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Tang 2012
Tang 2012
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 5
http://www.thecochranelibrary.com
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
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ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 3.
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Figure 4.
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Figure 5.
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Figure 6.
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Figure 7.
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Figure 8.
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Figure 9.
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ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Metformin versus placebo or no treatment, Outcome 1 Live birth rate. . . . . . .
Analysis 1.2. Comparison 1 Metformin versus placebo or no treatment, Outcome 2 Adverse events (gastrointestinal side
effects). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Metformin versus placebo or no treatment, Outcome 3 Clinical pregnancy rate. . . .
Analysis 1.4. Comparison 1 Metformin versus placebo or no treatment, Outcome 4 Ovulation rate. . . . . . .
Analysis 1.5. Comparison 1 Metformin versus placebo or no treatment, Outcome 5 Menstrual frequency. . . . .
Analysis 1.6. Comparison 1 Metformin versus placebo or no treatment, Outcome 6 Miscarriage rate. . . . . . .
Analysis 1.7. Comparison 1 Metformin versus placebo or no treatment, Outcome 7 Body Mass Index (kg/m2). . .
Analysis 1.8. Comparison 1 Metformin versus placebo or no treatment, Outcome 8 Waist-hip ratio. . . . . . .
Analysis 1.9. Comparison 1 Metformin versus placebo or no treatment, Outcome 9 Blood pressure - systolic (mm Hg).
Analysis 1.10. Comparison 1 Metformin versus placebo or no treatment, Outcome 10 Blood pressure - diastolic (mm
Hg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.11. Comparison 1 Metformin versus placebo or no treatment, Outcome 11 Serum testosterone (nmol/L).
Analysis 1.12. Comparison 1 Metformin versus placebo or no treatment, Outcome 12 Serum sex hormone-binding
globulin (nmol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.13. Comparison 1 Metformin versus placebo or no treatment, Outcome 13 Fasting glucose (mmol/L). .
Analysis 1.14. Comparison 1 Metformin versus placebo or no treatment, Outcome 14 Fasting insulin (mIU/L). . .
Analysis 1.15. Comparison 1 Metformin versus placebo or no treatment, Outcome 15 Total cholesterol (mmol/l). .
Analysis 1.16. Comparison 1 Metformin versus placebo or no treatment, Outcome 16 Triglyceride levels (mmol/L). .
Analysis 2.1. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 1 Live birth rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.2. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 2 Adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.3. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 3 Clinical pregnancy rate. . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.4. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 4 Ovulation rate (grouped by sensitivity to clomiphene). . . . . . . . . . . . . . . .
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Analysis 2.5. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 5 Ovulation rate (grouped by BMI). . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.6. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 6 Miscarriage rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.7. Comparison 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone,
Outcome 7 Multiple pregnancy rate. . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Metformin versus clomiphene citrate, Outcome 1 Live birth: Participants with BMI < 30kg/m2
or 32kg/m2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Metformin versus clomiphene citrate, Outcome 2 Live birth: Participants with BMI
30kg/m2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Metformin versus clomiphene citrate, Outcome 3 Clinical pregnancy rate. . . . . .
Analysis 3.4. Comparison 3 Metformin versus clomiphene citrate, Outcome 4 Ovulation rate. . . . . . . . .
Analysis 3.5. Comparison 3 Metformin versus clomiphene citrate, Outcome 5 Miscarriage rate. . . . . . . . .
Analysis 3.6. Comparison 3 Metformin versus clomiphene citrate, Outcome 6 Multiple pregnancy. . . . . . .
Analysis 4.1. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 1 Ovulation. . . . . . .
Analysis 4.2. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 2 Body Mass Index (kg/m2).
Analysis 4.3. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 3 Waist-hip ratio. . . . .
Analysis 4.4. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 4 Blood pressure - systolic (mm
Hg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.5. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 5 Blood pressure - Diastolic (mm
Hg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.6. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 6 Serum testosterone (nmol/L).
Analysis 4.7. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 7 Serum sex hormone-binding
globulin (nmol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.8. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 8 Fasting glucose (mmol/L). .
Analysis 4.9. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 9 Fasting insulin (mIU/L). .
Analysis 4.10. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 10 Cholesterol (mmol/L). .
Analysis 4.11. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 11 Triglyceride levels (mmol/L).
Analysis 5.1. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 1 Ovulation rate. . . . . .
Analysis 5.2. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 2 Menstrual frequency. . . .
Analysis 5.3. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 3 Body Mass Index (kg/m2). .
Analysis 5.4. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 4 Waist-hip ratio. . . . . .
Analysis 5.5. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 5 Blood pressure-systolic (mm Hg).
Analysis 5.6. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 6 Blood pressure-diastolic (mm
Hg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.7. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 7 Testoserone (nmo/l).
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Analysis 5.8. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 8 serum sex hormone-binding globulin
(nmol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.9. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 9 Fasting glucose (mmol/L). . .
Analysis 5.10. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 10 Fasting insulin (mIU/L). .
Analysis 5.11. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 11 Cholesterol. . . . . . .
Analysis 5.12. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 12 Triglyceride levels. . . .
Analysis 6.1. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 1 Menstrual frequency. . . . .
Analysis 6.2. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 2 Body Mass Index (kg/m2). . .
Analysis 6.3. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 3 Waist-hip ratio. . . . . . .
Analysis 6.4. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 4 Serum testosterone (nmol/L). .
Analysis 6.5. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 5 Serum sex hormone-binding globulin
(nmol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 6.6. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 6 Fasting insulin (mIU/L).
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ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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CONTRIBUTIONS OF AUTHORS . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
INDEX TERMS
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Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
iii
[Intervention Review]
and Gynaecology, Bradford Teaching Hospitals NHS Trust, Bradford, UK. 2 Royal Cornwall Hospital, Peninsula Medical
School, Truro, UK. 3 Obstetrics & Gynaecology, Robinson Institute, University of Adelaide, Adelaide, Australia. 4 Reproductive Medicine
Unit, Clarendon Wing, The General Infirmary of Leeds, Leeds, UK. 5 Reproductive Medicine and Surgery, United Leeds Teaching
Hospitals, Leeds, UK
Contact address: Adam H Balen, Reproductive Medicine and Surgery, United Leeds Teaching Hospitals, RMU, Clarendon Wing,
Leeds general Infirmary, Leeds, LS29NS, UK. Adam.balen@leedsth.nhs.uk.
ABSTRACT
Background
Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation (anovulation), high levels of male hormones
(hyperandrogenaemia) and high levels of insulin (hyperinsulinaemia secondary to increased insulin resistance). Hyperinsulinaemia is
associated with an increase in cardiovascular risk and the development of diabetes mellitus. Insulin-sensitising agents such as metformin
may be effective in treating the features of PCOS, including anovulation.
Objectives
To assess the effectiveness of insulin-sensitising drugs in improving reproductive outcomes and metabolic parameters for women with
PCOS.
Search methods
We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (October 2011), the Cochrane Central Register
of Controlled Trials (CENTRAL) (The Cochrane Library, 3rd Quarter 2011), CINAHL (October 2011), MEDLINE (January 1966
to October 2011), and EMBASE (January 1985 to October 2011).
Selection criteria
Randomised controlled trials of insulin sensitising drugs compared with either placebo, no treatment, or an ovulation induction agent
for women with PCOS, menstrual disturbance and subfertility.
Data collection and analysis
Two review authors independently assessed studies for inclusion and trial quality, and extracted data.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
Forty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women.
There was no evidence that metformin improved live birth rates, whether it was used alone (pooled OR 1.80, 95% CI 0.52 to 6.16,
3 trials, 115 women) or in combination with clomiphene (pooled OR 1.16, 95% CI 0.85 to 1.56, 7 trials, 907 women). However,
clinical pregnancy rates were improved for metformin versus placebo (pooled OR 2.31, 95% CI 1.52 to 3.51, 8 trials, 707 women)
and for metformin and clomiphene versus clomiphene alone (pooled OR 1.51, 95% CI 1.17 to 1.96, 11 trials, 1208 women). In the
studies that compared metformin and clomiphene alone, there was evidence of an improved live birth rate (pooled OR 0.3, 95% CI
0.17 to 0.52, 2 trials, 500 women) and clinical pregnancy rate (pooled OR 0.34, 95% 0.21 to 0.55, 2 trials, 500 women) in the group
of obese women who took clomiphene.
Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (pooled OR 4.27,
95% CI 2.4 to 7.59, 5 trials, 318 women) but no serious adverse effects were reported.
Authors conclusions
In agreement with the previous review, metformin was associated with improved clinical pregnancy but there was no evidence that
metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene.
Therefore, the role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Metformin compared to placebo or no treatment for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Patient or population: Women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Settings:
Intervention: Metformin
Comparison: placebo or no treatment
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)
Comments
Corresponding risk
69 per 1000
OR 1.8
(0.52 to 6.16)
115
(3 studies)
low1,2
OR 2.31
(1.52 to 3.51)
707
(8 studies)
moderate1
Ovulation rate
OR 1.81
(1.13 to 2.93)
1208
(15 studies)
low3
Miscarriage rate
42 per 1000
16 per 1000
(4 to 61)
OR 0.36
(0.09 to 1.47)
279
(3 studies)
moderate4
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
There was lack of clarity around attrition bias in the majority of trials
The summary effect crossed the line of no effect and substantive benefit or harm
3 The majority of trials demonstrated lack of clarity on attrition and reporting biases. Allocation concealment was unclear in seven of
fifteen trials.
4
One of the three trials demonstrated lack of clarity on all measures of bias
2
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BACKGROUND
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
OBJECTIVES
To assess the effectiveness of insulin-sensitising drugs in improving
reproductive outcomes and metabolic parameters for women with
PCOS.
METHODS
Types of studies
Randomised controlled trials (RCTs). Quasi RCTs were not included. Crossover studies were included but only data from the
first phase will be included in meta-analyses.
Types of participants
Women with oligo and anovulatory PCOS based on the diagnostic
criteria set by the Rotterdam consensus (ESHRE /ASRM 2004).
Types of interventions
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hyperinsulinaemia
Primary outcomes
Electronic searches
Secondary outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Odds ratio (OR), with 95% confidence interval, was used as the
measure of effect for each dichotomous outcome using the MantelHaenszel method; whilst continuous outcome differences between
the two groups were presented as mean difference (MD) with 95%
confidence interval. A fixed-effect model was initially employed in
the analysis, unless a significant heterogeneity occurred; a randomeffects model analysis was used in order to account for the extra
uncertainty due to heterogeneity.
A funnel plot was used to assess publication bias.
Details of abbreviations used in this review and conversion factors
of biochemical results can be found in Table 1 and Table 2, respectively.
Subgroup analysis and investigation of heterogeneity
In order to reduce heterogeneity in the analysis, where possible
studies were divided into obese and non-obese groups. Obese was
defined as BMI equal to or over () 30 kg/m2 (or in the case of
PCOSMIC 2010 >32 kg/m2 ). Non-obese was defined as mean
BMI under (<) 30 kg/m2 (or in the case of PCOSMIC 2010, equal
to or under ()32 kg/m2 ).
Sensitivity analysis
Assessment of heterogeneity
Heterogeneity reflects any type of variability among the studies in
a systematic review. A consistent treatment effect among the included studies suggests there is sufficient homogeneity for pooled
analysis. The I2 statistic is used to quantify the inconsistency
among the studies, with a value < 25% indicating low heterogeneity; the ranges 25% to 50% and over 75% suggest moderate and
high heterogeneity, respectively.
RESULTS
Description of studies
Data synthesis
Statistical analyses were performed according to the statistical
guidelines for review authors developed by The Cochrane Collaboration and published in the Cochrane Handbook for Systematic
Reviews of Interventions. All the statistical analyses were performed
by using Review Manager Version 5, provided by the Cochrane
Menstrual Disorders and Subfertility Group.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
11
In the first review (Lord 2003), 24 RCTs met the initial eligibility
criteria. Nine studies were excluded, leaving 15 to be included in
the analysis.
In the first updated search period (January 2003 to September
2008), 37 RCTs were identified and 17 were subsequently excluded (Tang 2009). Four studies included in the first review were
excluded (Azziz 2001; Kocak 2002; Nestler 1996; Pasquali 2000).
Including the studies in the first review (Lord 2003) (n = 11, total
as amended), a total of 31 studies were included in the analysis in
the first updated review (Tang 2009) (Figure 3).
In the current second updated search period (October 2008 to
October 2011), 15 studies were identified but four were excluded
and one is awaiting classification (Studies awaiting classification).
Therefore, 10 new studies were identified in this search period (Ben
Ayed 2009; Boudhraa 2010; Karimzadeh 2010; Ladson 2011;
Lam 2011; Otta 2010; PCOSMIC 2010; Romualdi 2010; Siebert
2009; Williams 2009) (Figure 3).
After further consideration, five previously excluded studies were
re-included in this updated review (Brettenthaler 2004; Carmina
2004; Khorram 2006; Pasquali 2000; Sahin 2004). Furthermore,
we re-classified two publications (Rautio 2006a; Rautio 2006b) in
the first updated review (Tang 2009) into a single study (Rautio
2006) in this second updated review. We also removed Kelly
2002, which was in the first updated review (Tang 2009), after
a protocol update for this review (we removed hirsutism from
secondary outcomes). Hence, a total of 44 studies were included
in the current analysis (Figure 3).
Included studies
Nine out of the 10 newly included studies (Ben Ayed 2009;
Boudhraa 2010; Karimzadeh 2010; Ladson 2011; Otta 2010;
PCOSMIC 2010; Romualdi 2010; Siebert 2009; Williams 2009)
from this new search period (between October 2008 and October
2011) assessed the benefits of using metformin for women with
PCOS. The remaining study (Lam 2011) investigated the the
effects of rosiglitazone on women with PCOS.
In total, including the first review and the last update (Lord 2003;
Tang 2009), 38 out of 44 trials assessed the benefits of using metformin for women with PCOS. One of the 38 trials compared metformin and rosiglitazone groups with a placebo group (Baillargeon
2004). Furthermore, two studies (Maciel 2004; Onalan 2005) subdivided the data analysis into obese and non-obese groups. These
results were entered separately in our meta-analysis. We also entered the data from Hoeger 2004 separately in the analysis (metformin versus placebo; metformin versus lifestyle).
The remaining six included studies investigated the effects of the
other insulin-sensitising drugs (two rosiglitazone, two pioglitazone, two D-chiro-inositol).
The majority of the included studies (33) were double blinded,
Participants
The number of women in the studies ranged from 16 to 626. In
total, 3992 women (3495 metformin, 497 other insulin-sensitising drugs) were included in this updated review; 58% had a mean
BMI over 30 kg/m2 (range 24.3 to 39.4 kg/m2 ).
All the women had a menstrual cycle length over 35 days. The
age range of the women was between 24.2 and 32.8 years with
the range of fasting insulin concentrations between 6.3 and 54.67
mIU/l and testosterone levels between 1.3 and 4.67 nmol/l.
Most women recruited in the studies using rosiglitazone, pioglitazone or D-chiro-inositol (Rautio 2006; Glintborg 2005; Glintborg
2005; Brettenthaler 2004 Lam 2011) were not planning a pregnancy due to the uncertainty of the safety of using these products
in pregnancy.
Interventions
Eighteen trials compared metformin alone with placebo or no
treatment (Baillargeon 2004; Carmina 2004; Fleming 2002;
Hoeger 2004; Jakubowicz 2001; Karimzadeh 2007; Karimzadeh
2010; Ladson 2011; Lord 2006; Nestler 1998; Ng 2001; Onalan
2005; Otta 2010; Pasquali 2000; PCOSMIC 2010; Tang 2006;
Vandermolen 2001; Yarali 2002) whilst 19 studies investigated
the benefits of using metformin combined with clomiphene on
reproductive outcomes (Ben Ayed 2009; Boudhraa 2010; El-Biely
2001; Hwu 2005; Jakubowicz 2001; Karimzadeh 2010; Khorram
2006; Legro 2007; Malkawi 2002; Moll 2006; Nestler 1998;
Ng 2001; PCOSMIC 2010; Sahin 2004; Siebert 2009; Sturrock
2002; Vandermolen 2001; Williams 2009; Zain 2009). Five studies compared metformin with clomifene (Karimzadeh 2010; Legro
2007; Palomba 2005; PCOSMIC 2010; Zain 2009).
