Tang 2012

Insulin-sensitising drugs (metformin, rosiglitazone,
pioglitazone, D-chiro-inositol) for women with polycystic

ovary syndrome, oligo amenorrhoea and subfertility (Review)
Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH
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
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Outcome 2 Adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Outcome 3 Clinical pregnancy rate. . . . . . . . . . . . . . . . . . . . . . . . . . .
Outcome 4 Ovulation rate (grouped by sensitivity to clomiphene). . . . . . . . . . . . . . . .
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Outcome 5 Ovulation rate (grouped by BMI). . . . . . . . . . . . . . . . . . . . . . .
Outcome 6 Miscarriage rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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).
. . .
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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CONTRIBUTIONS OF AUTHORS . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
INDEX TERMS
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iii
[Intervention Review]
Insulin-sensitising drugs (metformin, rosiglitazone,

pioglitazone, D-chiro-inositol) for women with polycystic
ovary syndrome, oligo amenorrhoea and subfertility
Thomas Tang1 , Jonathan M Lord2 , Robert J Norman3 , Ephia Yasmin4 , Adam H Balen5
1 Obstetrics
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.
Editorial group: Cochrane Menstrual Disorders and Subfertility Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 5, 2012.
Review content assessed as up-to-date: 2 October 2011.
Citation: Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, Dchiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews
2012, Issue 5. Art. No.: CD003053. DOI: 10.1002/14651858.CD003053.pub5.
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.
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.
PLAIN LANGUAGE SUMMARY

Insulin-sensitising drugs for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Women with polycystic ovary syndrome (PCOS) typically have infrequent or absent periods and increased hair growth and acne.
Women with PCOS are also at risk of developing metabolic syndrome, such as diabetes, high blood pressure and high cholesterol levels.
High insulin levels are thought to play a role in PCOS and are generally worse with obesity. Insulin-sensitising drugs considered in
this review are metformin, rosiglitazone, pioglitazone and D-chiro-inositol. This updated review showed that the use of medications
to lower insulin levels, such as metformin either alone or in combination with drugs to induce ovulation (for example clomiphene
citrate), does not increase the chance of having a live birth. Metformin was also associated with increased gastrointestinal symptoms
such as nausea and diarrhoea.
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
Illustrative comparative risks* (95% CI)
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence

(GRADE)
Comments
Corresponding risk
Placebo or no treatment Metformin

Live birth rate
69 per 1000
118 per 1000

(37 to 313)
OR 1.8
(0.52 to 6.16)
115
(3 studies)

low1,2
Clinical pregnancy rate
109 per 1000
221 per 1000

(157 to 301)
OR 2.31
(1.52 to 3.51)
707
(8 studies)

moderate1
Ovulation rate
215 per 1000
332 per 1000

(237 to 446)
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.
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
Description of the condition

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting at least 5% to 15% of women of reproductive age
(Adams 1986; Balen 1999; Balen 2007; Legro 1998; Michelmore
1999; Tsilchorozidou 2004). Polycystic ovary syndrome is characterised by high levels of male hormones (hyperandrogenism),
menstrual disturbance (irregular or infrequent periods), anovulatory infertility (infrequent or absent ovulation) and obesity. Obesity often magnifies the clinical features of PCOS (Pasquali 2006).
PCOS is also a heterogeneous disorder, ranging from a classic presentation as described by Stein and Leventhal (Stein 1935) with
features of obesity, amenorrhoea and hirsutism to women with
normal cyclicity and yet with ultrasound (US) evidence of a polycystic ovarian appearance (Michelmore 1999; Polson 1988). In
the last 15 years, a large body of evidence has indicated that increased insulin resistance and compensatory high insulin concentrations (hyperinsulinaemia) play a key role in the pathogenesis
of PCOS (Balen 1999; Diamanti-Kandarakis 2006; Legro 1998;
Tsilchorozidou 2004).
PCOS encompasses a broad spectrum of signs and symptoms of
ovarian dysfunction, which have been highlighted in a 2003 Rotterdam consensus workshop (ESHRE /ASRM 2004). The panel
of experts concluded that PCOS remains a syndrome of ovarian
dysfunction with the cardinal features of menstrual disturbance,
hyperandrogenism and polycystic ovary (PCO) morphology. No
single diagnostic criterion (such as hyperandrogenism or PCO) is
sufficient for the clinical diagnosis.
The revised diagnostic criteria of PCOS are as follows, with two
of the following being required:
1. oligo or anovulation, or both, that is menstrual disturbance;
2. clinical or biochemical signs, or both, of hyperandrogenism;
3. PCO on ultrasound;
4. exclusion of other aetiologies (such as congenital adrenal hyperplasia, androgen-secreting tumours, Cushings syndrome) by
appropriate investigation of menstrual disturbance and hyperandrogenism.
The 2003 Rotterdam consensus also defined the diagnostic criteria
for ultrasound (US) PCO morphology as either 12 or more follicles
measuring 2 to 9 mm in diameter or increased ovarian volume,
over 10 cm3 , by using a trans-vaginal US scan. The distribution
of follicles and a description of the stroma are not required in
the diagnosis (Balen 2003). The threshold of 12 follicles of 2 to
9 mm diameter per ovary offered the best specificity (99%) and
sensitivity (75%) for the diagnosis of PCOS (Jonard 2003).
Insulin resistance occurs in both slim and overweight women with
PCOS, although there is debate on the proportion of women
with PCOS with reduced insulin sensitivity (Cibula 2004). At
least 50 % of women with PCOS are obese (Balen 1995) and
they are more insulin resistant than weight-matched individuals
with normal ovaries (Dunaif 1995; Morles 1996). Obesity, and

particularly abdominal obesity as indicated by an increased waist
to hip ratio, is correlated with reduced fecundity (Lord 2002;
Pasquali 2003; Zaadstra 1993), menstrual disorders and hyperinsulinaemia (Conway 1990). Obesity correlates with an increased
rate of menstrual cycle disturbance and infertility (Conway 1990;
Kiddy 1990). Weight loss improves the endocrine profile, menstrual cyclicity and the likelihood of ovulation and of a healthy
pregnancy (Huber-B 1999; Kiddy 1992; Pasquali 1989).
Women with PCOS and insulin resistance have a significantly
higher level of testosterone and a higher prevalence of hirsutism
than women with non-insulin resistant PCOS (Legro 2006a). In
addition, insulin resistant women with PCOS also have a lower
ovulation rate and are more likely to develop clomiphene resistance compared with women with non-insulin resistant PCOS.
Robinson et al reported that women with PCOS who developed
menstrual disturbance had a lower insulin sensitivity than controls; whilst those with regular cycles had a normal insulin sensitivity, similar to controls (Robinson 1993).
Furthermore, women with PCOS are at a higher risk of developing
type II diabetes (Legro 2006a) and the prevalence of type II diabetes is exacerbated by obesity. Dahlgren et al first reported a longterm follow-up study on women with PCOS after ovarian wedge
resection (Dahlgren 1992). Compared with controls, women with
PCOS showed a marked increase in prevalence of central obesity,
higher levels of fasting insulin and a higher prevalence of diabetes
(Dahlgren 1992). Legro et al (1999) reported that the prevalence
of impaired glucose tolerance (IGT) was 31.3%, and 7.5% of the
index population had undiagnosed diabetes according to World
Health Organization (WHO) criteria (Legro 1999). Norman et al
(2001) conducted a prospective study of 67 women with PCOS
with an average follow-up period of 6.2 years (Norman 2001).
The report revealed that 9% of women who were normoglycaemic
at baseline developed IGT and a further 8% developed type II
diabetes, with a conversion rate of 2.6% per annum. In addition,
59% of PCOS women with IGT at baseline developed type II
diabetes, with a conversion rate of 8.7% per annum. Likewise,
obese PCOS women (BMI > 30 kg/m2 ) had a 10-fold increase
in the risk of developing IGT or type II diabetes compared with
non-obese PCOS women with a BMI less than 25 kg/m2 .
Polycystic ovary syndrome also shares with metabolic syndrome a
lot of common clinical and abnormal metabolic manifestations.
Metabolic syndrome is a cluster of risk factors that confer an increased risk for cardiovascular disease (Apridonidze 2005; Dokras
2005; Ford 2004; Isomaa 2001) and type II diabetes (Hansen
2006). Women with metabolic syndrome may have a higher mortality from cardiovascular disease overall (hazard ratio (HR) 1.37,
95% CI 1.02 to 1.85), coronary heart disease (HR 1.29, 95% CI
0.95 to 1.59) and stroke (HR 1.68, 95% CI 0.86 to 3.27) compared with those women without the syndrome (Ford 2004). The
prevalence of metabolic syndrome among women with PCOS was
estimated to be nearly two-fold higher than in the general pop-
ulation (43% versus 24%) (Apridonidze 2005). The prevalence

also varies amongst different ethnic groups, and this is likely to
be influenced by the background prevalence of insulin resistance
(Hahn 2007; Park 2007; Shroff 2007; Soares 2007; Weerakiet
2007). Furthermore, women with PCOS and metabolic syndrome
tend to have a higher BMI, waist circumference, blood pressure, fasting glucose and insulin concentration than those without
(Ehrmann 2006). These findings suggest that women with PCOS
and metabolic syndrome have a greater insulin resistance. Therefore, PCOS not only commonly affects reproductive health but
also poses potential significant, long-term health risks.
Description of the intervention

The major insulin-sensitising agents are metformin (a biguanide
antihyperglycaemic drug) and thiazolidinediones including troglitazone, rosiglitazone and pioglitazone. Thiazolidinedione is a selective ligand of the nuclear transcription factor perioxisomes proliferator activated receptor . These are widely available standard
medications for the treatment of non-insulin dependent diabetes
mellitus (NIDDM). Whilst they lower elevated sugar levels in diabetics, when given to non-diabetic people they only lower insulin
levels; blood glucose levels will not change. Other insulin-sensitising agents such as D-chiro-inositol, which mediates the action of
insulin, are also being studied (Nestler 1999).
Troglitazone had been used as a therapy for diabetics and in some
trials involving women with PCOS. However, rare cases of liver
damage were reported during its marketed use. The liver damage
was usually reversible but very rare cases of hepatic failure, leading to death or liver transplant, were reported (Graham 2003).
Injury had occurred after both short and long-term troglitazone
treatment. Troglitazone was withdrawn from the market in March
2000 (FDA 2002).
Rosiglitazone and pioglitazone do not carry the same degree of
risk of hepatotoxicity and are commonly used in clinical trials
on women with PCOS. However, these two drugs are classified
as pregnancy category C drugs according to the Food and Drug
Administration (FDA) due to the potential risk of causing fetal
growth restriction in animal experiments (Yki-Jarvinen 2004). A
high incidence of weight gain among the users further hampers
their use in obese women with PCOS (Baillargeon 2004; Ortega-G
2005).
Why it is important to do this review

This is the second update of a previous review (Lord 2003; Tang
2009).
The first Cochrane review on the use of insulin-sensitising drugs
for PCOS indicated that metformin is an effective treatment for
anovulation in women with PCOS (Lord 2003). However, the
study populations in the review had a wide range of BMI. Therefore, it was difficult to interpret the findings when all the results
were combined for the analysis. Furthermore most of the included
studies had a relatively small sample size, with the highest number
recruited (94 women) in the study by Fleming 2002.
In the first updated review (Tang 2009), a number of large appropriately powered RCTs (Legro 2007; Moll 2006; Tang 2006) were
included. In this second updated review, we have included studies
up to October 2011.
OBJECTIVES
To assess the effectiveness of insulin-sensitising drugs in improving
reproductive outcomes and metabolic parameters for women with
PCOS.
METHODS
Criteria for considering studies for this review
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
How the intervention might work

