.005), malondialdehyde (MDA) (p=0.01),
transforming growth factor-beta (TGF-β)(p< 0.001) and also increased
the expression of sirtuin 1 (SIRT1) (p< 0.001) and superoxide dismutase
(SOD) (p=0.004) in both granulosa and theca cells. Moreira-Pinto
et al.
23
found that resveratrol can play a main role in the prevention of
ROS formation (p< 0.005) in cell line COV434 and human granulosa
cells. In addition, Ortega et al.
24
investigated the effects of resveratrol
on theca-interstitial cells. They concluded that resveratrol supplementa-
tion could inhibit cytochrome P450c17 (CYP17a) (p=0.003), CYP11a1
(p=0.01), hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid
delta-isomerase1 (HSD3B1) (p=0.001) mRNA expression in theca-
interstitial cells. Ortega and Duleba
25
showed that incubation with res-
veratrol (1–10 μM) for 24 h could significantly decrease the expression
levels of CYP17 and CYP21 (p< 0.005), phosphatidylinositol 3-kinase
2KARIMI ET AL.
TABLE 1 Characteristics of studies investigating the potential roles of resveratrol on PCOS
Authors name Study design
Number and type of
subjects
Dosage and type of
administration Assay
Study
duration Route Main results
Moreira-Pinto, Costa,
Felgueira, Fonseca,
Rebelo
23
In vitro Cell line COV434 and
human granulosa
cells (hGC)
0.001–20 μM ELISA, Western blot, real-time –
PCR, ROS measurement,
fluorospectophotometry
24–72 h –Significant decrease
•ROS/RNS production (p< 0.005)
Wang, Wang, Wang,
Zhang, Wang, Xiang,
Zhuang, Shen, Wang,
Gao
22
In vitro Granulosa cells (GC)
and theca cells
50 μM ELISA, Western blot, real-time -PCR
apoptosis assay, ICP-OES assay,
ROS measurement
24 h –Significant decrease
•ROS (p< 0.005), MDA (p=0.01),
TGF-β(p< 0.001), phosphorylation of
p66Shc (p< 0.005)
Significant increase
•SIRT1 (p< 0.001) and SOD (p=0.004)
Marti, Bouchoucha, Sauter,
Flück
26
In vitro H295R cells 5 μM ELISA, Western blot, methyl-
thiazolyl-tetrazolium assay,
Apoptosis assay,
fluorospectophotometry
72 h –Significant decrease
•CYP17 and CYP21 (p< 0.005)
Significant decrease
•SIRT3 gene expression in H295R cells
(p< 0.005)
Ortega and Duleba
25
In vitro Theca-interstitial cells 1–10 μM ELISA, Western blot, real-time -PCR
apoptosis assay
48 h –Significant decrease
•CYP17 (p< 0.005), CYP21 (p< 0.005),
PI-3 K/Akt (p< 0.005), NF-Κb
(p< 0.001), VGEF (p< 0.001), COX
(p< 0.05), and HMGCR (p< 0.001)
Ortega, Villanueva, Wong,
Cress, Sokalska, Stanley,
Duleba
24
In vitro Theca-interstitial cells 3–10 μM ELISA, Western blot, methyl-
thiazolyl-tetrazolium assay
48 h –Significant decrease
•CCYP17a (p=0.003), CYP11a1
(p=0.01), and HSD3B1 (p=0.001)
Ortega, Villanueva, Wong,
Cress, Sokalska, Stanley,
Duleba
28
In vitro Theca-interstitial cells 1–10 μM ELISA, Western blot, methyl-
thiazolyl-tetrazolium assay
48 h –Significant decrease
•Androgen production, AMH, VEGF,
Akt/PKB, and CYP17a1 (p< 0.001)
No change
•Progesterone (p> 0.05)
Ortega, Wong, Villanueva,
Cress, Sokalska, Stanley,
Duleba
27
In vitro Granulosa cells 10, 30 and 50 μM ELISA, Western blot, real-time -PCR 48 –Significant decrease
•Caspase-3, caspase-7, VEGF, and
CYP19 (p< 0.001)
No change
•Cell morphology, progesterone, and
AMH expression (p> 0.05)
Ortega, Cress, Villanueva,
Sokalska, Stanley,
Duleba
78
In vitro Theca-interstitial cells 3–10 μM ELISA, real-time –PCR, apoptosis
assay
48 h –Significant decrease
•CYP17a, CYP11a1, androstenedione,
and androsterone, (p< 0.05)
Wong, Villanueva, Cress,
Sokalska, Ortega,
Duleba
79
In vitro Theca-interstitial cells 30 and 50 mM ELISA, real-time –PCR, apoptosis
assay, gene expression
48 h –Significant decrease
•HMGCR synthesis (p< 0.001)
(Continues)
KARIMI ET AL.3
TABLE 1 (Continued)
Authors name Study design
Number and type of
subjects
Dosage and type of
administration Assay
Study
duration Route Main results
Wong, Villanueva, Cress,
Duleba
80
In vitro Rat T-I cells 30–100 mM ELISA, real-time –PCR, apoptosis
assay, gene expression
48 h –Significant decrease
•Caspase-3, caspase-7, apoptosis,
insulin (p< 0.05)
Zhang, Zhuang, Gai, Shan,
Wang, Li, Chen, Zhao,
Liu
81
In vivo Rats (n=30) 40, 80, and 160 mg/
kg
Transmission electron microscopy,
RNA isolation and analysis, real-
time PCR, ELISA, histopathological
examination, protein
determination, Western blot
30 days Oral Significant increase
•Adiponectin and 17βestradiol
(p< 0.001), nesfatin-1 and aromatase
at the RNA and protein
levels (p< 0.05)
Huang, Duan, Wu, Wang,
Wang
29
In vivo Rats (n=30) 100 mg/kg ELISA, Western blot, real-time –
PCR, histological analysis, ROS
measurement, Assay of
malondialdehyde, protein
carbonyl, and O2•production,
Oxidative stress measurement
