BMC

Zhao et al.
Reprod Health (2021) 18:171

https://doi.org/10.1186/s12978-021-01207-7
RESEARCH Open Access
Comparative efficacy of oral insulin

sensitizers metformin, thiazolidinediones,
inositol, and berberine in improving endocrine
and metabolic profiles in women with PCOS:
a network meta‑analysis
Han Zhao, Chuan Xing, Jiaqi Zhang and Bing He*
Abstract
Background: Multiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine,
have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen
in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin
sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the
clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading
to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral
insulin sensitizers on endocrine and metabolic profiles in women with PCOS.
Methods: We identified randomized controlled trials for PCOS from a variety of databases, published from January
2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and
glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed.
Results: Twenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with met-
formin, treatment with myo-inositol + d-chiro-inositol was associated with a greater improvement in menstrual
frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31–93.58]). Myo-inositol + d-chiro-inositol and met-
formin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total
testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + d-chiro-inositol were
associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences:
− 0.72 [95% CI (− 1.11)–(− 0.34)] to − 0.89 [95% CI (− 1.460)–(− 0.32)]). Metformin + thiazolidinediones treatment was
associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while
thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fast-
ing plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events.
Conclusions: Ours is the first study to report that for women with PCOS, myo-inositol combined with d-chiro-inositol
and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance
and decreasing total testosterone. Myo-inositol combined with d-chiro-inositol is particularly efficacious in menstrual
*Correspondence: [email protected]
Department of Endocrinology, Shengjing Hospital, China Medical
University, Shenyang 110000, Liaoning, People’s Republic of China
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco
mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Zhao et al. Reprod Health (2021) 18:171 Page 2 of 12
recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than
metformin alone.
Trial registration PROSPERO CRD42020211524
Plain English summary

This study aimed to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with
polycystic ovary syndrome (PCOS). A random-effects network meta-analysis including 22 trials was conducted. For
women with PCOS, myo-inositol combined with d-chiro-inositol and metformin combined with thiazolidinediones
appear superior to metformin alone in improving insulin resistance and decreasing total testosterone level. Myo-inosi-
tol combined with d-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin
combined with thiazolidinediones improve lipid metabolism better than metformin alone.
Keywords: Polycystic ovary syndrome, Oral insulin sensitizers, Metformin, Thiazolidinediones, Inositol, Berberine,
Endocrine, Metabolic, Network meta-analysis
Background Materials and methods

Polycystic ovary syndrome (PCOS) is a common and The methods and results are reported following the
complex endocrinopathy that affects 4–21% of women Preferred Reporting Items for Systematic Reviews and
of reproductive age worldwide [1, 2]. It is character- Meta-Analyses statement [7]. The protocol was regis-
ized by ovulatory dysfunction, hyperandrogenism, and tered at PROSPERO as CRD42020211524.
a polycystic ovarian morphology. These features are
accompanied by various metabolic abnormalities, such
as insulin resistance, hyperinsulinemia, and adiposity. Search strategy and selection criteria
PCOS has a long-term impact on overall health, such as Systematic literature searches were performed in the
an increased risk of endometrial cancer, type 2 diabetes following databases from January 2005 to October
mellitus, and cardiovascular events [3, 4]. Metformin 23rd, 2020: PubMed, Embase, Web of Science, the
(Met), a recognized insulin sensitizer, has been widely Cochrane Central Register of Controlled Trial (CEN-
used for women with PCOS due to benefits, such as TRAL), CBM Database, CNKI Database, the WanFang
improving menstruation and hyperinsulinemia, hyper- Database, the WeiPu Database, and ClinicalTrials.gov.
androgenism, and abnormal metabolism, and it may We used different combinations of the following search
also have a preventive effect on long-term cardiovas- terms: “polycystic ovary syndrome,” “metformin,” “thia-
cular diseases [5]. However, the persistent use of Met zolidinediones,” “inositol,” and “berberine.” The PICO
is accompanied by gastrointestinal adverse side effects, framework was used to identify relevant trials [8],
such as diarrhea and stomachache [6]. Multiple oral without language, ethnicity, or regional restrictions.
insulin-sensitizing agents, such as thiazolidinediones We included randomized controlled trials (RCTs) in
(TZDs), inositols, and berberine, have been proven women, aged 18 to 49 years, diagnosed with PCOS
safe and efficacious in improving the endocrine, meta- based on the Rotterdam consensus, the Androgen
bolic, and reproductive abnormalities seen in PCOS, Excess and PCOS Society criteria, the National Insti-
providing more options for healthcare providers and tute of Health, and Guidelines for diagnosis and treat-
patients. These oral insulin sensitizers are more con- ment of PCOS in China [9–12]. Eligible trials included
venient, practical, and economic than agents that need those where treatments were followed-up for at least
to be injected. However, a comparison of the clinical 12 weeks, consisting at least one of the predefined out-
effectiveness of the four different classes of oral insu- comes namely, menstruation, hyperandrogenism, and
lin sensitizers in PCOS has not been explored, lead- metabolism, and comparison of the effects of insulin
ing to clinical uncertainty about the optimal treatment sensitizers. Additionally, treatments combined with
pathway. Here, a network meta-analysis (NMA) was either oral contraceptives or ovulation-inducing agents,
designed using metformin as control to compare the and patients with other diseases, such as nonclassic
efficacy of the four different classes of oral insulin sen- congenital adrenal hyperplasia, premature ovarian fail-
sitizers in improving menstruation, hyperandrogenism, ure, hyperprolactinemia, hypothyroidism, hyperthy-
and abnormal metabolism in patients with PCOS, along roidism, Cushing’s syndrome, and androgen-secreting
with an assessment of their relative safety profiles. tumors were excluded.
Outcomes a summary statistic for cumulative ranking. The efficacy