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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12
Allocation
Sequence generation
Sequence generation was unclear in 15 studies (Ben Ayed 2009;
Boudhraa 2010; Brettenthaler 2004; Carmina 2004; Jakubowicz
2001; Karimzadeh 2010; Malkawi 2002; Moghetti 2000; Nestler
1998; Nestler 1999; Romualdi 2010; Sahin 2004; Sturrock 2002;
Williams 2009; Zain 2009).
Excluded studies
In the current second updated search period, between October
2008 and October 2011, two studies were excluded as they were
not randomised (Aroda 2009; Santonocito 2009).
In total, 20 studies were excluded in this updated review.
Mantzoros 1997; Azziz 2001; Azziz 2003; Dunaif 1996 were excluded as troglitazone has been withdrawn from the market. As the
effect on hirsutism has been removed from the outcome measure
in the current revised protocol, Kelly 2002 was also excluded in
this updated review.
Five studies are awaiting classification (Chaudhury 2008;
Costantino 2009; Farzadi 2006; Morin-Papunen 2010; Refaie
2005: see Studies awaiting classification)
Allocation concealment
Allocation concealment was unclear in 22 studies (Ben Ayed 2009;
Boudhraa 2010; Brettenthaler 2004; Carmina 2004; El-Biely
2001; Gerli 2003; Karimzadeh 2010; Khorram 2006; Malkawi
2002; Nestler 1998; Onalan 2005; Otta 2010; Palomba 2005;
Rautio 2006; Sahin 2004; Siebert 2009; Sturrock 2002; Trolle
2007; Vandermolen 2001; Williams 2009; Yarali 2002; Zain
2009) whilst one study was an open label trial (Hwu 2005).
Blinding
The majority of the studies (33/44) were described as double
blinded, although nine out of 33 studies provided inadequate information to clarify the blinding method (Gerli 2003; Malkawi
2002; Onalan 2005; Otta 2010; Palomba 2005; Rautio 2006;
Sturrock 2002; Williams 2009; Yarali 2002).
Risk of bias related to blinding was unclear in five studies (Ben
Ayed 2009; Boudhraa 2010; Carmina 2004; El-Biely 2001;
Karimzadeh 2010) and high in six studies (Hwu 2005; Khorram
2006; Nestler 1998; Sahin 2004; Siebert 2009; Zain 2009).
Selective reporting
Selective reporting was not identified in any of the included studies. However, low risk of selective reporting was carefully assessed
only in 13 studies (Eisenhardt 2006; Glintborg 2005; Hoeger
2004; Karimzadeh 2010; Ladson 2011; Lam 2011; Legro 2007;
Lord 2006; Moll 2006; PCOSMIC 2010; Tang 2006; Trolle
2007).
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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13
Effects of interventions
See: Summary of findings for the main comparison Metformin
compared to placebo or no treatment for women with polycystic
ovary syndrome, oligo amenorrhoea and subfertility; Summary of
findings 2 D-chiro-inositol compared to placebo or no treatment
for women with polycystic ovary syndrome, oligo amenorrhoea
and subfertility; Summary of findings 3 Rosiglitazone compared
to placebo or no treatment for women with polycystic ovary
Figure 4. Forest plot of comparison: 1 Metformin versus placebo or no treatment, outcome: 1.1 Live birth
rate.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14
Figure 5. Forest plot of comparison: 1 Metformin versus placebo or no treatment, outcome: 1.2 Adverse
events (gastrointestinal side effects).
participants; OR 1.50, 95% CI 0.95 to 2.37) were found to benefit from using metformin. Furthermore, heterogeneity was much
higher in the non-obese group compared with the obese group (I
2
= 76% versus I2 = 20%). Heterogeneity in the non-obese group
improved after removing Baillargeon 2004 from the analysis (I2
= 53% versus I2 = 20%) without altering the inference. Heterogeneity further improved after sensitivity analysis by study quality which included only six studies (Fleming 2002; Hoeger 2004;
Ladson 2011; Lord 2006; Ng 2001; PCOSMIC 2010), with an
overall I2 of 0% (472 participants; OR 1.37, 95% CI 0.89 to
2.11), without altering the inference.
1.5 Menstrual frequency (Analysis 1.5)
Metformin improved the menstrual pattern with an OR of 1.72
(95% CI 1.14 to 2.61, 7 RCTs, 427 participants). A significant
heterogeneity was seen in the analysis (I2 = 54%). Due to only one
trial in the non-obese group, subgroup analysis did not improve
heterogeneity. Sensitivity analysis by study quality included five
studies (Chou 2003; Eisenhardt 2006; Fleming 2002; Hoeger
2004; Tang 2006); this did not improve heterogeneity and did not
change the inference.
1.6 Miscarriage (Analysis 1.6)
Three studies, with a total of 279 participants, reported miscarriage
rates and there was no evidence of an effect (OR 0.36, 95% CI
0.09 to 1.47) with low heterogeneity (I2 = 0%).
1.7 Multiple pregnancy
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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biochemical assays used in different studies could contribute towards this heterogeneity. Sensitivity analysis by study quality did
not improve the heterogeneity. However, removing the two extreme results (Baillargeon 2004; Jakubowicz 2001) improved heterogeneity (non-obese group I2 = 49%; obese group I2 = 44%)
without altering the inference.
b) Sex hormone binding globulin: metformin did not improve
serum SHBG levels (15 RCTs, 626 participants; MD -0.05, 95%
CI -2.33 to 2.24; I2 = 61%, Analysis 1.12). Neither the subgroup
analysis nor the sensitivity analysis by study quality improved heterogeneity or changed the inference.
1.10 Metabolic outcomes
a) Glucose; the effect of metformin on fasting glucose levels was
small (14 RCTs, 596 participants; MD -0.15 mmol/l, 95% CI 0.25 to -0.06, Analysis 1.13 ) with a moderate heterogeneity in
the analysis (I2 = 42%). Subgroup analysis only improved heterogeneity in the obese group (I2 = 12%) without changing the interference. Sensitivity analysis by study quality (Baillargeon 2004;
Chou 2003; Fleming 2002; Hoeger 2004; Maciel 2004; Pasquali
2000; Tang 2006) eliminated overall heterogeneity (I2 = 0%) and
the results indicated metformin did not change fasting glucose
concentrations (MD 0 mmol/l, 95% CI -0.13 to 0.12).
b) Insulin: metformin reduced fasting insulin levels with a MD of
-3.51 mIU/L (14 RCTs, 573 participants; 95% CI -6.50 to 0.53,
Analysis 1.14 ) but with significant heterogeneity (I2 = 63%). Subgroup analysis showed that metformin significantly reduced fasting
insulin concentrations in the non-obese group (MD -5.65 mIU/
l, 95% CI -10.25 to -1.06) but not in obese women with PCOS
(MD -2.72 mIU/L, 95% CI -6.50 to 1.05). The meta-regression
analysis was unable to show any impact of the confounding factors
(BMI, the daily dose of metformin and the duration of treatment)
on the finding. Sensitivity analysis by study quality (Chou 2003;
Fleming 2002; Hoeger 2004; Lord 2006; Maciel 2004; Ng 2001;
Pasquali 2000; Tang 2006) did not improve the heterogeneity.
Once again, the heterogeneity was likely to be caused by different
background prevalences of hyperandrogenism and insulin resistance among different study populations.
c) Cholesterol: in general, the current review showed that metformin had no effect on serum cholesterol (10 RCTs, 562 participants; MD -0.14 mmol/l, 95% CI -0.31 to 0.02; I2 = 62%,
Analysis 1.15). Neither subgroup analysis nor sensitivity analysis
by study quality changed the inference.
d) Triglycerides: in general, the current review showed that metformin had no effect on serum triglycerides (7 RCTs, 309 participants; MD 0.14 mmol/l, 95% CI -0.05 to 0.32; I2 = 0%, Analysis
1.15). Neither subgroup analysis nor sensitivity analysis by study
quality changed the inference.
2. Metformin with ovulation induction agent clomiphene
versus clomiphene alone
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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Figure 6. Forest plot of comparison: 2 Metformin combined with ovulation induction agent clomifene
versus clomifene alone, outcome: 2.1 Live birth rate.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17
Figure 7. Forest plot of comparison: 2 Metformin combined with ovulation induction agent clomifene
versus clomifene alone, outcome: 2.2 Adverse events.
peared to be homogeneous (I2 = 0%). The heterogeneity was unchanged when the analysis was stratified into the non-obese group
(I2 = 45%) and the obese group (I2 = 73%). Sensitivity analysis
by study quality (Legro 2007; Moll 2006; Ng 2001; PCOSMIC
2010) did not improve the heterogeneity or change the inference.
2.5 Menstrual frequency
Data were not available for this outcome.
2.6 Miscarriage rate (Analysis 2.6)
There was a trend, although not significant, for metformin combined with clomiphene to have a higher miscarriage rate than
clomifene alone (7 RCTs, 937 participants; OR 1.61, 95% CI
1.00 to 2.60; I2 = 0% ). Sensitivity analysis by study quality (Legro
2007; Moll 2006; PCOSMIC 2010) did not alter the inference.
2.7 Multiple pregnancy rate (Analysis 2.7)
There was no effect for metformin combined with clomiphene
versus clomiphene alone (6 RCTs, 916 participants; OR 0.56,
95% CI 0.18 to 1.68; I2 = 0% ). Sensitivity analysis by study
quality (Legro 2007; Moll 2006; PCOSMIC 2010) did not alter
the inference.
Other outcomes: Data were not available for anthropometric,
endocrine or metabolic outcomes.
3. Metformin versus clomiphene citrate
3.1 Live birth rate (Analysis 3.1, Analysis 3.2, Figure 8, Figure 9)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
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Figure 8. Forest plot of comparison: 3 Metformin versus clomiphene citrate, outcome: 3.1 Live birth:
Participants with BMI < 30kg/m2 or 32kg/m2.
Figure 9. Forest plot of comparison: 3 Metformin versus clomiphene citrate, outcome: 3.2 Live birth:
Participants with BMI 30kg/m2.
The overall heterogeneity was high (I2 = 74%) and the data were
not appropriate to be pooled. However, subgroup analysis improved heterogeneity. In the non-obese group, women who took
metformin achieved a similar ovulation rate as those who took
clomiphene (2 RCTs, number of cycles = 497; OR 0.87, 95% CI
0.60 to 1.26; I2 = 0%). In the obese group, clomiphene treatment
was demonstrated to have a better ovulation rate (2 RCTs, number of cycles = 2044; OR 0.43, 95% CI 0.36 to 0.51; I2 = 0%).
Sensitivity analysis by study quality did not change the inference.
3.5 Menstrual frequency
Data were not available for this outcome.
3.6 Miscarriage rate (Analysis 3.5)
A high heterogeneity was observed (4 RCTs, 173 participants; OR
1.24, 95% CI 0.60 to 2.58; I2 = 78%). Neither the subgroup
analysis nor sensitivity analysis by study quality improved the heterogeneity.
3.7 Multiple pregnancy rate (Analysis 3.6)
There was no difference between metformin and clomiphene treatment (5 RCT, 403 participants; OR 0.41, 95% CI 0.08 to 2.08;
I2 = 0%). Sensitivity analysis by study quality did not change the
inference.
Other outcomes: Data were not available for anthropometric,
endocrine or metabolic outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
Although two trials were included (Gerli 2003; Nestler 1999), the
number of women in the analysis remained small. Furthermore,
one of the trials (Gerli 2003) reported analysable data for only one
outcome of interest (ovulation rate). It would be difficult to make
any conclusions based on the current findings.
4.1 Live birth
Data were not available for this outcome.
4.2 Adverse events
Data were not available for this outcome.
4.3 Clinical pregnancy
Data were not available for this outcome.
4.4 Ovulation rate (Analysis 4.1)
D-chiro-inositol did not improve ovulation rate (2 RCTs, 327
participants; OR 5.38, 95% CI 0.70 to 41.31; I2 = 81%). Neither
a subgroup analysis nor sensitivity analysis were possible due to
the inadequate number of studies.
Other outcomes: Data were not available for other reproductive
outcomes.
1.8 Anthropometric outcomes (Analysis 4.2; Analysis 4.3;
Analysis 4.4; Analysis 4.5)
Only one study (Nestler 1999) (44 participants) was included in
the analysis. D-chiro-inositol did not have any effects on BMI,
waist-hip ratio or blood pressure.
1.9, 1.10 Endocrine and metabolic outcomes (Analysis 4.6;
Analysis 4.7; Analysis 4.9; Analysis 4.8; Analysis 4.10; Analysis
4.11)
Only one study (Nestler 1999) (44 participants) was included
in the analysis. D-chiro-inositol did not have any effects on
these parameters (i.e. testosterone, sex hormone binding globulin
(SHBG), fasting glucose, fasting insulin, lipids (total cholesterol,
triglycerides) except for serum SHBG levels.
Data were not available for primary outcomes, but were available
for some secondary outcomes, including menstrual frequency and
anthropometric, endocrine and metabolic outcomes.
Pioglitazone improved the menstrual pattern (2 RCTs, 70 participants; OR 8.88, 95% CI 2.35 to 33.61; I2 = 0%, Analysis 6.1).
There were no effects on anthropometric outcomes (BMI, WHR:
Analysis 6.2; Analysis 6.3), endocrine outcomes (testosterone,
SHBG: Analysis 6.4; Analysis 6.5;) or metabolic outcomes (fasting insulin: Analysis 6.6)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
D-chiro-inositol compared to placebo or no treatment for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Patient or population: Women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Settings:
Intervention: D-chiro-inositol
Comparison: placebo or no treatment
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)
OR 5.38
(0.7 to 41.31)
327
(2 studies)
moderate1
Comments
Corresponding risk
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1
Method of randomisation was unclear in one trial and in the other trial allocation concealment and blinding were unclear. reporting bias
was unclear in both trials
21
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rosiglitazone compared to placebo or no treatment for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Patient or population: Women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Settings:
Intervention: Rosiglitazone
Comparison: placebo or no treatment
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)
OR 1.91
(0.7 to 5.22)
64
(1 study)
very low1,2,3
Comments
Corresponding risk
Study population
344 per 1000
Moderate
344 per 1000
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1
2
3
22
Attrition exceeded 20% in the intervention group and reporting bias was unclear
The summary effect crossed the line of no effect and substantive benefit or harm
Evidence was based on a single trial
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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Pioglitazone compared to placebo or no treatment for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Patient or population: Women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Settings:
Intervention: Pioglitazone
Comparison: placebo or no treatment
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)
OR 8.88
(2.35 to 33.61)
70
(2 studies)
moderate1
Comments
Corresponding risk
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1
One of the trials lacked clarity for all of the risk of bias options
23
DISCUSSION
Summary of main results
Our systematic review showed that metformin did not improve
live birth rates, whether it was used alone or in combination with
clomiphene. However, both ovulation and pregnancy rates were
higher in women with PCOS taking metformin as monotherapy
or combined with clomiphene. Metformin did not reduce miscarriage; although miscarriage rates were not commonly reported in
most of the trials.
Metformin has a significant effect in reducing fasting insulin levels; however, the reduction was only observed in the non-obese
group (BMI < 30 kg/m2 ). A treatment effect on serum testosterone concentration was also observed but the magnitude of the
reduction was greater in the non-obese group compared with the
obese group. Metformin has no effect on serum lipid profiles. Metformin was also associated with a significantly higher incidence
of gastrointestinal disturbance, but there was no increase in the
incidence of adverse effects such as miscarriage and multiple pregnancy.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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24
treat women with PCOS who have hirsutism. However, this clinical effect is uncommonly reported in clinical trials (Lord 2003).