28 days i.p Significant decrease
•Sex hormones, ovarian cell apoptosis,
abnormal mitochondria, LH, FSH,
testosterone, body weight, ovarian
weight, Bax, caspase-9, and ROS
(p< 0.001)
Significant increase
•SOD and GPX levels (p< 0.001)
Ashkar, Eftekhari, Tanideh,
Koohpeyma, Mokhtari,
Irajie, Iraji
30
In vivo Rats (n=10) 20 mg/kg ELISA, real-time –PCR, histological
analysis
63 days Oral Significant increase
•GPX and TAC (p< 0.001), preantral
follicles, antral and graafian follicles,
and corpus luteum (p< 0.05)
Significant decrease:
•TC, LDL-C, HOMA-IR, insulin, TNF-α,
and MDA (p< 0.001)
•Ovarian weight, atretic follicles, cystic
follicles, and body weight (p< 0.05)
No changes:
•HDL-C, TG, serum glucose and SOD
levels (p> 0.05)
Wang, Wang, Wang,
Zhang, Wang, Xiang,
Zhuang, Shen, Wang,
Gao
22
In vivo Rats (n=7) 100 mg/kg ELISA, gene expression, histological
analysis, assay of malondialdehyde
and protein carbonyl,
oxidative stress measurement
36 days i.p Significant increase
•SOD, SIRT1, and estradiol
levels (p< 0.05)
Significant decrease
•MDA, testosterone, body weight, and
ovarian weight (p< 0.05)
Ghowsi, Khazali,
Sisakhtnezhad
35
In vivo Rats (n=5) 10 mg/kg ELISA, assay of glutathione,
malondialdehyde, protein
carbonyl, and O2•production,
Oxidative stress measurement
28 days i.p Significant decrease
•TNF-αand IL-6 levels and body
weight (p< 0.01)
Ghowsi, Khazali,
Sisakhtnezhad
31
In vivo Rats (n=5) 10 mg/kg ELISA, cell count, protein content,
histopathologic examination,
oxidative stress measurement
28 days i.p Significant increase
•TAC level (p< 0.05)
Significant decrease
4KARIMI ET AL.
TABLE 1 (Continued)
Authors name Study design
Number and type of
subjects
Dosage and type of
administration Assay
Study
duration Route Main results
•MDA, HOMA-IR, serum glucose, and
insulin resistance (p< 0.01)
No changes
•Body weight and ovary
weight (p> 0.05)
Rencber, Ozbek, Eraldemır,
Sezer, Kum, Ceylan,
Guzel
13
In vivo Rats (n=9) 20 mg/kg/day ELISA, western blot, real-time –PCR 28 days i.p Significant increase
•SIRT1 and AMPK (p< 0.001)
Significant decrease
•TNF-α, MDA, LH, AMH, and
testosterone levels (p< 0.01)
•Body weight and ovary
weight (p< 0.05)
No change
•FSH (p> 0.05)
Ergenoglu, Yildirim,
Yildirim, Yeniel, Erbas,
Yavasoglu, Taskiran,
Karadadas
32
In vivo Rats (n=7) 10 mg/kg ELISA, Western blot, real-time –
PCR, histological analysis
4 weeks i.p Significant increase
•GPX and progesterone and estradiol
levels (p< 0.05)
Significant decrease
•IGF-1, testosterone, and AMH
levels (p< 0.05)
No change
•CAT (p> 0.05)
Pektas¸, Pektas¸, Sürmen,
Aktepe, Fatma
33
In vivo Rats (n=5) Enriched diet was
prepared by adding
500 grams of
resveratrol in one
ton of standard
pellet chow
ELISA, histopathological
examination, histological analysis
6 months Oral Significant increase
•TAC (p< 0.05)
Significant decrease
•MDA, HOMA-IR, serum glucose, TG,
insulin resistance, oestradiol, and body
weight (p< 0.05)
Benrick, Maliqueo, Miao,
Villanueva, Feng,
Ohlsson, Duleba, Stener-
Victorin
34
In vivo Rats (n=10) 400 mg/ kg ELISA, Western blot, real-time –
PCR, histological analysis
6 weeks i.p Significant increase
•Oestrogen-related receptor αgene
expression (p< 0.05)
No changes
•Insulin sensitivity and body
weight (p> 0.05)
Abbreviations: Akt, protein kinase B; AMH, anti-mullerian hormone; AMPK, AMP-activated protein kinase; BAX, BCL-2-associated X-protein; BMI, body mass index; CYP11A1, cytochrome P450 family 11
subfamily A member 1; CYP17A1, cytochrome P450 17A1; CYP21, cytochrome P450c21; CAT, catalase; COX, cyclooxygenase; ELISA, enzyme-linked immunosorbent assay; FBG, fasting blood glucose; FSH,
follicle-stimulating hormone; GKG, glucokinase; GPX, glutathione peroxidase; hGC, human granulosa cells; HDL-C, high-density lipoprotein cholesterol; HMGCR, hydroxy-3-methylglutaryl-CoA; HOMA-IR,
homeostasis model of assessment-insulin resistance; HSD3B1, hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1; ICP-OES, inductively coupled plasma optical emission
spectrometry; IGF1, insulin like growth factor 1; IL, interleukin; IR, insulin resistance; LDL-C, low-density lipoprotein cholesterol; LH, luteinizing hormone; MDA, malondialdehyde; NF-Κb, nuclear factor-κB;
PCOS, polycystic ovarysyndrome; PCR, Polymerase chain reaction; PI3K, phosphatidylinositol 3-kinase; RNS, reactive nitrogen species; ROS, reactive oxygen species; SIRT, sirtuin; SOD, super oxide dismutase;
TAC, total antioxidant capacity; TGF-β, transforming growth factor β;TNF-α, tumour necrosis factor α; TG, triglycerides; TC, total cholesterol; VLDL, very low-density lipoprotein; VEGF, vascular endothelial
growth factor.