The outcomes included menstruation frequency, param- of each intervention was expressed as a percentage [38].
eters of hyperandrogenism [total testosterone (TT), sex We conducted comparison-adjusted funnel plots using
hormone-binding globulin (SHBG), androstenedione Stata software to examine the publication bias.
(AND), and the modified Ferriman–Gallwey score (mF-G
score)], parameters of glucolipid metabolism, includ-
ing fasting plasma glucose (FPG), fasting insulin (FINS), Results
Homeostatic Model Assessment of Insulin Resistance Study search and study characteristics
(HOMA-IR), and lipids [triglyceride (TG), total choles- A total of 8645 publications were retrieved; of these, 22
terol (TC), high-density lipoprotein cholesterol (HDL- RCTs (n = 1079 participants) were included in the pre-
C), and low-density lipoprotein cholesterol (LDL-C)]. sent network meta-analysis. A flow chart depicting the
Obesity-related indexes, such as body mass index (BMI) literature search process based on PICO is presented
and waist–hip ratio (WHR), and adverse events were also in Fig. 1. Overall, two studies evaluated and compared
considered. myo-inositol (MI) and myo-inositol + d-chiro-inosi-
tol (MI + DCI) combination treatment (72 women),
one study compared MI and DCI (50 women), and the
Data extraction and quality assessment remaining RCTs offered a comparison of Met (19 trials;
Two independent reviewers (H.Z. and C.X.) screened the 455 women) and the following interventions: thiazoli-
titles and abstracts and assessed the full texts of poten- dinediones (TZDs) (ten trials; 280 women), Met + TZDs
tial reports. The data extracted from the original trials (three trials; 89 women), MI (four trials; 110 women),
included study, year, region, intervention, sample size, MI + DCI (one trial; 32 women), berberine (BBR) (one
follow-up duration, and outcomes of interest (Table 1). trial; 26 women), and Met + BBR (two trials; 70 women).
Risk of bias assessment was assigned by two independent The evidence map for the aforementioned interventions
investigators (H.Z. and J.Z.) using the revised Cochrane is shown in Fig. 2.
Collaboration risk of bias tool RoB 2.0 across five Table 1 shows the characteristics of the included stud-
domains [35]. Each trial was evaluated by two review- ies. These RCTs were conducted in various countries,
ers (H.Z. and C.X.), any discrepancies were resolved by published in English or Chinese, and participants were
a consensus-based discussion with another author (B.H.). recruited from an outpatient clinic or a hospital. Trials
were generally similar with respect to patient baseline
Data synthesis and analyses characteristics for most outcomes. In summary, a total
The efficacy of different treatment regimens was com- of 1079 women with PCOS were randomized to receive
pared simultaneously using a traditional pairwise meta- eight different interventions (Met, TZDs, BBR, MI, DCI,
analysis (TMA) and network meta-analysis (NMA) [36]. MI + DCI, Met + TZDs, and Met + BBR).
Initially, we conducted a random-effect TMA using The risk of bias assessment is shown in Fig. 3. Of the
Review Manager 5.4 (the Cochrane Collaboration, Lon- 22 included trials, seven were at low risk of bias across
don, UK). Continuous variables were represented by the all domains, four studies were at a high risk of bias, and
weighted mean differences (MDs) with 95% confidence we judged the remaining eleven trials to have some con-
intervals (CIs), and for dichotomous variables, we cal- cerns. Overall, concerns regarding the randomization
culated the combined odds ratios (ORs) with 95% CIs process and missing outcome data were the main cause
[37]. Between-study heterogeneity was determined using of potential bias. The comparison-adjusted funnel plot
Chi-squared test, combining I2 and P values, for which for outcomes appeared minor asymmetry or no publica-
I2 > 50% or P < 0.05, indicated substantial heterogeneity. tion bias (shown in Additional file 1: Appendix S1.1). In
The random-effect NMA was subsequently performed addition, the analyses of inconsistency were identified in
to combine the direct and indirect comparisons of agents the network meta-analysis of triglyceride, and the incon-
into one analysis with Stata software (version 15.1, Stata sistency model was fitted in the network meta-analysis,
Corp LLC, 4905 Lakeway Drive, College Station, TX, the detailed results of the assessment for inconsistency
USA). We calculated the pooled estimates of MDs or are shown in Additional file 1: Appendix S1.
ORs with 95% CIs in order to compare multiple interven-
tions to each other. Network inconsistency was evaluated
using the node-splitting method and inconsistency mod- Efficacy outcomes
els, and significance was assessed at the 0.05 level. Finally, Table 2A, B summarizes the NMA and TMA results for
to summarize the probabilities, we calculated the surface positive efficacy outcomes. Furthermore, other efficacy
under the cumulative ranking (SUCRA) curve to provide outcomes, details of the Forest plots, and SUCRA curves
are presented in Additional file 1: Appendix S2.
Table 1 Characteristics of studies included in the network meta-analysis

Study Year Region Drugs Size F-up Efficacy
(wks)
Ahmad [13] 2008 India Met vs TZDs Met 850 mg bid 31 24 w FPG, FINS, HOMA-IR, BMI, WHR, TT, AND, mF-G score,
Rosi 2 mg bid 30 Menstrual frequency, Adverse events
Mohiyidid- 2013 UK Met 500 mg bid 17 12 w FPG, FINS, TC, TG, HDL, LDL, BMI, TT, SHBG, Menstrual
den [14] Rosi 4 mg qd 18 frequency, Adverse events
Yilmaz [15] 2005 Turkey Met 850 mg bid 25 12 w BMI, WHR, AND, HOMA-IR, TC, TG, LDL, HDL, Menstrual
Rosi 4 mg qd 25 frequency, Adverse events
Sangeeta 2012 India Met 500 mg bid 50 24 w FINS, HOMA-IR, TC, HDL, mF-G score, TT, SHBG, Men-
[16] Pio 15 mg qd 50 strual frequency, Adverse events
Naka [17] 2011 Greece Met 850 mg bid 15 24 w FPG, FINS, TC, TG, HDL, LDL, mF-G score, TT, SHBG, BMI,
Pio 30 mg qd 14 WHR, Adverse events
Jensterl [18] 2008 Slove- Met 850 mg bid 15 24 w FPG, FINS, HOMA-IR, TC, TG, HDL, LDL, BMI, TT, AND,
nia Rosi 4 mg qd 11 Menstrual frequency, Adverse events
Ortega [19] 2005 Mexico Met 850 mg tid 18 24 w FPG, FINS, HOMA-IR, TC, TG, HDL, LDL, BMI, WHR, mF-G
Pio 30 mg qd 17 score, AND, Adverse events
Zeng [20] 2020 China Met vs Met 500 mg tid 44 12 w FPG, FINS, HOMA-IR, TC, TG, HDL, LDL, BMI, TT, Adverse
Met + TZDs Met + Pio 500 mg + 15 mg bid 44 events
Wang X [21] 2014 China Met 1000 mg tid 43 24 w FPG, FINS, HOMA-IR, HDL, LDL, BMI, WHR, TT, SHBG,
Met + Pio 1000 mg + 5 mg tid 43 mF-G score, Menstrual frequency, Adverse events
Liang [22] 2019 China Met vs TZDs vs Met 500 mg tid 22 12 w FPG, FINS, HOMA-IR, HDL, LDL, TC, TG, BMI, WHR, TT,
Met + TZDs Pio 30 mg tid 21 Menstrual frequency
Met + Pio 500 mg + 30 mg tid 23

Sohrevardi 2016 Iran Met 500 mg tid 22 12 w PFG, FINS, HOMA-IR, TC, TG, HDL, LDL, BMI, TT, WHR,
[23] Pio 30 mg qd 21 Menstrual frequency, Adverse events
Met + Pio 500 mg + 30 mg tid/qd 23

