Gynecological Endocrinology

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Effectiveness of inositol, metformin and their

combination in women with PCOS undergoing
assisted reproduction: systematic review and
meta-analysis

Ara Unanyan, Laura Pivazyan, Ekaterina Krylova, Andrey Eskin, Araksya

Zakaryan, Antonina Sarkisova & Anatoly Ishchenko

To cite this article: Ara Unanyan, Laura Pivazyan, Ekaterina Krylova, Andrey Eskin, Araksya
Zakaryan, Antonina Sarkisova & Anatoly Ishchenko (2022): Effectiveness of inositol, metformin and
their combination in women with PCOS undergoing assisted reproduction: systematic review and
meta-analysis, Gynecological Endocrinology, DOI: 10.1080/09513590.2022.2136160

To link to this article: https://doi.org/10.1080/09513590.2022.2136160

Published online: 26 Oct 2022.

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Gynecological Endocrinology
https://doi.org/10.1080/09513590.2022.2136160

Review

Effectiveness of inositol, metformin and their combination in women with

PCOS undergoing assisted reproduction: systematic review and meta-analysis
Ara Unanyana , Laura Pivazyanb , Ekaterina Krylovab , Andrey Eskinb , Araksya Zakaryanb ,
Antonina Sarkisovab and Anatoly Ishchenkoa
a
National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Healthcare
of Russian Federation, Moscow, Russia; bI.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

ABSTRACT ARTICLE HISTORY

Objective:  Our study aims to compare the effect of metformin, inositol and their combinations on Received 13 June 2022
the efficiency in improving outcomes of assisted reproductive technologies in women with PCOS. Revised 15 September
Data sources:  PubMed, The Cochrane Library, ClinicalTrials.gov, Embase, MEDLINE. The search was 2022
Accepted 10 October 2022
performed on studies published before November 14, 2021, to identify articles evaluating the Published online 26
effectiveness of treatment metformin and inositol on ART outcomes. October 2022
Study selection:  The systematic review was conducted according to the PRISMA 2020 checklist and
registered in the PROSPERO 2021 CRD42021287887. Randomized controlled trials (RCTs) in English KEYWORDS
that compared metformin or inositol or metformin + inositol treatment with placebo or no treatment metformin; inositol;
in women with PCOS undergoing assisted reproduction were included. In addition, RCTs with Polycystic Ovary Syndrome;
ovulation induction; IVF
comparison combination and single metformin or inositol treatment were also included.
Data extraction and synthesis:  35 RCTs were included for qualitative analysis reporting on 4668
participants. In group of Metformin treatment were included 1891 patients, in Myo-inositol group
− 281, in inositol + metformin group were included 110 participants and in control group (placebo
or absence of treatment) − 1865 women with PCOS. 5 meta-analyses were performed. CPR in
comparison of metformin and placebo in 1312 patients were higher in metformin group (RR = 1.30,
95% CI: 1.12 to 1.50, p = 0.0004). OHSS was less in metformin (RR = 0.34, 95% CI: 0.17 to 0.69,
p = 0.003). However, LBR were not statistically significant (RR = 1.12, 95% CI: 0.93 to 1.36, p = 0.24).
In comparison of inositol and no treatment there was also no difference in CPR (RR = 1.37, 95% CI:
0.79 to 2.38, p = 0.26). As for metformin and inositol meta-analysis in 220 patients with PCOS, CPR
were higher in inositol group (RR = 1.52, 95% CI: 1.05 to 2.18, p = 0.03). Combination treatment
included only two RCTs and was illegible for meta-analysis.
Conclusion:  To our knowledge, it is the first meta-analysis that estimates inositol treatment compared to
metformin. Based on our systematic review and meta-analysis, metformin seems to be a good option for
improving ART outcomes in women with PCOS. However, it is not clear whether inositol usage is adequate.
Nevertheless, we need more clinical trials of good quality to answer all questions thoroughly.