Increased insulin resistance, hyperandrogenism and obesity have a
significant impact on menstrual cyclicity and reproductive health.
It is logical to assume that therapy that achieves a fall in serum
insulin concentrations should improve the symptoms and pregnancy outcomes of women with PCOS.
1) Metformin, rosiglitazone or pioglitazone versus placebo or no

therapy
2) Metformin, rosiglitazone or pioglitazone in conjunction with
an ovulation induction agent versus the ovulation induction agent
3) Metformin, rosiglitazone or pioglitazone versus clomiphene
Since troglitazone has been withdrawn from the market, studies
involving troglitazone were excluded from the current review.
Types of outcome measures
Hyperinsulinaemia
Primary outcomes
Electronic searches
1. Live birth rate

2. Adverse events ( gastrointestinal side effects)
See Appendix 1; Appendix 2; Appendix 3; Appendix 4.

Searching other resources
Secondary outcomes
3. Clinical pregnancy rate

4. Ovulation rate
5. Menstrual frequency
6. Miscarriage
7. Multiple pregnancy
8. Anthropometric outcomes:
a) Body mass index (BMI)
b) waist-hip ratio
c) blood pressure
9. Endocrine outcomes
a) Serum testosterone
b) Serum sex hormone-binding globulin
10. Metabolic outcomes
a) Fasting blood glucose
b) Fasting insulin
c) Cholesterol
d) Triglycerides
Search methods for identification of studies

The literature search aimed to locate RCTs reported in all languages. The original search was conducted in 2003. The first updated searches were completed on 11th September 2008 and the
second updated searches were completed on 3 October 2011.
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).
All electronic databases were searched using the following keywords:
Polycystic Ovary Syndrome (PCOS)
Metformin
Rosiglitazone
Pioglitazone
Troglitazone
D-chiro-Inositol
Insulin-lowering
Hypoglycemic agents
Biguanides
Plasminogen activator Inhibitor-1
Hyperandrogenism
We also handsearched the reference sections of all trials obtained.

All 12 of the pharmaceutical companies listed in the British National Formulary as manufacturing or distributing metformin,
rosiglitazone, troglitazone and pioglitazone were contacted in July
2001 by a previous review author (JML) to request relevant data
on all RCTs on their files, including unpublished trials.
Data collection and analysis

Selection of studies
The previous review was undertaken by three review authors (JM
Lord, IH Flight and RJ Norman), two of whom work in reproductive medicine (JML, RJN). The current update was conducted by
three review authors (T Tang, E Yasmin, AH Balen). The search
strategy described previously was employed to obtain titles and,
where possible, abstracts of studies that were potentially relevant
to the review. The titles and abstracts were screened by two review
authors (TT and EY), who discarded studies that were clearly ineligible but aimed to be overly inclusive rather than risk losing
relevant studies. Copies of the full text articles were obtained. Two
review authors (TT and AHB) independently assessed whether
the studies met the inclusion criteria, with disagreements resolved
by discussion. Further information was sought from the authors
where papers contained insufficient information to make a decision about eligibility.
Data extraction and management
The summary of included trials is presented in the table Characteristics of included studies. This information includes the following.
Studies characteristics
1. Method of randomisation
2. Blinding to treatment allocation
3. Quality of allocation concealment
4. Number of women randomised
5. Location, duration and timing of the trial
Characteristics of women
1. Mean age, BMI, testosterone, fasting insulin and glucose
levels
2. Study inclusion and exclusion criteria
3. Drop out rate
Interventions
1. Type of insulin-sensitising drug

2. Co-interventions such as clomiphene or lifestyle advice
Outcomes
1. Ovulation
2. Arthropometric measurements (BMI, waist-hip ratio, blood
pressure)
3. Hormones (testosterone, sex hormone binding globulin
(SHBG))
4. Metabolic markers (fasting glucose, fasting insulin, lipid
profile)
Assessment of risk of bias in included studies
This is in accordance with the recommendations described in the
Cochrane Handbook for Systematic Reviews of Interventions.
1) Sequence generation
Low risk (for example, computer generated random
numbers, random number table)
high risk (systematic methods such as alternation;
assignment based on case record number, date of presentation or
date of birth)
unclear risk (insufficient information in the study or from
the author about the process of sequence generation)
2) Allocation concealment
Low risk (for example, central randomisation, sequentially
numbered, opaque, sealed envelopes)
high risk (for example, open label trial, assignment base on
case record number, date of presentation or date of birth)

the author about the process of allocation concealment)
3) Blinding
Low risk (double blind study: participants, providers and
assessors blinded)
high risk (unblinded)
the author about the level of blinding)
4) Incomplete outcome data addressed
Low risk (for example, no missing data, reasons for missing
data were reported and were unlikely to influence the outcomes,
or missing data was balanced across the groups)
high risk (for example, reasons for missing data were not
addressed, missing data likely to affect the outcomes, or data
analysed per protocol)
the author about the detail of incomplete outcome data)
5) Selective outcome reporting
Low risk (for example, the study protocol was available,
pre-specified outcome measures were reported)
high risk (for example, the study protocol was unavailable
and pre-specified outcome measures were not reported)
the author about process of outcome reporting)
A summary of the Risk of bias table can be found in the figure
section (Figure 1 and Figure 2).
Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.
Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
Measures of treatment effect

Odds ratio (OR) was used as the measure of effect for each dichotomous outcome and the mean difference (MD) for each continuous outcome.
Unit of analysis issues

Data from only the first phase of crossover trials was used (such
as before crossover) when the washout period was less than two
months in order to reduce a carry-over of treatment effect. The
rationale is that oligo amenorrhoea is usually accepted as a menstrual cycle length over five to eight weeks. Therefore, the washout
period of treatment effect on ovulation should ideally be more
than eight weeks.
Dealing with missing data

Where possible, missing data were sought from the authors. When
this information was not available, the analysis was performed
using the original number of women randomised.
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.
Sensitivity analysis was performed after excluding studies with

unclear or high risk of bias in sequence generation, allocation
concealment or the blinding method.
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.
See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of studies awaiting classification.
See Characteristics of included studies and Characteristics of
excluded studies for full details of the trials.
Results of the search
In this updated review there are 44 included studies (Figure 3).
10
Figure 3. Study flow diagram
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,
except (Ben Ayed 2009; Boudhraa 2010; Carmina 2004; El-Biely

2001; Hwu 2005; Karimzadeh 2010; Khorram 2006; Nestler
1998; Sahin 2004; Siebert 2009; Zain 2009). Overall, two studies
were crossover trials (Sturrock 2002; Trolle 2007). Only the first
phase was analysed from Sturrock 2002 as the washout period was
considered to be short (four weeks). Although the study by Trolle
2007 was also a crossover study, there was an eight-week washout
period and no women became pregnant during the trial period.
We therefore decided to include the published data of this study
after the crossover period (second phase).
The included studies originated from a number of countries, including Argentina, Tunisia, Venezuela, Brazil, Germany, Egypt,
UK, Italy, USA, Taiwan, Iran, Turkey, Malaysia, Netherlands,
Hong Kong, Finland, New Zealand, South Africa and Denmark.
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).
12
Specific advice on lifestyle modification was included in the

study protocol in 10 trials (Ben Ayed 2009; Boudhraa 2010;
Brettenthaler 2004; Hoeger 2004; Karimzadeh 2010; Ladson
2011; Otta 2010; Pasquali 2000; Romualdi 2010; Tang 2006).
The duration of the trials ranged from 4 to 48 weeks with an
average of 19.5 weeks. The median daily dose of metformin used
in the trials was 1500 mg.
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).
Primary outcome measures

Pregnancy was reported by most trials but live birth rates were
reported in only 10 studies (Ng 2001; PCOSMIC 2010; Yarali
2002; Boudhraa 2010; Moll 2006; PCOSMIC 2010; Legro 2007;
Sahin 2004; Vandermolen 2001; Zain 2009). The three largest
studies reporting live birth rate were Legro 2007; PCOSMIC
2010; Moll 2006. Only two studies (Legro 2007; PCOSMIC
2010) identified live birth rate as a primary outcome measure.
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)
Risk of bias in included studies

See Figure 1 for risk of bias and Figure 2 for a summary of the risk
of bias.
Sensitivity analysis was carried out by including only the data
from the studies with low risk of bias, determined by sequence
generation, allocation concealment and blinding method. Only
17 out of 44 studies met this criterion (Baillargeon 2004; Chou
2003; Eisenhardt 2006; Fleming 2002; Glintborg 2005; Hoeger
2004; Karimzadeh 2007; Ladson 2011; Lam 2011; Legro 2007;
Lord 2006; Maciel 2004; Moll 2006; Ng 2001; Pasquali 2000;
PCOSMIC 2010; Tang 2006) with 15 out of the 17 studies investigating the effects of metformin. Furthermore, 15 out of the
17 were published after the CONSORT statement (Moher 2001).
Three out of the 10 newly included studies, in the search period between October 2008 and October 2011, met this criterion
(Ladson 2011; Lam 2011; PCOSMIC 2010).
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).
Incomplete outcome data

Eleven studies were at high risk of attrition bias due to high drop
out rates, unequal drop outs between the groups or use of per
protocol analysis (Baillargeon 2004; Brettenthaler 2004; Fleming
2002; Gerli 2003; Jakubowicz 2001; Ladson 2011; Otta 2010;
Pasquali 2000; Rautio 2006; Sturrock 2002; Zain 2009). Only
eight studies were at low risk of attrition bias (Hoeger 2004; Hwu
2005; Malkawi 2002; Moghetti 2000; Nestler 1998; Nestler 1999;
PCOSMIC 2010; Trolle 2007).
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).
13
Other potential sources of bias

Overall eight studies appeared to be at high risk of other sources
of bias (Baillargeon 2004; Hoeger 2004; Hwu 2005; Lam 2011;
Legro 2007; Moghetti 2000; Nestler 1998; Trolle 2007) although
the majority of the studies did not provide sufficient information
for analysis.
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
syndrome, oligo amenorrhoea and subfertility; Summary of

findings 4 Pioglitazone compared to placebo or no treatment for
women with polycystic ovary syndrome, oligo amenorrhoea and
subfertility
1. Metformin versus placebo or no treatment
1.1 Live birth rate (Analysis 1.1, Figure 4)

There was no evidence that metformin improved live birth when it
was used alone (3 RCTs, 115 participants; OR 1.80, 95% CI 0.52
to 6.16) although only a limited number of studies reported live
birth rate (Ng 2001; PCOSMIC 2010; Yarali 2002). Nevertheless,
overall heterogeneity was low with I2 = 0%. Subgroup analysis
by BMI was not performed as there was inadequate information
to separate the data. Sensitivity analysis (excluding studies with
unclear or high risk of bias) left only one study (PCOSMIC 2010),
which showed no difference in the live birth rates.
Figure 4. Forest plot of comparison: 1 Metformin versus placebo or no treatment, outcome: 1.1 Live birth
rate.
1.2 Adverse events (Analysis 1.2, Figure 5)
14
Figure 5. Forest plot of comparison: 1 Metformin versus placebo or no treatment, outcome: 1.2 Adverse
events (gastrointestinal side effects).
Consistent with the previous review, participants in the metformin

group experienced a significantly higher incidence of nausea and
vomiting (3 RCTs, 73 participants; OR 3.91, 95% CI 0.98 to
15.64; I2 = 0%) and other gastrointestinal side effects (5 RCTs, 318
participants; OR 4.27, 95% CI 2.4 to 7.59; I2 = 72%) compared
with the placebo group. Sensitivity analysis by study quality did
not change the inference.
1.3 Clinical pregnancy rate (Analysis 1.3)
Metformin improved clinical pregnancy rate compared with
placebo (8 RCTs, 707 participants; OR 2.31, 95% CI 1.52 to
3.51). Subgroup analysis showed that the benefit was confined to
the non-obese group (4 RCTs, 413 participants; OR 2.35, 95%
CI 1.44 to 3.82) with significant heterogeneity (I2 = 75%) compared with the obese group (4 RCTs, 294 participants; OR 2.21,
95% CI 0.98 to 4.98; I2 = 0%).
Sensitivity analysis by study quality included six studies (Fleming
2002; Karimzadeh 2007; Lord 2006; Ng 2001; PCOSMIC 2010;
Tang 2006) and did not alter the inference nor improve the heterogeneity.
1.4 Ovulation rate (Analysis 1.4)
A random-effect models was employed in this analysis as the overall heterogeneity was moderately high (I2 = 48%). Metformin appeared to improve the ovulation rate (16 RCTs, 1208 participants;
OR 1.81, 95% CI 1.13 to 2.93). However, in the subgroup analysis neither the non-obese group (5 RCTs, 441 participants; OR
2.94, 95% CI 0.81 to 10.61) nor the obese group (11 RCTs, 767
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
15
Data were not available for this outcome.