KARIMI ET AL.5
(PI3K)/protein kinase B (p< 0.005), NF-κB(p< 0.001), vascular endo-
thelial growth factor (VGEF) (p< 0.001), cyclooxygenase (p<0.05),
and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
(p < 0.001) in theca-interstitial cells.
All in vitro studies indicated that the administration of resveratrol
led to the reduced expression of CYP17, especially CYP17A1, the
gene that is responsible for the increased production of 17a-hydroxy-
lase, which is the main enzyme for androgen synthesis.
24–28
2.4 |In vivo studies
2.4.1 | The effects of resveratrol on ovarian
histomorphology in PCOS
Five animal studies analysed ovarian histology, including the weight
and morphology of the ovary. Three animal studies showed that
resveratrol supplementation significantly improved ovarian morphol-
ogy and ovarian weight. Huang et al.
29
indicated that resveratrol
administration at a dose of 100 mg/kg body weight for 28 days
improved ovarian weight architecture (p=0.01) in PCOS rats. In three
animal studies, a significant ovarian weight loss (p< 0.05) was
observed after treatment with resveratrol (Ashkar et al.,
30
Wang
et al.
22
and Rencber et al.
13
). In addition, Ashkar et al.
30
reported that
resveratrol improved preantral follicles, antral follicles, graafian folli-
cles, and corpus luteum (p< 0.05) in theca cells and decreased atretic
and cystic follicles (p<0.05) in PCOS rats. However, Ghowsi et al.
31
found that resveratrol treatment at a dose of 10 mg/kg body weight
for 28 days had no significant effect (p> 0.05) on the ovarian weight
of PCOS rats.
Overall, most of the included studies suggested that treatment
with resveratrol decreased ovarian weight, increased normal follicles
in ovaries, and improved the histology of the uterus, which is similar
to metformin effects.
TABLE 2 Summary of the human studies on the effects of resveratrol on PCOS
References Sample size Age
Dosage and
type of
administration Sources Study duration Maine results
Mansour, Samadi,
Sanginabadi, Gerami,
Karimi, Hosseini,
Shirzad, Hekmatdoost,
Mahdavi-Gorabi,
Mohajeri-Tehrani,
Qorbani
21
78 18–40 1000 mg Iran 3 months Significant decrease
•Hair loss (p=0.009)
Significant increase
•Menstruation rate (p=0.03)
No significant change
•Ovarian and adrenal androgens levels, FAI,
glycoinsulinaemic metabolism, lipid profile,
haemoglobin A1c, HOMA-IR, FSH, SHBG, DHEA,
testosterone and body weight (p> 0.05)
Brenjian, Moini, Yamini,
Kashani, Faridmojtahedi,
Bahramrezaie,
Khodarahmian, Amidi
38
40 <30 800 mg/day Iran 40 days Significant decrease
•IL-6, IL-1β, TNF-α, IL-18, NF-Κb, CRP as well as
expression levels of CHOP, GRP78 and XBP1
(p< 0.001 for all)
Significant increase
•Expression levels of ATF4 (p< 0. 05) and ATF6
(p< 0.001)
Bahramrezaie, Amidi,
Aleyasin, Saremi,
Aghahoseini, Brenjian,
Khodarahmian,
Pooladi
36
61 <30 800 mg/day Iran 40 days Significant decrease
•Serum levels of testosterone (p< 0.05)
•Expression of VEGF and HIF1 (p=0.001)
Significant increase
•Serum levels of FSH and TSH (p< 0.05)
No significant change
•Number of mature oocytes, cleavage rate,
fertilization rat and fertility rate (p> 0.05)
Banaszewska, Wroty
nska-
Barczy
nska, Spaczynski,
Pawelczyk, Duleba
37
34 <30 1500 mg/day USA 3 months Significant decrease
•Total testosterone (p=0.01), DHEAS (p=0.01) and
fasting insulin level (p=0.007)
Significant increase
•Insulin sensitivity index (p=0.04)
No significant change
•Gonadotropins, lipid profile as well as markers of
inflammation and endothelial function
Abbreviations: ATF, activating transcription factor; CHOP, CCAAT/enhancer-binding protein homologous protein; CRP, C-reactive protein; DHEAS,
dehydroepiandrosterone sulphate; FAI, free androgen index; FSH, follicle-stimulating hormone; GRP78, glucose-regulated protein 78; HIF1, hypoxia-
inducible factor 1; HOMA-IR, homeostatic model assessment for insulin resistance; IL, interleukin; NF-ΚB, nuclear factor kappa-light-chain-enhancer of
activated B cells; PCOS, polycystic ovarysyndrome; SHBG, sex hormone binding globulin; SHBG, sex hormone binding globulin; TNF-α, tumour necrosis
factor α; VEGF, vascular endothelial growth factor; XBP1, X-box–binding protein 1.