Introduction means that Assisted Reproductive Technology (ART) therapies,

Polycystic ovary syndrome (PCOS) is one of the most prevalent
endocrine diseases that influence women of reproductive age.
[1] PCOS strike 12%–21% of reproductive-age women, more
often among those who are overweight. [2] PCOS is tied with
various diseases such as hormonal and metabolic disorders, ovar-
ian dysfunction, and menstrual irregularities. According to the
Rotterdam criteria created in 2003, PCOS is diagnosed if two
of the three following criteria: chronic oligo- or anovulation,
anatomically polycystic ovaries on ultrasonography, and clinical
and/or biochemical hyperandrogenism. [1] Ovulatory disturbance
is an important diagnostic feature of PCOS associated with
infertility also women with PCOS have unfavorable pregnancy
outcomes. [3]
Resistance to and inefficiency of ovulation induction and
failure to overcome other accompanying reasons of infertility
including In-vitro fertilization (IVF) and intracytoplasmic sperm
injection (ICSI) used in male factor infertility, have a role in
PCOS. The clinical practice questions include indications, timing
and comparative efficacy with other treatments, yet RCTs in this
domain are limited in women with anovulatory PCOS. According
to research, metformin and inositol may be drugs that improve
ART quality. Metformin lessens lipogenesis, gluconeogenesis and
reinforces glucose absorption in the liver, muscle, adipose tissue
and ovaries. The efficacy of metformin in improving clinical
outcomes is uncertain. Inositol (myo-inositol and di-chiro ino-
sitol) is a nutritional supplement that works as a second mes-
senger and plays a role in insulin signaling transmission. The
addition of inositol to the primary treatment reinforces ovulation
frequency and menstrual cycle. [4]
Therefore, we decided to compare the effect of metformin,
inositol, and their combinations on the efficiency in improving

CONTACT Laura Pivazyan laurapivazyan98@gmail.com National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After
Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, Oparina Street, 4, 117997 Moscow, Russia
© 2022 Informa UK Limited, trading as Taylor & Francis Group
2 A. UNANYAN ET AL.
outcomes of assisted reproductive technologies in women
with PCOS.
Methods
This study has been registered in the PROSPERO international
prospective register of systematic reviews by the National
Institute for Health Research (NIHR). Protocol and registration
number: CRD42021287887 PROSPERO 2021.
Our systematic review was conducted according to the
updated PRISMA 2020 guidelines [5]. Institutional Review Board
(IRB) approval was not requested since the present study is
a review.
Types of studies
Randomized controlled trials (RCTs) comparing metformin or
inositol or metformin + inositol treatment with placebo or no
treatment in women with PCOS undergoing assisted reproduc-
tion were included. In addition, RCTs with comparison combi-
nation and single metformin or inositol treatment were also
included.
Non-randomized studies were excluded, as they are associated
with a high risk of bias. Proceedings of scientific meetings and
abstracts were also excluded. All types of studies were selected,
and each potentially relevant study was obtained in full text and
assessed for inclusion independently by the authors.
Types of participants
Women of reproductive age (18–45) diagnosed with PCOS that
undergo assisted reproductive technologies (ovulation induction/
IVF/intrauterine insemination/ICSI). Diagnosis of PCOS was based
on Rotterdam criteria [1], which included at least two of the three
following criteria: oligo-ovulation or anovulation, clinical and/or
biochemical signs of hyperandrogenism and polycystic ovaries
detected by ultrasonography. For studies published before 2005,
PCOS can be defined according to National Institutes of Health
criteria (NIH) [6], which included the only presence of clinical
and/or biochemical hyperandrogenism and oligo/anovulation.
Types of interventions
The studies that use and compare metformin, inositol or met-
formin + inositol treatment with placebo or no treatment in
women with PCOS who underwent assisted reproductive tech-
nologies (ovulation induction/IVF/ICSI/IUI) were included.
Types of outcomes
The primary outcomes were evaluated clinical pregnancy rates
(defined as evidence of a gestational sac, confirmed by ultra-
sound, at six to eight weeks of gestation) and incidence of OHSS
after the intervention. The secondary outcome was live birth
rate (baby born after 20 weeks of gestation).
Retrieval strategy
The following databases were used: PubMed, The Cochrane
Library, ClinicalTrials.gov, Embase, MEDLINE, and the search
was performed without any time limitation (last searched
November 14 2021). For the database search, the following key-
words were used: “metformin”, “inositol”, “IVF”, “PCOS”, “ovu-
lation induction”. MeSH terms were used in PubMed (("Polycystic
Ovary Syndrome"[Mesh]) AND "Ovulation Induction"[Mesh])
AND ("inositol"[Mesh] OR "metformin"[Mesh]); in the Cochrane
Library the following additional terms were used: [Polycystic
Ovary Syndrome] explode all trees and with qualifier(s): [drug
therapy - DT] in Trials. All found articles were screened (the
title and the abstract). After that, the full texts of articles that
were considered relevant were analyzed. Finally, the reference
lists of the selected articles were searched for additional potential
studies.
The search strategy in the electronic database Pubmed was
the following. Firstly, using the advanced search builder on
PUBMED, the following combination of the search terms was
conducted: (metformin OR inositol) AND (IVF OR ovulation
induction) AND (polycystic ovarian syndrome), no filters and
limits were used. 481 studies were identified from PubMed: 96
– (metformin) AND (IVF) AND (polycystic ovarian syndrome);
30 - (inositol) AND (IVF) AND (polycystic ovarian syndrome);
313 - (metformin) AND (ovulation induction) AND (polycystic
ovarian syndrome); 42 - (inositol) AND (ovulation induction)
AND (polycystic ovarian syndrome), of these 82 were duplicates.
Additionally, 208 studies were identified after using MeSH-terms
on PubMed (("Polycystic Ovary Syndrome"[Mesh]) AND
"Ovulation Induction"[Mesh]) AND ("inositol"[Mesh] OR "met-
formin"[Mesh]). The last date when the electronic database
PUBMED was searched was November 13 2021.
Four independent reviewers (E.K.,A.S.,A.Z.,A.E) searched
databases and used a standardized data extraction form. Any
discrepancies were resolved by consensus or consultation with
the fifth reviewer (L.P.). The characteristics and general infor-
mation was extracted, including authors, time of publication,
inclusion/exclusion criteria of participants, intervention, com-
parison group, outcomes and follow-up period.
Risk of bias assessment was carried out for each included
study using the Cochrane Handbook for Systematic Reviews of
Interventions. The quality of evidence (QoE) was assessed
according to the GRADE system.
Statistical methods
RevMan 5.3 statistical software was used for the meta-analysis.
According to the Cochrane Handbook for Systematic Reviews
of Interventions, and I2 value of 0 indicates no observed het-
erogeneity, whereas I2 values from 30 to 60% may represent
moderate heterogeneity, I2 values from 50% to 90% may repre-
sent substantial heterogeneity and I2 values from 75% to 100%
represent considerable heterogeneity.
Results
1675 articles were found after the search, 593 of which were
duplicates and therefore excluded. One thousand eighty-two
reports were reviewed by title and abstract, and 1026 studies
were eliminated because they were not RCTs or had another
topic. A total of 56 reports were included in the full-text review.
Of these four were eliminated due to eligible intervention, two
were eliminated due to eligible participants, nine trials had other
outcomes, four studies were published as conference abstracts,
and five were not completed. After the reference lists of the
 Gynecological Endocrinology 3