1.8 Anthropometric outcomes
a) BMI: there was no evidence of an effect of metformin on BMI at
the end of the studies (16 RCTs, 630 participants; MD -0.05, 95%
CI -0.31 to 0.20, Analysis 1.7) with an average duration of treatment of 5.75 months and average dose of 1500 mg. Furthermore,
overall heterogeneity was not observed (I2 = 0%); although it was
moderately high in the non-obese group (I2 = 59%). Sensitivity
analysis by study quality (Baillargeon 2004; Chou 2003; Fleming
2002; Hoeger 2004; Ladson 2011; Lord 2006; Maciel 2004; Ng
2001; Pasquali 2000; Tang 2006) improved heterogeneity (nonobese group I2 = 0%; obese group I2 = 0%) but did not change
the inference.
b) Waist-hip ratio: there was evidence of a marginal effect of metformin on waist-hip ratio (10 RCTs, 449 participants; MD -0.01,
95% CI -0.01 to 0.00, Analysis 1.8). The magnitude of heterogeneity was low in both the non-obese and the obese subgroups (I2
= 0% and I2 = 12%, respectively). The sensitivity analysis by study
quality (Baillargeon 2004; Chou 2003; Fleming 2002; Lord 2006;
Pasquali 2000; Tang 2006) demonstrated a similar inference.
c) Blood pressure: metformin reduced systolic blood pressure with
a mean difference (MD) of -3.59 mm Hg (95% CI -5.13 to -2.04;
7 RCTs, 379 participants, Analysis 1.9) and significant heterogeneity (I2 = 57%). However, a similar benefit was not observed in
the diastolic blood pressure (6 RCTs, 292 participants; MD -0.14,
95% CI -1.35 to 1.07; I2 = 21%, Analysis 1.10 ). Furthermore,
neither subgroup analysis (Analysis 1.9) nor sensitivity analysis by
study quality (Baillargeon 2004; Chou 2003; Lord 2006; Maciel
2004; Tang 2006) improved heterogeneity in the systolic blood
pressure analysis.
1.9 Endocrine outcomes
a) Testosterone: metformin reduced serum total testosterone levels with a MD of -0.60 nmo/L (14 RCTs, 610 participants; 95%
CI -0.73 to -0.48, Analysis 1.11). However, a significant heterogeneity was observed (I2 = 92%) and the subgroup analysis did not alter the heterogeneity. The magnitude of the reduction appeared to be greater among non-obese women compared
with obese women with PCOS (MD -1.68 versus -0.29 nmol/L).
Therefore, a meta-regression method was employed to assess the
confounding factors (BMI, the daily dose of metformin and the
duration of the treatment period) which may have influenced the
outcomes. However, none of these factors could explain the degree of heterogeneity (data not shown). Linear regression analysis
did not demonstrate any correlation between the baseline mean
BMI and the mean fasting insulin concentrations among all the
included studies (data not shown). Furthermore, a positive correlation between the baseline mean fasting insulin concentrations
and the mean testosterone concentrations was not observed (data
not shown). These data suggested that the heterogeneity may be
caused by the different background prevalences of hyperandrogenism and insulin resistance among different study populations
(Wijeyaratne 2002; Wijeyaratne 2004). Furthermore, different
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
2.1 Live birth rate (Analysis 2.1, Figure 6)
16
Figure 6. Forest plot of comparison: 2 Metformin combined with ovulation induction agent clomifene
versus clomifene alone, outcome: 2.1 Live birth rate.
There was no evidence that metformin in combination with

clomifene improved live births compared with clomiphene citrate alone (7 RCTs, 907 participants; OR 1.16, 95% CI 0.85
to 1.56; I2 = 35%). Subgroup analysis reduced heterogeneity in
the obese group (I2 = 0%) but not in the non-obese group (I2
= 68%). Sensitivity analysis by study quality (Legro 2007; Moll
2006; PCOSMIC 2010), with 714 participants, did not change
the inference nor improve heterogeneity.
2.2 Adverse events (Analysis 2.2, Figure 7)
17
Figure 7. Forest plot of comparison: 2 Metformin combined with ovulation induction agent clomifene
versus clomifene alone, outcome: 2.2 Adverse events.
Participants in the metformin group experienced a significantly

higher incidence of gastrointestinal side effects including nausea
and vomiting (2 RCTs, 489 participants; OR 3.31, 95% CI 2.11
to 5.20; I2 = 0%) compared with the control group. Sensitivity
analysis by study quality did not change this finding.
When combined with clomiphene, women who took metformin
had a significantly better pregnancy rate than those who took
clomiphene alone (11 RCTs, 1208 participants; OR 1.51, 95%
CI 1.17 to 1.96), although a moderate degree of heterogeneity was
observed (I2 = 49%). Subgroup analysis reduced heterogeneity in
the obese group (I2 = 33%) but not in the non-obese group (I2
= 63%). The benefit appeared to be confined to the obese group.
Sensitivity analysis by study quality (Legro 2007; Moll 2006),
with 643 participants, did not change the inference or improve
heterogeneity.
2.4 Ovulation rate (Analysis 2.4; Analysis 2.5)
There was a significant effect for metformin combined with
clomiphene versus clomiphene alone (18 RCTs, number of cycles
= 3265; OR 1.74, 95% CI 1.50 to 2.00), with a moderate degree
of heterogeneity (I2 = 62%). We stratified the analysis based on
sensitivity to clomiphene (Analysis 2.4) and BMI (Analysis 2.5).
A significant heterogeneity was observed in a group of trials when
the status of clomiphene sensitivity was not defined (I2 = 67%). In
contrast, as might be expected, the clomiphene resistant group ap-
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
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)
18
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.
Four RCTs reported this outcome (Legro 2007; PCOSMIC 2010;

Palomba 2005; Zain 2009) They were inappropriate for pooling
due to high heterogeneity (I2 = 89%). In subgroup analysis, heterogeneity was limited to the two studies in the non-obese group (I
2 = 93%). The study by Palomba 2005 demonstrated a treatment
benefit for live birth in non-obese women with PCOS who took
metformin as first therapy compared with those taking clomiphene
alone. However, PCOSMIC 2010 reported the opposite effect.
In studies of the obese group (Legro 2007; Zain 2009), clomiphene
treatment was associated with a better live birth rate than metformin alone, without heterogeneity (OR 0.30, 95% CI 0.17 to
0.52; I2 = 0%).
3.2 Adverse events
The overall heterogeneity was high (I2 = 86%) 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 higher pregnancy rate compared to those
who took clomiphene (3 RCTs, 349 participants; OR 1.94, 95%
CI 1.19 to 3.16; I2 = 44%) whilst an opposite effect was observed
in the obese group (2 RCTs, 500 participants; OR 0.34, 95% CI
0.21 to 0.55; I2 = 0%). Sensitivity analysis by study quality did
not change the inference.
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
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
19
4 D-chiro-inositol versus placebo or no treatment
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
4.2 Adverse events
4.3 Clinical pregnancy
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.
5 Rosiglitazone versus placebo or no treatment
Three trials were included in the current review. Not surprisingly,

because of the withdrawal of troglitazone from the market, the
drug used in the trials was either rosiglitazone or pioglitazone.

Data were not available for primary outcomes, but were available for some secondary outcomes, including ovulation rate, menstrual frequency and anthropometric, endocrine and metabolic
outcomes.
Rosiglitazone appeared to improve the ovulation rate based on one
study (Baillargeon 2004) (64 participants; OR 31, 95% CI 3.76
to 255.3).
5.5 Menstrual frequency (Analysis 5.2)
An improvement in menstrual pattern was observed (2 RCTs, 100
participants; OR 5.59, 95% CI 2.20 to 14.19; I2 =12%).
5.8 Anthropometric outcomes
Women who took rosiglitazone were found to have an increased
BMI (3 RCTs, 132 participants; MD 0.68, 95% CI 0.40 to 0.96; I
2 = 15%, Analysis 5.3 ). Rosiglitazone was found to have a marginal
benefit on WHR (3 RCTs, 132 participants; MD -0.01, 95%
CI -0.02 to 0.00; I2 = 0%, Analysis 5.4). Based on one study
(Baillargeon 2004), the effect on blood pressure was small (Analysis
5.5; Analysis 5.6).
5.9, 5.10 Endocrine and metabolic outcomes
The effects on testosterone, SHBG, insulin, glucose, cholesterol
and triglyceride were found to be minimal (Analysis 5.7; Analysis
5.8; Analysis 5.10; Analysis 5.9; Analysis 5.11; Analysis 5.12)
6 Pioglitazone versus placebo or no treatment
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)
20
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
Settings:
Intervention: D-chiro-inositol
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
OR 5.38
(0.7 to 41.31)
327
(2 studies)

moderate1
Comments
Corresponding risk
placebo or no treatment D-chiro-inositol

Ovulation
805 per 1000
957 per 1000

(743 to 994)
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
Rosiglitazone compared to placebo or no treatment for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Settings:
Intervention: Rosiglitazone
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
OR 1.91
(0.7 to 5.22)
64
(1 study)

very low1,2,3
Comments
Corresponding risk
Placebo or no treatment Rosiglitazone

Ovulation rate
Study population
344 per 1000
500 per 1000

(268 to 732)
Moderate
344 per 1000
500 per 1000

(269 to 732)
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
Pioglitazone compared to placebo or no treatment for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
Settings:
Intervention: Pioglitazone
Outcomes
Assumed risk
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
OR 8.88
(2.35 to 33.61)
70
(2 studies)

moderate1
Comments
Corresponding risk
Placebo or no treatment Pioglitazone

Improved menstrual pat- 171 per 1000
tern
648 per 1000

(327 to 874)
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.
Overall completeness and applicability of