6KARIMI ET AL.
2.4.2 | The effects of resveratrol on reproductive
hormones in PCOS
Seven animal studies examined the effect of resveratrol on reproduc-
tive hormones in PCOS. The effects of resveratrol administration on
oestradiol, luteinizing hormone (LH) and testosterone levels in PCOS
were assessed in three animal studies. Ergenoglu et al.
32
exhibited
that resveratrol administration at a dose of 20 mg/kg/day decreased
the anti-Mullerian hormone and testosterone levels (p< 0.05) in rats
with PCOS. In addition, resveratrol could regulate steroidogenesis by
improving oestradiol and progesterone levels (p< 0.05). Pektas¸
et al.
33
have investigated the effects of resveratrol on PCOS rats. In
this study, PCOS rats were supplemented with resveratrol for
6 months. The findings revealed that resveratrol significantly reduced
oestradiol levels (p< 0.05). In another study, Benrick et al.
34
reported
that administration of 400 mg/kg/day of resveratrol for 6 weeks sig-
nificantly increased oestrogen-related receptor α(EER alpha) gene
expression (p< 0.05) in PCOS rats.
2.4.3 | The effects of resveratrol on metabolic
profile in PCOS
Glycaemic parameters
Four animal studies evaluated the potential effects of resveratrol on
the glycaemic parameters in PCOS. Studies have evaluated changes in
insulin levels, glucose levels, insulin resistance, as well as homeostatic
model assessment for insulin resistance (HOMA-IR) after the resvera-
trol treatment. Pektas¸ et al.
33
indicated that the resveratrol-enriched
diet significantly reduced serum levels of HOMA-IR, serum glucose,
FIGURE 1 Flowchart of the process for selecting studies for the systematic review
KARIMI ET AL.7
triglyceride and insulin resistance (p< 0.05), compared to the control
group. Moreover, another study performed by Ghowsi et al.
35
demon-
strated that resveratrol treatment for 28 days significantly decreased
serum levels of HOMA-IR, serum glucose and insulin resistance
(p< 0.01) in PCOS rats, compared to the control group. They reported
that resveratrol's hypoglycaemic activity is not due to the stimulation
FIGURE 2 Human risk of bias
FIGURE 3 Animal risk of bias
8KARIMI ET AL.
of insulin secretion, but it is because of its effects on improving blood
glucose levels via reducing hepatic glucose secretion by the liver and
increasing glucose uptake by peripheral tissues through enhancing
insulin signalling. Ashkar et al.
30
reported that resveratrol intake at a
dose of 20 mg/kg body weight resulted in a reduction in plasma levels
of HOMA-IR and insulin (p< 0.001) in PCOS rats, while it had no sig-
nificant effect on serum glucose concentration (p> 0.05). They also
suggested that resveratrol might reduce insulin resistance by increas-
ing the expression of protein kinase B, peroxisome proliferator-
activated receptor-gamma and glucose transporter type 4.
Lipid profile
Two animal studies assessed lipid profiles following resveratrol sup-
plementation in PCOS. Pektas¸ et al.
33
indicated that the resveratrol-
enriched diet reduced serum levels of triglyceride (p< 0.05), compared
to the control group. Ashkar et al.
30
found that treatment with resver-
atrol for 63 days significantly decreased the serum total cholesterol
(TC) and low-density lipoprotein-cholesterol (LDL-C) levels (p< 0.05).
However, it did not change the levels of high-density lipoprotein-
cholesterol (HDL-C) and triglyceride (p> 0.05) in PCOS rats, com-
pared to the control group.
2.4.4 | The effects of resveratrol on oxidative stress
and inflammation in PCOS
The effectiveness of resveratrol on inflammation and oxidative stress
in PCOS was assessed in nine animal studies. Administration of res-
veratrol inhibited the expression of inflammation-related genes
including NF-κB, protein kinase B and p66Shc in PCOS. Besides, res-
veratrol significantly decreased serum levels of IL-6, IL-1βand TNF-α,
as well as the expression of nuclear factor erythroid 2–related factor
2 (Nrf2). However, treatment with resveratrol significantly increased
serum levels of glutathione peroxidase (GPX), SOD, catalase (CAT),
and glutathione reductase in seven animal studies, as well as their
expression levels in two in vitro studies. Ergenoglu et al.
32
found that
treatment with resveratrol for 63 days significantly decreased the
serum GPX levels (p< 0.05). However, it did not change the levels of
CAT (p> 0.05) in PCOS rats, compared to the control group. Ghowsi
et al.
31
reported that resveratrol intake at a dose of 10 mg/kg body
weight increased the plasma levels of total antioxidant capacity
(p< 0.05) in PCOS rats, while it decreased serum MDA concentration
(p< 0.01). In addition, in a study by Rencber et al.
13
PCOS rats were
treated orally with resveratrol at a dose of 20 mg/kg/day for 28 days.
The findings demonstrated that resveratrol treatment decreased TNF-
αand MDA levels (p< 0.01) and increased SIRT1and AMP-activated
protein kinase (AMPK) expressions (p< 0.001) in PCOS rats. Ghowsi
et al.
31
concluded that resveratrol significantly reduced TNF-αand
IL-6 levels (p< 0.01) in PCOS mice. In another study, Wang et al.
22
revealed that administration of 100 mg/kg body weight of resveratrol
for 36 days significantly increased the expressions of SOD and SIRT1
and decreased MDA levels (p< 0.05) in PCOS rats.