selected articles searching, 3 RCTs were included. A flowchart [27, 31–33] but authors of the other four studies [25,26, 28,29]
showing search results is shown in Figure 1. As a result, 35 determined the following: when metformin was prescribed, the
studies were included in the qualitative synthesis (Table 1). results were not statistically significant compared to the control
group of patients (p > 0.05).
As well, a statistically significant improvement in the LBR at
Comparison of metformin versus placebo or no treatment method of ART ovulation induction with CC, letrozole or rFSH
was observed in two studies [21, 40] but authors of the other
A statistically significant improvement (p < 0.05) in the clinical
seven studies [7, 12, 14, 17, 23,24, 41] determined that when
pregnancy rate at method of ART IVF or ICSI was observed in
metformin was prescribed, the results were not statistically sig-
four studies [27, 31–33] but authors of the other five studies
nificant (p > 0.05).
[25,26, 28–30, 34] determined that when metformin was pre-
The primary analysis was aimed at clinical pregnancy rates
scribed, the results were not statistically significant (p > 0.05)
between metformin and placebo groups. This comparison
compared to the control group of patients.
included 12 studies evaluating 1312 patients (RR = 1.30, 95%
Also, a statistically significant improvement in the CPR as
CI: 1.12 to 1.50, p = 0.0004). The heterogeneity for this compar-
method of ART ovulation induction with CC, letrozole or rFSH
ison was 53%. Based on this meta-analysis, clinical pregnancy
was observed in seven studies [8–11, 19, 21, 40] but authors of
rates were statistically significant higher in the metformin group
the other eight studies [7, 12, 14–17, 20, 23] determined that
(Figure 2).
when metformin was prescribed, the results were not statistically
The next comparison included OHSS cases in 5 studies
significant (p > 0.05).
including 428 patients (RR = 0.34, 95% CI: 0.17 to 0.69,
According to the PCOS phenotype, Hosseini et  Al. [20]
p = 0.003). The heterogeneity for this comparison was 0%. Hence,
divided subjects into 4 groups. Women with all phenotypes had
ovarian hyperstimulation syndrome occurred less in the met-
no improvement.
formin group compared with placebo (Figure 3).
We included data from 14 studies for this outcome [13, 18,19,
As for live birth rate, it was evaluated in 7 studies assessing
22,23, 25,26, 28–34]. In 4 studies [18, 28, 30,31], the authors
644 patients with no statistically significant difference in met-
found out that metformin significantly reduced the incidence of
formin and placebo groups (RR = 1.12, 95% CI: 0.93 to 1.36,
OHSS in women during IVF/ICSI. In studies 7,13,16,17 [13, 19,
p = 0.24). The heterogeneity for this comparison was 59%
22,23] OHSS rate in patients treated metformin with CC/FSH
(Figure 4).
decreased, but differences with placebo or no treatment group
did not reach statistically significance(p > 0.05). In addition, in
the other 4 studies [26, 29, 32, 34] there was no statistically Comparison of inositol versus placebo or no treatment
significant difference in this parameter (p > 0.05).
A statistically significant improvement (p < 0.05) in the live In 1 study, Emekçi Özay, O., 2017 [35], the authors found out
birth rate at method of ART IVF was observed in four studies that inositol significantly increased the CPR (p = 0.02) when FSH

Figure 1.  PRISMA 2020 flow diagram.