evidence
The efficacy of metformin in PCOS was first described by
Velazquez 1997. A number of small, and often short duration,
observational studies followed, which showed variable outcomes.
Most of the randomised studies have involved only a small number
of participants. Indeed, in a systematic review by Costello 2003
nine out of the 12 published studies on the effects of metformin
alone on the menstrual cycle in women with PCOS had a sample
size of less than 30 women. The first Cochrane review by Lord
2003 included nearly 1000 women from 15 RCTs. However, most
of the studies had relatively small sample sizes with the largest one
containing 94 women (Fleming 2002). In this second updated review, 44 RCTs (nearly 4000 women) were included with the two
largest being by Moll 2006 and Legro 2007 with sample sizes of
225 and 626 women respectively.
In agreement with the previous review, metformin is of benefit
in improving spontaneous and menstrual patterns. These may result in an improvement in clinical pregnancy rates. However, this
marginal benefit is unlikely to be significant in terms of live birth,
especially as obesity poses a significant negative impact on pregnancy outcomes (see below). We were unable to demonstrate that
metformin reduces miscarriage. Although the number of included
studies in this review was small, this finding seems to be in agreement with the other systematic review (Palomba 2009). Furthermore, we were unable to demonstrate that metformin enhances
weight reduction in either non-obese or obese women with PCOS,
with an average duration of treatment of 5.75 months and an average dose of 1500 mg (Analysis 1.7).
Metformin reduces serum testosterone levels in the non-obese

group and the reduction appears to be marginally significant in
the obese group. Meta-regression did not support any effect of the
daily dose or the duration of metformin treatment on the magnitude of the reduction in testosterone levels. High insulin levels
stimulate an increase in androgen production from the ovaries and
therefore an inadequate reduction of insulin concentrations induced by metformin in obese women with PCOS may be a reason
why the reduction of testosterone was less marked in the obese
group. In contrast, metformin significantly reduces fasting insulin
levels in the non-obese group.
Clomiphene is traditionally employed as a first line ovulation induction therapy for anovulatory women with PCOS. The cumulative pregnancy rate is between 50% to 60% after six cycles of
the treatment (Laven 2006). The ovulation rates in women with
PCOS taking metformin with clomiphene have been found to be
significantly better than for those taking clomiphene alone. In the
subgroup analysis, women who previously developed clomiphene
resistance achieved a better response to the combined therapy than
women who were non-clomiphene resistant or of undefined status. In addition, heterogeneity was low in the analysis of ovulation rates in the clomiphene resistant group and the funnel plot
was also acceptable (data not shown). Therefore, clomiphene resistance can be a useful discriminatory factor to predict the response
to the combined therapy.
If BMI was used as a discriminatory factor, the number of cycles needed to treat in both the non-obese and obese groups was
high, 7.1 and 7.1 respectively. Since most women would usually
receive only six cycles of clomiphene treatment in clinical practice,
the benefit of co-therapy with metformin appears to be limited.
This may explain why the clinical pregnancy rates were not significantly improved with the combined treatment compared with using clomiphene alone in non-obese women with PCOS, since this
group of women tends to respond to clomiphene treatment better than the obese group. On the contrary, the clinical pregnancy
rate was improved in the obese group of women with PCOS who
had been on the combined therapy. Caution is needed to interpret
these findings as moderate heterogeneity occurred in the analysis.
The heterogeneity was likely to have resulted from the combination of clomiphene resistant and clomiphene sensitive participants
in the analysis. It would be difficult to separate the two groups
before the analysis as the status was not always defined in the trials. Unfortunately, the improved pregnancy rate did not translate
to an improved live birth rate (Analysis 2.1) despite miscarriage
rates not being different for the combined and clomiphene groups
(Analysis 2.6). This is likely to have resulted from the negative
impact of obesity on pregnancy outcomes (see below).
Moll 2006 reported that ovulation rates, pregnancy rates and
live birth rates were not improved with combined therapy compared with using clomiphene alone. There were no differences between the two groups in miscarriage rates or in the proportion
of women who developed clomiphene resistance. However, a sig-
24
nificant number of women experienced side effects when taking

metformin. The study concluded that the effect of metformin on
ovulation may not be strong enough to improve the high ovulation
rates with clomiphene monotherapy in non-obese women with
PCOS (Moll 2006).
Although the study by Legro 2007 reported an increase in ovulation rates by adding metformin during clomiphene treatment,
live birth rates were not significantly different between the combined therapy and clomiphene monotherapy. Legro 2007 also revealed that BMI poses a significant negative impact on cumulative
live birth rates and that adverse pregnancy complications such as
pre-eclampsia and gestational diabetes were high among the obese
women with PCOS. Although there was a significant improvement in insulin resistance in the group who took metformin and
clomiphene compared with the group on clomiphene alone, this
was largely due to a significant increase in insulin resistance in
the clomiphene group. There were no significant changes in the
fasting insulin levels and insulin resistance within the combined
metformin and clomiphene group at the end of the trial period.
The current updated review showed that metformin improves ovulation rates in women with PCOS. Therefore, it can be considered as a first line therapy for women with PCOS and anovulatory subfertility, as an alternative to clomiphene. However, subgroup analysis demonstrated that ovulation, pregnancy and live
birth rates were only significantly better in obese PCOS women
taking clomiphene compared with those taking metformin as a
monotherapy (Analysis 3.4; Analysis 3.3; Analysis 3.2) with a
much more acceptable heterogeneity compared with the nonobese group. In contrast, non-obese women who took metformin
had a better pregnancy rate than those who took clomiphene.
Furthermore, heterogeneity was too high in the analysis of live
births in non-obese women for the results to be pooled for analysis. The heterogeneity observed between the non-obese and the
obese groups in these analyses could be explained by the fact that
metformin was found to have limited effect on reducing serum
insulin concentrations in the obese group compared with the nonobese group of women with PCOS (Analysis 1.14). Furthermore,
obese women with PCOS have been shown to have a higher insulin resistance (higher serum insulin concentrations) than nonobese women with PCOS (Tang 2006).
With both miscarriage and multiple pregnancy rates being similar
between the two groups (Analysis 3.5; Analysis 3.6), metformin
can be considered as an alternative ovulation induction agent for
non-obese women with PCOS (Analysis 3.4). However, a high incidence of gastrointestinal side effects would hamper clinical compliance (Analysis 1.2; Analysis 2.7). Considering most women are
usually given five days of clomiphene treatment per cycle, compared with daily intakes of metformin, clomiphene remains the
first line ovulation induction agent.
The current review also demonstrates that metformin reduces
serum testosterone and fasting insulin concentrations, in particular among non-obese women with PCOS. It may be useful to
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
25
2002; Norman 2004; Tang 2006).

There is yet to be any long-term data on the use of metformin
for women with PCOS in reducing the risk of developing diabetes or metabolic syndrome. Our analysis did not show that metformin is of benefit in improving weight loss, insulin sensitivity or
lipid profiles. The magnitude of reduction of systolic blood pressure (MD -3.859 mm Hg) is unlikely to be clinically significant.
Hence, a long-term prophylactic treatment with metformin is unlikely to prevent progression to diabetes. The Diabetes Prevention
Program Research group studied over 3000 obese women (mean
BMI 34 kg/m2 ) with an average follow-up period of 2.8 years
(Knowler 2002). They reported that both the metformin and the
lifestyle intervention groups (7.8 and 4.8 cases per 100 person
years respectively) had a lowered incidence of diabetes compared
with the placebo group (11 per 100 person years). However, the
lifestyle intervention group achieved a significantly better reduction compared with the metformin group (58% versus 31%). Furthermore, the initial modest weight loss in the metformin group
was not sustainable after three years of follow-up. In contrast, in
the lifestyle group an average of 4% weight loss was still maintained after four years of follow-up. Likewise, the Finnish Diabetes
Prevention Study demonstrated that weight loss improved insulin
sensitivity, waist circumference and serum triglyceride levels compared with controls in 150 obese women with impaired glucose
tolerance (Uusitupa 2000). These findings were confirmed in a
recent meta-analysis (Gillies 2007). This review also concluded
that the lifestyle interventions were more effective in obese women
and that the treatment effect of metformin was not sustained after
treatment stopped.
In respect to the use of rosiglitazone and pioglitazone in women
with PCOS, our analysis, with a limited number of trials, showed
that these drugs improve ovulation rate without much effect on
biochemical parameters. On the hand, these drugs are classified as
category C (FDA 2002) and hence most of the recruited women
were not planning a pregnancy. Therefore, it would be difficult
to assess the effects on pregnancy outcomes. Furthermore, a high
incidence of weight gain (Analysis 5.3) among the users further
hampers its use in obese women with PCOS (Baillargeon 2004;
Ortega-G 2005). There is also concern about a link between
rosiglitazone and an increase in the risk of myocardial infarction (Lago, 2007). Therefore, it is unlikely that thiazolidinediones
would have a major role in treating women with PCOS.

Overall, 17 out the 44 included studies were graded as having
low risk of bias related to sequence generation, allocation concealment and blinding; hence most of the included studies were
methodologically weak (Figure 2). However, sensitivity analysis
on the studies with adequate sequence generation, allocation concealment and blinding method did not alter the clinical findings
except on fasting serum glucose concentrations.
Potential biases in the review process

A systematic review is only valid if the included women in all the
studies represent the same overall population. Although a large
number of participants were included in the current review, and
the included women also met the Rotterdam diagnostic criteria
for PCOS (ESHRE /ASRM 2004), a significant heterogeneity was
still observed in the analysis. This was particularly in the biochemical outcomes even after adjustment for BMI, dosage of metformin
and the duration of the treatment. Heterogeneity remained unchanged after sensitivity analysis by study quality. These can be
explained by the fact that the prevalence and magnitude of insulin resistance are influenced by ethnicity (Wijeyaratne 2002;
Wijeyaratne 2004). Hence, combining trials from different study
populations would introduce heterogeneity despite the fact that
they all met the diagnostic criteria of PCOS. Another possible
explanation is that different biochemical assays used in different
studies may introduce some heterogeneity.
We have also conducted funnel plot assessments on analyses of
clinical pregnancy, ovulation, fasting serum insulin and glucose
(data not shown) and publication bias appeared to be low in our
review.
Agreements and disagreements with other

studies or reviews
Our findings are in agreement with the recent consensus on infertility treatment related to PCOS (ESHRE/ASRM-sponsored
PCOS consensus workshop group 2007) (ESHRE/ASRM 2008).
The first line treatment for anovulatory infertility is clomiphene;
whilst obese women should be advised to undergo lifestyle modifications.
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
26
to undergo lifestyle changes before fertility treatment (The Thessaloniki ESHRE/ASRM sponsored PCOS consensus workshop
group, 2007) (ESHRE/ASRM 2008).
Implications for research

It has been suggested in observational studies that metformin may
reduce the risk of first trimester miscarriage. If this is true, then
it is possible that metformin would result in a higher live birth
rate than other methods of ovulation induction even if it were
no more effective than the other methods in inducing ovulation.
A recent systematic review suggested that metformin may result
in a more predictable follicular response to ovulation induction,
theoretically reducing the risk of ovarian hyperstimulation and
multiple pregnancies (Costello 2006). These observations need to
be explored in larger randomised controlled trials which report,
as defined outcome measures, live birth rates and the risk of miscarriage and multiple pregnancies. Although there is no current
evidence that metformin is teratogenic, if it is used widely to treat
anovulation then it is possible that rare effects may be unmasked.
Metformin therapy therefore needs to be kept under continuing
surveillance and adverse outcomes reported.
The magnitude of insulin resistance is influenced by ethnicity
(Wijeyaratne 2002; Wijeyaratne 2004). Future trials should subdivide the analysis according to the ethnic origin of women. These
subgroups may reduce the heterogeneity in the meta-analysis.
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.
REFERENCES
References to studies included in this review