Harborne 2003 conducted a randomised controlled trial comparing the treatment effects on hirsutism between metformin and Dianette (ethinyl estradiol 35 g, cyproterone acetate 2 mg) among
52 women with PCOS. The results showed that metformin is potentially an effective treatment for moderate to severe hirsutism,
based on the Ferriman-Gallwey score and patient self-assessment
methods. However, women who received Dianette were found
to have a significantly greater reduction of serum testosterone
concentrations compared with those who received metformin. A
Cochrane review (Costello 2007) indicated that limited data were
available to compare the effects of metformin with combined oral
contraceptives on hirsutism and acne. On the other hand, combined oral contraceptives are more effective in reducing serum
testosterone concentrations (MD 0.54, 95% CI 0.22 to 0.86) and
the free androgen index (MD 3.69, 95% CI 2.56 to 4.83). Hence,
metformin is unlikely to replace combined oral contraceptives as
a first line therapy for hirsutism.
Insulin sensitivity correlates positively with serum sex hormone binding globulin (SHBG) concentrations (Kiddy 1992;
Jaynagopal 2003; Morles 1996; Robinson 1993; Tang 2006). The
serum SHBG levels and the waist circumference have been considered as reliable surrogate markers for insulin resistance (Jaynagopal
2003). Since neither of these two parameters changed significantly
in our analysis (Analysis 1.8; Analysis 1.12), these findings suggest
that there was no real improvement in insulin sensitivity in our
study population, especially among the obese group.
A wealth of evidence indicated that weight loss improves menstrual frequency, insulin sensitivity, androgen and SHBG levels
(Butzow 2000; Crave 1995; Dunaif 1996; Hoeger 2001; Holte
1995; Huber-B 1999; Kiddy 1989; Kiddy 1990; Kiddy 1992)
although the effect on lipid profiles is less clear when women
remain overweight despite weight loss (Hoeger 2004). Despres
2001 suggested that a 5% to10% weight reduction may result
in a 30% loss of visceral fat mass, which is the metabolically active fat and key to insulin resistance. Additionally, the success of
fertility therapies is often lower in obese women with or without PCOS (Hamilton-Fairley1992; Hassan 2004; Zaadstra 1993).
Cedergren 2004 conducted a prospective population based study
on 3480 morbidly obese mothers (BMI over 40 kg/m2 ) and the
study demonstrated that they have a higher incidence of adverse
pregnancy outcomes compared with a group with normal weight:
pre-eclampsia (4.82, 95% CI 4.04 to 5.74), stillbirth (2.79, 95%
CI 2.49 to 2.90), fetal distress (2.52, 95% CI 2.12 to 2.99), early
neonatal death (3.41, 95% CI 2.07 to 5.63) and large for gestational age babies (3.82, 95% CI 3.50 to 4.16). This evidence
strongly emphasises the benefit of weight loss on reproductive,
metabolic and pregnancy outcomes. With metformin being less effective in obese women with PCOS, lifestyle modification should
be the first line management approach and form an integral part of
managing obese PCOS women suffering from infertility (Norman
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
AUTHORS CONCLUSIONS
Implications for practice
In agreement with the previous review, metformin is associated
with improved clinical pregnancy rates, but there is no evidence
that metformin improves live births, whether it is used alone or in
combination with clomiphene. In addition, metformin has limited effects on weight loss and metabolic parameters (insulin and
lipid profiles), especially in obese women with PCOS. Therefore,
the role of metformin in improving reproductive outcomes or in
reducing the risk of developing metabolic syndrome in women
with PCOS appears to be limited. In obese women with PCOS
clomiphene is associated with higher rates of live birth, clinical
pregnancy and ovulation than metformin. However as obesity
poses a significant negative impact on pregnancy outcomes (Legro
2007), anovulatory obese women with PCOS should be advised
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
26
to undergo lifestyle changes before fertility treatment (The Thessaloniki ESHRE/ASRM sponsored PCOS consensus workshop
group, 2007) (ESHRE/ASRM 2008).
Some women with PCOS may benefit from using insulin-sensitising drugs. More research is needed to improve patient selection.
There is some evidence that lifestyle modifications have a positive
effect on resuming ovulation and in reducing the risk of developing diabetes. Therefore, trials should focus on the long-term
impact of lifestyle changes and the use of insulin-sensitising drugs
to modulate the risk of developing metabolic syndrome.
ACKNOWLEDGEMENTS
We would like to thank the corresponding authors of the following
trials who took time to respond to our requests for further data,
some of whom took the trouble to perform repeat analyses for us:
Chou 2003; Fleming 2002; Glintborg 2005; Hoeger 2004; Hwu
2005; Jakubowicz 2001; Ladson 2011; Legro 2007; Lord 2006;
Malkawi 2002; Moghetti 2000; Nestler 1997; Nestler 1999; Ng
2001; Rautio 2006; Sturrock 2002; Trolle 2007; Vandermolen
2001; Yarali 2002.
We would also like to thank the Cochrane Menstrual Disorders
and Subfertility Review Group in Auckland, and in particular their
Managing Editor (to 2011) Jane Clarke, for all their help and
support. We are also grateful to Rafael Perera of the UK Cochrane
Centre for statistical advice.
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Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
27
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
29
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30
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31
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amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
35
CHARACTERISTICS OF STUDIES
RANDOMISED TRIAL
SETTING: Venezuela
METHOD OF RANDOMISATION: fixed block of 8 randomisation which was performed in the investigational pharmacist
BLINDING: Double
NUMBER RANDOMISED: 128
Participants
Interventions
Outcomes
OVULATION: weekly progesterone measurement with a level over 4ng/ml was considered to be ovulation
ANTHROPOMETRIC: Weight, BMI, WHR, blood pressure.
HORMONES: testosterone, SHBG, free testosterone, DHEAS
METABOLIC MARKERS: fasting glucose, AUCglucose and fasting glucose to insulin
ratio
OTHERS: menstrual pattern
Notes
This study randomised 128 women into 4 groups (metformin alone, rosiglitazone alone,
combined metformin and rosiglitazone, placebo alone). The combined group was included in our analysis. The metformin and rosiglitazone groups were analysed separately.
The results from these two groups were compared with the same group of women who
took placebo.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
36
Baillargeon 2004
(Continued)
Authors judgement
Low risk
Double blinded
High risk
DROP OUTS - 4 (12.5%) in the metformin arm, 10 (31.3%) in the rosiglitazone group and 2 (6.3%) in the placebo
group. Details not provided
Unclear risk
unclear
Other bias
High risk
RANDOMISED TRIAL
SETTING: Tunisia
METHOD OF RANDOMISATION: Not stated
BLINDING: Not stated
NUMBER RANDOMISED: 32
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
(Continued)
Outcomes
Notes
Risk of bias
Bias
Authors judgement
inadequate information
Unclear risk
inadequate information
inadequate information
Unclear risk
inadequate information
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Boudhraa 2010
Methods
RANDOMISED TRIAL
SETTING: Tunisia
METHOD OF RANDOMISATION: not stated*
BLINDING: unblinded
NUMBER RANDOMISED: 63
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
Boudhraa 2010
(Continued)
Interventions
Outcomes
Notes
Study protocol is too brief. Inadequate information to assess the quality of the study. No
reply from author*
Risk of bias
Bias
Authors judgement
inadequate information
Unclear risk
inadequate information
inadequate information
Unclear risk
inadequate information
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Brettenthaler 2004
Methods
RANDOMISED TRIAL
SETTING: Switzertland
METHOD OF RANDOMISATION: Unclear*
BLINDING: Double
NUMBER RANDOMISED: 40
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
Brettenthaler 2004
(Continued)
Interventions
Outcomes
Notes
Participants in this study are very heterogeneous (65% European, 30% Turkish and 5%
Asian).
No serious side-effects or abnormal liver function tests were reported. Nevertheless,
women who took pioglitazone experienced more side effects compared with those who
took placebo; mild peripheral oedema (18% versus 0%), mastopathy (11.7% versus 5%)
, sleeping disorders (23% versus 5%), headache (23% vs 5%) and stomach arch (23%
versus %%)
* = No reply from the author
Risk of bias
Bias
Authors judgement
inadequate information
inadequate information
Unclear risk
Identical trial and placebo tablets. In adequate information to assess the methodology
High risk
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
Brettenthaler 2004
(Continued)
Other bias
Unclear risk
Participants in this study are very heterogeneous (65% European, 30% Turkish and
5% Asian). Inadequate information to assess. No reply from author
Carmina 2004
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: random table
BLINDING: Not stated
NUMBER RANDOMISED: 24
Participants
Interventions
Outcomes
Notes
This study evaluated the efficacy of metformin in women with anovulation who do not
have evidence of hyperandrogenism; although over 79% of included women had USS
evidence of PCO; hence, met the Rotterdam diagnostic criteria of PCOS
Risk of bias
Bias
Authors judgement
inadequate information
Unclear risk
inadequate information
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
41
Carmina 2004
(Continued)
Unclear risk
Unclear risk
Other bias
Low risk
Chou 2003
Methods
RANDOMISED TRIAL
SETTING: Brazil
METHOD OF RANDOMISATION: participants were randomised by a third party
by using a table with random numbers (odd number assigned for the metformin group,
even number assigned for the placebo group).*
BLINDING: Double
NUMBER RANDOMISED: 32
Participants
Interventions
Outcomes
Notes
This study was designed to evaluate the benefit of using metformin in obese women
(BMI>30) with PCOS. Three participants in each arm were found to have glucose
intolerance according to WHO criteria
The results of the women who dropped out from the study were excluded from the
analysis
* information kindly provided by the author that was not in the original paper
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
42
Chou 2003
(Continued)
Risk of bias
Bias
Authors judgement
Low risk
Double blinded
Unclear risk
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Eisenhardt 2006
Methods
RANDOMISED TRIAL
SETTING: Germany
METHOD OF RANDOMISATION: computer generated random numbers with randomisation in block of 6. The code was sealed by a third party until the end of the study
period
BLINDING: Double
NUMBER RANDOMISED: 45
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43
Eisenhardt 2006
(Continued)
Outcomes
Notes
The objective of this study is to evaluate the effects of metformin in women with PCOS
according to the status of insulin resistance. Insulin resistance is defined as fasting glucose
to insulin ratio less than 4.5. Thirty-two out of 45 women (71.1%) were classified as
insulin resistant PCOS
Insulin resistant PCOS women responded better than non-insulin resistant PCOS
women in terms of improvement in menstrual cyclicity
The results were presented in median and range. Hence, these data was not able to be
included in the meta-analysis. We are currently still waiting for a reply from the author
for the converted results in a format of mean and standard deviation
*= still awaiting for a reply from the author
Risk of bias
Bias
Authors judgement
The code was sealed by a third party until the end of the study period. Trial drugs
were provided by a pharmaceutical company which did not involve study design
and data analysis
Low risk
Double blinded
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
44
Eisenhardt 2006
(Continued)
Low risk
Other bias
Unclear risk
inadequate information
El-Biely 2001
Methods
RANDOMISED TRIAL
SETTING: Egypt
METHOD OF RANDOMISATION: computer based, blocked (block size not stated)
BLINDING: not stated; presumed to be unblinded
NUMBER RANDOMISED: 90
Participants
Interventions
Outcomes
Notes
The inclusion criteria did not include previous response to clomiphene. Overall, 65% of
those receiving clomiphene and placebo ovulated (compared to 85% of those receiving
clomiphene and metformin)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
45
El-Biely 2001
(Continued)
This trial reported a significantly higher mean number of mature follicles in the metformin group (3.1 versus 1.9, P<0.0001), but a significantly lower rate of ovarian hyperstimulation syndrome (4 versus 31, P<0.001)
Risk of bias
Bias
Authors judgement
Computer randomised
Unclear risk
Not stated
Not stated
Unclear risk
Unclear risk
inadequate information
Other bias
Unclear risk
Fleming 2002
Methods
RANDOMISED TRIAL
SETTING: UK
METHOD OF RANDOMISATION: computer generated randomisation by pharmacy
in blocks of four
BLINDING: Double blind
NUMBER RANDOMISED: 94
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
46
Fleming 2002
(Continued)
, 29.2(5.6)
Mean BMI ( SD) 34.2(8.6), 35.0(8.2)
Mean fasting insulin mIU/L ( SD) 16.7(12.7), 18.4(13.6)
Mean total testosterone mol/L ( SD) 3.0(1.5), 3.8(1.6)
DROP OUTS - 30(32%), with 22 in the treatment arm and 8 in the placebo, mainly
due to gastrointestinal side-effects in metformin group. Overall, 58% of the metformin
arm completing the trial and 83% of the placebo arm. Included in intention-to-treat
analysis
Interventions
Outcomes
Notes
Diagnostic criteria different to other trials - using U/S not hyperandrogaenemia (although
90% did have raised androgens, and mean entry free androgen index 10 with 5% CI
8.6). Subgroup analysis showed that those who ovulated in response to metformin had
significantly lower androgens
High rate of background ovulation (64% on placebo ovulated at some stage)
*= Information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
Fleming 2002
(Continued)
Low risk
Double blinded
High risk
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Gerli 2003
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: computer generated random numbers table.*
BLINDING: Double
NUMBER RANDOMISED: 283
Participants
Interventions
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
48
Gerli 2003
(Continued)
Outcomes
Notes
This is the largest study being published so far on the effects of inositol on ovarian
function and metabolic factors in women with PCOS. Women were recruited from
gynaecology, endocrine and infertility outpatient clinics in the study centre. Nearly half
of the subjects presented with history of infertility. However, only 42 women declared a
wish to conceive before the start of the trial. Therefore, it would be difficult to interpret
the pregnancy rate accurately.
*= No further information from the author
Risk of bias
Bias
Authors judgement
Unclear risk
Not stated
Not stated
High risk
Unclear risk
Inadequate information
Other bias
Unclear risk
Inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
49
Glintborg 2005
Methods
RANDOMISED TRIAL
SETTING: Denmark
METHOD OF RANDOMISATION: computer generated numbers. Randomization
was conducted in the local pharmacist. The code was kept in the pharmacist department
until the end of the trial.*
BLINDING: Double*
NUMBER RANDOMISED: 30
Participants
Interventions
Outcomes
Notes
The main objective of this study was to investigate the effect of pioglitazone on growth
hormone levels in women with PCOS. The secondary endpoint measures include
changes in arthropometric and hormonal parameters
The participants were recruited from the local endocrine and infertility clinics. All the
women were instructed to use barrier contraception combined with spermatocidal cream
provided by the department throughout the trial period due to the potential risks in
pregnancy
No serious side effects were reported. All participants had normal liver functions at the
end of the trial period
* information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
50
Glintborg 2005
(Continued)
The code was kept in the pharmacist department until the end of the trial
Low risk
Double blinded
Unclear risk
Low risk
Other bias
Low risk
Hoeger 2004
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: computer generated random number, randomisation conducted by the pharmacy department.*
BLINDING: Double
NUMBER RANDOMISED: 38
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
51
Hoeger 2004
(Continued)
Outcomes
Notes
This trial was designed to investigate the combined effects of metformin and intensive
lifestyle modification in overweight women with PCOS. The subjects were recruited
through a direct advertisement, referral from physician and reproductive endocrinology
outpatient clinic in the same study centre. The subjects were randomised into four groups
(metformin alone, placebo alone, combined lifestyle changes and metformin and lifestyle changes alone). We decided to separate the analysis into two groups; metformin
versus placebo and combined lifestyle and metformin versus lifestyle
We also decided to analysis the results for those completed the trial at 24 weeks as there
were too many drop outs at the end of the trial period at 48 weeks
*=information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Low risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
52
Hoeger 2004
(Continued)
Low risk
DROP OUTS - 3 (33.3%) in the metformin arm and 2 (22.2%)in the placebo
arm at 24 months of the trial. Further 4(44.