Jamilian [24] 2017 Iran Met vs MI Met 500 mg tid 30 12 w BMI, SHBG, TT, mF-G score
MI 2g bid 30
Shokrpour 2019 Iran Met 500 mg tid 27 12 w FPG, FINS, HOMA-IR, BMI, TC, TG, HDL-C, LDL-C
[25] MI 2g bid 26
Fruzzetti [26] 2016 Italy Met 500 mg tid 22 24 w HOMA-IR, BMI, mF-G score, Menstrual frequency,
MI 4g qd 24 Adverse events
Nehra [27] 2017 India Met 500 mg tid 30 12–24 w FPG, FINS, HOMA-IR, TC, TG, HDL, LDL, TT, BMI, WHR
MI 1g bid 30
Du [28] 2018 China Met vs MI + DCI Met 500 mg bid 32 24 w FPG, FINS, HOMA-IR, TC, TG, HDL, LDL, AND, TT, SHBG,
MI + DCI 550 mg + 13.8 mg bid 32 Menstrual frequency, Adverse events
Pizzo [29] 2014 Italy MI vs DCI MI 4g qd 25 24 w HOMA-IR, BMI, mF-G score, TT, AND, SHGB, Menstrual
DCI 1g qd 25 frequency
Donne [30] 2019 Italy MI vs MI + DCI MI 4g qd 10 12–24 w mF-G score, WHR, BMI, Menstrual frequency
MI + DCI 1.1 g + 27.6 mg qd 12
Nordio [31] 2012 Italy MI 2g bid 24 12–24 w BMI, WHR, FPG, FINS, HOMA-IR, TT, SHBG, AND, Men-
MI + DCI 550 mg + 13.8 mg bid 26 strual frequency
Li [32] 2017 China Met vs BBR Met 500 mg bid 29 12 w FPG, FINS, HOMA-IR, TC, TG, HDL, LDL, BMI, TT, Adverse
BBR 300 mg tid 26 events
Wang P [33] 2016 China Met vs Met 500 mg tid 42 12 w HOMA-IR, BMI, WHR
Met + BBR Met + BBR 500 mg + 500 mg tid 42
Wang L [34] 2011 China Met 500 mg tid 28 12 w FPG, FINS, HOMA-IR, BMI, TT
Met + BBR 500 mg + 500 mg tid 28
Met Metformin, TZDs thiazolidinediones, Rosi rosiglitazone, Pio pioglitazone, MI myo-inositol, DCI d-chiro-inositol, BBR berberine, TT total testosterone, SHBG sex
hormone binding globulin, AND androstenedione, mF-G score modified Ferriman–Gallwey score, BMI body mass index, WHR waist–hip ratio, FPG fasting plasma
glucose, FINS fasting insulin, HOMA-IR Homeostatic Model Assessment of Insulin Resistance, TG triglyceride, TC total cholesterol, HDL-C high density lipoprotein
cholesterol, LDL-C low density lipoprotein cholesterol
Fig. 1 Prisma flow diagram of the study selection process. RCT randomized controlled trial
Menstrual frequency Hyperandrogenism

With respect to improving menstrual frequency, our In terms of reducing TT, the TMA and NMA both
TMA showed that Met + TZDs (OR 3.91 [95% CI 1.75– revealed that Met + BBR [(TMA: MD − 11.53 [95% CI
8.72]; P = 0.88, I2 = 0%) was more efficacious than Met (− 16.91)–(− 6.15)]; P = 1.00, I2 = 0%; NMA: MD − 11.53
alone, while MI + DCI (OR 21.92 [95% CI 2.99–160.44]; [95% CI (− 17.62)–(− 5.44)]) and Met + TZDs [(TMA:
P = 0.38, I2 = 0%) was more efficacious than MI alone. MD − 3.14 [95% CI (− 6.19)–(− 0.09)]; P = 0.44, I2 = 0%;
The NMA revealed that MI + DCI was more efficacious NMA: MD − 3.66 [95% CI (− 6.60)–(− 0.72)] were supe-
than Met (OR 14.70 [95% CI 2.31–93.58]) and MI (OR rior to Met alone. The NMA revealed that MI + DCI was
16.51 [95% CI 2.56–106.64]). MI + DCI was ranked best more efficacious than Met, MI, and DCI [MDs rang-
at improving menstrual frequency. ing from − 6.72 [95% CI (− 10.24)–(− 3.20)] for Met
ranging from − 1.85 [95% CI (− 2.76)–(− 0.94)] for

Met to − 3.08 [95% CI (− 4.10)–(− 2.05)] for TZDs).
Met + BBR ranked best among all the treatments at
reducing BMI. However, both the TMA and NMA
revealed that there was no significant difference between
the groups with respect to WHR reduction.
Glycometabolism
With respect to lowering FPG, the TMA revealed that
there were no significant differences between each of the
investigated agents. The NMA revealed that TZDs (MD
− 0.21 [95% CI (− 0.21)–(− 0.02)]) were more efficacious
than Met. Additionally, with respect to lowering FINS,
the TMA revealed that Met + TZDs (MD − 1.83 [95% CI
(− 3.12)–(− 0.55)]; P = 0.19, I2 = 37%) was more effica-
cious than Met alone. The NMA did not reveal any sig-
nificant differences among the groups.
Fig. 2 Evidence graph of all agents. The size of the circles is
proportional to sample size, and the width of the lines is proportional
With respect to decrease in HOMA-IR, the TMA
to the number of trials. Met Metformin, TZDs thiazolidinediones, MI showed that TZDs (MD − 0.92 [95% CI (− 1.64)–
myo-inositol, DCI d-chiro-inositol, BBR Berberine (− 0.19)]; P < 0.00001, I2 = 97%), Met + TZDs (MD
− 0.85 [95% CI (− 1.21)–(− 0.49)]; P = 0.04, I2 = 65%),
and Met + BBR (MD − 0.25 [95% CI (− 0.36)–(− 0.14)];
to − 7.70 [95% CI (− 14.90)–(− 0.50)] for DCI]). Treat- P = 0.37, I2 = 0%) were more efficacious than Met
ment with TZDs was less efficacious than Met (MD 3.90 alone. The NMA revealed that TZDs, Met + TZDs, and
[95% CI 1.10–6.71]). The SUCRA values were as follows: MI + DCI were all superior to Met (MDs ranging from
Met + BBR (92.2%), MI + DCI (75.4%), and Met + TZDs − 0.72 [95% CI (− 1.11)–(− 0.34)] for TZDs to − 0.89
(59.4%). No difference was found in comparisons of [95% CI (− 1.46)–(− 0.32)] for MI + DCI), with MI + DCI
SHBG, AND, and mF-G scores. being ranked the best with a SUCRA value of 80.8%. The
SUCRA values for the other agents were as follows: 79.9%
Obesity and 68.6% for Met + TZDs and TZDs, respectively.
With respect to BMI reduction, the TMA showed that
Met + BBR (MD − 1.85 [95% CI (− 2.76)–(− 0.94)]; Lipid levels
P = 0.32, I2 = 0%) was superior to Met monotherapy, Parameters assessed for improvement in blood lipids
whereas the NMA revealed that Met + BBR was more included TG, TC, HDL-C, and LDL-C. In terms of
efficacious than Met, MI, TZDs, and Met + TZDs (MDs reducing TG and TC levels, the TMA revealed that
As percentage (inten on-to-treat)

Overall Bias
Selec on of the reported result
Measurement of the outcome
Mising outcome data
Devia ons from intended interven ons
Randomiza on process
0 10 20 30 40 50 60 70 80 90 100
Low risk Some concerns High risk