Baillargeon 2004 {published data only}
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Ben Ayed 2009 {published data only}
Ben Ayed B, Dammak Dit Mlik S, Ben Arab H, Trabelssi
H, Chahtour H, Mathlouthi N. Metformin effects on
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Boudhraa 2010 {published data only}
Boudhraa, Jellouli, Amri, Farhat, Torkhani, Gara.
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Tunisie Medicale 2010;88(5):33540.
Brettenthaler 2004 {published data only}
Aigner E, Bachofner N, Klein K, De Geyter C, Hohla F,
Patsch W, Datz C. Retinol-binding protein 4 in polycystic
ovary syndrome--association with steroid hormones and

response to pioglitazone treatment. Journal of Clinical
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Brettenthaler N, De Geyter C, Huber PR, Keller U. Effect
of the insulin sensitizer pioglitazone on insulin resistance,
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with polycystic ovary syndrome. Journal of Clinical
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Carmina 2004 {published data only}
Carmina E, Lobo RA. Does metformin induce ovulation in
normoandrogenic anovulatory women?. American Journal
of Obstetrics and Gynecology 2004;191:15804.
Chou 2003 {published data only}
Chou KH, von Eye Corleta H, Capp E, Spritzer PM.
Clinical, metabolic and endocrine parameters in response to
metformin in obese women with polycystic ovary syndrome:
a randomized, double-blind and placebo-controlled trial.
Hormone and Metabolic Research 2003;35:8691.
Eisenhardt 2006 {published data only}
Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A,
von Wolff M, Hamann A, et al.Early effects of metformin
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of Clinical Endocrinology and Metabolism 2006;91:94652.
El-Biely 2001 {published data only}
El-Biely MM, Habba M. The use of metformin to augment
the induction of ovulation in obese infertile patients with
polycystic ovary syndrome. Middle East Fertility Society
Journal 2001;6(1):439.
Fleming 2002 {published data only}
Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar

N. Ovarian function and metabolic factors in women with
oligomenorrhea treated with metformin in a randomized
double blind placebo-controlled trial. Journal of Clinical
Fleming R, Hopkinson ZE, Wallace E, Greer IA, Sattar
N. Metformin treatment improves ovulation frequency
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38990.
Gerli 2003 {published data only}
Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on
ovarian function and metabolic factors in women with
PCOS: a randomized double blind placebo-controlled trial..
European Review for Medical and Pharmacological Sciences
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Gerli S, Papaleo E, Ferrari A, Di Renzo GC. Randomized,
double blind placebo-controlled trial: effects of myoinositol on ovarian function and metabolic factors in
women with PCOS. European Review for Medical and
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Glintborg 2005 {published data only}
Glintborg D, Frystyk J, Hojlund K, Andersen KK,
Henriksen JE, Hermann A, et al.Total and high molecular
weight (HMW) adiponectin levels and measures of glucose
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16574.
Glintborg D, Hermann AP, Andersen M, Hagen C,
Beck-Nielsen H, Veldhuis JD, Henriksen JE. Effect
of pioglitazone on glucose metabolism and luteinizing
hormone secretion in women with polycystic ovary
syndrome. Fertility and Sterility 2006;86:38597.
Glintborg D, Hojlund K, Andersen M, Henriksen JE, BeckNielsen H, Handberg A. Soluble CD36 and risk markers
of insulin resistance and atherosclerosis are elevated in
polycystic ovary syndrome and significantly reduced during
pioglitazone treatment. Diabetes Care 2008;31:32834.
Glintborg D, Stoving RK, Hagen C, Hermann AP,
Frystyk J, Veldhuis JD, et al.Pioglitazone treatment
increases spontaneous growth hormone (GH) secretion and
stimulated GH levels in polycystic ovary syndrome. Journal
of Clinical Endocrinology and Metabolism 2005;90:560512.
[: original article]
Hoeger 2004 {published data only}
Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK,
Guzick DS. A randomized, 48-week, placebo-controlled
trial of intensive lifestyle modification and/or metformin

therapy in overweight women with polycystic ovary
syndrome: a pilot study.. Fertility and Sterility 2004;82:
4219.
Hwu 2005 {published data only}
Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK. Ultrashort metformin pretreatment for clomiphene citrateresistant polycystic ovary syndrome. International Journal of
Gynaecology and Obstetrics 2005;90:3943.
Jakubowicz 2001 {published data only}
Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-armas
O, Rivas-santiago A, Koistinen H, et al.Insulin reduction
with metformin increases luteal phase serum glycodelin and
insulin-like growth factor-binding protein 1 concentrations
and enhances uterine vascularity and blood flow in the
polycystic ovary syndrome. Journal of Clinical Endocrinology
and Metabolism 2001;86(3):112633.
Karimzadeh 2007 {published data only}
Karimzadeh M, Tayebi N, Eftekhar M, Sakhavat L,
Taheripanah R, Zare F. The effect of administration of
metformin on lipid profile changes and insulin resistance
in patients with polycystic ovary syndrome. Middle East
Fertility Society Journal 2007;12(3):1748.
Karimzadeh 2010 {published data only}
Karimzadeh MA, Javedani M. An assessment of lifestyle
modification versus medical treatment with clomiphene
citrate, metformin, and clomiphene citrate-metformin
in patients with polycystic ovary syndrome. Fertility and
Sterility 2010;94(1):21620.
Khorram 2006 {published data only}
Khorram O, Helliwell JP, Katz S, Bonpane CM, Jaramillo
L Khorram O, et al.Two weeks of metformin improves
clomiphene citrate-induced ovulation and metabolic profiles
in women with polycystic ovary syndrome. Fertility and
Sterility 2006;85:144851.
Ladson 2011 {published data only}
Ladson G, Dodson WC, Sweet SD, Archibong AE,
Kunselman AR, Demers LM, et al.The effects of metformin
with lifestyle therapy in polycystic ovary syndrome: a
randomized double-blind study. Fertility and Sterility 2011;
95(3):105966.e1-7.
Lam 2011 {published data only}
Lam PM, Tam WH, Ma RC, Cheung LP, Tsui MH,
Tong PC, et al.The reproductive and metabolic effect of
rosiglitazone on Chinese women with polycystic ovarian
syndrome?a double-blind randomized placebo-controlled
study. Fertility and Sterility 2011;96(2):44551.
Legro 2007 {published data only}
Cataldo N, Barnhart H, Legro R, Myers E, Schlaff W, Carr
B, Diamond MP, et al.Extended-release metformin does
not reduce the clomiphene citrate dose required to induce
ovulation in polycystic ovary syndrome. Journal of Clinical
Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond
MP, Carson SA, et al.Clomiphene, metformin, or both for
28
infertility in the polycystic ovary syndrome. New England

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Lord 2006 {published data only}
Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The
effect of metformin on fat distribution and the metabolic
syndrome in women with polycystic ovary syndrome--a
randomised, double-blind, placebo-controlled trial. British
Journal of Obstetrics and Gynaecology 2006;113:81724.
Maciel 2004 {published data only}
Maciel GA, Soares Jr JM, Alves da Motta EL, Abi Haidar
M, de Lima GR, Baracat EC, et al.Nonobese women
with polycystic ovary syndrome respond better than obese
women to treatment with metformin. Fertility and Sterility
2004;81:35560.
Malkawi 2002 {published data only}
Malkawi HY, Qublan HS. The effect of metformin plus
clomiphene citrate on ovulation and pregnancy rates
in clomiphene-resistant women with polycystic ovary
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[MEDLINE: 22065897]
Moghetti 2000 {published data only}
Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo
M, et al.Metformin effects on clinical features, endocrine
and metabolic profiles, and insulin sensitivity in polycystic
ovary syndrome: a randomized, double-blind, placebocontrolled 6-month trial, followed by open, long-term
clinical evaluation. Journal of Clinical Endocrinology and
Metabolism 2000;85(1):13946.
Moll 2006 {published data only}
Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der
Veen F. Effect of clomifene citrate plus metformin and
clomifene citrate plus placebo on induction of ovulation in
women with newly diagnosed polycystic ovary syndrome:
randomised double blind clinical trial. BMJ 2006;332:
1485. [: original article]
Moll E, Korevaar JC, Bossuyt PM, van der Veen F. Does
adding metformin to clomifene citrate lead to higher
pregnancy rates in a subset of women with polycystic ovary
syndrome?. Human Reproduction 2008;23(8):18304.
Nestler 1998 {published data only}
Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects
of metformin on spontaneous and clomiphene-induced
ovulation in the polycystic ovary syndrome. New England
Journal of Medicine 1998;338(26):187680.
Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan
G. Ovulatory and metabolic effects of D-chiro-inositol in
the polycystic ovary syndrome. New England Journal of
Medicine 1999;340(17):131420.
Ng 2001 {published data only}
Ng EHY, Wat NMS, Ho PC. Effects of metformin
on ovulation rate, hormonal and metabolic profiles in
women with clomiphene-resistant polycystic ovaries: A
randomized, double-blinded placebo-controlled trial.
Human Reproduction 2001;16(8):162531.
Onalan 2005 {published data only}

Onalan G, Goktolga U, Ceyhan T, Bagis T, Onalan R,
Pabuccu R. Predictive value of glucose-insulin ratio in PCOS
and profile of women who will benefit from metformin
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Journal of Obstetrics, Gynecology, and Reproductive Biology
2005;123:20411.
Otta 2010 {published data only}
Otta CF, Wior M, Iraci GS, Kaplan R, Torres D, Gaido MI,
Wyse EP. Clinical, metabolic, and endocrine parameters in
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Palomba 2005 {published data only}
Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, et
al.Prospective parallel randomized, double-blind, doubledummy controlled clinical trial comparing clomiphene
citrate and metformin as the first-line treatment for
ovulation induction in nonobese anovulatory women with
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Palomba S, Orio F Jr, Falbo A, Russo T, Tolino A, Zullo F.
Effects of metformin and clomiphene citrate on ovarian
vascularity in patients with polycystic ovary syndrome.
Fertil and Sterility 2006;86:1694701.
Pasquali 2000 {published data only}
Casimirri F, Biscotti M, Gambineri A, Calzoni F, Eliana
B, Pasquali R. Metformin improves insulin, body fat
distribution, and androgens in obese women with and
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Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi
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fat distribution, and androgen and insulin levels in
abdominally obese women with and without the polycystic
ovary syndrome. Journal of Clinical Endocrinology and
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PCOSMIC 2010 {published data only}
Johnson NP, Stewart AW, Falkiner J, Farquhar CM, Milsom
S, Singh V-P, et al.on behalf of REACT-NZ (REproduction
And Collaborative Trials in New Zealand), a multi-centre
fertility trials group. PCOSMIC: a multi-centre randomized
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Rautio 2006 {published data only}
Rautio K, Tapanainen JS, Ruokonen A, Morin-Papunen
LC. Rosiglitazone treatment alleviates inflammation
and improves liver function in overweight women with
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29
overweight women with PCOS: a randomized placebocontrolled study. Human Reproduction 2006;21:14007.
Romualdi 2010 {published data only}
Romualdi D, Giuliani M, Cristello F, Fulghesu AM,
Selvaggi L, Lanzone A, Guido M. Metformin effects on
ovarian ultrasound appearance and steroidogenic function
in normal-weight normoinsulinemic women with polycystic
ovary syndrome: a randomized double-blind placebocontrolled clinical trial. Fertility and Sterility 2010;93(7):
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Sahin 2004 {published data only}
Sahin Y, Yirmibes U, Kelestimur F, Aygen E. The effects
of metformin on insulin resistance, clomiphene-induced
ovulation and pregnancy rates in women with polycystic
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and Reproductive Biology 2004;113:21420.
Siebert 2009 {published data only}
Siebert T, Kruger T, Lombard C. Evaluating the equivalence
of clomiphene citrate with and without metformin in
ovulation induction in PCOS patients. Journal of Assisted
Reproduction and Genetics 2009;26(4):16571.
Sturrock 2002 {published data only}
Sturrock NDC, Lannon B, Fay TN. Metformin does
not enhance ovulation induction in clomiphene resistant
polycystic ovary syndrome in clinical practice. British
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[MEDLINE: 2002180629]
Tang 2006 {published data only}
Tang T, Glanville J, Hayden CJ, White D, Barth JH,
Balen AH. Combined lifestyle modification and metformin
in obese patients with polycystic ovary syndrome. A
randomized, placebo-controlled, double-blind multicentre
study. Human Reproduction 2006;21:809.
Trolle 2007 {published data only}
Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of
metformin in obese and non-obese women with polycystic
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Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of
metformin in obese and non-obese women with polycystic
ovary syndrome: a randomized, double-blinded, placebocontrolled cross-over trial. Obstetrics and Gynecological
Survey 2008;63(2):968.
Vandermolen 2001 {published data only}
Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma
SW, Nestler JE. Metformin increases the ovulatory rate and
pregnancy rate from clomiphene citrate in patients with
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Williams 2009 {published data only}
Williams SC, Pastore LM, Shelly WB, Bailey AP, Baras DC,
Bateman BG. A randomized, placebo-controlled study of
the influence of instant-release metformin on response to
clomiphene citrate and time to conception in polycystic
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105.
Yarali 2002 {published data only}
Yarali H, Yildiz BO, Demirol A, Zeyneloglu HB, Yigit N,