4%) in the metformin/life-style arm and 2
(18.2%)in the placebo/lifestyle arm at 24
months of the trial. Baseline characteristics between the subjects completed and the
drop outs were similar
Low risk
Other bias
High risk
Hwu 2005
Methods
RANDOMISED TRIAL
SETTING: Taiwan
METHOD OF RANDOMISATION: computer generated random numbers, block of
two randomisation process*
BLINDING: No*
NUMBER RANDOMISED: 80
Participants
Interventions
MAIN INTERVENTION: metformin 500mg TDS per day versus no treatment. Metformin was commenced on day one after induced menstruation followed by a 5 days
course of clomiphene 150mg treatment from day 13 of the cycle. When there were evident of follicles over 12 mm in diameter three days after the last dose of clomiphene,
metformin was continued until the dominant follicles reached 20mm. Intramuscular
hCG 5000 IU was then administrated and the participants were instructed to have intercourse in the following two days
DURATION: one cycle
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
53
Hwu 2005
(Continued)
OVULATION: confirmed by USS and serum progesterone over 5ng/ml on day 7 after
hCG injection
ARTHROPOMETRIC:
HORMONES:
METABOLIC MARKERS:
OTHERS: pregnancy and miscarriage rates
Notes
Risk of bias
Bias
Authors judgement
High risk
Not blinded
Low risk
No drop outs
Unclear risk
inadequate information
Other bias
High risk
Using hCG injection triggering ovulation. The sequence of allocation was not
concealed and this study was unblinded.
Therefore, bias cannot be excluded
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
54
Jakubowicz 2001
Methods
RANDOMISED TRIAL
SETTING: Venezuela (63% Caucasian, 31% Hispanic, 4% Arabic, 2% South American
Indian)
METHOD OF RANDOMISATION: sequentially numbered, identical containers of
identical drugs*
BLINDING: double blind
NUMBER RANDOMISED: 48
Participants
Interventions
Outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
55
Jakubowicz 2001
(Continued)
Women that were given metformin and ovulated received an extra weeks course of
treatment when compared with the placebo group
High drop out rate between recruitment and randomisation (24%) as only those who
ovulated with clomiphene prior to randomisation were included
The primary outcome measures are not relevant to this review, but the other parameters
reported are
It is assumed that the units quoted for testosterone are mmol/dl and not mmol/l
*= Information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Not stated
Low risk
Double blind
High risk
Unclear risk
The primary outcome measures are not relevant to this review, but the other parameters such as ovulation reported are
Other bias
Low risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
56
Karimzadeh 2007
Methods
RANDOMISED TRIAL
SETTING: Iran
METHOD OF RANDOMISATION: computer generated sequences that was sealed
in envelopes
BLINDING: Double
NUMBER RANDOMISED: 200
Participants
Interventions
Outcomes
Notes
Women were recruited from a single centre. The primary objective of this study was to
investigate the effect of metformin on lipid profile. The duration of the trial was relatively
short. Therefore, it was difficult to ascertain the reliability on both of the ovulation rates
and the improvement in menstrual patterns
Risk of bias
Bias
Authors judgement
Low risk
Double blinded
Unclear risk
Not stated
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
57
Karimzadeh 2007
(Continued)
Other bias
Unclear risk
Karimzadeh 2010
Methods
RANDOMISED TRIAL
SETTING: Iran
METHOD OF RANDOMISATION: not stated
BLINDING: not stated
NUMBER RANDOMISED: 343
Participants
Interventions
Outcomes
Notes
This study compared the effect of clomifene, metformin, combined clomifene and metformin and lifestyle modifcation on subfertile women with PCOS
Very little information can be extracted from the study protocol
A large sample size without any dropping out.
Some of the women may have been included in the previous trial Karimzadeh 2007.
No reply from author.
Risk of bias
Bias
Authors judgement
inadequate information
Unclear risk
inadequate information
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
58
Karimzadeh 2010
(Continued)
Unclear risk
Inadequate information
Low risk
Other bias
Low risk
Khorram 2006
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: picking a card out of a box.
BLINDING: unblinded
NUMBER RANDOMISED: 31
Participants
Interventions
Outcomes
Notes
This study was designed to evaluate the effect of a shot course of metformin treatment
on the outcomes of clomifene ovulation induction therapy.
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
59
Khorram 2006
(Continued)
All subjects are Hispanic except one African American in the clomifene only group and
one Caucasian in the combined group. None of the participants had taken clomifene
before.
The trial was unblinded. The method of randomization and concealment were inadequate. Therefore, potential bias may be introduced
Risk of bias
Bias
Authors judgement
inadequate information
Unclear risk
Unblinded
Unclear risk
No missing data
Unclear risk
inadequate information
Other bias
Unclear risk
Insufficient information
Ladson 2011
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: computer generated random number
BLINDING: Double
NUMBER RANDOMISED: 114
Participants
Interventions
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
60
Ladson 2011
(Continued)
Outcomes
Notes
This study investigated whether combined lifestyle changes and metformin would be
superior to lifestyle and placebo in improving the PCOS phenotype
As there were high drop out rates in both groups, we only included the data at 3 months
trial period. (metformin 31 and placebo 25)
*Results kindly provided by the authors.
Risk of bias
Bias
Authors judgement
Computer generated
Low risk
High risk
Low risk
Other bias
Low risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
61
Lam 2011
Methods
RANDOMISED TRIAL
SETTING: Hong Kong
METHOD OF RANDOMISATION: computer generated random number, block of
10
BLINDING: Double
NUMBER RANDOMISED: 70
Participants
Interventions
Outcomes
Notes
This study investigated the effect of using rosiglitazone on Chinese women with PCOS.
It is unclear whether the subjects were infertile
Risk of bias
Bias
Authors judgement
Low risk
double blind
Unclear risk
Low risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
62
Lam 2011
(Continued)
Other bias
High risk
A much higher drop out rate in the rosiglitazone group than the placebo group
Legro 2007
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: a large multi-centre randomised placebo-controlled study. (see Legro 2006b for detail)
BLINDING: Double
NUMBER RANDOMISED: 626
Participants
Interventions
Outcomes
Notes
This is the largest randomised controlled trial being published so far on the effects of
metformin on women with PCOS. A total of 626 infertile women with PCOS were
randomised into three groups (metformin and placebo, metformin and clomiphene,
clomiphene and placebo)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
63
Legro 2007
(Continued)
The sample size calculation was based on the live birth rates. The secondary outcomes
included the rate of pregnancy loss, singleton birth and ovulation
Based on the initial sample size calculation, 678 was needed to detect a 15% absolute
difference in live birth rates with a power of 80% and a type I error of 0.05. Due to
limitations in the supplying metformin and the matching placebo tablets, the number
of required women was reduced to 626. This was approved after the assessment by the
data safety and monitoring board. Because the observed live birth rate was lower than
projected, the number of recruited participants (626) was sufficient to detect a 15%
difference with the same magnitude of power and type I error
The backgrounds of the participants were relatively heterogeneous. Two-third of the
participants was white and about one-third was Hispanic or Latino origin. Only 40%
of the women have not had previous exposure to metformin or clomiphene
Ovulation was confirmed when two consecutive measurements of progesterone levels >
5ng/ml in one to two weeks apart
Ultrasound monitoring of ovarian response was not included in the study protocol.
Ovulation triggering with hCG and intrauterine insemination were not employed in
this study
Metformin combined with clomiphene did not achieve a better live birth rate compared
with clomiphene therapy. The metformin group was found to have a significantly inferior
pregnancy and live birth rates compared with the combined therapy (metformin and
clomiphene) and the clomiphene groups. This study also demonstrated that BMI poses
a significant negative impact on live births
Risk of bias
Bias
Authors judgement
Low risk
Double blind
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
64
Legro 2007
(Continued)
Low risk
Other bias
High risk
Lord 2006
Methods
RANDOMISED TRIAL
SETTING: UK
METHOD OF RANDOMISATION: randomisation was conducted centrally by computer at the hospital pharmacy department using a block with sequential numbers. The
code was kept sealed until the trial was completed.*
BLINDING: Double
NUMBER RANDOMISED: 44
Participants
Interventions
Outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
65
Lord 2006
(Continued)
This study is to ascertain the effects of metformin on metabolic parameters, visceral and
subcutaneous fat distributions in women with PCOS
The fat distribution was measured with areal planimetry (CT scan). There were no significant changes in any of the measures of fat distribution between the metformin and the
placebo groups. Although, metformin significantly reduced serum cholesterol concentrations, treatment effects on androgens, insulin, triglycerides, ovulation and pregnancy
were not observed
* information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Low risk
Double blinded
Unclear risk
Low risk
Other bias
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
66
Maciel 2004
Methods
RANDOMISED TRIAL
SETTING: Brazil
METHOD OF RANDOMISATION: computer generated random numbers.
BLINDING: Double
NUMBER RANDOMISED: 30
Participants
Interventions
Outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
67
Maciel 2004
(Continued)
Notes
The primary objective of this study was to compare the clinical, hormonal and biochemical effects of metformin therapy in the obese PCOS group (BMI>30) with the nonobese group (BMI<30). The results of the obese group were entered separately in the
analysis
The results indicated that non-obese participants responded better than obese participants with PCOS to metformin 1.5g per day. Non-obese women experienced an improvement in menstrual cyclicity, decrease in serum androgen levels and fasting insulin
concentrations; whilst, obese women showed a significant reduction of free testosterone
levels. Caution is needed to interpret the results as 5 of the original 34 enrolled participants did not complete the trial and these findings were not included in the analysis
Risk of bias
Bias
Authors judgement
Low risk
Double blinded
Unclear risk
Unclear risk
Other bias
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
68
Malkawi 2002
Methods
RANDOMISED TRIAL
SETTING: Jordan
METHOD OF RANDOMISATION: centralised randomisation process with women
receiving a sequential number*
BLINDING: double blind*
NUMBER RANDOMISED: 28
Participants
Interventions
Outcomes
Notes
Risk of bias
Bias
Authors judgement
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
69
Malkawi 2002
(Continued)
Low risk
No drop outs
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Moghetti 2000
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: sequentially numbered, identical containers of
identical drugs*
BLINDING: double blind
NUMBER RANDOMISED: 23
Participants
Interventions
Outcomes
ANTHROPOMETRIC: BMI,
Waist-hip ratio
REPRODUCTIVE HORMONES: free testosterone
Androstenedione
DHEAS
SHBG
FSH
LH
METABOLIC MARKERS: fasting glucose
fasting insulin
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
70
Moghetti 2000
(Continued)
Placebo group had significantly higher BMI (P<0.05) at baseline and higher fasting
insulin (N/S), but similar insulin sensitivity. Metformin group had higher androgens
(N/S)
Mild side effects in 5 in metformin group and 2 in placebo group
It is assumed that the figures quoted in the publication are for standard errors
*= Information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Not stated
Low risk
Double blind
Low risk
No drop outs
High risk
Other bias
High risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
71
Moll 2006
Methods
RANDOMISED TRIAL
SETTING: Holland, Netherlands multicentre
METHOD OF RANDOMISATION: computer generated blocks of four.
BLINDING: Double blind
NUMBER RANDOMISED: 225
Participants
SUMMARY: non-PCOS
INCLUSION CRITERIA: PCOS (according to Rotterdam consensus), normal FSH
concentrations
EXCLUSION CRITERIA: age over 40, abnormal liver function tests or creatinine levels
over 95umol/l, history of heart disease, history of male factor infertility with total motile
sperm count less than 10X106
BASELINE CHARACTERISTICS OF EACH GROUP:
Mean age (SD) 27.9 (3.7), 28.4(4.7)
Mean BMI (SD) 28.5(7.1), 27.8(6.7)
Mean fasting insulin mIU/L (SD)
Mean total testosterone nmol/L (SD) 3.49(3.68), 3.55 (3.54)
DROP OUTS-No significant difference in the drop rates, 28 (25%) in the metformin
arm, 21 (18%) in the placebo arm
Interventions
Outcomes
OVULATION: progesterone over 14nmol/l in the second half of menstrual cycle, biphasic basal body temperature curve, follicular diameter over 16mm on TVUSS or pregnancy
ARTHROPOMETRIC:
HORMONES:
METABOLIC MARKERS:
OTHERS: pregnancy, miscarriage and clomiphene resistance
Notes
A large multicentre RCT. The sample size calculation was based on the ovulation rate.
In total, 228 women were initially screened and three were subsequently excluded. One
hundred and eleven women were randomised to receive metformin and clomiphene;
whilst 114 received placebo and clomiphene
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
72
Moll 2006
(Continued)
Low risk
Randomisation was carried out in the coordinating centre (Armsterdam) and the list
was kept until inclusion was completed
Unclear risk
Low risk
Other bias
Unclear risk
inadequate information
Nestler 1998
Methods
RANDOMISED TRIAL
SETTING: USA (3 participants), Venezuela (54 participants), Italy (4 participants)*
METHOD OF RANDOMISATION: centralised randomisation process*.
BLINDING: Single blind - participants blinded
NUMBER RANDOMISED: 61
Participants
Interventions
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
73
Nestler 1998
(Continued)
CO-INTERVENTIONS: those that did not ovulate after 34 days had clomiphene 50mg
for 5 days and continued metformin / placebo for a total of 53 days
Outcomes
Notes
Risk of bias
Bias
Authors judgement
Inadequate information
Unclear risk
Low risk
No drop outs
Unclear risk
inadequate information
Other bias
High risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
74
Nestler 1999
Methods
RANDOMISED TRIAL
SETTING: Venezuela (White 73%, Hispanic 16%, Afro-Hispanic 4.5%, Arabic 4.5%,
Asian 2%)
METHOD OF RANDOMISATION: drug and placebo packaged at same time and
labelled according to subject number. Randomisation in blocks of four.
BLINDING: Double blind
NUMBER RANDOMISED: 44
Participants
Interventions
Outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
75
Nestler 1999
(Continued)
Notes
All women had ultrasound features of PCO, but this was not an inclusion criteria
None of the participants had diabetes mellitus, but 10 (23%) had impaired glucose
tolerance (6 in treatment arm, 4 in placebo arm).
*= Information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Low risk
Double blind
Low risk
No drop outs
Unclear risk
Insufficient information
Other bias
Unclear risk
Insufficient information
Ng 2001
Methods
RANDOMISED TRIAL
SETTING: Hong Kong (Chinese women)
METHOD OF RANDOMISATION: computer generated list in sealed envelopes
BLINDING: Double blind
NUMBER RANDOMISED: 20
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
76
Ng 2001
(Continued)
Outcomes
Notes
Risk of bias
Bias
Authors judgement
In sealed envelopes. Double, identical appearance and packed by the hospital pharmacy. Code kept in the pharmacy department until the end of the trial
Low risk
Double blind
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
77
Ng 2001
(Continued)
Unclear risk
Low risk
Other bias
Unclear risk
Onalan 2005
Methods
RANDOMISED TRIAL
SETTING: Turkey
METHOD OF RANDOMISATION: computer generated randomisation in blocks of
four
BLINDING: Double*
NUMBER RANDOMISED: 139 were randomised into six main group according to
the fasting glucose/insulin ratio (with a level less than 4.5 classified as hyperinsulinemia)
and BMI (<25, 25-29.9 and > 30)
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
78
Onalan 2005
(Continued)
Outcomes
Notes
Risk of bias
Bias
Authors judgement
Not stated
Unclear risk
inadequate information
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
79
Onalan 2005
(Continued)
placebo groups
Selective reporting (reporting bias)
Unclear risk
Other bias
Unclear risk
Otta 2010
Methods
RANDOMISED TRIAL
SETTING: Argentina
METHOD OF RANDOMISATION: computer generated
BLINDING: Double
NUMBER RANDOMISED: 30
Participants
Interventions
Outcomes
Notes
This study investigated the effects of combined metformin and lifestyle changes on
endocrine and metabolic parameters in women with PCOS
Methodology and study protocol were too brief. Unable to determine the quality of the
trial
Only 5 out of 30 subjects were trying to conceive.