Table 1. Description of articles included in the systematic review.
№ Study (first author)
1. Zain, M. M., 2009 [7]
2. Maged, A.M., 2015 [8]
Study design
Randomized controlled trial
Prospective randomized study
4
ART/type of ovulation
Participants Interventions Comparison Outcomes induction
77 women with PCOS Metformin 1500 mg/day. The dose was No treatment CPR 21.1% (8/38) vs 15.4% Ovulation induction with CC
gradually increased from 500 mg/ (n = 39) (6/39), P = 0.416
day during the first 3 weeks (n = 38) LBR 18.4% (7/38) vs
14.4% (6/39), P = 0.126
120 women with PCOS Metformin 1500 mg/day (n = 40) No treatment CPR 10% (4/40) vs 10% Ovulation induction with CC
A. UNANYAN ET AL.

(n = 40) (4/40), p = 0.05

3. Hwu, Y.M., 2005 [9] Prospective randomized, 80 women with PCOS Metformin 1500 mg/day (n = 40) No treatment CPR 15% (6/40) vs 0, Ovulation induction with CC
controlled study (n = 40) P = 0.026
4. Vandermolen, D., 2001 Randomized, double-blind, 27 women with PCOS Metformin 1500 mg/day (n = 11) Placebo (n = 14) CPR 55% (6/11) vs 7% Ovulation induction with CC
[10] placebo-controlled trial (1/14), P = 0.02
5. Basirat, Z., 2012 [11] Multicenter, single-blind, 334 women with PCOS Metformin 1500 mg/day (n = 167) No treatment CPR 28.7% (48/167) vs Ovulation induction with CC
randomized controlled trial (n = 167) 24.6% (41/167), P < 0.05
6. Johnson, N.P., 2010 [12] Multi-centre double-blind 171 women with PCOS Metformin 1500 mg/day. The dose was Placebo (n = 36) CPR 54% (19/35) vs 39% Ovulation induction with CC
placebo-controlled parallel BMI ≤ gradually increased from 500 mg/ (14/36), P = 0.35
randomized trial 32 kg/m2 (n = 106) day during the first 2 weeks (n = 35) LBR 43% (15/35) vs
36% (13/36), P = 0.46
7. Cheng, J., 2010 [13] prospective randomized 60 women with PCOS Metformin 1500 mg/day (n = 30) Placebo (n = 30) OHSS rate 6.6% (5/76) vs Ovulation induction with CC
placebo-controlled pilot 11.8% (9/76), NS
study
8. Kar, S., 2015 [14] Randomized controlled trial  105 women with PCOS Metformin 1700 mg/day (n = 24) No treatment CPR 50% (12/24) vs 31.2% Ovulation induction with CC
(n = 32) (10/32), NA
LBR 41.6% (10/24) vs
28.1% (9/32), P = 0.29
9. Şahin, Y., 2004 [15] Prospective randomized 21 women with PCOS Metformin 1700 mg/day (n = 11) No treatment CPR 45.5% (5/11) vs 30% Ovulation induction with CC
clinical study (n = 10) (3/10), NS
10. Kocak, M., 2002 [16] Prospective, randomized, 56 women with PCOS Metformin 1700 mg/day (n = 27) Placebo (n = 28) Total CPR n = 4 vs n = 0, Ovulation induction with CC
double-blind, P = 0.04
placebo-controlled study CPR per cycle n = 3 vs
n = 0, P = 0.07

11. Legro, R.S., 2007 [17] Randomized clinical trial 626 women Metformin 2000 mg/day. The dose was Placebo (n = 209) CPR 31.1% (65/209) vs Ovulation induction with CC
with PCOS gradually increased from 500 mg/ 23.9% (50/209), P = 0.1
day (n = 209) LBR 26.8% (56/209) vs
22.5% (47/209), P = 0.31

12. Moll, E., 2006 [18] Randomized double-blind 228 women with PCOS Metformin 2000 mg/day. The dose was Placebo (n = 114) LBR n = 21 vs n = 30, NA Ovulation induction with CC
clinical trial gradually increased from 500 mg/
day (n = 111)