Fig. 3 Risk of bias assessment in the RCTs
Table 2 (A) NMA and TMA results for menstrual frequency, total testosterone, BMI, and glycometabolism; (B) NMA and TMA results for
lipid levels and gastrointestinal adverse events
Outcomes Studies Participants Traditional pairwise meta-analysis (TMA) Network meta-analysis (NMA)
Heterogeneity Effect estimate (95% CI) Studies Effect estimate (95% CI)
(A)
Menstrual frequency
TZDs vs Met 6 299 (P = 0.002); I2 = 74% 1.17 [0.43, 3.17] 7 1.20 [0.52, 2.76]
TZDs + Met vs Met 3 167 (P = 0.88); I2 = 0% 3.91 [1.75, 8.72] 3 2.41 [0.75, 7.71]
MI vs Met 1 46 Not applicable 1.11 [0.24, 5.11] 4 0.89 [0.14, 5.56]
MI + DCI vs Met 1 64 Not applicable 11.67 [2.37, 57.36] 3 14.70 [2.31, 93.58]
MI + DCI vs MI 2 44 (P = 0.38); I2 = 0% 21.92 [2.99, 160.44] 3 16.51 [2.56, 106.64]
TT
TZDs vs Met 7 322 (P = 0.22); I2 = 27% 5.27 [0.98, 9.55] 8 3.90 [1.10, 6.71]
TZDs + Met vs Met 4 307 (P = 0.44); I2 = 0% − 3.14 [− 6.19, − 0.09] 4 − 3.66 [− 6.60, − 0.72]
MI vs Met 2 120 (P = 0.66); I2 = 0% 0.31 [− 0.69, 1.32] 6 0.37 [− 0.63, 1.37]
MI + DCI vs Met 1 64 Not applicable − 5.48 [− 10.27, − 0.69] 3 − 6.72 [− 10.24, − 3.20]
BBR + Met vs Met 2 140 (P = 1.00); I2 = 0% − 11.53 [− 16.91, − 6.15] 2 − 11.53 [− 16.91, − 6.15]
MI + DCI vs MI 2 72 (P = 0.63); I2 = 0% − 8.50 [− 13.60, − 3.40] 3 − 7.09 [− 10.62, − 3.56]
BMI
TZDs vs Met 8 322 (P = 0.42); I2 = 1% 1.26 [0.78, 1.75] 7 1.23 [0.75, 1.70]
TZDs + Met vs Met 4 171 (P = 0.68); I2 = 0% − 0.03 [− 1.02, 0.95] 3 0.22 [− 0.71, 1.14]
MI vs Met 5 279 (P = 0.47); I2 = 0% 0.28 [0.06, 0.50] 8 0.29 [0.09, 0.49]
MI + DCI vs Met / / / / 3 − 0.19 [− 1.61, 1.23]
BBR + Met vs Met 2 140 (P = 0.32); I2 = 0% − 1.85 [− 2.76, − 0.94] 2 − 1.85 [− 2.76, − 0.94]
MI + DCI vs MI 3 80 (P = 0.98); I2 = 0% − 0.48 [− 1.89, 0.93] 3 − 0.48 [− 1.89, 0.93]
FPG
TZD vs Met 7 272 (P < 0.00001); I2 = 86% − 0.10 [− 0.21, 0.01] 5 − 0.12 [− 0.21, − 0.02]
TZD + Met vs Met 5 307 (P = 0.79); I2 = 0% − 0.05 [− 0.15, 0.06] 5 0.00 [− 0.14, 0.15]
MI vs Met 3 173 (P = 0.22); I2 = 34% − 0.05 [− 0.12, 0.02] 5 − 0.05 [− 0.19, 0.09]
MI + DCI vs Met 1 64 Not applicable − 0.09 [− 0.17, − 0.01] 6 − 0.18 [− 0.37, 0.02]
MI + DCI vs MI 2 72 (P = 0.22); I2 = 35% − 0.25 [− 0.56, 0.05] 3 − 0.13 [− 0.33, 0.08]
FINS
TZDs vs Met 8 357 (P < 0.00001); I2 = 97% − 2.50 [− 6.23, 1.23] 7 − 2.38 [− 4.94, 0.19]
TZDs + Met vs Met 4 259 (P = 0.19); I2 = 37% − 1.83 [− 3.12, − 0.55] 4 − 2.56 [− 6.03, 0.92]
MI vs Met 3 173 (P = 0.23); I2 = 32% − 0.22 [− 0.75,0.32] 5 − 0.40 [− 4.08, 3.27]
MI + DCI vs Met 1 64 Not applicable − 1.37 [− 1.56, − 1.18] 3 − 1.38 [− 6.14, 3.38]
MI + DCI vs MI 2 72 (P = 0.36); I2 = 0% − 0.76 [− 1.94, 0.42] 3 − 0.98 [− 5.28, 3.33]
HOMA-IR
TZDs vs Met 6 317 (P < 0.00001); I2 = 97% − 0.92 [− 1.64, − 0.19] 4 − 0.72 [− 1.11, − 0.34]
TZDs + Met vs Met 4 259 (P = 0.04); I2 = 65% − 0.85 [− 1.21, − 0.49] 4 − 0.86 [− 1.29, − 0.43]
MI vs Met 4 219 (P = 0.004); I2 = 78% − 0.20 [− 0.42, 0.01] 6 − 0.28 [− 0.66, 0.10]
MI + DCI vs Met 1 64 Not applicable − 1.15 [− 1.25, − 1.05] 3 − 0.89 [− 1.46, − 0.32]
BBR + Met vs Met 2 140 (P = 0.37); I2 = 0% − 0.25 [− 0.36, − 0.14] 2 − 0.25 [− 0.81, 0.31]
MI + DCI vs MI 2 72 (P = 0.97); I2 = 0% − 0.39 [− 0.83, 0.06] 3 − 0.61 [− 1.18, − 0.05]
(B)
TG
TZDs vs Met 7 261 (P = 0.0002); I2 = 77% − 0.01 [− 0.19, 0.16] 7 − 0.66 [− 1.00, − 0.32]
TZDs + Met vs Met 3 178 (P = 0.74); I2 = 0% − 0.24 [− 0.43, − 0.06] 3 − 0.08 [− 0.16, − 0.00]
MI vs Met 3 173 (P = 0.60); I2 = 0% − 0.03 [− 0.06, 0.00] 3 0.14 [0.07, 0.21]
MI + DCI vs Met 1 64 Not applicable − 0.08 [− 0.16, − 0.00] 4 0.21 [− 0.26, 0.68]
TZDs + Met vs TZDs 2 88 (P = 0.10); I2 = 0% 0.15 [− 0.18, 0.48] 3 − 0.51 [− 0.88, − 0.14]
Table 2 (continued)
Outcomes Studies Participants Traditional pairwise meta-analysis (TMA) Network meta-analysis (NMA)
Heterogeneity Effect estimate (95% CI) Studies Effect estimate (95% CI)
TC
TZDs vs Met 8 346 (P < 0.00001); I2 = 93% − 0.06 [− 0.41, 0.29] 8 − 0.18 [− 0.46, 0.10]
TZDs + Met vs Met 3 178 (P = 0.98); I2 = 0% − 0.30 [− 0.53, − 0.07] 3 − 0.15 [− 0.57, 0.27]
MI vs Met 3 173 (P = 0.67); I2 = 0% 0.03 [− 0.01, 0.07] 3 0.19 [− 0.29, 0.66]
MI + DCI vs Met 1 64 Not applicable − 0.07 [− 0.16, 0.02] 4 − 0.07 [− 0.69, 0.55]
HDL
TZDs vs Met 8 346 (P < 0.00001); I2 = 96% 0.14 [− 0.03, 0.30] 8 0.13 [0.03, 0.24]
TZDs + Met vs Met 4 259 (P = 0.53); I2 = 0% − 0.00 [− 0.09, 0.09] 4 0.05 [− 0.10, 0.20]
MI vs Met 3 173 (P = 0.10); I2 = 57% 0.05 [0.03, 0.07] 3 0.02 [− 0.14, 0.17]
MI + DCI vs Met 1 64 Not applicable 0.00 [− 0.11, 0.11] 4 0.00 [− 0.28, 0.28]
LDL
TZDs vs Met 7 261 (P = 0.02); I2 = 59% − 0.11 [− 0.29, 0.08] 7 − 0.19 [− 0.27, − 0.11]
TZDs + Met vs Met 4 259 (P = 0.96); I2 = 0% − 0.10 [− 0.25, 0.05] 4 − 0.08 [− 0.24, 0.07]
MI vs Met 3 173 (P = 0.84); I2 = 0% 0.01 [− 0.03, 0.05] 3 0.01 [− 0.03, 0.05]
MI + DCI vs Met 1 64 Not applicable − 0.07 [− 0.21, 0.07] 4 − 0.07 [− 0.21, 0.07]
Gastrointestinal adverse events
TZDs vs Met 6 253 (P = 0.88); I2 = 0% 0.11 [0.03, 0.41] 6 0.13 [0.04, 0.46]
TZDs + Met vs Met 3 237 (P = 0.33); I2 = 11% 0.67 [0.23, 1.93] 3 0.76 [0.25,2.27]
MI vs Met 1 50 Not applicable 0.13 [0.01, 2.58] 1 0.13 [0.01, 2.58]
MI + DCI vs Met 1 64 Not applicable 0.08 [0.00, 1.45] 1 0.08 [0.00, 1.45]
BBR vs Met 1 60 Not applicable 3.10 [0.12, 79.23] 1 3.10 [0.12, 79.23]
Bolded results show statistical significance at the 0.05 level
Met Metformin, TZDs thiazolidinediones, MI myo-inositol, DCI d-chiro-inositol, BBR berberine, TT total testosterone, BMI body mass index, FPG fasting plasma glucose,
FINS fasting insulin, HOMA-IR Homeostatic Model Assessment of Insulin Resistance, TG triglyceride, TC total cholesterol, HDL-C high density lipoprotein cholesterol,
LDL-C low density lipoprotein cholesterol
Met + TZDs (TG: MD − 0.24 [95% CI (− 0.43)–(− 0.06)]; 0.03–0.41]; P = 0.88, I2 = 0%; NMA: OR 0.13 [95% CI
P = 0.74, I2 = 0%; TC: MD − 0.30 [95% CI (− 0.53)– 0.04–0.46]) was inferior to Met. With respect to the inci-
(− 0.07)]; P = 0.98, I2 = 0%) was more efficacious than dence of peripheral edema, the TMA revealed that TZDs
Met alone. In terms of reducing levels of TG, the NMA were more frequent than Met (OR 67.89 [95% CI 3.96,
showed that Met + TZDs was superior to Met (MD 1163.28]; P&I2 NA), no significant differences were found
− 0.08 [95% CI (− 0.16)–(0.00)]) and TZDs (MD − 0.51 in the NMA. Furthermore, both the TMA and NMA did
[95% CI (− 0.88)–(− 0.14)]), and was the best interven- not show any significant differences between the differ-
tion among treatments. The NMA also showed that BBR ent treatment regimens for the incidence rate of muscle
(MD − 0.03 [95% CI (− 0.06)–(0.00)]) was more effica- spasms, while no drug increased odds of transaminase
cious than Met. However, for TC no significant differ- abnormalities. Of note, these results should be inter-