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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80
Otta 2010
(Continued)
Unclear risk
Not stated
Not stated
High risk
Missing data not reported. One in metformin group and excluded from analysis
Unclear risk
Other bias
Low risk
Palomba 2005
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: computer generated random allocation sequence
in double block
BLINDING: Double
NUMBER RANDOMISED: 100
Participants
Interventions
Outcomes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Palomba 2005
(Continued)
Notes
This study was designed to compare the effectiveness of metformin and clomiphene
treatment as a first-line therapy in non-obese anovulatory women with PCOS.
The primary end point measure was the pregnancy rate.
Risk of bias
Bias
Authors judgement
Unclear risk
inadequate information
Unclear risk
Unclear risk
inadequate information
Other bias
Unclear risk
Insufficient information
Pasquali 2000
Methods
Randomised trial
Setting: Itlay
Method of randomisation: block of 4. Drug and placebo packaged and labelled according
to subject number
Double blind
Number randomised:20
Participants
Obese PCOS
Inclusion criteria: oligomenorrhoea (<4cycles in past 6 months), hyperandroenaemia,
USS of PCO, BMI over 25, WHR>0.8
Exclusion criteria: DM, adrenal hyperplasia, thyroid dysfunction, hyperprolactinamia,
cardiovascular, renal or liver dysfunction
Baseline characteristics:
Age: 30.8, 32.3
BMI: 39.8, 39.39
Mean fasting insulin mIU/L 43, 33.5
Mean total testosterone mol/L 2.37, 1.78
Drop outs: 2 from metformin arm due to pregnancy. Not included in analysis
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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82
Pasquali 2000
(Continued)
Interventions
Outcomes
Anthropometric parameters
Reproductive hormones and metabolic markers
Notes
The trial was designed to investigate the combined effects of diet and metformin on fat
distribution in women with PCOS. The study also included a control group who were
matched for age, weight and waist-hip ratio but with a regular menstrual cycles
Risk of bias
Bias
Authors judgement
Low risk
Double blinded
High risk
Unclear risk
Other bias
Unclear risk
inadequate information
PCOSMIC 2010
Methods
Participants
Women with PCOS according to Rotterdam consensus criteria and excluded couples
were had undergone previous fertility treatment involving more than 5 months treatment
with CC or metformin. Also excluded couple with tubal factor (at least one tube blocked)
, or with severe male factor (< 15 mil/ml) and important medical disorders
Interventions
Women with BMI > 32kg/m2 were randomised to receive either metformin 500mg
TDS (increasing dose over two weeks) or matching placebo
Women with BMI < or = 32 kg/m2 are randomised to receive either metformin 500mg
t.d.s, clomifene 50mg from day 2-6 (increasing up to 150mg over three months if no
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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83
PCOSMIC 2010
(Continued)
evidence of ovulation) or metformin 500mg tds combined with clomifene 50mg day 26 (increasing up to 150mg over three months if no evidence of ovulation)
Participants received up to two packages of 3 months treatments. All study drugs were
stopped once the participant was pregnant
Outcomes
Primary outcomes were clinical pregnancy (intrauterine gestation sac) and live birth
Secondary outcomes were ovulation, miscarriage, ectopic pregnancy or multiple pregnancy
Notes
Risk of bias
Bias
Authors judgement
Computerised
(blocks of 10)
block
randomisation
Low risk
allocation concealment was strictly maintained by a telephone call from the recruiting nurse to pharmacy, ...dispensing
preprepared drugs in a true third party randomisation
Low risk
Intention to treat analysis planned and protocol breach and losses to follow up were
reported in figure 3
Low risk
Other bias
Unclear risk
inadequate information
Rautio 2006
Methods
RANDOMISED TRIAL
SETTING: Finland
METHOD OF RANDOMISATION: computer generated random numbers (block of
5). Randomisation was conducted within the department.*
BLINDING: Double*
NUMBER RANDOMISED: 30
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
84
Rautio 2006
(Continued)
Participants
Interventions
Outcomes
Notes
The objective of this study was to assess the effects of rosiglitazone in obese women with
PCOS. All the participants were recruited from a single endocrine clinic
All the participants were advised to use some form of non-hormonal contraception
during the study as rosiglitazone is a category C drug
Rosiglitazone improves menstrual cyclicity, insulin resistance and hyperandrogenism
* information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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85
Rautio 2006
(Continued)
High risk
DROP OUTS - three (20%) in the rosiglitazone group (2 due to pregnancy); one (6.
6%) in the placebo group (personal reasons)
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Romualdi 2010
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: block of 10 sealed envelopes containing randomisation codes assigning 5 subjects to metformin and 5 to placebo group
BLINDING: Double
NUMBER RANDOMISED: 28
Participants
Interventions
Outcomes
OVULATION:
ARTHROPOMETRIC: BMI, WHR
HORMONES: testosterone, SHBG
METABOLIC MARKERS: lipid profiles
Notes
A small RCT investigated the effect of metformin on ovarian ultrasound appearance and
steroidogenic function in normal-weight normoinsulinaemic women with PCOS. Only
the metabolic data was included in our analysis
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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86
Romualdi 2010
(Continued)
Not stated
Low risk
Unclear risk
High risk
None identified
Other bias
Unclear risk
inadequate information
Sahin 2004
Methods
RANDOMISED TRIAL
SETTING: Turkey
METHOD OF RANDOMISATION: not stated*
BLINDING: not stated*
NUMBER RANDOMISED: 21
Participants
Interventions
MAIN INTERVENTION: metformin 850mg twice daily. Placebo was not used.
DURATION: metformin alone or no treatment for 3 months followed by combining
clomifene ovulation induction therapy for further 6 cycles or until pregnancy occurred.
CO-INTERVENTIONS: clomifene 100mg daily for 5 days from day 5 of the cycle.
Ovulation was triggered by administration of 10,000IU hCG (Pregnyl, Organon, Holland)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
87
Sahin 2004
(Continued)
Outcomes
Notes
Women were recruited from a single infertility unit. All subjects presented with primary
infertility. Tubal disease and male factor infertility were excluded. Of the women, 90%
presented with oligomenorrhoea and 10% amenorrhoea. In addition, half of the participants had Ferriman-Gallwey score over 8.
Since placebo was not used in the study, bias may exist in the trial period. We are
still waiting for a reply from the author regarding the method of randomization and
concealment. Furthermore, all the arthropometric, hormonal and metabolic data were
presented in a format of median and range. These results are unable to be entered in the
meta-analysis. Hence, the author was asked to provide the results in mean and standard
deviation.
Ovulation rates after the initial 3 months metformin treatment alone were not given.
The response to clomifene treatment was monitored by serial USS. When there were
fewer than four follicles with diameter > 15mm with a leading follicle of > 18mm in
diameter, 10,000 IU hCG was administrated intramuscularly.
Pregnancy was defined by USevidence of a gestational sac and the presence of fetal heart
activity
*= No reply from the author
Risk of bias
Bias
Authors judgement
inadequate information
Unclear risk
inadequate information
inadequate information
Unclear risk
Unclear risk
Other bias
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
88
Siebert 2009
Methods
RANDOMISED TRIAL
SETTING: South Africa
METHOD OF RANDOMISATION: computer generated random numbers.
BLINDING: unblinded
NUMBER RANDOMISED: 107
Participants
Interventions
Outcomes
Notes
A single centre RCT investigated the benefit of using metformin in clomifene ovulation
induction treatment. ITT was used in our analysis. Participant lost to follow-up classified
as non-responder; whilst pregnant participants did not attend follow up visit (one in
each arm) were classified as responder
Risk of bias
Bias
Authors judgement
Not stated
Unclear risk
Unblinded
Unclear risk
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
89
Siebert 2009
Other bias
(Continued)
Unclear risk
inadequate information
Sturrock 2002
Methods
RANDOMISED TRIAL
SETTING: UK
METHOD OF RANDOMISATION: performed by pharmacy*
BLINDING: double blind
NUMBER RANDOMISED: 19
Participants
Interventions
Outcomes
Notes
This was designed as a crossover trial, with six months in the treatment / placebo arm
followed by a 1 month washout and then a three month crossover. In this review, only
the first phase is considered
The inclusion criteria were simply for clomiphene-resistant anovulation and not specifically PCOS. However only two women did not have ultrasound criteria of PCOS, and
75% had a raised free androgen index*.
In this review, only those participants who had a raised free androgen index are included
in the analysis*
*= Information kindly provided by the author that was not in the original paper
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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90
Sturrock 2002
(Continued)
Risk of bias
Bias
Authors judgement
Performed by pharmacy
Unclear risk
Performed by pharmacy
inadequate information
High risk
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Tang 2006
Methods
RANDOMISED TRIAL
SETTING: UK
METHOD OF RANDOMISATION: a multi-centre randomised placebo controlled
trial. The randomisation was performed by the research pharmacy department centrally.
Using a random table, a block of 4 randomisation technique was employed in the study.
Medications were supplied centrally from the research pharmacy department. The code
was kept in the pharmacy department until the end of the trial period.
BLINDING: Double
NUMBER RANDOMISED: 143
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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91
Tang 2006
(Continued)
Outcomes
Notes
Risk of bias
Bias
Authors judgement
Low risk
Double blinded
DROP OUTS - 11 (15.9%) in the metformin arm, 6 (8.1%). The difference was
not significant. Details of the drop out subjects were not mentioned
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
92
Tang 2006
(Continued)
Low risk
Other bias
Unclear risk
inadequate information
Trolle 2007
Methods
RANDOMISED TRIAL
SETTING: Denmark
METHOD OF RANDOMISATION: random number table
BLINDING: Double, crossover
NUMBER RANDOMISED: 60
Participants
Interventions
Outcomes
Notes
This is a single centre randomised, double blinded, placebo controlled cross-over study
to assess the effects of metformin on menstrual frequency and metabolic parameters.
Women were randomised to receive either metformin or placebo tablets for 6 months.
After a 3 months wash-out period, the women received the alternate treatment.
Women who wished for fertility treatment were excluded.
* information kindly provided by the author that was not in the original article
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
93
Trolle 2007
(Continued)
Unclear risk
Double blinded
Low risk
Low risk
Other bias
High risk
Vandermolen 2001
Methods
RANDOMISED TRIAL
SETTING: USA, multi-centre
METHOD OF RANDOMISATION: computer generation in blocks of 6
BLINDING: Double blind
NUMBER RANDOMISED: 27
Participants
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
94
Vandermolen 2001
(Continued)
Outcomes
Notes
Although obesity was not an inclusion criteria, the mean BMI was high in this study
although similar in both arms
*= Information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Not stated
Unclear risk
Double blind
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
95
Vandermolen 2001
(Continued)
Unclear risk
Unclear risk
Inadequate information
Other bias
Unclear risk
Inadequate information
Williams 2009
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: not stated
BLINDING: Double blind
NUMBER RANDOMISED: 55
Participants
SUMMARY: PCOS
INCLUSION CRITERIA: not stated. Unknown BMI and age
EXCLUSION CRITERIA: unknown
BASELINE CHARACTERISTICS OF EACH GROUP: not stated
DROP OUTS - not stated
26 women underwent 99 blinded treatment cycles whilst 29 women underwent 88
blinded treatment cycles
Interventions
Outcomes
Ovulation
Pregnancy
Notes
A conference abstract presented in The 57th Annual Meeting of The Pacific Coast
Reproductive Society 2009
No reply from author regarding the detail of the study
Risk of bias
Bias
Authors judgement
inadequate information
inadequate information
Unclear risk
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
96
Williams 2009
(Continued)
inadequate information
Unclear risk
inadequate information
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Yarali 2002
Methods
RANDOMISED TRIAL
SETTING: Turkey
METHOD OF RANDOMISATION: computer generated numbers. Centralised randomisation process*
BLINDING: Double blind
NUMBER RANDOMISED: 32
Participants
Interventions
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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97
Yarali 2002
(Continued)
Notes
Free testosterone was significantly higher in the metformin group. Fasting insulin was
non-significantly higher with a wide SD compared with placebo
*= Information kindly provided by the author that was not in the original paper
Risk of bias
Bias
Authors judgement
Unclear risk
inadequate information
inadequate information
Unclear risk
DROP OUTS - 2(6%) from the metformin / placebo part of the trial owing to
pregnancy. They were excluded from analysis
Unclear risk
Insufficient information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
98
Yarali 2002
Other bias
(Continued)
Unclear risk
Insufficient information
Zain 2009
Methods
RANDOMISED TRIAL
SETTING: Malaysia
METHOD OF RANDOMISATION: picking a card out of a box
BLINDING: no
NUMBER RANDOMISED: 124
Participants
Interventions
Outcomes
Notes
This study was designed to compare the live birth rates in women received clomiphene,
metformin and combined clomiphene and metformin treatments. Placebo tablets were
not used in this unblinded randomised controlled trial. Therefore, potential bias may be
introduced.
Most women are Malay (about 90%).
Analysis was based on analysis per protocol, not ITT.
Risk of bias
Bias
Authors judgement
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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99
Zain 2009
(Continued)
Unclear risk
unblinded
High risk
Unclear risk
inadequate information
Other bias
Unclear risk
inadequate information
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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100
Study
Aroda 2009
The aim of the study was to evaluate the effects of pioglitazone on insulin action and ovarian androgen
production in women with PCOS. This is a randomised placebo controlled trial but the details of randomisation were not provided. Furthermore, the recruited subjects did not have history of subfertility
Azziz 2001
Randomised double blind study comparing troglitazone (150mg, 300mg, 600mg daily) with placebo
Randomisation method was unclear and no reply from the author
Troglitazone has been withdrawn from the market due to risk of hepatic damage
Azziz 2003
Randomised double blind study comparing troglitazone (150mg, 300mg, 600mg daily) with placebo
Randomisation method was unclear and no reply from the author
Troglitazone has been withdrawn from the market due to risk of hepatic damage
Crave 1995
De Leo 1999
Randomised trial in women with clomiphene-resistant PCOS having 75IU FSH for ovulation induction,
comparing pre-treatment with metformin 500mg tds with no metformin pre-treatment
The aims and outcome measures were different from the other included trials (main outcome measures were
number of FSH ampoules, days of treatment and markers of ovarian hyperstimulation). The trial reported
treatment cycles rather than participants, and combined the results of each group in a crossover type analysis.
Therefore the data was not suitable for inclusion in this meta-analysis
Dunaif 1996
Randomised double blind trial in women with PCOS comparing troglitazone 200mg and troglitazone
400mg daily
This trial only randomised for dose of troglitazone, and did not have a placebo or no treatment arm
Elter 2002
Randomised trial in non-obese women with PCOS comparing metformin and the combined oral contraceptive (ethinyl estradiol/cyproterone acetate) with the combined contraceptive alone
This trial did not compare metformin with placebo, no treatment or an ovulation induction agent
Hou 2000
Non-English trial in women with clomiphene resistant PCOS, comparing metformin with the Chinese
herbal formula tiangui fang
The paper makes no mention of randomisation and has therefore been classified as a controlled clinical trial.