13. Malkawi, 2002 [19] Randomized prospective trial 28 women with PCOS Metformin 1700 mg/day (n = 16) Placebo (n = 12) CPR 56.3% versus 16.6%, Ovulation induction with CC
p < 0.05
OHSS n = 0 vs n = 2, NS
14. Hosseini, M.A., 2013 Non-blind, prospective 359 women with PCOS Metformin 1500 mg/day (the dose was Folic acid mg/day CPR Ovulation induction with
[20] randomized clinical trial gradually increased from 500 mg/ type A (n = 95) Type A 39.2% vs 33.7%, letrozole
Patients’ PCOS day during the first 2 weeks) + folic type B (n = 10) p = 0.27
phenotypes were acid 1mg/day type C (n = 25) Type B 43.8% vs 20%, p
determined and type A (n = 79) type D (n = 56) = 0.21
recorded: type B (n = 16) Type C 44% vs 20%, p
type A (n = 174), type C (n = 25) = 0.064
type B (n = 26), type D (n = 52) Type D 36.5% vs 28.6%,
type C (n = 50), p = 0.279
type D (n = 108)
(Continued)
Table 1. Continued.
ART/type of ovulation
№ Study (first author) Study design Participants Interventions Comparison Outcomes induction
15. Begum, M.R., 2013 [21] Randomized controlled trial 165 women with PCOS Metformin 1500 mg/day (n = 55) No treatment CPR 54.55% (30/55) vs Ovulation induction with
(n = 55) 29.09% (16/55), P = 0.01 rFSH
LBR 43.63% (24/55) vs
21.82% (12/55), P = 0.01
16. Tasdemir, S., 2004 [22] Randomized prospective trial 32 women with PCOS Metformin 1700 mg/day (n = 16) No treatment OHSS 6.3% (1/16) vs 25% Ovulation induction with
(n = 16) (4/16), NS rFSH
17. Palomba, S., 2005 [23] Randomized controlled trial 70 women with PCOS Metformin 1700 mg/day (n = 35) Placebo (n = 35) CPR per cycle 21.2% Ovulation induction with
(18/85) vs 16.1% hpFSH + TI/IUI
(14/87), P = 0.392
LBR per pregnancy
94.4% (17/18) vs 85.7%
(12/14), P = 0.568
OHSS per cycle 0 (0/85)
vs 1.1% (1/87), p = 1
18. Morin-Papunen, L., 2012 Multicenter, randomized, 320 women with PCOS Metformin Placebo LBR 41.9% vs. 28.8%, Ovulation induction with CC,
[24] double-blind, BMI <27 kg/m2 1500 mg/day 87 nonobese P = 0.014 then gonadotropins/
placebo-controlled study (n = 177) 90 nonobese women, women Nonobese women letrozole, TI/IUI, IVF/ICSI
BMI >27 kg/m2 2000 mg/day 73 obese LBR 46.7% vs. 34.5%,
(n = 143) 70 obese women. women (n = 160) P = 0.09
The dose was gradually increased Obese women
from 500 mg/day (n = 160) LBR 35.7% vs. 21.9%,
P = 0.07
19. Abdalmageed, O.S., Randomized double-blind 102 women with PCOS Metformin 1000 mg/day (n = 51) Placebo (n = 51) CPR 33% (17/51) vs 27.5% IVF
2019 [25] placebo-controlled study BMI >24 kg/m2 (14/51), P = 0.52
LBR 25.5% (13/51) vs
17.6% (9/51), P = 0.34
OHSS n = 0 vs n = 0
20. Kjotrod, S.B., 2004 [26] Prospective, randomized, 73 women with PCOS Metformin 1000 mg/day. The dose was Placebo (n = 32) Total (mean) IVF/ICSI
double blind study BMI <28 kg/m2 gradually increased from 500 mg/ 13 normal CPR 0.48 vs 0.44, P = 0.8
(n = 33) day during the first 2 weeks (n = 31) weight women LBR 0.39 vs 0.34, P = 0.7
BMI >28 kg/m2 14 normal weight women 19 obese OHSS n = 1 vs n = 4,
(n = 40) 17 obese women women P = 0.3
Normal weight (mean)
CPR 0.57 vs 0.23,
P = 0.12
LBR 0.43 vs 0.15,
P = 0.12
OHSS n = 0 vs n = 3,
P = 0.13
Overweight (mean)
CPR 0.41 vs 0.58, P = 0.5
LBR 0.35 vs 0.47, P = 0.5
OHSS n = 1 vs n = 1,
P = 0.9
21. Wei, Z., 2008 [27] Prospective randomized study 56 women with PCOS Metformin 1000 mg/day (n = 26) No treatment CPR per cycle 38.2% IVF
(n = 28) (13/34) vs 16.7% (6/36),
P < 0.05
LBR per cycle 29.4%
(10/34) vs 13.9% (5/36),
P < 0.05
(Continued)
Gynecological Endocrinology
5