2.5 |Human studies
2.5.1 | The effects of resveratrol on reproductive
hormones in PCOS
The effects of resveratrol administration on oestradiol, LH and testos-
terone levels in PCOS were evaluated in two human studies. Bahram-
rezaie et al.
36
have found that oral supplementation with 800 mg/day
FIGURE 4 In vitro risk of bias
KARIMI ET AL.9
of resveratrol for 40 days in PCOS patients led to a significant
decrease in serum levels of testosterone (p=0.004), LH (p=0.007), a
significant increase in serum levels of follicle-stimulating hormone (FSH)
(p=0.048) and thyroid-stimulating hormone (p=0.042), compared to
the control group. The results also showed a reduction in the expression
of VEGF and hypoxia-inducible factor (HIF1) genes due to the effect of
resveratrol on the granulosa cells (p=0.0001), while there were no sig-
nificant changes in the number of mature oocytes, cleavage rate, fertili-
zation rate and fertility rate. However, the high-quality oocyte rate and
high-quality embryo rate were higher in the resveratrol group
(p=0.002 and p=0.024, respectively). Mansour et al.
21
reported that
supplementation with 1000 mg/day resveratrol for 3 months did not
significantly change dehydroepiandrosterone (DHEA), sex hormone-
binding globulin (SHBG), LH, FSH and ovarian and adrenal androgens
loss, glycoinsulinaemic metabolism and body weight (p> 0.05) in PCOS
patients. Another study by Banaszewska et al.
37
demonstrated that res-
veratrol supplementation at a dosage of 1500 mg/day led to a 23.1%
decrease in total testosterone level (p=0.01) and a 22.2% decrease of
DHEA sulphate concentration (p=0.01), indicating an effect on ovarian
as well as adrenal androgen production.
2.5.2 | The effects of resveratrol on metabolic
profile in patients with PCOS
Glycaemic parameters
One human study evaluated the potential effects of resveratrol on the
glycaemic parameters in PCOS patients. Banaszewska et al.
37
reported that 1500 mg/day of resveratrol supplementation for
3 months led to a 31.8% decrease in fasting insulin level (p=0.007),
an increase in the Matsuda-DeFronzo insulin sensitivity index
(p=0.04) and quantitative insulin sensitivity check index (p=0.002).
However, resveratrol supplementation did not cause a significant
change in fasting glucose level (p=0.58).
Lipid profile
The potential effect of resveratrol on lipid profile was assessed in two
human studies. Banaszewska et al.
37
reported that supplementation
with 1500 mg/day resveratrol for 3 months had no significant effect
on lipid profile (triglyceride, TC, HDL-C and LDL-C) (p> 0.05) in PCOS
patients. Moreover, in a recent clinical trial, Mansour et al.
21
showed
no significant difference in terms of lipid profile by resveratrol supple-
mentation (1000 mg/day for 3 months) in PCOS patients.
2.5.3 | The effects of resveratrol on oxidative stress
and inflammation in PCOS
The effectiveness of resveratrol on inflammation and oxidative stress
in PCOS was assessed in two human studies. Brenjian et al.
38
investi-
gated the effects of oral supplementation with 800 mg/day of resver-
atrol for 40 days in PCOS patients. In the resveratrol group, there was
a statistically significant decrease in serum levels of IL-18, NF-κB and
C-reactive protein (CRP) (p< 0.05 for all) and in the borderline TNF-α
(p=0.056), compared to the placebo group. Although serum levels of
IL-6 and IL-1βwere decreased in the resveratrol group, these decreases
were not statistically significant. Additionally, gene expression results
demonstrated that the expression levels of CCAAT/enhancer-binding
protein homologous protein (CHOP), glucose-regulated protein (GRP78)
and X-box binding protein 1 (XBP1) significantly decreased (p<0.001
for all). Moreover, resveratrol supplementation significantly increased
the expression of activating transcription factor 4 (ATF4) and ATF6
(p< 0.05 and p< 0.001, respectively) in PCOS patients. In another
study performed by Banaszewska et al.
37
oral supplementation with
1500 mg/day resveratrol for 3 months had no significant effects on
markers of inflammation and endothelial function including hs-CRP, sol-
uble vascular cell adhesion molecule 1 and soluble intracellular adhesion
molecule–1inPCOSpatients(p>0.05).
3|DISCUSSION
3.1 |Possible mechanisms of actions of resveratrol
on PCOS
The possible mechanisms of the actions of resveratrol on PCOS are
mentioned in six sections including the effects of resveratrol on
energy haemostasis and body weight, glucose metabolism and insulin
resistance, lipid metabolism and dyslipidaemia, inflammation, oxidative
stress and the reproductive system. The cellular and molecular mecha-
nisms of the potential roles of resveratrol on PCOS are shown in
graphical abstract.
3.2 |Resveratrol and energy haemostasis
There is a strong bidirectional relationship between obesity and PCOS
based on epidemiological data. Previous research projects concluded
that weight gain and obesity contributed to the development of
PCOS, as an obesity-related condition.
39
There were also mechanisms
whereby the development of PCOS could cause further weight gain.
40
Obesity worsens features of the metabolic syndrome, functions of the
reproductive system and insulin resistance as the main contributor to
PCOS through impairing PI3-kinase and intact mitogen-activated pro-
tein kinase post-receptor insulin pathways.
41,42
Therefore, successful
weight loss exerts favourable effects on obese and overweight
women with PCOS by improving insulin sensitivity, metabolic health
and hyperandrogenic features.