ences were found in the NMA. preted with caution since results for MI, MI + DCI, and
Furthermore, the TMA also suggested that MI (MD BBR were based on a single trial, and in some of the tri-
0.05 [95% CI 0.03–0.07]; P = 0.10, I2 = 57%) was associ- als the description of adverse events was subjective and
ated with higher HDL-C than Met. The NMA revealed unclear.
that treatment with TZDs was superior to Met in increas-
ing HDL-C (MD 0.13 [95% CI 0.03–0.24]) and decreasing Discussion
LDL-C (MD − 0.19 [95% CI (− 0.27)–(− 0.11)]) and was To our knowledge, this is the first report on an NMA
the best intervention among the different treatments. used to assess the efficacy and safety of oral insulin sen-
sitizers (metformin, thiazolidinediones, inositol, and
Adverse events berberine) as an adjunct therapy to improve irregular
In terms of the frequency of gastrointestinal adverse menses, hyperandrogenism, and glucolipid metabolism
events during treatment, both TMA and NMA revealed abnormalities in women with PCOS. The results obtained
that treatment with TZDs (TMA: OR 0.11 [95% CI are based on 22 trials that included 1079 women,
randomly assigned to eight different interventions. Over- superior to Met monotherapy at reducing FINS and TC
all, treatment with MI + DCI was associated with the level. Our previous NMA in overweight women with
best improvement in menstrual frequency. MI + DCI, PCOS revealed that Met + TZDs was superior to Met in
Met + TZDs, and Met + BBR were superior to Met for recovering menstrual function, whereas there were no
TT reduction, while MI + DCI, Met + TZDs, and TZDs evident differences in TT and FINS [44]. Different inclu-
significantly lowered HOMA-IR than Met alone. TZDs sion criteria might explain these discrepancies. Addition-
were superior to Met in decreasing FPG, TG, LDL-C lev- ally, three RCTs reported gastrointestinal discomfort in
els, and increasing HDL-C level, while Met + TZDs was the Met + TZDs group [20, 21, 23], which was not signifi-
associated with lower TG levels compared to Met and cantly different than the Met alone group.
TZDs monotherapy. Furthermore, Met + BBR was more Inositol acts as a second messenger with insulin-like
efficacious than Met alone in reducing BMI. functions and is safe and well-tolerated [45]. The two
Metformin is a classic insulin sensitizer, that inhibits most common isomers of inositol are MI, which has been
hepatic glucose production, thereby decreasing glucose shown to significantly improve ovulatory function [46],
levels [39]. Many studies have already demonstrated its and DCI, which is able to reduce peripheral insulin resist-
ability to improve menstruation frequency, reduce andro- ance in patients with PCOS [47]. Our NMA is in line
gen excess, and decrease insulin resistance in PCOS. with other pairwise meta-analyses, showing that there is
However, it also often associated with gastrointestinal no apparent benefit of MI or DCI alone compared with
side effects, such as diarrhea, nausea, and abdominal dis- Met [48–50]. Recent studies have proposed that a com-
comfort [40]. In the current study, in four of the RCTs, bination of both MI and DCI, at a plasma ratio of 40:1,
a total of 12 women withdrew due to intolerance rising can restore normal hormonal function quicker than MI
from gastrointestinal side effects [14, 19, 23, 26]. There or DCI alone [51]. This is the first report on the analysis
were other reports of mild stomach discomfort that of efficacy of Met and MI + DCI in women with PCOS;
resolved spontaneously within a few weeks [13, 15, 16, it revealed that among all of the agents investigated here
18, 20, 21, 28]. MI + DCI appeared to be the best intervention for restor-
Thiazolidinediones (TZDs) decrease hepatic and ing regular menses and decreasing HOMA-IR, while the
peripheral insulin resistance directly through activa- combination was also able to reduce TT better than Met.
tion of the nuclear hormone receptor PPARγ and have No side effects have been described in clinical studies
a well-documented effect of improving hyperglyce- examining the effect of inositol [26, 44].
mia and dyslipidemia. TZDs also improve the men- Berberine (BBR), a natural isoquinoline alkaloid, has
strual cycle and ovulation and reduce androgen levels been studied in various randomized clinical trials in
in women with PCOS [41, 42]. However, these clinical patients with PCOS and has been shown to be safe and
benefits have largely been ignored due to safety issues promising for decreasing insulin resistance, lowering
and side effects, such as weight gain, peripheral edema, blood lipids, and restoring ovulation [52–55]. In the only
and even heart failure [43]. In our study, one trial with previous pairwise meta-analysis that compared Met,
pioglitazone showed 40% of women with mild periph- BBR, and their combination in insulin resistant patients
eral edema and 11% with muscle spasms [16], although with PCOS, there were no significant differences between
other adverse events were not found and gastrointestinal the different treatment groups [56]. In the current study,
adverse events were less frequent with TZDs than Met. only one trial that examined BBR and Met was included.
Furthermore, compared with that by Met, TZDs had a As seen from the NMA, BBR was superior to Met in
more beneficial effect on improving glucolipid metabo- reducing TG. Met + BBR was associated with a greater
lism; our NMA revealed that treatment with TZDs was reduction in TT and BMI than that by Met alone and
associated with lower FPG, TG, LDL-C levels, and higher was the best intervention among the investigated agents
HDL-C level. The SUCRA analysis revealed that treat- tested here. These findings should be interpreted with
ment with TZDs was the best (among these treatments) caution since they are based on data from only two head-
for decreasing LDL-C and increasing HDL-C, indicating to-head trials of low quality [33, 34]. Further high-quality
its potential ability to reduce a patients’ risk of cardiovas- trials to verify these potential favorable effects in PCOS
cular diseases in PCOS. are therefore required. One person in the berberine
Our NMA revealed that the combination of group withdrew due to gastrointestinal side effects [32].
Met + TZDs was more effective than Met alone at
improving menstruation frequency, and reducing TT, Strengths and limitations
HOMA-IR, and TG. The SUCRA value showed that Our findings reflect the comparative efficacy and safety
Met + TZDs was the best intervention for reducing TG of monotherapy versus a combination of different oral
level. The TMA also demonstrated that Met + TZDs was insulin sensitizers (metformin, thiazolidinediones,
inositol, and berberine) in the treatment of PCOS. Pre- Acknowledgements