Table 1. Continued.
№ Study (first author)
22. Palomba, S., 2011 [28]
23. Doldi, N., 2006 [18]
24. Palomba, S., 2011 [29]
25. Qublan, H. S., 2009 [30]
26. Tang, T., 2006 [31]
27. Jacob, S.L., 2016 [32]
28. Kjotrod, S. B., 2011 [33]
29. Allan, G., 2005 [34]
Study design
Parallel, randomized,
double-blind,
placebo-controlled clinical
trial
Randomized
placebo-controlled study
Prospective, parallel,
randomized, double-blind,
placebo-controlled clinical
trial
Prospective, randomized,
double-blind,
placebo-controlled clinical
trial
Randomized,
placebo-controlled,
double-blind study
Randomized
placebo-controlled study
Multi-centre, prospective,
randomized, double-blind
study
prospective, randomized,
double-blind,
placebo-controlled study
6
ART/type of ovulation
Participants Interventions Comparison Outcomes induction
120 women with PCOS Metformin 1500 mg/day (n = 60) Placebo (n = 60) CPR 43.3% (26/60) vs 40% IVF
(24/60), P = 0.711
LBR 48.3% (29/60) vs
45% (27/60), P = 0.855
Incidence of OHSS 8.3%
A. UNANYAN ET AL.
(5/60) vs 30% (18/60),
P = 0.003
40 women with PCOS Metformin 1500 mg/day (n = 20) No treatment Incidence of OHSS 5% vs IVF
(n = 20) 15%, p < 0.05
88 women with PCOS Metformin 1500 mg/day (n = 44) Placebo (n = 44) CPR 29.5% (13/44) vs IVF
36.4% (16/44), P = 0.496
LBR 27.3% (12/44) vs
29.5% (13/44), P = 0.816
OHSS 0 (0/44) vs 4.5%
(2/44), P = 0.247
66 women with PCOS Metformin 1700 mg/day (n = 34) Placebo (n = 32) CPR 44.1% (15/34) vs IVF
28.1% (9/32), NS
Incidence of OHSS 0 vs
9.3% (3/32), p < 0.05
101 women with PCOS Metformin Placebo (n = 49) CPR per transfer 44.4% vs IVF/ICSI
1700 mg/day (n = 52) 19.1%, P = 0.022
LBR per transfer 37.8%
vs 14.3%, P = 0.025
Severe OHSS that
required hospitalization
3.8% vs 20.4%, P = 0.023
169 women with PCOS Metformin 1700 mg/day (n = 77) Placebo (n = 76) CPR per cycle 28.6% IVF/ICSI
BMI <35 (22/77) vs 48.7%
(37/76), p = 0.02
CPR per transfer 34.5%
(20/58) vs 54.7%
(35/64), P = 0.04
LBR per transfer 27.6%
(16/58) vs 51.6%
(33/64), p = 0.01
Incidence of moderate/
severe OHSS 16% vs
12.2%, P = 0.66
150 women with PCOS Metformin 2000 mg/day. The dose was Placebo (n = 75) CPR 50% (37/74) vs 33.3% IVF/ICSI
gradually increased from 500 mg/ (25/75), P = 0.0391
day during the first 2 weeks (n = 74) LBR 48.6% (36/74) vs
32.0% (24/75),
P = 0.0383
OHSS n = 12 vs n = 18,
NA
110 women with PCOS Metformin Placebo (n = 55) CPR 30.2% (16/53) vs 40% IVF/ICSI
1700 mg/day (22/55), P = 0.6
BMI <28 kg/m2; Mild OHSS n = 3 vs
2550 mg/day n = 4, NS
BMI >28 kg/m2
(n = 53)
(Continued)
Table 1. Continued.
ART/type of ovulation
№ Study (first author) Study design Participants Interventions Comparison Outcomes induction
30. Emekçi Özay, O., 2017 Randomized prospective trial 196 women with PCOS Myo-inositol 4 g/day + folic acid 400 mg/ Folic acid 400 mg/ CPR 18.6% (16/86) vs Ovulation induction with
[35] day (n = 86) day (n = 90) 12.2% (11/90), P = 0.02 rFSH + IUI