Ovulation was assessed by menstrual cyclicity and basal body temperature change but not by a biochemical
method
This trial did not have a placebo or no-treatment arm, and the only significant result reported was a reduction
in testosterone and BMI in the tiangui fang arm compared with baseline
Ibanez 2002
Randomised trial in lean, young women with anovulation, hyperinsulinaemia, and hyperandrogenaemia. It
had three arms: metformin only, flutamide only and metformin and flutamide together
This trial was not included because it had no placebo arm, and the anti-androgen flutamide is not an
ovulation induction agent
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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101
(Continued)
Kazerooni 2009
This study evaluated the effect of short-course pretreatment with metformin on hyperandrogenism, insulin
resistance, cervical scores and pregnancy rates in women with clomifene resistant PCOS
Apart from receiving clomifene treatment, all participants received 10,000U of hCG injection to stimulate
ovulation followed by time intercourse. Hence, all women received 2 ovulation induction agents per cycle
of treatment. Therefore, it would not be appropriate to combine these subjects in the current review as all
the included trial patient only received one type of ovulation induction agent with or without metformin
Kelly 2002
This study was published in 2002. The objective was to ascertain the effect of metformin on hirsutism in
women with PCOS. This outcome measure has been removed in the update review
Kocak 2002
Quasi-randomised trial comparing combined clomiphene and metformin with clomiphene on ovulation in
clomifene resistance women with PCOS
Inadequate randomisation and sequence generation (sequential by order of admission. Admission determined
by day of menses. Allocation performed by nurse blinded to the study. Odd numbers allocated metformin,
even numbers allocated placebo
Mantzoros 1997
Randomised double-blind trial in women with PCOS comparing troglitazone 200mg and troglitazone
400mg daily
This trial only randomised for dose of troglitazone, and did not have a placebo or no treatment arm
Morin-Papunen 2000
Randomised trial in obese women with PCOS comparing metformin 500mg bd and 1g bd with combined
oral contraceptive (ethinyl estradiol/cyproterone acetate)
This trial was not blinded and did not compare metformin with placebo, no treatment or an ovulation
induction agent
Nestler 1996
This study investigated hyperinsulinemia stimulates ovarian cytochrome P450c17 activity in women with
PCOS. Some of the subjects were not infertile
Nestler 1997
Partially randomised trial in lean women with PCOS comparing metformin 500mg tds with placebo
The method of randomisation was initially by pulling pieces out of a hat, but then continued as an observational study. The trial was initially single blind, with the patient blinded
The published data included both randomised and non-randomised participants, and an analysis to include
only the randomised participants was not possible
Ramzy 2003
An open labelled randomised trial comparing metformin 500mg t.d.s with placebo 6 weeks prior to
clomiphene treatment. In addition, randomisation was performed using alternate number. These factors
introduced significant bias
Rouzi 2006
Randomised trial comparing clomiphene and metformin with clomiphene 1.5 g and rosiglitazone 4mg in
clomiphene resistant women with PCOS
This trial did not compare metformin/clomiphene with clomiphene/placebo
Santonocito 2009
The objective of this study is to compare clomifene with metformin on ovulation rates. However, all subjects
also recieved 2000U of hCG injection once follicular diameter over 15mm on USS
Shobokshi 2003
The objective of this study was to compare the effects of combined rosiglitazone and clomiphene with
clomiphene monotherapy. Since placebo was not employed in the trial, both the clinician and participants
were not blinded. Therefore, bias may exist in this study
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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102
(Continued)
It was unclear whether the study was randomised. We are currently still waiting for a response from the
author
RCT
Participants
Interventions
Outcomes
Ovulation
Notes
Costantino 2009
Methods
RCT
Participants
Interventions
Outcomes
Notes
Farzadi 2006
Methods
RCT
Participants
Interventions
Outcomes
Notes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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103
Morin-Papunen 2010
Methods
RCT
Participants
Interventions
Outcomes
Notes
Conference abstract. Not enough information to separate the data for analysis. No reply from author
Refaie 2005
Methods
RCT
Participants
34 women with insulin resistant PCOS (another 21 women with non-insulin-resistant PCOS not included in
randomised comparison
Interventions
Outcomes
Notes
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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104
No. of
studies
No. of
participants
3
6
115
3
5
73
318
8
4
707
413
294
15
5
1208
441
11
767
7
1
427
23
404
3
16
6
279
630
166
11
464
10
4
449
136
313
379
96
283
292
Statistical method
Effect size
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
105
96
196
14
6
610
166
444
15
626
134
11
492
14
4
596
111
11
485
14
4
573
85
11
488
10
5
562
276
286
7
3
309
53
256
Comparison 2. Metformin combined with ovulation induction agent clomifene versus clomifene alone
No. of
studies
No. of
participants
7
3
907
359
548
2 Adverse events
2.1 Nausea and vomiting
2
1
489
418
Statistical method
Effect size
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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106
2.2 Gastrointestinal
disturbance (other than nausea
and vomiting)
3 Clinical pregnancy rate
3.1 Participants with BMI <
30kg/m2
3.2 Participants with BMI
30kg/m2
4 Ovulation rate (grouped by
sensitivity to clomiphene)
4.1 PCOS and clomifene
sensitive
4.2 PCOS and clomifene
resistant
4.3 PCOS and clomifene
sensitivity not defined
5 Ovulation rate (grouped by
BMI)
5.1 BMI <30 kg/m2
5.2 BMI 30kg/m2
6 Miscarriage rate
7 Multiple pregnancy rate
71
11
4
1208
513
695
18
3265
56
179
12
3030
17
3078
8
9
7
6
691
2387
837
916
No. of
studies
2
2
No. of
participants
Statistical method
Effect size
Subtotals only
500
5
3
349
Subtotals only
1.94 [1.19, 3.16]
500
4
2
497
Subtotals only
0.87 [0.60, 1.26]
2044
4
5
173
403
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
107
No. of
studies
No. of
participants
2
1
1
1
327
44
44
44
44
1
1
44
44
1
1
1
1
44
44
44
44
Statistical method
Effect size
No. of
studies
No. of
participants
1
2
3
3
1
1
64
100
132
132
52
52
1
3
54
132
3
2
2
1
132
80
80
26
Statistical method
Effect size
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
108
No. of
studies
No. of
participants
2
2
1
2
2
70
63
28
63
63
63
Statistical method
Effect size
Analysis 1.1. Comparison 1 Metformin versus placebo or no treatment, Outcome 1 Live birth rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
1/9
2/9
45.6 %
5/32
2/33
42.7 %
Yarali 2002
1/16
0/16
11.7 %
57
58
100.0 %
Ng 2001
Weight
Odds Ratio
M-H,Fixed,95% CI
10 100 1000
Favours metformin
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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Analysis 1.2. Comparison 1 Metformin versus placebo or no treatment, Outcome 2 Adverse events
(gastrointestinal side effects).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Control
n/N
n/N
Odds Ratio
Weight
5/11
2/12
48.2 %
3/9
1/9
30.8 %
1/16
0/16
21.0 %
36
37
100.0 %
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
15/45
5/47
26.1 %
Moghetti 2000
2/11
0/12
3.0 %
2/9
0/9
3.0 %
PCOSMIC 2010
10/32
11/33
59.6 %
Trolle 2007
29/60
2/60
8.3 %
157
161
100.0 %
Ng 2001
10 100 1000
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Analysis 1.3. Comparison 1 Metformin versus placebo or no treatment, Outcome 3 Clinical pregnancy rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
2/16
0/16
1.4 %
1/9
2/9
5.9 %
Karimzadeh 2007
40/100
11/100
21.9 %
Karimzadeh 2010
17/88
15/75
43.4 %
213
200
72.6 %
M-H,Fixed,95% CI
4/23
1/19
3.0 %
Lord 2006
3/22
2/22
5.7 %
Tang 2006
6/69
2/74
5.9 %
7/32
5/33
12.8 %
146
148
27.4 %
348
100.0 %
359
10 100 1000
Favours metformin
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
111
Analysis 1.4. Comparison 1 Metformin versus placebo or no treatment, Outcome 4 Ovulation rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Control
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
n/N
n/N
27/32
11/32
7.6 %
7/12
3/12
5.0 %
3/9
3/9
4.2 %
17/153
20/150
11.1 %
6/16
1/16
3.4 %
222
219
31.3 %
37/45
30/47
9.1 %
Hoeger 2004
4/9
3/9
4.4 %
Hoeger 2004
3/9
6/11
4.7 %
8/28
0/28
2.3 %
18/111
15/104
10.7 %
9/22
9/22
7.6 %
Nestler 1998
12/35
1/26
3.8 %
Onalan 2005
5/63
5/51
7.0 %
Otta 2010
7/14
6/15
6.1 %
17/32
13/33
9.0 %
Sturrock 2002
0/12
1/14
1.8 %
Vandermolen 2001
1/12
1/15
2.3 %
392
375
68.7 %
100.0 %
Jakubowicz 2001
Ladson 2011
Lord 2006
614
594
0.001 0.01 0.1
Favours control
10 100 1000
Favours metformin
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
112
(. . .
Study or subgroup
Metformin
Control
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Continued)
Odds Ratio
MH,Random,95%
CI
Favours control
10 100 1000
Favours metformin
Analysis 1.5. Comparison 1 Metformin versus placebo or no treatment, Outcome 5 Menstrual frequency.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
5/11
0/12
0.8 %
11
12
0.8 %
14/15
8/17
1.5 %
8/22
2/23
3.6 %
Hoeger 2004
2/9
2/11
4.1 %
Hoeger 2004
2/9
0/9
1.1 %
Sturrock 2002
5/12
6/14
9.4 %
Tang 2006
36/69
43/74
57.7 %
Trolle 2007
19/60
11/60
21.9 %
M-H,Fixed,95% CI
0.002
0.1
Favours control
10
500
Favours metformin
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
113
(. . .
Study or subgroup
Metformin
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
196
Continued)
Weight
Odds Ratio
208
99.2 %
220
100.0 %
M-H,Fixed,95% CI
207
0.002
0.1
Favours control
10
500
Favours metformin
Analysis 1.6. Comparison 1 Metformin versus placebo or no treatment, Outcome 6 Miscarriage rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Karimzadeh 2007
4/40
3/11
Karimzadeh 2010
0/88
0/75
1/32
2/33
31.1 %
160
119
100.0 %
Weight
Odds Ratio
M-H,Fixed,95% CI
68.9 %
0.01
0.1
Favours Metformin
10
100
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
114
Analysis 1.7. Comparison 1 Metformin versus placebo or no treatment, Outcome 7 Body Mass Index
(kg/m2).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
28
24.3 (0.53)
30
24.3 (0.55)
84.3 %
24.9 (7.1)
25.3 (5.1)
0.2 %
11
26 (4.64)
12
31.9 (3.81)
0.5 %
24.4 (4.3)
22.7 (3.5)
0.4 %
Romualdi 2010
13
22.1 (2.52)
10
23.2 (4.1)
0.8 %
Yarali 2002
16
29.8 (3.4)
16
29.8 (4.9)
0.8 %
87.0 %
83
83
14
34.9 (5)
16
37.2 (6.4)
0.4 %
Fleming 2002
25
35.2 (8.9)
39
35.3 (8.6)
0.3 %
Hoeger 2004
41.7 (9.2)
40.6 (8)
0.1 %
Hoeger 2004
36.1 (5.3)
36.4 (5.1)
0.2 %
Jakubowicz 2001
26
31.8 (1.52)
22
31.7 (1.52)
8.7 %
Ladson 2011
31
37.18 (5.86)
25
35.99 (7.96)
0.5 %
Lord 2006
16
34.6 (9.1)
16
35.3 (6.5)
0.2 %
36.5 (6.8)
36.2 (3.4)
0.2 %
Otta 2010
14
31.53 (4.93)
15
34.16 (4.95)
0.5 %
Pasquali 2000
10
36.4 (7.4)
38 (6.2)
0.2 %
Tang 2006
56
37.1 (5.1)
66
37.4 (6.3)
1.6 %
Vandermolen 2001
11
35.4 (10.28)
14
38.4 (7.43)
0.1 %
243
13.0 %
326
100.0 %
Maciel 2004
221
304
-10
-5
Favours metformin
10
Favours control
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
115
(. . .
Study or subgroup
Metformin
N
Heterogeneity:
Chi2
Mean
Difference
Control
Mean(SD)
= 16.95, df = 17 (P = 0.46);
I2
Mean(SD)
Mean
Difference
Weight
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI
=0.0%
-10
-5
Favours metformin
10
Favours control
Analysis 1.8. Comparison 1 Metformin versus placebo or no treatment, Outcome 8 Waist-hip ratio.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
Baillargeon 2004
28
0.8 (0.01)
30
0.81 (0.01)
91.6 %
Moghetti 2000
11
0.82 (0.07)
12
0.82 (0.07)
0.7 %
Romualdi 2010
13
0.75 (0.1)
10
0.76 (0.1)
0.4 %
Yarali 2002
16
0.8 (0.1)
16
0.8 (0.1)
0.5 %
93.2 %
68
68
14
0.95 (0.07)
16
0.93 (0.07)
1.0 %
Fleming 2002
26
0.88 (0.07)
38
0.88 (0.07)
2.0 %
Jakubowicz 2001
26
0.84 (1.02)
22
0.85 (0.05)
0.0 %
Lord 2006
16
0.83 (0.06)
15
0.88 (0.07)
1.1 %
Pasquali 2000
10
0.86 (0.07)
0.88 (0.05)
0.8 %
-0.2
-0.1
Favours metformin
0.1
0.2
Favours control
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
116
(. . .
Study or subgroup
Metformin
Tang 2006
Mean
Difference
Control
Mean(SD)
Mean(SD)
56
0.91 (0.1)
66
0.9 (0.1)
148
Mean
Difference
Weight
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI
1.9 %
165
6.8 %
233
100.0 %
216
-0.2
-0.1
Favours metformin
0.1
0.2
Favours control
Analysis 1.9. Comparison 1 Metformin versus placebo or no treatment, Outcome 9 Blood pressure systolic (mm Hg).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
28
119.5 (3.7)
30
122.7 (3.3)
72.9 %
101.4 (10.6)
106.3 (13)
1.7 %
11
119.1 (12.93)
12
133 (13.51)
2.0 %
76.7 %
46
50
14
121.6 (10.5)
16
126.1 (18.4)
2.1 %
Lord 2006
16
122.7 (13.5)
15
138.4 (11.3)
3.1 %
-20
-10
Favours metformin
10
20
Favours control
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
117
(. . .