Not applicable.
vious related meta-analyses have mainly been of pair-
wise design that focused on individual agents and have Authors’ contributions
given inconsistent results, our NMA incorporated both HZ, CX, JZ and BH conceived the study. HZ, CX and BH designed the study. HZ
wrote the study protocol and registered the study protocol. HZ, CX selected
direct and indirect comparisons of interventions into the articles and extracted the data. HZ and CX, JZ, and BH developed the
a single analysis and provided a ranking of the available statistical methods and analyzed the data. HZ wrote the first draft of the
interventions. Through a comprehensive search and a manuscript. BH critically checked its content and approved its final version. All
authors agreed with the results and conclusions of this article. All authors read
rigorous review of the design of the randomized clini- and approved the final manuscript.
cal trials, we aimed to reduce the likelihood of selection
bias. We focused on the analysis of menstrual and ovu- Funding
This work was supported by a grant from the National Natural Science Foun-
lation abnormalities, hyperandrogenism, obesity, glu- dation of China (Grant no. 81570765), and the 345 Talent Project of ShengJing
colipid metabolism, and adverse events in women with Hospital of China Medical University.
PCOS to provide a comprehensive reference for its clini-
Availability of data and materials
cal treatment. The datasets supporting the conclusions of this article are included within the
However, the present study still has some limitations article and its additional file.
that must be noted. First, very few literature reports met
the inclusion criteria of treatment without contraceptives Declarations
and/or intervention of ovulation inducing drugs to effec-
Ethics approval and consent to participate
tively verify the independent effects of drugs on efficacy. Not applicable.
Second, there were markedly different dosages, durations
of treatment, and small sample sizes that could contrib- Consent for publication
Not applicable.
ute to sample bias, selection bias, and high heterogene-
ity. Third, some of trials did not have a specific analysis of Competing interests
women who dropped out or missed a follow-up. The authors declare that they have no competing interests.
Received: 23 March 2021 Accepted: 17 July 2021