Bukulmez O, et al.Co-administration of metformin during
rFSH treatment in patients with clomiphene citrate-resistant
polycystic ovarian syndrome: a prospective randomized
trial. Human Reproduction 2002;17(2):28994.
Yarali H, Yyldyz B, Demirol A, Zeyneloglu H, Yigit N,
Bukulmez O. Co-administration of metformin during
recombinant follicle stimulating hormone (recombinant
FSH) treatment using the low-dose step protocol in patients
with clomiphene citrate resistant polycystic ovary syndrome
(PCOS): a prospective randomized trial. Fertility and
Sterility 2001;76 Suppl(3):36.
Zain 2009 {published data only}
Zain MM, Jamaluddin R, Ibrahim A, Norman RJ.
Comparison of clomiphene citrate, metformin, or the
combination of both for first-line ovulation induction,
achievement of pregnancy, and live birth in Asian women
with polycystic ovary syndrome: a randomized controlled
trial. Fertility and Sterility 2009;91(2):51421.
References to studies excluded from this review

Aroda 2009 {published data only}
Aroda V, Ciaraldi T, Burke P, Mudaliar S, Clopton
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randomized, placebo-controlled clinical trial. Journal of
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Azziz 2001 {published data only}
Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R,
Fereshetian AG, et al.Troglitazone improves ovulation and
hirsutism in the polycystic ovary syndrome: A multicenter,
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Legro RS, Azziz R, Ehrmann D, Fereshetian AG, OKeefe
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Azziz 2003 {published data only}
Azziz R, Ehrmann DA, Legro RS, Fereshetian AG, OKeefe
M, Ghazzi MN. Troglitazone decreases adrenal androgen
levels in women with polycystic ovary syndrome. Fertility
and Sterility 2003;79:9327.
Crave 1995 {published data only}
Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dechaud H,
Pugeat M. Effects of diet and metformin administration on
sex hormone-binding globulin, androgens, and insulin in
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hirsute and obese women. Journal of Clinical Endocrinology

and Metabolism 1995;80(7):205762.
De Leo 1999 {published data only}
De Leo V, La Marca A, Ditto A, Morgante G, Cianci A.
Effects of metformin on gonadotropin-induced ovulation
in women with polycystic ovary syndrome. Fertility and
Sterility 1999;72(2):2825.
Dunaif 1996 {published data only}
Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb
R. The insulin-sensitizing agent troglitazone improves
metabolic and reproductive abnormalities in the polycystic
Metabolism 1996;81(9):3299306.
Elter 2002 {published data only}
Elter K, Imir G, Durmusoglu F. Clinical, endocrine and
metabolic effects of metformin added to ethinyl estradiolcyproterone acetate in non-obese women with polycystic
ovarian syndrome: a randomized controlled study. Human
Reproduction 2002;17(7):172937. [MEDLINE: 785]
Hou 2000 {published data only}
Hou J, Yu J, Wei M. Study on treatment of
hyperandrogenism and hyperinsulinism in polycystic ovary
syndrome with Chinese herbal formula tiangui fang.
Zhongguo Zhong Xi Yi Jie He Za Zhi 2000;20(8):58992.
Ibanez 2002 {published data only}
Ibanez L, Valls C, Ferrer A, Ong K, Dunger D, De-Zegher
F. Additive effects of insulin-sensitizing and anti-androgen
treatment in young, nonobese women with hyperinsulinism,
hyperandrogenism, dyslipidemia, and anovulation. Journal
of Clinical Endocrinology and Metabolism 2002;87(6):
28704. [MEDLINE: 22045399]
Kazerooni 2009 {published data only}
Kazerooni T, Ghaffarpasand F, Kazerooni Y, Kazerooni
M, Setoodeh S. Short-term metformin treatment for
clomiphene citrate-resistant women with polycystic ovary
syndrome. International Journal of Gynaecology and
Obstetrics 2009;107(1):503.
Kelly 2002 {published data only}
Kelly CJ, Gordon D. The effect of metformin on hirsutism
in polycystic ovary syndrome. European Journal of
Endocrinology 2002;147(2):21721. [MEDLINE: 782]
Kocak 2002 {published data only}
Kocak M, Caliskan E, Simsir C, Haberal A. Metformin
therapy improves ovulatory rates, cervical scores, and
pregnancy rates in clomiphene citrate-resistant women with
polycystic ovary syndrome. Fertility and Sterility 2002;77
(1):1016.
Mantzoros 1997 {published data only}
Mantzoros CS, Dunaif A, Flier JS. Leptin concentrations
in the polycystic ovary syndrome. Journal of Clinical
Morin-Papunen 2000 {published data only}
Morin-Papunen LC, Vauhkonen I, Koivunen RM,
Ruokonen A, Martikainen HK, Tapanainen JS. Endocrine
and metabolic effects of metformin versus ethinyl estradiol-
cyproterone acetate in obese women with polycystic

ovary syndrome: a randomized study. Journal of Clinical
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome
P450c17 alpha activity and serum free testosterone after
reduction of insulin secretion in polycystic ovary syndrome.
New England Journal of Medicine 1996;335(9):61723.
Nestler JE, Jakubowicz DJ. Lean women with polycystic
ovary syndrome respond to insulin reduction with decreases
in ovarian P450c17 alpha activity and serum androgens.
Journal of Clinical Endocrinology and Metabolism 1997;82
(12):40759.
Ramzy 2003 {published data only}
Ramzy A, El-Kateb S, Al-Inany H, Aboulmaaty Z, Badie
M. The use of metformin in overweight and lean infertile
patients with polycystic ovarian syndrome: a randomised
controlled trial. Middle East Fertility Society Journal 2003;8:
1439.
Rouzi 2006 {published data only}
Rouzi AA, Ardawi MS. A randomized controlled trial
of the efficacy of rosiglitazone and clomiphene citrate
versus metformin and clomiphene citrate in women with
clomiphene citrate-resistant polycystic ovary syndrome.
Santonocito 2009 {published data only}
Santonocito V, Rapisarda V, Abruzzo SRM, Pollicino
R, Coco L, Zarbo G. Comparison between clomiphene
citrate and metformin for induction of ovulatory cycles in
infertile nonobese women with polycystic ovary syndrome.
Giornale Italiano di Ostetricia e Ginecologia. 2009;31(1112):45560.
Shobokshi 2003 {published data only}
Shobokshi A, Shaarawy M. Correction of insulin resistance
and hyperandrogenism in polycystic ovary syndrome by
combined rosiglitazone and clomiphene citrate therapy.
Journal of the Society for Gynecologic Investigation 2003;10:
99104.
References to studies awaiting assessment

Chaudhury 2008 {published data only}
Chaudhury K, Chaudhury S, Chowdhury S. Does
metformin augment the ovulation inducing effects of
clomiphene in non-obese women with polycystic ovary
syndrome?. Journal of the Indian Medical Association 2008;
106(10):6438.
Costantino 2009 {published data only}
Costantino D, Minozzi G, Minozzi F, Guaraldi C.
Metabolic and hormonal effects of myo-inositol in women
with polycystic ovary syndrome: A double-blind trial.
European Review for Medical and Pharmacological Sciences
2009;13(2):10510.
31
Farzadi 2006 {published data only}

Farzadi L, Salman S. Metformin-therapy effects in 50
clomiphene citrate resistant PCOS patients. Journal of
Medical Science 2006;6:76571.
Morin-Papunen 2010 {published data only}
Morin-Papunen L, Rantala A, Unkila-Kallio L, Tiitinen A,
Hippelainen M, Tinkanen H, et al.Metformin improves
pregnancy and live birth rates in women with polycystic
ovary syndrome - A multicentre placebo-controlled
randomised trial.. Human Reproduction.Conference:
26th Annual Meeting of the European Society of Human
Reproduction and Embryology, ESHRE Rome Italy. 2010;25:
i678.
Rantala AS, Unkila-Kallio L, Unkila-Kallio L, Tiitinen A,
Hippelainen M, Perheentupa A, et al.Prediction of pregnancy
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Indicates the major publication for the study
35
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Baillargeon 2004
Methods
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
SUMMARY: non-obese PCOS

INCLUSION CRITERIA: PCOS (oligomenorrhoea < 8 periods per year, hyperandrogenism total testosterone > 2.43nmol/l.
Normal prolactin and TFT, fasting insulin <15IU/mL and fasting glucose to insulin
ration over 4.5.
Normal OGTT.
Hormonal contraceptives were not used before the trial.
EXCLUSION CRITERIA: late onset adrenal hyperplasia, hypertension. Previous insulin-sensitiser users
BASELINE CHARACTERISTICS OF EACH GROUP:
Mean age (SD) metformin 27.7(4.7), rosiglitazone 27.9(5.16), placebo 27.2(4.9)
Mean BMI (SD) metformin 24.6(1.1), rosiglitazone 24.3(1.4), placebo 24.6(1.9)
Mean fasting insulin mIU/L (SD) metformin 6.3(5.8), rosiglitazone 11.2(5.6), placebo
7.9(2.0)
Mean total testosterone mol/L (SD) metformin 3.8(2.0), rosiglitazone 3.5(1.9), placebo
4.67(2.0)
DROP OUTS - 4 (12.5%) in the metformin arm, 10 (31.3%) in the rosiglitazone group
and 2 (6.3%) in the placebo group
Interventions
MAIN INTERVENTION: Metformin 850mg, Rosiglitazone 4mg or placebo tablets

twice daily
DURATION: 6 months
CO-INTERVENTIONS: None
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.
36
Baillargeon 2004
(Continued)
Women were predominantly European emigrants to Venezulea of Caucasian race.