Study or subgroup
Metformin
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
110 (17)
125 (13.7)
0.9 %
Tang 2006
56
121.7 (12.5)
66
121.4 (12.1)
12.4 %
Trolle 2007
42
126 (17)
44
130.2 (16.5)
4.8 %
147
23.3 %
197
100.0 %
Maciel 2004
136
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI
182
-20
-10
Favours metformin
10
20
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
118
Analysis 1.10. Comparison 1 Metformin versus placebo or no treatment, Outcome 10 Blood pressure diastolic (mm Hg).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
28
81.4 (2.6)
30
81.5 (2.7)
78.6 %
71.4 (10.6)
67.5 (8.8)
1.5 %
11
76.7 (10.96)
12
85.5 (11.78)
1.7 %
81.8 %
46
50
14
84.6 (10)
16
84.8 (10.4)
2.7 %
Lord 2006
15
76.7 (10.9)
15
79.5 (13)
2.0 %
73.8 (7.3)
81.6 (11)
1.4 %
56
77.2 (10)
66
75.5 (9.5)
12.1 %
103
18.2 %
153
100.0 %
Maciel 2004
Tang 2006
93
139
-20
-10
Favours metformin
10
20
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
119
Analysis 1.11. Comparison 1 Metformin versus placebo or no treatment, Outcome 11 Serum testosterone
(nmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Treatment
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
Moghetti 2000
11
2.3 (1.3)
12
2.3 (0.8)
2.0 %
Baillargeon 2004
28
1.28 (0.7)
30
4.15 (0.76)
11.1 %
Yarali 2002
16
5.83 (1.56)
16
5.15 (2.74)
0.7 %
Ng 2001
1.3 (0.5)
1.7 (0.7)
4.0 %
Maciel 2004
2.25 (0.69)
3.57 (0.83)
2.6 %
13
1.52 (0.5)
10
2 (1.42)
1.8 %
22.2 %
Romualdi 2010
83
83
16
2.51 (0.64)
15
2.26 (0.61)
8.1 %
Tang 2006
56
1.9 (0.6)
66
2.3 (0.7)
29.4 %
Jakubowicz 2001
26
1.33 (1.78)
22
3.73 (1.92)
1.4 %
Chou 2003
14
1.6 (0.67)
16
2.27 (0.87)
5.1 %
1.57 (0.58)
2.36 (0.66)
3.1 %
Vandermolen 2001
11
2.46 (0.81)
14
2.67 (0.65)
4.5 %
Trolle 2007
42
2.3 (0.89)
45
2.54 (0.6)
15.2 %
Fleming 2002
25
2.74 (1.07)
36
2.81 (0.94)
5.8 %
Hoeger 2004
2.1 (0.34)
1.89 (0.8)
4.3 %
Maciel 2004
3.73 (0.79)
3.52 (1.55)
0.9 %
236
77.8 %
319
100.0 %
Hoeger 2004
208
291
-4
-2
Favours metformin
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
120
Analysis 1.12. Comparison 1 Metformin versus placebo or no treatment, Outcome 12 Serum sex hormonebinding globulin (nmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Treatment
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
Ng 2001
25.7 (11.7)
31.8 (16.2)
2.5 %
Maciel 2004
169.5 (67)
274.3 (74.1)
0.1 %
Romualdi 2010
13
45.1 (15.5)
10
49.6 (18.8)
2.5 %
Moghetti 2000
11
44.6 (35.16)
12
34.4 (18.91)
1.0 %
Baillargeon 2004
28
208 (91.8)
30
232 (95)
0.2 %
6.3 %
67
67
23.8 (8.2)
30.3 (12.1)
4.0 %
Lord 2006
16
27.41 (10)
15
30.3 (9.4)
11.2 %
Tang 2006
56
24.7 (12.1)
66
24.4 (12.9)
26.5 %
Jakubowicz 2001
26
196 (66.29)
22
120 (42.21)
0.5 %
Fleming 2002
25
29.2 (12.3)
36
28.6 (16.8)
9.8 %
Nestler 1998
35
93 (59.16)
26
124 (86.68)
0.3 %
Vandermolen 2001
11
61 (39.8)
14
71 (36.67)
0.6 %
Chou 2003
14
24.3 (11)
16
23.9 (10.8)
8.5 %
Pasquali 2000
10
16.7 (8.1)
13.8 (2.1)
19.1 %
Ladson 2011
31
28.23 (11.82)
25
30.83 (16.7)
8.7 %
Hoeger 2004
37.2 (4.8)
34.4 (15.2)
4.5 %
Maciel 2004
194.2 (110.9)
236.5 (134)
0.0 %
Hoeger 2004
-100
-50
Favours control
50
100
Favours metformin
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
121
(. . .
Study or subgroup
Treatment
N
Mean
Difference
Control
Mean(SD)
242
Mean(SD)
Mean
Difference
Weight
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI
250
93.7 %
317
100.0 %
309
-100
-50
Favours control
50
100
Favours metformin
Analysis 1.13. Comparison 1 Metformin versus placebo or no treatment, Outcome 13 Fasting glucose
(mmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Treatment
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
28
4.7 (0.7)
30
4.5 (0.7)
6.8 %
Ng 2001
5.1 (0.3)
5.1 (0.5)
4.9 %
Maciel 2004
4.59 (0.62)
4.34 (0.24)
3.7 %
11
4.4 (0.33)
12
4.9 (0.35)
11.4 %
26.8 %
Moghetti 2000
54
57
10
5.04 (0.952)
5.32 (0.616)
1.7 %
Fleming 2002
25
5.05 (0.64)
38
4.95 (0.45)
10.6 %
-4
-2
Favours metformin
Favours control
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
122
(. . .
Study or subgroup
Treatment
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
Vandermolen 2001
11
4.42 (0.84)
14
5.04 (0.63)
2.5 %
Trolle 2007
38
5.17 (0.42)
41
5.4 (0.5)
21.4 %
Otta 2010
14
4.77 (0.62)
15
4.98 (0.61)
4.4 %
Lord 2006
16
5.03 (0.53)
15
5.05 (0.48)
7.0 %
Chou 2003
14
5.06 (0.69)
16
5.12 (0.61)
4.0 %
Jakubowicz 2001
26
4.3 (1.02)
22
5 (0.94)
2.9 %
5.11 (0.57)
5.22 (0.49)
2.3 %
56
4.87 (0.65)
66
4.95 (0.85)
12.4 %
Hoeger 2004
4.97 (0.59)
5.53 (0.36)
2.7 %
Maciel 2004
4.74 (0.73)
4.73 (0.78)
1.4 %
257
73.2 %
314
100.0 %
Hoeger 2004
Tang 2006
228
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI
282
-4
-2
Favours metformin
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
123
Analysis 1.14. Comparison 1 Metformin versus placebo or no treatment, Outcome 14 Fasting insulin
(mIU/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Treatment
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Random,95% CI
IV,Random,95% CI
6.3 (1.59)
14.1 (3.96)
11.0 %
11
10.2 (7.3)
12
21.3 (13.51)
6.0 %
7.1 (1.9)
9.3 (5.7)
9.7 %
16
16.4 (32.71)
16
12.2 (7)
2.6 %
29.3 %
42
43
14
39.4 (14.6)
16
36.9 (24.3)
3.3 %
Fleming 2002
25
16.8 (9.7)
37
18.4 (12.3)
8.7 %
Hoeger 2004
16.7 (10.6)
17.5 (6)
5.0 %
Hoeger 2004
17.9 (6.5)
21.1 (10.8)
5.8 %
Jakubowicz 2001
26
13.17 (11.9)
22
46.01 (30.49)
3.5 %
Lord 2006
16
17.35 (8.9)
15
15.4 (6.3)
8.8 %
21.1 (9.33)
23.2 (12.3)
4.2 %
Otta 2010
14
9.42 (5.13)
15
15.31 (5.36)
10.3 %
Pasquali 2000
10
21.6 (31.2)
19 (14.4)
1.6 %
Tang 2006
56
24.2 (39)
66
18.9 (17.1)
4.6 %
Trolle 2007
45
13.5 (12.8)
38
13.5 (9.8)
9.3 %
Vandermolen 2001
11
10.4 (6.97)
14
14.4 (15.71)
5.7 %
70.7 %
100.0 %
Maciel 2004
235
253
277
296
-100
-50
Favours metformin
50
100
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
124
Analysis 1.15. Comparison 1 Metformin versus placebo or no treatment, Outcome 15 Total cholesterol
(mmol/l).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Experimental
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
100
4.89 (1.52)
100
5.19 (1.11)
19.9 %
4.35 (0.79)
3.82 (0.85)
3.9 %
11
4.61 (0.4)
12
4.42 (0.69)
13.0 %
4.5 (0.9)
5.2 (1.6)
1.5 %
13
3.93 (0.58)
10
3.73 (0.75)
8.6 %
46.9 %
139
137
14
4.18 (0.52)
16
5.11 (1.4)
5.0 %
Fleming 2002
26
4.61 (0.82)
34
4.93 (0.96)
13.3 %
Lord 2006
16
4.78 (0.82)
15
5.65 (1.15)
5.4 %
4.88 (0.77)
4.3 (1.13)
2.5 %
Otta 2010
14
4.12 (0.77)
15
4.81 (0.75)
8.8 %
Tang 2006
56
5.14 (1.03)
66
4.88 (1.15)
18.1 %
152
53.1 %
289
100.0 %
Maciel 2004
134
273
-2
-1
Favours metformin
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
125
Analysis 1.16. Comparison 1 Metformin versus placebo or no treatment, Outcome 16 Triglyceride levels
(mmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Treatment
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
1.42 (0.86)
0.73 (0.39)
7.1 %
11
0.98 (0.37)
12
1.12 (0.8)
13.5 %
0.9 (0.4)
1.2 (0.7)
9.9 %
30.6 %
26
27
14
1.69 (1.24)
16
1.64 (0.64)
6.6 %
Fleming 2002
26
1.62 (0.97)
34
1.4 (0.49)
20.6 %
Lord 2006
16
1.44 (0.71)
14
1.34 (0.62)
15.1 %
1.63 (1.05)
1.29 (0.48)
5.1 %
56
2.04 (1.01)
66
1.78 (1.21)
22.1 %
136
69.4 %
163
100.0 %
Maciel 2004
Tang 2006
120
146
-1
-0.5
Favours metformin
0.5
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
126
Analysis 2.1. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 1 Live birth rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 1 Live birth rate
Study or subgroup
Met + clomifene
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
M-H,Fixed,95% CI
11/32
4/31
3.4 %
21/111
31/114
31.8 %
15/35
13/36
9.4 %
178
181
44.7 %
Moll 2006
56/209
47/209
44.2 %
Sahin 2004
3/11
3/10
2.9 %
Vandermolen 2001
4/12
1/15
0.8 %
Zain 2009
7/41
7/41
7.5 %
273
275
55.3 %
456
100.0 %
451
0.01
0.1
Favours clomifene
10
100
Favours met+clomifene
(1) Ovulation induction with CC. All patients had BMI <33
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
127
Analysis 2.2. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 2 Adverse events.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 2 Adverse events
Study or subgroup
MF + clomifene
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
72/209
28/209
84.4 %
209
209
84.4 %
11/35
5/36
15.6 %
35
36
15.6 %
245
100.0 %
M-H,Fixed,95% CI
244
10 100 1000
Favours clomifene
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
128
Analysis 2.3. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 3 Clinical pregnancy rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 3 Clinical pregnancy rate
Study or subgroup
MF + clomifene
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
6/40
0/40
0.4 %
13/90
11/90
10.1 %
9/16
2/12
1.1 %
57/111
64/114
32.8 %
257
256
44.4 %
13/45
4/45
3.0 %
5/16
0/15
0.4 %
Legro 2007
80/209
62/209
40.9 %
Sahin 2004
5/11
3/10
1.8 %
Sturrock 2002
3/12
4/14
3.0 %
Vandermolen 2001
6/12
1/15
0.5 %
Zain 2009
8/41
7/41
6.0 %
346
349
55.6 %
605
100.0 %
M-H,Fixed,95% CI
603
0.002
0.1
Favours clomifene
10
500
Favours MF + clomifene
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
129
Analysis 2.4. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 4 Ovulation rate (grouped by sensitivity to clomiphene).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 4 Ovulation rate (grouped by sensitivity to clomiphene)
Study or subgroup
MF+ clomifene
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
26/28
22/28
0.5 %
28
28
0.5 %
M-H,Fixed,95% CI
17/40
5/40
1.0 %
Malkawi 2002
11/16
3/12
0.4 %
4/9
1/9
0.2 %
Sturrock 2002
5/12
4/14
0.8 %
Vandermolen 2001
9/12
4/15
0.3 %
89
90
2.6 %
Ng 2001
10/16
6/16
0.8 %
Boudhraa 2010
17/32
10/31
1.7 %
El-Biely 2001
35/45
29/45
2.2 %
7/16
1/15
0.2 %
Legro 2007
582/964
462/942
64.7 %
Moll 2006
84/141
98/168
12.6 %
Nestler 1998
19/21
2/25
0.1 %
PCOSMIC 2010
27/35
23/36
1.8 %
Sahin 2004
38/51
34/55
2.9 %
Siebert 2009
34/52
36/55
4.2 %
Williams 2009
20/99
17/88
5.0 %
Khorram 2006
0.05
0.2
Favours clomifene
20
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
130
(. . .
Study or subgroup
Zain 2009
MF+ clomifene
clomifene
Odds Ratio
M-H,Fixed,95% CI
Weight
Continued)
Odds Ratio
n/N
n/N
38/41
24/41
0.6 %
M-H,Fixed,95% CI
1513
1517
96.8 %
1635
100.0 %
1630
0.05
0.2
Favours clomifene
20
Analysis 2.5. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 5 Ovulation rate (grouped by BMI).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 5 Ovulation rate (grouped by BMI)
Study or subgroup
MF+ clomifene
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
10/16
6/16
0.8 %
Boudhraa 2010
17/32
10/31
1.8 %
El-Biely 2001
35/45
29/45
2.4 %
Hwu 2005
17/40
5/40
1.1 %
Malkawi 2002
11/16
3/12
0.4 %
84/141
98/168
13.3 %
4/9
1/9
0.2 %
M-H,Fixed,95% CI
Moll 2006
Ng 2001
0.002
0.1
Favours clomifene
10
500
(Continued . . . )
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
131
(. . .