Conclusions
In conclusion, for women with PCOS, MI combined with
DCI and Met combined with TZDs appear to be supe-
rior than Met alone in improving insulin resistance and References
decreasing total testosterone. MI combined with DCI 1. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D,
Natterson-Horowtiz B, Teede HJ, Yildiz BO. Polycystic ovary syndrome.
appears to be particularly efficacious in menstrual recov- Nat Rev Dis Primers. 2016;267(2):2056–676. https://doi.org/10.1038/nrdp.
ery. TZDs and TZDs combined with Met seem to offer 2016.57.
the additional advantage of improving lipid metabolism. 2. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R.
Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil
However, our findings are limited by the small number Steril. 2016;106(1):6–15. https://doi.org/10.1016/j.fertnstert.2016.05.003.
and low quality of available studies, and therefore more 3. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T,
rigorous and high-level RCTs are needed to further guide Norman RJ, International PCOS Network. Recommendations from the
international evidence-based guideline for the assessment and manage-
the clinical management of women with PCOS, espe- ment of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364–79.
cially those with insulin resistance. https://doi.org/10.1016/j.fertnstert.2018.05.004.
4. Aversa A, La Vignera S, Rago R, Gambineri A, Nappi RE, Calogero AE,
Ferlin A. Fundamental concepts and novel aspects of polycystic ovarian
Abbreviations syndrome: expert consensus resolutions. Front Endocrinol (Lausanne).
PCOS: Polycystic ovary syndrome; Met: Metformin; TZDs: Thiazolidinediones; 2020;11:516. https://doi.org/10.3389/fendo.2020.00516.
MI: Myo-inositol; DCI: D-chiro-inositol; BBR: Berberine; TT: Total testosterone; 5. McCartney CR, Marshall JC. CLINICAL PRACTICE. Polycystic Ovary Syn-
SHBG: Sex hormone binding globulin; AND: Androstenedione; mF-Gscore: drome. N Engl J Med. 2016;375(1):54–64. https://doi.org/10.1056/NEJMc
Modified Ferriman–Gallwey score; BMI: Body mass index; WHR: Waist–hip ratio; p1514916
FPG: Fasting plasma glucose; FINS: Fasting insulin; HOMA-IR: Homeostatic 6. Renato P. Metformin in women with PCOS, Pros. Endocrine.
Model Assessment of Insulin Resistance; TG: Triglyceride; TC: Total cholesterol; 2015;48(2):422–6. https://doi.org/10.1007/s12020-014-0311-1.
HDL-C: High density lipoprotein cholesterol; LDL-C: Low density lipoprotein 7. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred
cholesterol. reporting items for systematic reviews and meta-analyses: the PRISMA
statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journ
al.pmed.1000097.
Supplementary Information 8. Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO
The online version contains supplementary material available at https://doi. framework to improve searching PubMed for clinical questions. BMC Med
org/10.1186/s12978-021-01207-7. Inform Decis Mak. 2007;7:16. https://doi.org/10.1186/1472-6947-7-16.
9. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Group. Revised 2003 consensus on diagnostic criteria and long-term
Additional file 1: Appendix S1. Details on study methods. health risks related to polycystic ovary syndrome (PCOS). Hum Reprod.
2004;19(1):41–7. https://doi.org/10.1093/humrep/deh098.
10. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale randomized controlled clinical trial. Gynecol Endocrinol. 2019;35(5):406–
HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel 11. https://doi.org/10.1080/09513590.2018.1540570.
SF, Androgen Excess Society. Positions statement: criteria for defining 26. Fruzzetti F, Perini D, Russo M, Bucci F, Gadducci A. Comparison of two
polycystic ovary syndrome as a predominantly hyperandrogenic syn- insulin sensitizers, metformin and myo-inositol, in women with polycystic
drome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. ovary syndrome (PCOS). Gynecol Endocrinol. 2017;33(1):39–42. https://
2006;91(11):4237–45. https://doi.org/10.1210/jc.2006-0178. doi.org/10.1080/09513590.2016.1236078.
11. Chinese Endocrinologist Association, Chinese Medical Doctor Associa- 27. Nehra J, Kaushal J, Singhal SR, Ghalaut VS. A comparative study of myo
tion. Endocrinologist consensus on the management of polycystic ovary inositol versus metformin on biochemical profile in polycystic ovarian
syndrome. Chin J Endocrinol Metab. 2018;34(1):1–7. https://doi.org/10. syndrome in women. Int J Pharm Res. 2017;8(4):1664–70. https://doi.org/
3760/cma.j.issn.1000-6699.2018.01.001. 10.13040/IJPSR.0975-8232.8(4).1664-70.
12. Zawadri J. Diagnostic criteria for polycystic ovary syndrome: towards a 28. Du J, Wu RR, Lin XF, Ke WN, Du Y. Clinical effect of myo-inositol combined
rational approach. Polycystic ovary syndrome. Current issues in endocri- with D-chiro-inositol on insulin resistant polycystic ovary syndrome.
nology and metabolism. 1992. China Med. 2018;13(9):1389–93. https://doi.org/10.3760/j.issn.1673-4777.
13. Ahmad J, Shukla N, Khan AR, Ahmed F, Siddiqui MA. Comparison of 2018.09.027.
metabolic effects of metformin and rosiglitazone in the management of 29. Pizzo A, Laganà AS, Barbaro L. Comparison between effects of myo-
polycystic ovary syndrome [PCOS]: a prospective, parallel, randomized, inositol and D-chiro-inositol on ovarian function and metabolic factors in
open-label study. Diabetes Metab Syndr. 2008;2(1):37–46. https://doi.org/ women with PCOS. Gynecol Endocrinol. 2014;30:205–8. https://doi.org/
10.1016/j.dsx.2007.12.003. 10.3109/09513590.2013.860120.
14. Mohiyiddeen L, Watson AJ, Apostolopoulos NV, Berry R, Alexandraki KI, 30. Le Donne M, Metro D, Alibrandi A, Papa M, Benvenga S. Effects of three
Jude EB. Effects of low-dose metformin and rosiglitazone on biochemi- treatment modalities (diet, myoinositol or myoinositol associated
cal, clinical, metabolic and biophysical outcomes in polycystic ovary with D-chiro-inositol) on clinical and body composition outcomes in
syndrome. J Obstet Gynaecol. 2013;33(2):165–70. https://doi.org/10.3109/ women with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci.
01443615.2012.745839. 2019;23:2293–301. https://doi.org/10.26355/eurrev_201903_17278.
15. Yilmaz M, Bukan N, Ayvaz G, Karakoç A, Törüner F, Cakir N, Arslan M. The 31. Nordio M, Proietti E. The combined therapy with myo-inositol and
effects of rosiglitazone and metformin on oxidative stress and homocyst- D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight
eine levels in lean patients with polycystic ovary syndrome. Hum Reprod. patients compared to myo-inositol supplementation alone. Eur Rev Med
2005;20(12):3333–40. https://doi.org/10.1093/humrep/dei258. Pharmacol Sci. 2012;16:575–81.
16. Sangeeta S. Metformin and pioglitazone in polycystic ovarian syndrome: 32. Li XB, Kuang H, Luo Y, Chen QX. Clinical observation of berberine in
a comparative study. J Obstet Gynaecol India. 2012;62(5):551–6. https:// intervening insulin resistance of polycystic ovary syndrome. J Guangzhou
doi.org/10.1007/s13224-012-0183-3. Univ Tradit Chin Med. 2017;1(2):172–7. https://doi.org/10.13359/j.cnki.
17. Naka KK, Kalantaridou SN, Kravariti M, Bechlioulis A, Kazakos N, Calis gzxbtcm.2017.02.006.
KA, Makrigiannakis A, Katsouras CS, Chrousos GP, Tsatsoulis A, Micha- 33. Wang P, Wang H, Wang Y. Clinical analysis of metformin combined with
lis LK. Effect of the insulin sensitizers metformin and pioglitazone on berberine in the treatment of obese polycystic ovary syndrome. Chin
endothelial function in young women with polycystic ovary syndrome: a Prim Health Care. 2016;30:77–8. https://doi.org/10.3969/j.issn.1001-568X.
prospective randomized study. Fertil Steril. 2011;95(1):203–9. https://doi. 2016.10.0032.
org/10.1016/j.fertnstert.2010.06.058. 34. Wang LX, Kong YZ, Ren YW, Shen M. Therapeutic effect of berberine
18. Jensterle M, Sebestjen M, Janez A, Prezelj J, Kocjan T, Keber I, Pfeifer M. combined with dfformin for women with polycystic ovary syndrome and
Improvement of endothelial function with metformin and rosiglitazone insulin resistance. J Zhejiang Chin Med Univ. 2011;5:713–5. https://doi.
treatment in women with polycystic ovary syndrome. Eur J Endocrinol. org/10.3969/j.issn.1005-5509.2011.05.034.
2008;159(4):399–406. https://doi.org/10.1530/EJE-08-0507. 35. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates
19. Ortega-González C, Cardoza L, Coutiño B, Hidalgo R, Arteaga-Troncoso G, CJ, Cheng H-Y, Corbett MS, Eldridge SM, Emberson JR, Hernán MA,
Parra A. Insulin sensitizing drugs increase the endogenous dopaminergic Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson
tone in obese insulin-resistant women with polycystic ovary syndrome. J T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K,
Endocrinol. 2005;184(1):233–9. https://doi.org/10.1677/joe.1.05844. White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of
20. Zeng H, Huang Y, Wu J, Xie TQ, Liu DK, Huang QL, Chen Z, Liu JP. Effects bias in randomised trials. BMJ. 2019;366:l4898. https://doi.org/10.1136/
of pioglitazone hydrochloride and metformin hydrochloride tablets on bmj.l4898.
metabolic parameters and hormones in polycystic ovary syndrome. Prog 36. Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence synthesis for decision
Obstet Gynecol. 2020;29(11):7–10. https://doi.org/10.13283/j.cnki.xdfckjz. making 2: a generalized linear modeling framework for pairwise and
2020.11.031. network meta-analysis of randomized controlled trials. Med Decis Mak.
21. Wang X, Gao S, Zhang X. Metformin and pioglitazone plus metformin for 2013;33(5):607–17. https://doi.org/10.1177/0272989X12458724.
patients with polycystic ovary syndrome combined with insulin resist- 37. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from
ance. Cent South Pharm. 2014. https://doi.org/10.7539/j.issn.1672-2981. the median, range, and the size of a sample. BMC Med Res Methodol.
2014.02.023. 2005;5:13. https://doi.org/10.1186/1471-2288-5-13.
22. Liang N, Zhang Z. Effects of metformin and pioglitazone on sexual hor- 38. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical sum-
mones and metabolic level in patients with polycystic ovary syndrome. maries for presenting results from multiple-treatment meta-analysis: an
Guangxi Med J. 2019;41:148–52. https://doi.org/10.11675/j.issn.0253- overview and tutorial. J Clin Epidemiol. 2011;64(2):163–71. https://doi.
4304.2019.02.02. org/10.1016/j.jclinepi.2010.03.016.
23. Sohrevardi SM, Nosouhi F, Hossein Khalilzade S, Kafaie P, Karimi-Zarchi M, 39. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN.
Halvaei I, Mohsenzadeh M. Evaluating the effect of insulin sensitizers met- Metformin: an old medication of new fashion: evolving new molecular
formin and pioglitazone alone and in combination on women with poly- mechanisms and clinical implications in polycystic ovary syndrome. Eur J
cystic ovary syndrome: an RCT. Int J Reprod Biomed. 2016;14(12):743–54. Endocrinol. 2010;162(2):193–212. https://doi.org/10.1530/EJE-09-0733.
24. Jamilian M, Farhat P, Foroozanfard F, Afshar Ebrahimi F, Aghadavod E, 40. Rena G, Hardie DG, Pearson ER. The mechanisms of action of met-
Bahmani F, Badehnoosh B, Jamilian H, Asemi Z. Comparison of myo- formin. Diabetologia. 2017;60(9):1577–85. https://doi.org/10.1007/
inositol and metforminon clinical, metabolic and genetic parameters in s00125-017-4342-z.
polycystic ovary syndrome: a randomized controlled clinical trial. Clin 41. Macut D, Bjekić-Macut J, Rahelić D, Doknić M. Insulin and the polycystic
Endocrinol. 2017;87(2):194–200. https://doi.org/10.1111/cen.13366. ovary syndrome. Diabetes Res Clin Pract. 2017;130:163–70. https://doi.
25. Shokrpour M, Foroozanfard F, Afshar Ebrahimi F, Vahedpoor Z, Aghadavod org/10.1016/j.diabres.2017.06.011.
E, Ghaderi A, Asemi Z. Comparison of myo-inositol and metformin on 42. Panunzi S, Maltese S, Verrastro O, Labbate L, De Gaetano A, Pompili M,
glycemic control, lipid profiles, and gene expression related to insulin Capristo E, Bornstein SR, Mingrone G. Pioglitazone and bariatric surgery
and lipid metabolism in women with polycystic ovary syndrome: a are the most effective treatments for non-alcoholic steatohepatitis: a
hierarchical network meta-analysis. Diabetes Obes Metab. 2020. https:// Gynecol Endocrinol. 2018;34(7):545–50. https://doi.org/10.1080/09513
doi.org/10.1111/dom.14304.10.1111/dom.14304. 590.2017.1421632.
43. Lebovitz HE. Thiazolidinediones: the forgotten diabetes medica- 52. Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H, Ma Y, Zhang Y, Zhang
tions. Curr Diabetes Rep. 2019;19(12):151. https://doi.org/10.1007/ H, Guan Y. A clinical study on the short-term effect of berberine in com-
s11892-019-1270-y. parison to metformin on the metabolic characteristics of women with
44. Xing C, Li CZ, He B. Insulin sensitizers for improving the endocrine and polycystic ovary syndrome. Eur J Endocrinol. 2012;166(1):99–105. https://
metabolic profile in overweight women with PCOS. J Clin Endocrinol doi.org/10.1530/EJE-11-0616.
Metab. 2020;105(9):2950–63. https://doi.org/10.1210/clinem/dgaa337. 53. Rondanelli M, Infantino V, Riva A, Petrangolini G, Faliva MA, Peroni G,
45. Sortino MA, Salomone S, Carruba MO, Drago F. Polycystic ovary Naso M, Nichetti M, Spadaccini D, Gasparri C, Perna S. Polycystic ovary
syndrome: insights into the therapeutic approach with inositols. Front syndrome management: a review of the possible amazing role of ber-
Pharmacol. 2017;8:341. https://doi.org/10.3389/fphar.2017.00341. berine. Arch Gynecol Obstet. 2020;301(1):53–60. https://doi.org/10.1007/
46. Bevilacqua A, Bizzarri M. Inositols in insulin signaling and glucose metab- s00404-020-05450-4.
olism. Int J Endocrinol. 2018;2018:1968450. https://doi.org/10.1155/2018/ 54. Ju J, Li J, Lin Q, Xu H. Efficacy and safety of berberine for dyslipidaemias:
1968450. a systematic review and meta-analysis of randomized clinical trials.
47. Ravanos K, Monastra G, Pavlidou T, Goudakou M, Prapas N. Can high Phytomedicine. 2018;50:25–34. https://doi.org/10.1016/j.phymed.2018.
levels of D-chiro-inositol in follicular fluid exert detrimental effects on 09.212.
blastocyst quality? Eur Rev Med Pharmacol Sci. 2017;21(23):5491–8. 55. Xie L, Zhang D, Ma H, He H, Xia Q, Shen W, Chang H, Deng Y, Wu Q, Cong
https://doi.org/10.26355/eurrev_201712_13940. J, Wang CC, Wu X. The effect of berberine on reproduction and metabo-
48. Facchinetti F, Orrù B, Grandi G, Unfer V. Short-term effects of metformin lism in women with polycystic ovary syndrome: a systematic review
and myo-inositol in women with polycystic ovarian syndrome (PCOS): and meta-analysis of randomized control trials. Evid Based Complement
a meta-analysis of randomized clinical trials. Gynecol Endocrinol. Altern Med. 2019. https://doi.org/10.1155/2019/7918631.
2019;35(3):198–206. https://doi.org/10.1080/09513590.2018.1540578. 56. Li MF, Zhou XM, Li XL. The effect of berberine on polycystic ovary syn-
49. Arentz S, Smith CA, Abbott J, Bensoussan A. Nutritional supplements drome patients with insulin resistance (PCOS-IR): a meta-analysis and sys-
and herbal medicines for women with polycystic ovary syndrome; a tematic review. Evid Based Complement Altern Med. 2018;2018:2532935.
systematic review and meta-analysis. BMC Complement Altern Med. https://doi.org/10.1155/2018/2532935.
2017;17(1):500. https://doi.org/10.1186/s12906-017-2011-x.
50. Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin-sensitising
drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for Publisher’s Note
women with polycystic ovary syndrome, oligo amenorrhoea and subfer- Springer Nature remains neutral with regard to jurisdictional claims in pub-
tility. Cochrane Database Syst Rev. 2017;11(11):CD003053. https://doi.org/ lished maps and institutional affiliations.
10.1002/14651858.CD003053.pub6.
51. Gateva A, Unfer V, Kamenov Z. The use of inositol(s) isomers in the
management of polycystic ovary syndrome: a comprehensive review.
Ready to submit your research ? Choose BMC and benefit from:
• fast, convenient online submission