41,43
Resveratrol was recommended as
a proper weight-lowering agent by a large number of experimental
studies. It has been found that resveratrol can reduce body mass gain
by regulating energy haemostasis, increasing satiety, suppressing fat
accumulation and stimulating lipolytic pathways.
44
A recent clinical
study by Mansour et al.
21
demonstrated no significant changes in
anthropometric parameters including weight and waist circumference
after resveratrol supplementation. However, a remarkable decline in
the lean mass and an increase in the fat mass were observed.
10 KARIMI ET AL.
Furthermore, another clinical trial by Banaszewska et al.
37
found no
significant effect on body mass index by resveratrol treatment. A lon-
ger follow-up period of investigation and higher dosage of resveratrol
supplementation may influence anthropometric indices more effec-
tively in these studies. In addition, a larger sample size may reduce the
risk of bias and strengthen obtained findings.
3.3 |Resveratrol and glucose metabolism
Polycystic ovary syndrome, as a reproductive hormonal abnormality, is
frequently associated with insulin resistance. Affected women have ele-
vated insulin resistance, independent of obesity.
45
Several clinical studies
have proposed that PCOS is associated with a higher risk of T2DM and
impaired glucose tolerance.
46
The origin of insulin resistance in PCOS and
the related mechanisms are not yet fully understood.
45
Although, testos-
terone and the CAG repeat number within the androgen receptor are
considered contributors to insulin resistance in PCOS.
47
PCOS is also
associated with post-receptor effects specific to PI3-kinase, which medi-
ates insulin metabolism.
48,49
Due to the crucial role of insulin resistance in
the pathogenesis of PCOS, therapies improving insulin resistance are
helpful in such patients. Increasing evidence demonstrates that resveratrol
alleviates glucose haemostasis and insulin resistance through enhancing
insulin secretion by the pancreas, increasing glucose uptake by skeletal
muscle and activating SIRT1, which acetylates and coactivates down-
stream targets and affects glucose and lipid homeostasis in the liver.
50
Mansouretal.
21
indicated that resveratrol supplementation did not signif-
icantly change the indicators of metabolic control, including insulin,
C-peptide, haemoglobin A1c, fasting blood sugar and HOMA-IR.
However, based on the findings of Banaszewska et al.
37
a significant
decrease in fasting insulin levels and an increase in insulin sensitivity index
were observed after 3 months of resveratrol treatment. It is important to
note that discrepancies between foremost results may be due to various
dosages of resveratrol supplementation, dissimilar follow-up periods of
investigations and different study populations.
3.4 |Resveratrol and lipid metabolism
Dyslipidaemia, including elevated serum levels of LDL-C and TG and
decreased serum concentrations of HDL-C, is usually found in women
with PCOS. However, a substantial percentage of PCOS patients
might still have normal lipid profiles.
51
Insulin resistance and obesity,
which coexist in PCOS, exert independent and interactive impacts on
lipid metabolism.
49
However, the mechanisms of these interactions
remain underexplored. Within adipocytes, insulin resistance causes
elevated catecholamine-induced lipolysis and the release of fatty acids
into the bloodstream. Raised free fatty acid flux to the liver induces
the assembly of very-low-density lipoprotein (VLDL) particles. Conse-
quently, the secretion of VLDL into circulation is promoted and leads
to hypertriglyceridaemia, one of the main lipid disorders in PCOS.
52
Thus, potential therapy targeting the aforementioned mechanisms
which are responsible for dyslipidaemia in PCOS is recommended.
Resveratrol was found to effectively alleviate dyslipidaemia by upre-
gulating the expression of liver X receptor-αand ATP-binding cassette
transporter (ABC)-A1 resulting in cholesterol efflux process, down-
regulating lipoprotein lipase expression, which in turn increases lipid
uptake, decreasing lipoprotein (a) levels, hepatic HMG-CoA reductase
activity, and cholesterol ester transport protein concentrations, acti-
vating SIRT1, and increasing apolipoprotein A1concentrations.
53,54
A
recent clinical trial evaluating the effects of resveratrol on PCOS
showed no significant difference in terms of lipid profile post-inter-
vention. Consistently, Banaszewska et al.
37
proposed no significant
changes in lipid profile by resveratrol supplementation. Insignificant
effects of resveratrol on lipid profile may be explained by the low dos-
age or duration of supplementation in these studies.
3.5 |Resveratrol and inflammation
Emerging evidence has suggested that PCOS is accompanied by
chronic low-grade inflammation. Independent of obesity, a dietary
trigger such as glucose results in an inflammatory response of
women's mononuclear cells (MNC) with PCOS.
55
MNC-derived mac-
rophages, a primary source of cytokine production in excess adipose
tissue, release pro-inflammatory biomarkers, including IL-6 and TNF-α.
Glucose-stimulated TNF-αrelease from MNC is a known mediator
of insulin resistance in PCOS.
56
Additionally, increased abdominal adi-
posity in all weight classes in PCOS is considered another contributor
to inflammatory load in such patients.
57
Moreover, the ovarian theca
cell steroidogenic enzyme that produces androgen, which leads to
hyperandrogenism, is stimulated by pro-inflammatory markers.
58
Therefore, natural compounds with anti-inflammatory properties
might be useful for the treatment of PCOS and its symptoms.