31. Papaleo, E., 2009 [36] Prospective, controlled, 60 women with PCOS Myo-inositol 4 g/day + folic acid 400 mg/ Folic acid (n = 30) CPR 26.6% (8/30) vs 23.3% ICSI
randomized trial day (n = 30) (7/30), NS
32. Raffone, E., 2009 [37] Randomized prospective trial 120 women with PCOS Metformin 1500 mg/day (n = 60) Myo-inositol 4 g/ CPR 36.6% (22/60) vs Ovulation induction with
day + folic acid 48.3% (29/60), P = 0.19 rFSH
400 mg/day
(n = 60)
33. Rajasekaran, K., 2021 Double-blinded randomized 102 women with PCOS Metformin 1700 mg/day (n = 52) Myo-inositol 4 g/ CPR 18% (9/50) vs 36% IVF
[38] controlled study day (n = 50) (18/50), P = 0.04
LBR n = 13 vs n = 23, NS
Mild OHSS 20% (10/50)
vs 10% (5/50), NS
34. Prabhakar, P., 2020 [39] Prospective randomized 116 women with PCOS Myo-inositol 4 g/day + metformin Myo-inositol 4 g/ CPR 42% (21/50) vs 45.5% Ovulation induction with
controlled trial 1500 mg/day (n = 50) day (n = 55) (25/55), NS letrozole
Ongoing pregnancy rate
and LBR 40% (20/50) vs
41.8% (23/ 55),
p = 0.849

35. Agrawal, A., 2019 [40] Randomized controlled trial 120 women with PCOS Metformin 1500 mg + myo-inositol Metformin CPR 63.3% (38/60) vs Ovulation induction with CC
1800 mg/day (n = 60) 1500 mg/day 33.3% (20/60), P = 0.001 and gonadotropins + IUI
(n = 60) LBR 55% (33/60) vs
26.67% (16/60),
P = 0.002
OHSS n = 5 vs n = 0, NA
Gynecological Endocrinology
7
8 A. UNANYAN ET AL.

Figure 2.  Meta-analysis of clinical pregnancy rates in groups: metformin or placebo.

Figure 3.  Meta-analysis of ovarian hyperstimulation syndrome in groups: metformin or placebo.

Figure 4.  Meta-analysis of live birth rates in groups: metformin or placebo.

Figure 5.  Meta-analysis of clinical pregnancy rates in groups: myo-inositol or not myo-inositol.

ovulation was stimulated. However, in the study Papaleo, E.,
2009 [36], no statistically significant difference was found out
during ICSI (p > 0.05).
Based on quantitive synthesis (meta-analysis), the clinical
pregnancy rate was not statistically significant in comparison
- inositol vs. no treatment (RR = 1.37, 95% CI: 0.79 to 2.38,
p = 0.26). The heterogeneity for this comparison was 0%. Thus,
myo-inositol treatment has no statistically significant difference
with no treatment. However, only two studies involving 236
patients were included in this meta-analysis (Figure 5).