• thorough peer review by experienced researchers in your field
• rapid publication on acceptance
• support for research data, including large and complex data types
• gold Open Access which fosters wider collaboration and increased citations
• maximum visibility for your research: over 100M website views per year
At BMC, research is always in progress.
Learn more biomedcentral.com/submissions

BMC

Uploaded by

Copyright:

Available Formats

BMC

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

BMC

Uploaded by

Copyright:

Available Formats

Zhao et al.

Reprod Health (2021) 18:171

RESEARCH Open Access

Comparative efficacy of oral insulin

Plain English summary

Background Materials and methods

Outcomes a summary statistic for cumulative ranking. The efficacy

Table 1 Characteristics of studies included in the network meta-analysis

Met + Pio 500 mg + 30 mg tid 23

Met + Pio 500 mg + 30 mg tid/qd 23

Menstrual frequency Hyperandrogenism

ranging from − 1.85 [95% CI (− 2.76)–(− 0.94)] for

As percentage (inten on-to-treat)

Selec on of the reported result

Measurement of the outcome

Mising outcome data

Devia ons from intended interven ons

Low risk Some concerns High risk

inositol, and berberine) in the treatment of PCOS. Pre- Acknowledgements

Received: 23 March 2021 Accepted: 17 July 2021

Ready to submit your research ? Choose BMC and benefit from:

• fast, convenient online submission

At BMC, research is always in progress.

Learn more biomedcentral.com/submissions

You might also like