Resveratrol, an anti-inflammatory phytochemical, has been of great
interest in recent decades. As a pharmacological agent, resveratrol
exerts protective effects against inflammation by increasing the levels
and activity of SIRT1, stimulating the activity of AMPK, inhibiting the
expression of iNOS, Janus kinase 1, phosphorylation of the extracellu-
lar signal-regulated kinase (ERK), c-Jun N-terminal kinase, signal trans-
ducer and activator of transcription 6 and p65 subunit of NF-kB, and
attenuating NF-kB signalling pathway.
50
A clinical study performed by
Brenjian et al.
38
found a remarkable decline in levels of inflammatory
biomarkers including IL-6, TNF-α, NF-kB and CRP by resveratrol
supplementation. However, based on the findings of Banaszewska
et al.
37
resveratrol did not significantly change the markers of inflam-
mation and endothelial function in subjects with PCOS. It should be
mentioned that intervention with different dosages and various types
of resveratrol supplements for a variable timeframe may cause
discrepancies between foremost findings.
3.6 |Resveratrol and oxidative stress
Emerging evidence suggests that oxidative stress, an imbalance
between the production and scavenging of reactive oxygen/nitrogen
KARIMI ET AL.11
species, is associated with PCOS.
59
Although the role of oxidative
stress in the pathogenesis of PCOS has remained unclear, it seems to
be involved in PCOS by disturbing steroidogenesis in the ovaries,
which subsequently results in elevating androgen levels, disrupting
follicular development and infertility.
60
In addition, obesity, insulin
resistance and chronic inflammation are associated with oxidative
stress in PCOS.
61
Since obese patients are expected to have increased
levels of lipid peroxidation and protein peroxidation markers, obesity
is considered one of the impact factors leading to the elevated oxida-
tive stress in PCOS pathogenesis.
62,63
Also, as the core mechanism of
PCOS pathogenesis, insulin resistance stimulates oxidative stress by
increasing the production of ROS by exchanging excess glucose or
free fatty acids for a high amount of reducing metabolites in cells.
64,65
Moreover, there is a close relationship between chronic low-grade
inflammation and oxidative stress in PCOS. During exposure to two
pro-inflammatory cytokines including IL-1βand TNF-α, ROS are gen-
erated through the NADPH oxidase system.
66,67
Therefore, potential
therapeutic approaches targeting the aforementioned mechanisms,
which are responsible for oxidative stress in PCOS, are highly pro-
posed. Resveratrol, a molecule with antioxidant properties, increases
the expression of various antioxidant enzymes, decreases mitochon-
drial superoxide generation through stimulating mitochondria biogen-
esis, inhibits superoxide production from uncoupled endothelial nitric
oxide through upregulating the tetrahydrobiopterin-synthesizing
enzyme GTP cyclohydrolase I, and attenuates NADPH oxidase-
mediated production of ROS through down-regulating the expression
and activity of the oxidase.
68
Brenjian et al.
38
reported that the
expression of five genes in the endoplasmic reticulum stress response
pathway, including ATF4, ATF6, CHOP, GRP78 and X-box binding
protein 1 (XBP1s) were affected by resveratrol supplementation.
Although expression levels of ATF4 and ATF6 significantly increased,
a remarkable decline in the expression levels of CHOP, GRP78, and
XBP1 was observed. It should be mentioned that the complexity of
the mechanisms responsible for exerting endoplasmic reticulum stress
effects was difficult to explain in PCOS conditions.
32
3.7 |Resveratrol and reproductive system
The hormonal imbalance, which occurs in PCOS, results in ovarian
dysfunction. Monthly ovulation is not occurring in women with
PCOS.
69
Several human studies have reported that reduced levels of
FSH and elevated concentrations of LH, androgens and insulin were
observed in PCOS patients.
70
The aforementioned hormonal distur-
bances can manifest as infrequent or lack of menstruation.
71
In addi-
tion, clinical features such as tiny cysts on the surface of the ovaries
(polycystic) and hair and skin symptoms are caused by underproduc-
tion of oestrogen and overproduction of androgens, including testos-
terone, dehydroepiandrosterone and androstenedione.
58
Insulin
resistance, frequently appearing in PCOS, causes compensatory
hyperinsulinaemia that induces LH-stimulated androgen production,
either via its receptors or via insulin growth factor receptors.
72
Emerg-
ing evidence from animal and human studies has found that
resveratrol shows profitable effects on PCOS and its symptoms.
25
Resveratrol inhibits 17α-hydroxylase/C17-20-lyase enzymatic activ-
ity, reduces the growth of theca cells by inhibition of the mevalonate
pathway and HMG-COA reductase expression and activity, and atten-
uates mRNA expression of Cyp17a1 by suppressing the Akt/
PKB-signalling pathway.
73
A recent study examining the effects of
resveratrol supplementation on menstrual cyclicity and hyperandro-
genism in PCOS patients exhibited no significant changes in endocrine
indicators including DHEA, SHBG, LH and FSH after 3 months of res-
veratrol treatment. However, the authors showed that resveratrol
could be an effective treatment to decrease the degree of hair loss
and improve menstrual regularity. The suspected mechanisms
involved in the restoration of menstrual function are attributed to the
improvement of insulin sensitivity and serum androgens. The mea-
surement of total testosterone in this study may not be sensitive
enough to detect the alterations in androgen levels. Therefore, this
may elucidate the lack of correlation between alleviation of hyperandro-
genism signs and androgen levels. Another clinical trial by Banaszewska
et al.
37
found a 22.2% decrease in DHEA by resveratrol treatment. In
addition, Bahramrezaie et al.
36
showed that resveratrol supplementation
led to a significant decrease in serum levels of total testosterone and
LH, while serum FSH levels increased. The discrepancy between the
findings explained here may be due to the dissimilarities in the physio-
logical characteristics of study patients including absorption ability and
hormonal status, their ethnic groups, and lifestyle factors.