Figure 6.  Meta-analysis of clinical pregnancy rates in groups: myo-inositol or metformin.
Comparison of metformin versus inositol
Rajasekaran, K., 2021 [38] revealed that inositol significantly
increased the CPR compared with metformin during IVF
(p = 0.04). However, in the study Raffone, E., 2009 [37], there
was no statistically significant difference in the stimulation of
FSH ovulation (p = 0.19).
Myo-inositol was found to be as effective as metformin in
reducing the risk of OHSS in women with PCOS before IVF
cycles in study Rajasekaran, K., 2021 [38] (p > 0.05).
There was no statistically significant difference in the LBR
when using metformin or inositol during IVF in study
Rajasekaran, K., 2021 [38] (p > 0.05).
Only one meta-analysis was applicable to compare clinical
pregnancy rates in the metformin and myo-inositol group. It
included only two studies with 220 patients with PCOS (RR
= 1.52, 95% CI: 1.05 to 2.18, p = 0.03). The heterogeneity for
this comparison was 3%. Thus, clinical pregnancy rates were
statistically significant higher in the myo-inositol group
(Figure 6).
Comparison of metformin + inositol versus metformin or
inositol
In study Agrawal, A., 2019 [40], it was found that taking a
combination of metformin and inositol, compared with taking
metformin, significantly increases the CPR (p = 0.001) and LBR
(p = 0.002) in women undergoing ovulation stimulation with
clomiphene and gonadotropins.
In the study by Prabhakar, P., 2020 [39], there was no sta-
tistically significant difference in pregnancy rates (p > 0.05) and
LBR (p = 0.849) when taking a combination of metformin and
inositol compared with inositol in women undergoing ovulation
stimulation with letrozole.
Four review authors (E.K., A.S., A.Z., A.E.) independently
assessed included studies for risk of bias using the Cochrane
‘Risk of bias tool for randomized trials. Any disagreements were
resolved by discussion or consultation with a fifth review author
(L.P.). Visualization tools were created by the ROBVIS app [42]
(Figure 7). Using GRADE, we assessed the certainty of the evi-
dence to be moderate to high for outcomes for which data were
available.
The data were pooled in meta-analysis using RevMan software
(Review Manager version 5.4, the Cochrane Collaboration, 2011).
Discussion
The main biochemical and cellular mechanism that is involved
in the formation of resistance is a decrease in insulin sensitivity
secondary to a post-binding abnormality in insulin
receptor-mediated signal transduction, with a less substantial
but significant decrease in insulin responsiveness [43]. Many
Gynecological Endocrinology 9
studies have determined that agents that increase insulin sensi-
tivity, such as metformin and myoinositol, positively affect the
disease. Metformin reduces the intake of glucose in the liver
and increases its absorption by peripheral tissues, reducing the
glucose level in the blood and increasing tolerance to it. In
addition, metformin reduces the production of androgens in the
ovaries. [44] But scientists wonder whether metformin can be
used as a first-line drug for ovulation induction. As presented
in our review, many researchers demonstrated the effectiveness
of metformin as an additional method of ovulation induction
on clinical pregnancy rate [8–11, 19, 21, 40]; others disagree
with this [7, 12, 14–17, 20, 23]. Myo-inositol, like metformin,
is an insulin sensitizer, but inositol does not cause side effects
from the gastrointestinal tract [45]. Inositol acts by a
membrane-associated sodium-dependent inositol co-transporter
GLUT4 as a post-receptor mediator (second messenger) of insu-
lin signal and decreases hyperinsulinemia. It reduces the amount
of androgens in the blood serum, decreases the luteinizing hor-
mone/follicle-stimulating hormone (LH/FSH) ratio and improves
ovarian function [46]. However, metformin has received much
attention in scientific articles, whereas studies on inositol
appeared later and there are much fewer of them. Fruzzetti et  al
compared the efficacy between myoinositol and metformin for
PCOS treatment and concluded that both drugs improve insulin
sensitivity, reduce BMI, and improve ovarian function without
significant differences between the two treatments [47]. However,
a Cochrane review published in 2018 failed to identify the ben-
efits of myoinositol among infertile women with PCOS. There
are still active disputes about which of the molecules is better
- metformin or inositol [48].
Our review was able to consider the effectiveness of met-
formin, inositol and their combination concerning rates of clin-
ical pregnancy, live birth and the risk of OHSS in women with
PCOS undergoing ART.
To our knowledge, our review is the first to assess the impact
of treatment with inositol in comparison with metformin on
ART outcomes in patients with PCOS.
Also, none of the previously published reviews included an
assessment of the effectiveness of combined treatment (inosi-
tol + metfomin) for these outcomes in their analysis.
As for limitations, there is a lack of trials evaluating the
effectiveness of inositol and its combinations with metformin
or comparing these two formulations and their efficiency con-
cerning women struggling with PCOS while using ART. At the
same time, we do not have much research with a high-quality
rate. There are only two trials on inositol, which affects the
credibility of the results. Therefore, we cannot clearly say that
inositol has a better effect on the outcome of pregnancy because
more research is needed. In addition, in our meta-analysis (sys-
tematic review), studies with a high risk of bias were included.
Furthermore, as we have not restricted publication date, not all
studies used the Rotterdam criteria. Also, in the trials, the
criteria for PCOS diagnosis did not indicate that 8 years had
10 A. UNANYAN ET AL.

Figure 7. Rob 2 tool for risk of bias assessment.


passed since menarche according to guideline recommendation
[3]. Finally, our review included studies with different dosages
and different medication duration.
In the future, well-designed studies evaluating pregnancy rates
and the risk of OHSS, using the Rotterdam criteria for the
diagnosis of PCOS, can help to determinate the effectiveness of
these meds for researchers and med personnel, which will allow
them to be used more confidently when using ART in women
with PCOS
Further studies are needed to investigate the use of the com-
bination treatment (inositol + metformin) on ART outcomes in
women with PCOS.
Conclusion
Based on our systematic review and meta-analysis, metformin
seems to be a good option for improving ART outcomes in
women with PCOS. Although the review does not provide defin-
itive evidence of effect combined treatment (inositol + metfomin),
it very clearly highlights the absence of good-quality evidence
and heterogeneity of published studies, which we consider helpful
new information to guide clinical practice and direct future
research.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The author(s) reported there is no funding associated with the work featured
in this article.
ORCID
Ara Unanyan http://orcid.org/0000-0002-2283-2356
Laura Pivazyan http://orcid.org/0000-0002-6844-3321
Ekaterina Krylova http://orcid.org/0000-0002-0220-0474
Andrey Eskin http://orcid.org/0000-0001-9546-6062
Araksya Zakaryan http://orcid.org/0000-0003-0919-465X
Antonina Sarkisova http://orcid.org/0000-0001-8462-3894
Anatoly Ishchenko http://orcid.org/0000-0003-3338-1113
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