Due to delays in the delivery of the drug rosiglitazone to the research centre, this results
in a higher dropout rates in this group after the participants being randomised
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Low risk

bias)
Fixed block of 8 randomisation which was

performed in the investigational pharmacist
Allocation concealment (selection bias)
Trial drugs packed in coded boxes which

were allocated by the research nurse. Trial
drugs were similar in appearance
Low risk
Blinding (performance bias and detection Low risk

bias)
All outcomes
Double blinded
Incomplete outcome data (attrition bias)

All outcomes
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
Selective reporting (reporting bias)
Unclear risk
unclear
Other bias
High risk
Disproportion in drop out rates among the

study groups.
Due to delays in the delivery of the drug
rosiglitazone to the research centre, this results in a higher dropout rates in this group
after the participants being randomised
Ben Ayed 2009

Methods
RANDOMISED TRIAL
SETTING: Tunisia
METHOD OF RANDOMISATION: Not stated
BLINDING: Not stated
Participants

INCLUSION CRITERIA: Rotterdam criteria
EXCLUSION CRITERIA: late onset adrenal hyperplasia, Cushings Syndrome, abnormal TFT, hyperprolactinaemia, androgen secreting tumour
Mean age 32.81, 29.38
37
Ben Ayed 2009
(Continued)
Mean BMI; 28, 28

Interventions
MAIN INTERVENTION: metformin 1700mg per day or placebo

DURATION: unclear
CO-INTERVENTIONS: clomifene 100mg from day 3 to day 7 of the cycle. Life style
advise on the obese subjects
Outcomes
Ovulation: USS follicular tracking with follicular size over 16mm
Notes
Inadequate information in the protocol to assess the quality of the trial

No reply from author.
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Unclear risk

bias)
inadequate information
Unclear risk
Blinding (performance bias and detection Unclear risk

bias)
All outcomes

All outcomes
Unclear risk
Unclear risk
Other bias
Unclear risk
Boudhraa 2010
Methods
RANDOMISED TRIAL
SETTING: Tunisia
METHOD OF RANDOMISATION: not stated*
BLINDING: unblinded
Participants
SUMMARY: PCOS non-obese

INCLUSION CRITERIA: unclear. ? diagnostic criteria of PCOS used
EXCLUSION CRITERIA: male factor infertility, tubal disease
Mean age 30.55, 30.72
Mean BMI 29.9, 29.77
DROP OUTS - none
38
Boudhraa 2010
(Continued)
Interventions
MAIN INTERVENTION: metformin 850mg

DURATION: not stated
CO-INTERVENTIONS: recommendations on healthy diet. Five days 100mg clomifene
treatment
Outcomes
Ovulation: method to confirm ovulation not stated

Live birth
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

bias)
Unclear risk

bias)
All outcomes

All outcomes
Unclear risk
Unclear risk
Other bias
Unclear risk
Brettenthaler 2004
Methods
RANDOMISED TRIAL
SETTING: Switzertland
METHOD OF RANDOMISATION: Unclear*
BLINDING: Double
Participants
SUMMARY: PCOS non-obese

INCLUSION CRITERIA: menstrual dysfunction (oligo- or amenorrhea), hirsutism
with Ferriman-Gallwey score over 7 or serum total testosterone > 2.5nmol/l and SHBG
< 50nmol/l.
EXCLUSION CRITERIA: adrenal disease, thyroid dysfunction, diabetes, hyperprolactinaemia
Pregnancy or desire for pregnancy, basal FSH > 20IU/l.
Medication known to affect reproductive or metabolic functions
Previous hysterectomy
39
Brettenthaler 2004
(Continued)
History of liver disease or alcohol abuse.

Abnormal liver function tests.
Mean age (SD) 30.2(5.7), 30.6(5.1)
Mean BMI (SD) 29.4(7), 27.5(5.1)
Mean fasting insulin mIU/L (SD)
Mean total testosterone nmol/L (SD)
DROP OUTS - 3 in the treatment group and 2 in the placebo group. The details were
not given (lost in follow-up and protocol violation)
Interventions
MAIN INTERVENTION: pioglitazone 30mg or placebo tablet once daily

DURATION: three months
CO-INTERVENTIONS: recommendations on healthy diet and physical activity for
weight maintenance four weeks prior to the study
Outcomes
OVULATION: progesterone > 9nmol/l

ANTHROPOMETRIC: BMI, WHR
HORMONES: testosterone, SHBG, DHEAS
METABOLIC MARKERS: insulin, glucose, AUCinsulin, AUCglucose, cholesterol,
triglyceride
OTHERS: hirsutism
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

bias)
Unclear risk

bias)
All outcomes
Identical trial and placebo tablets. In adequate information to assess the methodology

All outcomes
High risk
Missing data not reported
Unclear risk
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
Participants
SUMMARY: Non obesePCOS

INCLUSION CRITERIA: chronic anovulation with serum progesterone less than 2ng/
ml on day 22 of cycle, in 2 consecutive cycles
Normal TFT
No clinical and biochemical features of hyperandrogenism
EXCLUSION CRITERIA:
Mean age 24.6, 24.2
Mean BMI 25.2, 25.8
Mean fasting insulin mIU/L 11.8, 12.0
Mean total testosterone nmol/L 1.3, 1.4
DROP OUTS - none
Interventions
MAIN INTERVENTION: metformin 500mg tds, placebo

CO-INTERVENTIONS:
Outcomes
Ovulation: method to confirm ovulation not stated
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

bias)
Unclear risk

bias)
All outcomes
41
Carmina 2004
(Continued)

All outcomes
Unclear risk
Limited information to assess
Unclear risk
Limited information to assess
Other bias
Low risk
Only 79% of the subjects were PCOS.
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
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (less than 6 menstrual cycles), clinical or
biochemical hyperandrogenism.
BMI over 30
Non-smoker. Participants had not used any medication three months before the start of
the trial
EXCLUSION CRITERIA: renal or liver disease. CAH (serum 17-hydroxyprogesterone
over 12 ng/dl one hour after 0.25mg ACTH intramuscular injection)
Mean age (SD) 24(5), 24.5(6.1)
Mean BMI (SD) 35.6(4.9), 37.4(6)
Mean fasting insulin mIU/L (SD) 44.3(21.6), 46.8(41.4)
Mean total testosterone mmol/L (SD) 2.02(0.70), 2.41(1.1)
DROP OUTS - one in each arm (protocol violation)
Interventions
MAIN INTERVENTION: Metformin 500mg or placebo tablet TDS

CO-INTERVENTIONS:
Outcomes
ANTHROPOMETRIC: BMI, WHR, blood pressure*

HORMONES: testosterone, SHBG*
METABOLIC MARKERS: insulin, glucose, cholesterol, LDL, HDL and triglyceride.*
OTHERS: Menstrual pattern
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
42
Chou 2003
(Continued)
Risk of bias
Bias
Authors judgement

bias)
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
Trial drugs were similar in appearance.

Randomisation carried out a third party
who kept the code until the end of the study
Low risk

bias)
All outcomes
Double blinded

All outcomes
Unclear risk
The results of the women who dropped

out from the study were excluded from the
analysis. Details of the excluded subjects
were not given
Unclear risk
Other bias
Unclear risk
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
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (cycle length >35days or less than 9 periods per year) or amenorrhoea (cycle length >12weeks), PCO on USS (Rotterdam consensus 2003), Clinical or biochemical hyperandrogenism (testosterone >2.1nmol/l or
androstenedione >10.1nmol/l).
Age between 21 to 36 years old.
EXCLUSION CRITERIA: hyperprolactinemia, diabetes, thyroid disease, CAH, Cushingss syndrome.
Medications that influence hormonal profiles or anti obesity drugs within 6 months
before the start of the study
BASELINE CHARACTERISTICS OF EACH GROUP:*
43
Eisenhardt 2006
(Continued)
Median age 27, 29.7

Median BMI 28.9, 32.4
Median fasting insulin (mIU/L) 20.0, 22.0
Median testosterone (mmol/l) 1.59, 1.66
DROP OUTS- one in the metformin arm, three in the placebo arm. Details were not
given. Furthermore, one in the metformin group and two in the placebo became pregnant
and were also excluded in the analysis
Interventions
MAIN INTERVENTION: metformin 500mg or placebo tablet TDS

DURATION: 12 weeks
CO-INTERVENTIONS: none
Outcomes
ANTHROPOMETRIC: BMI, weight*

HORMONES: testosterone, androstenedione, SHBG, oestradiol, DHEAS, LH, FSH.
*
METABOLIC MARKERS: glucose, insulin, AUC glucose, AUC insulin*
OTHERS: hirsutism, menstrual pattern*
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

bias)
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. Trial drugs
were provided by a pharmaceutical company which did not involve study design
and data analysis
Low risk

bias)
All outcomes
Double blinded

All outcomes
DROP OUTS - one in the metformin arm,

two in the placebo arm. Details were not
given
Unclear risk
44
Eisenhardt 2006
(Continued)
Low risk
All primary outcome measures (menstrual

frequency and metabolic parameters) reported
Other bias
Unclear risk
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
Participants
SUMMARY: PCOS, obese

INCLUSION CRITERIA: PCOS (oligomenorrhoea, ultrasound findings of >=10 ovarian cysts measuring 2-8mm around a dense stroma), hyperinsulinaemia (fasting insulin
>30mIU/L),
BMI >28kg/m2,
Waist:hip ratio >0.85,
Normal semen analysis,
No tubal disease
EXCLUSION CRITERIA: diabetes mellitus, thyroid dysfunction, raised prolactin
BASELINE CHARACTERISTICS OF EACH GROUP: Mean age ( SD) 26.4(4.5),
25.7(4.3)
Mean BMI ( SD) 28.7(5.9), 27.4(3.6)
Mean fasting insulin mIU/L ( SD) 39.3(8.1), 39.2(8.5)
Mean total testosterone mmol/L ( SD) 3.1(2.1), 3.0(1.5)
DROPOUTS: only as a result of pregnancy (13 from metformin group, 4 from no
metformin)
Interventions
MAIN INTERVENTION: one of: metformin 500mg tds, no treatment

DURATION: 6 months
CO-INTERVENTIONS: clomiphene 50mg on days 5-9, increased each cycle if not
ovulated by 50mg up to a maximum of 150mg.
hCG 10,000IU given to trigger ovulation.
Outcomes
OVULATION: by serum progesterone (>15.9nmol/L) nine days after hCG

METABOLIC MARKERS: fasting insulin
OTHERS: pregnancy
Number of mature follicles
Diameter of largest follicle
Premature ovulation rate
Ovarian hyperstimulation syndrome (not defined)
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)
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

bias)
Computer randomised
Unclear risk
Not stated

bias)
All outcomes
Not stated

All outcomes
Unclear risk
Only as a result of pregnancy (13 from metformin group, 4 from no metformin)
Unclear risk
Other bias
Unclear risk
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)
Fleming 2002
Methods
RANDOMISED TRIAL
SETTING: UK
METHOD OF RANDOMISATION: computer generated randomisation by pharmacy
in blocks of four
BLINDING: Double blind
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: PCOS (oligomenorrhoea <8 cycles per year, exclusion of
other endocrinopathy, ultrasound finding of PCO),
Age<35
EXCLUSION CRITERIA: diabetes mellitus
adrenal hyperplasia
thyroid dysfunction
hyperprolactinaemia
medication likely to influence hormonal profiles
BASELINE CHARACTERISTICS OF EACH GROUP: Mean age (+/- SD) 28.6(5.8)
46
Fleming 2002
(Continued)
, 29.2(5.6)
Mean BMI ( SD) 34.2(8.6), 35.0(8.2)
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
MAIN INTERVENTION: one of: metformin 850mg bd, placebo