3.8 |Side effects
Resveratrol does not appear to have side effects at short-term doses
(1.0 g). On the other hand, at doses of 5 g/day or more per day, side
effects might occur, such as nausea, vomiting, diarrhoea and liver dys-
function.
74
Our understanding of resveratrol dose-dependency and
administration route is complicated, as orally administrated resveratrol
gets metabolized by gut microbiota which makes it difficult to deter-
mine which effects are solely due to resveratrol or both resveratrol
and its metabolites.
74
4|FURTHER RESEARCH DIRECTIONS
AND CONCLUSIONS
Overall, the reviewed reports indicated that resveratrol supplementa-
tion may be effective in improving PCOS-related symptoms by reduc-
ing insulin resistance, alleviating dyslipidaemia, improving ovarian
morphology and anthropometric indices, regulating the reproductive
hormones, as well as reducing inflammation and oxidative stress by
affecting biological pathways.
The current review has the strength of assessing comprehensively
and systematically the effectiveness of resveratrol on PCOS, consider-
ing all available and eligible in vitro, animal and human studies, provid-
ing a proper sample size, and mentioning most of the discovered
mechanisms of action of resveratrol on PCOS. Nonetheless, regarding
12 KARIMI ET AL.
the most remarkable weakness of this review, there is a wide variation
in terms of applied dosages for evaluating the effects of resveratrol in
selected studies. Therefore, it's difficult to compare included studies
with each other. It should be mentioned that the profitable effects of
resveratrol on PCOS and its related complications need to be inde-
pendently established by further robust human randomized clinical tri-
als before proceeding to clinical settings. It is recommended that
future studies considering the lifestyle modification of study patients,
larger sample sizes, longer follow-up periods and a greater dose of
resveratrol supplementation should assess the efficiency and safety of
resveratrol therapy in PCOS patients.
5|METHODS
5.1 |Search strategy
Online searches in electronic databases such as PubMed, Science Direct,
Google Scholar, Scopus, ISI Web of Science, ProQuest and Embase were
conducted using keywords “Resveratrol”[MESH] and “PCOS”[Title/
Abstract] OR “polycystic ovary syndrome”[MESH] OR “dysmetabolic
syndrome”[Title/Abstract] OR “sclerotic ovary syndrome”[Title/
Abstract] by two independent authors (A.K. and F.N). This search was lim-
ited to English-language articles published up to August 2021. Findings
from this systematic review were reported based on Preferred Reporting
Items for Systematic Review and Meta-Analysis guidelines.
5.2 |Eligibility criteria
All randomized clinical trials, animal, and in vitro studies published in
English-language journals were included in the present systematic review.
Letters, comments, and review articles were excluded. We also excluded
studies in which resveratrol was combined with other supplements.
5.3 |Data extraction
The reviewed articles were imported into EndNote software
(Thomson Reuters, Philadelphia, PA, USA). All relevant articles were
extracted to screen for articles based on the scope of this study and
duplicate articles were eliminated. The full texts of the screened arti-
cles were then assessed by two authors (A.K. and F.N.) separately for
eligibility and data extraction. A third author (M.V.) evaluated the
extracted information in terms of accuracy and quality. Any disagree-
ments were referred to the principal investigator for resolution.
5.4 |Risk of bias assessment
The risk of bias was assessed by two authors (A.K. and F.N.) for the
human, animal and in vitro studies. The overall degree of bias in ran-
domized controlled trials was assessed using the Cochrane risk of
bias.
75
The SYRCLE risk of bias tool was applied to assess the overall
risk of bias in animal studies.
76
Also, the quality of the in vitro studies
was assessed using the OHAT risk of bias tool.
77
These tools have
seven domains including allocation concealment, random sequence gen-
eration, performance bias, attrition bias, reporting bias, detection bias
and other bias sources. Based on any methodological defect that might
affect the findings, each domain was ascribed a “high risk”score. A
“low risk”score was assigned to each domain if there was no defect for
that domain. If the information was not sufficient to determine the
effect, it would get an “unclear risk”score. If this test is “low-risk”for
all domains, it is a high-quality, completely low-risk study.
AUTHOR CONTRIBUTIONS
The authors' responsibilities were as follows: AK, FN, MV, and HT
wrote the original paper; AK, MM, ASR, and FNP contributed to data
collection; HT contributed to the final revision of the manuscript. All
authors read and approved the final version of the manuscript.
ACKNOWLEDGEMENTS
The authors would like to thank the Tabriz University of Medical
Sciencesfor its support.
CONSENT FOR PUBLICATION
All authors have read and approved the final manuscript.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
DATA AVAILABILITY STATEMENT
All data generated or analysed during this study are included in this
published article.
ORCID
Arash Karimi https://orcid.org/0000-0001-6407-8286
Helda Tutunchi https://orcid.org/0000-0002-4795-1757
Majid Mobasseri https://orcid.org/0000-0002-8108-5979
Farzad Najafipour https://orcid.org/0000-0003-1950-0702
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How to cite this article: Karimi A, Tutunchi H, Naeini F,
Vajdi M, Mobasseri M, Najafipour F. The therapeutic effects
and mechanisms of action of resveratrol on polycystic ovary
syndrome: A comprehensive systematic review of clinical,
animal and in vitro studies. Clin Exp Pharmacol Physiol. 2022;
1‐15. doi:10.1111/1440-1681.13698
KARIMI ET AL.15