Study or subgroup
MF+ clomifene
clomifene
Odds Ratio
M-H,Fixed,95% CI
Weight
Continued)
Odds Ratio
n/N
n/N
27/35
23/36
1.9 %
M-H,Fixed,95% CI
1.91 [ 0.67, 5.41 ]
334
357
21.8 %
26/28
22/28
0.6 %
7/16
1/15
0.2 %
582/964
462/942
68.1 %
Nestler 1998
19/21
2/25
0.1 %
Sahin 2004
38/51
34/55
3.1 %
Siebert 2009
34/52
36/55
4.5 %
Sturrock 2002
5/12
4/14
0.8 %
Vandermolen 2001
9/12
4/15
0.3 %
38/41
24/41
0.6 %
1197
1190
78.2 %
1547
100.0 %
Zain 2009
1531
0.002
0.1
Favours clomifene
10
500
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
132
Analysis 2.6. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 6 Miscarriage rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 6 Miscarriage rate
Study or subgroup
MF + clomifene
clomifene
n/N
n/N
2/40
0/40
1.7 %
Legro 2007
24/209
16/209
52.6 %
Moll 2006
13/111
12/114
38.8 %
PCOSMIC 2010
3/35
0/36
1.7 %
Sahin 2004
1/11
0/10
1.7 %
Vandermolen 2001
2/6
0/1
1.9 %
Zain 2009
1/8
0/7
1.6 %
420
417
100.0 %
Hwu 2005
Odds Ratio
Weight
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
10 100 1000
Favours clomifene
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
133
Analysis 2.7. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 7 Multiple pregnancy rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Comparison: 2 Metformin combined with ovulation induction agent clomifene versus clomifene alone
Outcome: 7 Multiple pregnancy rate
Study or subgroup
MF + clomifene
clomifene
n/N
n/N
1/90
2/90
22.4 %
Legro 2007
2/209
3/209
33.6 %
Moll 2006
1/111
3/114
33.2 %
1/35
1/36
10.8 %
Vandermolen 2001
0/6
0/1
Not estimable
Zain 2009
0/8
0/7
Not estimable
459
457
Karimzadeh 2010
PCOSMIC 2010
Odds Ratio
Weight
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
100.0 %
10 100 1000
Favours clomifene
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
134
Analysis 3.1. Comparison 3 Metformin versus clomiphene citrate, Outcome 1 Live birth: Participants with
BMI < 30kg/m2 or 32kg/m2.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
metformin
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Palomba 2005
26/50
9/50
PCOSMIC 2010
10/35
19/35
Weight
Odds Ratio
M-H,Fixed,95% CI
0.02
0.1
Favours clomiphene
10
50
Favours metformin
Analysis 3.2. Comparison 3 Metformin versus clomiphene citrate, Outcome 2 Live birth: Participants with
BMI 30kg/m2.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Legro 2007
Zain 2009
metformin
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
15/208
47/209
87.2 %
4/42
7/41
12.8 %
250
250
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours clomiphene
10
100
Favours metformin
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
135
Analysis 3.3. Comparison 3 Metformin versus clomiphene citrate, Outcome 3 Clinical pregnancy rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
metformin
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
M-H,Fixed,95% CI
17/88
11/90
37.9 %
Palomba 2005
31/50
16/50
26.3 %
14/35
14/36
35.8 %
173
176
100.0 %
25/208
62/209
89.5 %
4/42
7/41
10.5 %
250
250
100.0 %
0.02
0.1
Favours clomiphene
10
50
Favours metformin
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
136
Analysis 3.4. Comparison 3 Metformin versus clomiphene citrate, Outcome 4 Ovulation rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Clomifene
n/N
n/N
Odds Ratio
Weight
129/205
148/221
87.2 %
23/35
23/36
12.8 %
240
257
100.0 %
296/1019
462/942
98.2 %
4/42
7/41
1.8 %
1061
983
100.0 %
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
0.01
0.1
Favours clomiphene
10
100
Favours metformin
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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137
Analysis 3.5. Comparison 3 Metformin versus clomiphene citrate, Outcome 5 Miscarriage rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Clomiphene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
10/25
16/62
42.4 %
Palomba 2005
3/31
6/16
54.9 %
PCOSMIC 2010
4/14
0/14
2.7 %
0/4
0/7
74
99
Legro 2007
Zain 2009
Weight
Odds Ratio
M-H,Fixed,95% CI
Not estimable
100.0 %
0.01
0.1
Favours metformin
10
100
Favours clomiphene
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
138
Analysis 3.6. Comparison 3 Metformin versus clomiphene citrate, Outcome 6 Multiple pregnancy.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Metformin
Clomiphene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Karimzadeh 2010
0/88
2/99
44.1 %
Legro 2007
0/25
3/62
37.8 %
Palomba 2005
0/31
0/16
PCOSMIC 2010
1/35
1/36
0/4
0/7
183
220
Zain 2009
Weight
Odds Ratio
M-H,Fixed,95% CI
Not estimable
18.1 %
100.0 %
0.01
0.1
Favours metformin
10
100
Favours clomiphene
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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139
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Control
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
n/N
n/N
128/136
130/147
54.8 %
Nestler 1999
19/22
6/22
45.2 %
158
169
100.0 %
Gerli 2003
0.01
0.1
Favours control
10
100
Favours D-chiro-inositol
Analysis 4.2. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 2 Body Mass Index
(kg/m2).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
31.5 (2.4)
22
31 (2.2)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-10
-5
Favours D-chiro-inositol
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
140
Analysis 4.3. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 3 Waist-hip ratio.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
0.84 (0.06)
22
0.85 (0.08)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-0.5
-0.25
Favours D-chiro-inositol
0.25
0.5
Favours control
Analysis 4.4. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 4 Blood pressure systolic (mm Hg).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
126 (7)
22
128 (6)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-10
-5
Favours D-chiro-inositol
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
141
Analysis 4.5. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 5 Blood pressure Diastolic (mm Hg).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
85 (6)
22
89 (5)
22
Weight
Mean
Difference
100.0 %
100.0 %
IV,Fixed,95% CI
IV,Fixed,95% CI
22
-10
-5
Favours treatment
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
S-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
2.11 (1.14)
22
2.74 (1.35)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-10
-5
Favours D-chiro-inositol
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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142
Analysis 4.7. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 7 Serum sex
hormone-binding globulin (nmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
166.6 (76.34)
22
97.16 (31.23)
22
Weight
Mean
Difference
100.0 %
IV,Fixed,95% CI
IV,Fixed,95% CI
22
-1000
-500
500
Favours control
1000
Favours treatment
Analysis 4.8. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 8 Fasting glucose
(mmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
5.04 (1.06)
22
5.32 (1.34)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-10
-5
Favours D-chiro-inositol
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
143
Analysis 4.9. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 9 Fasting insulin
(mIU/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
22 (21)
22
42 (52)
22
Weight
Mean
Difference
100.0 %
100.0 %
IV,Fixed,95% CI
IV,Fixed,95% CI
22
-100
-50
50
Favours D-chiro-inositol
100
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
4.99 (1.51)
22
5.22 (1.01)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-10
-5
Favours D-chiro-inositol
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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144
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
12.1 (6.71)
22
14.3 (6.93)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
100.0 %
-10
-5
Favours D-chiro-inositol
10
Favours control
Analysis 5.1. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 1 Ovulation rate.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Baillargeon 2004
16/32
11/32
100.0 %
32
32
100.0 %
M-H,Fixed,95% CI
0.1 0.2
0.5
Favours control
10
Favours Rosiglitazone
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
145
Analysis 5.2. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 2 Menstrual frequency.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Lam 2011
16/35
6/35
83.0 %
Rautio 2006
10/15
2/15
17.0 %
50
50
100.0 %
Weight
Odds Ratio
M-H,Fixed,95% CI
0.01
0.1
Favours Rosiglitazone
10
100
Favours control
Analysis 5.3. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 3 Body Mass Index
(kg/m2).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Mean
Difference
Weight
Mean
Difference
24.3 (0.55)
98.8 %
30
26 (6.9)
0.7 %
14
34 (4.5)
0.4 %
100.0 %
Study or subgroup
Rosiglitazone
N
Mean(SD)
Mean(SD)
Baillargeon 2004
22
25 (0.47)
30
Lam 2011
24
24.2 (5.2)
Rautio 2006
12
34.1 (6.2)
Control
58
IV,Fixed,95% CI
IV,Fixed,95% CI
74
-10
-5
Favours Rosiglitazone
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
146
Analysis 5.4. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 4 Waist-hip ratio.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
Baillargeon 2004
22
0.8 (0.01)
30
0.81 (0.01)
97.4 %
Lam 2011
24
0.8 (0.05)
30
0.81 (0.08)
2.4 %
Rautio 2006
12
0.8 (0.2)
14
0.88 (0.07)
0.2 %
100.0 %
58
IV,Fixed,95% CI
IV,Fixed,95% CI
74
-10
-5
Favours Rosiglitazone
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
147
Analysis 5.5. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 5 Blood pressuresystolic (mm Hg).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Mean
Difference
Control
Mean(SD)
Mean(SD)
Baillargeon 2004
22
120.7 (3.7)
30
122.7 (3.3)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
30
100.0 %
100.0 %
-10
-5
Favours Rosiglitazone
10
Favours control
Analysis 5.6. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 6 Blood pressurediastolic (mm Hg).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Mean
Difference
Study or subgroup
Rosiglitazone
Control
Mean(SD)
Mean(SD)
Baillargeon 2004
22
81.3 (2.8)
30
81.5 (2.7)
22
Weight
Mean
Difference
100.0 %
100.0 %
IV,Fixed,95% CI
IV,Fixed,95% CI
30
-10
-5
Favours Rosiglitazone
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
148
Analysis 5.7. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 7 Testoserone (nmo/l).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Experimental
Lam 2011
Mean
Difference
Control
Mean(SD)
Mean(SD)
24
2.29 (1.02)
30
2.09 (1)
24
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
30
100.0 %
100.0 %
-4
-2
Favours experimental
Favours control
Analysis 5.8. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 8 serum sex hormonebinding globulin (nmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Mean
Difference
Weight
Mean
Difference
232 (95)
12.2 %
30
38.2 (28.7)
43.5 %
14
36.2 (17.2)
44.3 %
100.0 %
Study or subgroup
Rosiglitazone
N
Mean(SD)
Mean(SD)
Baillargeon 2004
22
163 (97.6)
30
Lam 2011
24
40.9 (24.7)
Rautio 2006
12
36.9 (18)
Control
58
IV,Random,95% CI
IV,Random,95% CI
74
-100
-50
Favours Rosiglitazone
50
100
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
149
Analysis 5.9. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 9 Fasting glucose
(mmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
Baillargeon 2004
22
4.5 (0.7)
30
4.5 (0.7)
20.8 %
Lam 2011
24
4.29 (0.37)
30
4.53 (0.67)
38.9 %
Rautio 2006
12
5.2 (0.35)
14
5.5 (0.37)
40.2 %
100.0 %
58
IV,Fixed,95% CI
IV,Fixed,95% CI
74
-4
-2
Favours Rosiglitazone
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
150
Analysis 5.10. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 10 Fasting insulin
(mIU/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
Lam 2011
24
11.4 (12.7)
30
14.3 (12)
65.9 %
Rautio 2006
12
14.56 (11.94)
14
20.62 (12.04)
34.1 %
100.0 %
36
IV,Fixed,95% CI
IV,Fixed,95% CI
44
-20
-10
Favours Rosiglitazone
10
20
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
Lam 2011
24
4.96 (0.82)
30
4.99 (0.97)
0.1 %
Rautio 2006
12
5.23 (0.016)
14
5.43 (0.02)
99.9 %
100.0 %
36
IV,Fixed,95% CI
IV,Fixed,95% CI
44
-100
-50
Favours Rosiglitazone
50
100
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
151
Analysis 5.12. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 12 Triglyceride levels.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Rosiglitazone
Rautio 2006
Mean
Difference
Control
Mean(SD)
Mean(SD)
12
18.5 (0.17)
14
17.5 (0.1)
12
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
14
100.0 %
100.0 %
-100
-50
Favours Rosiglitazone
50
100
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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152
Analysis 6.1. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 1 Menstrual frequency.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Pioglitazone
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
7/20
1/20
39.4 %
12/15
5/15
60.6 %
35
35
100.0 %
Brettenthaler 2004
Glintborg 2005
Weight
Odds Ratio
M-H,Fixed,95% CI
0.5
0.7
Favours control
1.5
Favours Pioglitazone
Analysis 6.2. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 2 Body Mass Index
(kg/m2).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Pioglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
Brettenthaler 2004
17
30.1 (7)
18
27.7 (5.1)
46.7 %
Glintborg 2005
14
33.8 (4.35)
14
34.2 (5.85)
53.3 %
31
100.0 %
32
-10
-5
Favours Pioglitazone
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
153
Analysis 6.3. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 3 Waist-hip ratio.
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Pioglitazone
Mean
Difference
Control
Mean(SD)
Mean(SD)
Glintborg 2005
14
0.88 (0.06)
14
0.86 (0.06)
14
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
14
100.0 %
100.0 %
-10
-5
Favours Pioglitazone
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
154
Analysis 6.4. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 4 Serum testosterone
(nmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Pioglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
Brettenthaler 2004
17
2.1 (0.8)
18
2.5 (0.8)
59.2 %
Glintborg 2005
14
2.11 (0.67)
14
1.83 (1.02)
40.8 %
31
100.0 %
32
-10
-5
Favours Pioglitazone
10
Favours control
Analysis 6.5. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 5 Serum sex hormonebinding globulin (nmol/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Pioglitazone
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
Brettenthaler 2004
17
40.8 (13.6)
18
35.8 (16.9)
62.5 %
Glintborg 2005
14
31 (19.2)
14
32 (16)
37.5 %
31
100.0 %
32
-10
-5
Favours Pioglitazone
10
Favours control
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
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Analysis 6.6. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 6 Fasting insulin
(mIU/L).
Review:
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Study or subgroup
Pioglitazone
Mean
Difference
Control
Weight
Mean
Difference
Mean(SD)
Mean(SD)
Brettenthaler 2004
17
8.87 (3.6)
18
10.3 (5.9)
IV,Fixed,95% CI
61.0 %
IV,Fixed,95% CI
Glintborg 2005
14
9 (6.25)
14
10.5 (4.46)
39.0 %
31
100.0 %
32
-10
-5
Favours Pioglitazone
10
Favours control
ADDITIONAL TABLES
Table 1. Abbreviations used
Abbreviation
Definition
BMI
CI
Confidence interval
CT
DHEAS
Dehydroepiandrosterone sulphate
FSH
GTT
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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(Continued)
HbA1C
Glycosylated haemoglobin
HDL
IGFBP-1
LDL
LH
Luteinising hormone
NIDDM
PAI-1
PCOS
RCT
rFSH
SD
Standard deviation
SE
SHBG
VLDL
vs
Versus
MD
mean difference
Convert to
Conversion factor
Cholesterol
mg/dl
mmol/L
0.026
Triglycerides
mg/dl
mmol/L
0.11
Insulin
pmol/L
mIU/L (=microIU/ml)
0.1667
Glucose
mg/dl
mmol/L
0.056
Progesterone
ng/ml
nmol/L
3.18
Testosterone
ng/dl
nmol/L
0.03467
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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(Continued)
Androstenedione
ng/dl
nmol/L
0.0349
Estradiol
ng/dl
pmol/L
36.71
17-beta oestradiol
ng/dl
pmol/L
36.71
Dehydroepiandrosterone
sulphate
microg/dl
micromol/L
0.02714
microg/dl
nmol/L
34.7
Standard deviation
Standard error
Standard deviation
Sqrt n
Confidence Intervals
Confidence Intervals
Standard error
APPENDICES
Appendix 1. Cochrane Central Register of Controlled Trials search strategy
1Polycystic Ovary Syndrome/ (562)
2 PCOS.ti,ab,sh. (549)
3 polycystic ovar$.ti,ab,sh. (846)
4 PCOD.ti,ab,sh. (21)
5 (stein-leventhal or leventhal).tw. (8)
6 (ovar$ adj (scelerocystic or polycystic or degeneration)).tw. (2)
7 or/1-6 (913)
8 Metformin/ (954)
9 metformin.ti,ab,sh. (1342)
10 (dimethylbiguanidium or dimethylguanylguanidine or glucophage or glucovance).tw. (22)
11 exp Hypoglycemic Agents/ (8785)
12 Thiazolidinediones/ (775)
13 glitazone$.tw. (18)
14 Rosiglitazone.tw. (431)
15 Pioglitazone.tw. (411)
16 Troglitazone.tw. (143)
17 exp Inositol/ (207)
18 D-chiro-Inositol.tw. (11)
19 chiro-Inositol.tw. (11)
20 mesoinositol.tw. (0)
21 myoinositol.tw. (15)
22 exp Biguanides/ (2229)
23 Biguanides.tw. (38)
24 Plasminogen Activator Inhibitor 1/ (416)
25 Plasminogen Activator Inhibitor-1.tw. (430)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
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160
WHATS NEW
Last assessed as up-to-date: 2 October 2011.
Date
Event
Description
19 April 2012
New citation required but conclusions have not changed New studies added but no change to conclusions
2 October 2011
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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(Continued)
HISTORY
Protocol first published: Issue 2, 2001
Review first published: Issue 3, 2003
Date
Event
Description
6 December 2010
1 March 2010
Amended
12 June 2008
7 December 2006
Substantive amendment
CONTRIBUTIONS OF AUTHORS
JML - primary literature search, initial assessment of trials and quality analysis, data collection, analysis, initial draft of full review (2003
version)
IF - developing protocol, checking literature search, secondary assessment of trials and quality analysis (blinded), reviewing data
collection and analysis, revising first draft of full review (2003 version)
RN - developing protocol, final arbiter to resolve differences in quality assessment between other reviewers, finalising final review,
content and Cochrane expert (2003 version)
TT - literature search, assessment of trials, data collection and analysis in the update period (January 2003 to November 2010).
Preparation of the revised review (2008 and 2010 version).
EY - checking literature search and secondary assessment of trials (2008 and 2010 version)
AB - secondary assessment of trials and quality analysis. Revising and finalizing the final revised review (2008 and 2010 version)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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DECLARATIONS OF INTEREST
None declared
SOURCES OF SUPPORT
Internal sources
Peninsula Medical School, UK.
University of Adelaide, Australia.
Department of Reproductive Medicine, Leeds, UK.
External sources
No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)
Insulin Resistance; Anovulation [ drug therapy]; Clomiphene [therapeutic use]; Hypoglycemic Agents [adverse effects; therapeutic
use]; Infertility, Female [ drug therapy]; Inositol [therapeutic use]; Live Birth; Metformin [adverse effects; therapeutic use]; Ovulation
Induction; Polycystic Ovary Syndrome [ complications]; Pregnancy Rate; Randomized Controlled Trials as Topic; Thiazolidinediones
[therapeutic use]
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility (Review)
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