DURATION: 12-16 weeks
CO-INTERVENTIONS: first week of treatment at 850mg od
Outcomes
OVULATION: by twice weekly serum oestradiol. Where oestradiol>300pmol/L, LH

and progesterone (>8nmol/l in >=2 successive samples defined ovulation*) were determined
ANTHROPOMETRIC: BMI
Waist-hip ratio
REPRODUCTIVE HORMONES: total testosterone
Free testosterone
Androstenedione
Estradiol
SHBG
FSH
LH
METABOLIC MARKERS: fasting glucose
fasting insulin
area under curve of insulin during GTT
Leptin
Inhibin-B
Cholesterol
HDL
LDL
VLDL
Triglycerides
OTHERS: ovarian ultrasound
pregnancy
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
47
Fleming 2002
(Continued)

bias)
Computer generated randomisation by

pharmacy in blocks of four
Remote allocation. Identical metformin

and placebo tablets. Randomisation code
kept in the pharmacy department until the
end of the trial
Low risk

bias)
All outcomes
Double blinded

All outcomes
High risk
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 completed the trial and 83%
of the placebo arm
Unclear risk
Other bias
Unclear risk
Gerli 2003
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: computer generated random numbers table.*
BLINDING: Double
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: PCO on USS, oligomenorrhoea (cycle length >40 days or
less than 8 cycles per year) or amenorrhoea, clinical and biochemical hyperandrogenism.
Age < 35
EXCLUSION CRITERIA: CAH, thyroid dysfunction, hyperprolactinemia
Mean age (SD) 28.6(10.1), 29.2(9.3)
Mean BMI (SD) 34.2(14.8), 35(15.4)
Mean fasting insulin mIU/L (SD) 16.7(22), 18.4(24.2)
Mean total testosterone mol/L (SD) 3.0(2.3), 3.8(2.4)
DROP OUTS - significantly more women withdrew in the treatment group (n=15)
compared with the placebo group (n=5). Reasons not given
Interventions
MAIN INTERVENTION: inositol 100mg or placebo tablet twice daily

DURATION: 16 weeks
48
Gerli 2003
(Continued)
Outcomes
OVULATION: progesterone > 6nmol/l

ANTHROPOMETRIC: BMI, WHR*
HORMONES:
METABOLIC MARKERS: insulin, glucose, AUCinsulin, leptin, cholesterol, VLDL
cholesterol, LDL cholesterol, HDL cholesterol, triglyceride.*
OTHERS: Menstrual pattern, pregnancy*
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

bias)
Computer generated random numbers table
Unclear risk
Not stated

bias)
All outcomes
Not stated

All outcomes
High risk
DROP OUTS - significantly more women

withdrew in the treatment group (n=15)
compared with the placebo group (n=5).
Reasons not given
Unclear risk
Inadequate information
Other bias
Unclear risk
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*
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (cycle length longer than 35 days), free
testosterone > 0.035nmol/l or clinical evidence of hirsutism
Fasting insulin level greater than 50 pmol/l and or BMI over 30
Participants stopped oral contraceptives for at least 3 months before the trial
Normal TFT and prolactin levels.
EXCLUSION CRITERIA: diabetes, hypertension, renal dysfunction, heart disease or
abnormal liver function tests
Mean age (SD) 32(2.4), 34(2.25)
Mean BMI (SD) 33.4(3.3), 33.6(5.9)
DROP OUTS - two in total. One in the placebo group due to pregnancy. Another
subject in the treatment group experienced side effect from pioglitazone (ankle oedema,
anxiety, dizziness). No serious side effects were reported in this study and all women had
normal liver function tests at the end of the trial
Interventions
MAIN INTERVENTION: pioglitazone 30mg or placebo once daily

DURATION: 16 weeks
CO-INTERVENTIONS:
Outcomes
ARTHROPOMETRIC: BMI, WHR, waist circumference

HORMONES: testosterone, SHBG, free testosterone
OTHERS: menstrual pattern, hirsutism
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
Risk of bias
Bias
Authors judgement
50
Glintborg 2005
(Continued)

bias)
Computer generated numbers. Randomisation was conducted in the local pharmacist
The code was kept in the pharmacist department until the end of the trial
Low risk

bias)
All outcomes
Double blinded

All outcomes
Unclear risk
DROP OUTS - two in total, one in each

group
Low risk
All primary measures reported
Other bias
Low risk
Primary objective investigated the effect of

pioglitazone on growth hormone levels in
women with PCOS. All subjects were instructed to use contraception
Hoeger 2004
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: computer generated random number, randomisation conducted by the pharmacy department.*
BLINDING: Double
Participants

INCLUSION CRITERIA: PCOS (oligomenorrhoea with less than 6 menses per year
and evidence of hyperandrogenism),BMI over 25, normal TSH, prolactin and FSH
concentrations
No hormonal treatment within 2 months before the trial commenced.
EXCLUSION CRITERIA: adrenal disease.
Mean age (SD) 29.5(6.4), 27.1(4.5)
Mean BMI (SD) 37.1(4.9), 37.1(4.6)
Mean total testosterone nmol/L (SD) 2.1(0.8), 2.0 (0.60)
DROP OUTS - 3 (33.3%) in the metformin arm and 2 (22.2%)in the placebo arm at
24 months of the trial
INCLUSION CRITERIA: PCOS (oligomenorrhoea with less than 6 menses per year
and evidence of hyperandrogenism),BMI over 25, normal TSH, prolactin and FSH
concentrations
51
Hoeger 2004
(Continued)
No hormonal treatment within 2 months before the trial commenced.

EXCLUSION CRITERIA: adrenal disease.
Mean age (SD) 30.4(5.4), 27.1(4.3)
Mean BMI (SD) 41.7(6.2), 40(7.4)
Mean total testosterone nmol/L (SD) 2.43(0.59), 2.00(0.66)
DROP OUTS - 4(44.4%) in the metformin/lifestyle arm and 2 (18.2%)in the placebo/
lifestyle arm at 24 months of the trial
Interventions
MAIN INTERVENTION: metformin 850mg b.d. or placebo

DURATION: 24 months
CO-INTERVENTIONS: lifestyle modification program aiming for a reduction of calorie intake by 500-1000kcal per day. All subjects were provided with an individual healthy
balanced meal plan. The lifestyle team consisted of a dietitian and exercise physiology.
No life style modification for the non-obese group
Outcomes
ARTHROPOMETRIC: weight, BMI, hirsutism

HORMONES: total testosterone, SHBG, FAI, AUCglucose, AUCinsulin, fasting glucose, fasting insulin*
METABOLIC MARKERS:
OTHERS: menstrual pattern*
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

bias)
Computer generated random number
Low risk
Randomisation conducted by the pharmacy department

bias)
All outcomes
Double. Drug and placebo packaged and

labelled according to subject number by the
pharmacy
52
Hoeger 2004
(Continued)

All outcomes
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
Study protocol available. Pre-specified outcome measures (ovulation and testosterone

levels) were reported
Other bias
High risk
A higher drop outs rates in the metformin

group than the placebo group
Hwu 2005
Methods
RANDOMISED TRIAL
SETTING: Taiwan
METHOD OF RANDOMISATION: computer generated random numbers, block of
two randomisation process*
BLINDING: No*
Participants
SUMMARY: clomiphene resistant PCOS

INCLUSION CRITERIA: oligomenorrhoea (less than six menses per year), clinical or
biochemical hyperandrogenism (total testosterone over 2.42nmol/l), PCO on USS (12
or more follicles 2-9mm in diameter per ovary)
clomiphene resistance was defined as no follicular development after 2 cycles up to
150mg clomiphene treatment for 5 days
EXCLUSION CRITERIA: Not mentioned
Mean age (SD) 29.07(4.45), 27.8(3.75)
Mean BMI (SD) 25.27(3.3), 24.11(3.58)
DROP OUTS- None
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
53
Hwu 2005
(Continued)
CO-INTERVENTIONS: clomiphene 150mg, hCG 5000IU (Pregnyl; Organon, Holland)

Outcomes
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
This study is to evaluate the effect of a short course of metformin as a co-therapy in

ovulation induction with clomiphene 150 mg in women with PCOS who developed
clomiphene resistance in the previous treatment cycles. Compared with the other included studies, clomiphene treatment was commenced at day 13 of the menstrual cycle
rather than at early follicular phase
Intramuscular hCG (5000IU) was used to trigger ovulation when a dominant follicle
reached a diameter of 20mm
The sequence of allocation was not concealed and this study was unblinded. Therefore,
bias cannot be excluded
Risk of bias
Bias
Authors judgement

bias)
Computer generated random numbers,

block of two randomisation process*
The sequence of allocation was not concealed
High risk
Blinding (performance bias and detection High risk

bias)
All outcomes
Not blinded

All outcomes
Low risk
No drop outs
Unclear risk
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
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
Participants
SUMMARY: obese PCOS, clomiphene sensitive

INCLUSION CRITERIA: PCOS (oligomenorrhoea <=8 cycles per year,
elevated free testosterone,
exclusion of other endocrinopathy,
ultrasonographic finding of PCO),
ovulation with clomiphene 150mg (demonstrated by serum progesterone >12.7pmol/l
and ultrasound)
EXCLUSION CRITERIA: adrenal hyperplasia,
thyroid dysfunction,
hyperprolactinaemia,
diabetes mellitus,
failure to ovulate with clomiphene as described above, medication that could affect
insulin sensitivity*
BASELINE CHARACTERISTICS OF EACH GROUP: Mean age ( SD) 27(5.1), 27
(4.7)
Mean BMI ( SD) 31.8(1.5), 31.7(1.4)
Mean fasting insulin mIU/L (- SD) 34.33(23.0), 54.67(40.7)
DROP OUTS - After randomisation, 8 (14%), 2 in metformin arm and 6 in placebo.
Not included in analysis
Interventions
MAIN INTERVENTION: one of: metformin 500mg tds, placebo

DURATION: 4-5 weeks prior to clomiphene, then for a further 19 days after commencing clomiphene
CO-INTERVENTIONS: clomiphene 150mg for 5 days
Outcomes
OVULATION: by serum progesterone >12.7pmol/L and ultrasound. Ovulation

checked on two occasions on day 23: once after metformin/placebo cycle and once after
subsequent metformin/placebo with clomiphene
ANTHROPOMETRIC: BMI,
Waist-hip ratio
Free testosterone, androstenedione, DHEAS
17-beta estradiol
SHBG
fasting insulin
area under curve of insulin and glucose during GTT
OTHERS: glycodelin
IGFBP-1
Endometrial thickness
55
Jakubowicz 2001
(Continued)
Endometrial vascular penetration

Resistance index of uterine spiral arteries
Notes
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
Risk of bias
Bias
Authors judgement

bias)
Not stated
Sequentially numbered, identical containers of identical drugs
Low risk

bias)
All outcomes
Double blind

All outcomes
High risk
DROP OUTS - after randomisation, 8

(14%), 2 in metformin arm and 6 in
placebo. Not included in analysisMissing
data not reported
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
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 clomifene prior to randomisation were included
56
Karimzadeh 2007
Methods
RANDOMISED TRIAL
SETTING: Iran
METHOD OF RANDOMISATION: computer generated sequences that was sealed
in envelopes
BLINDING: Double
Participants

INCLUSION CRITERIA: Rotterdam criteria 2003
EXCLUSION CRITERIA: hyperprolactinemia, CSH, thyroid disease, Cushings syndrome, androgen secreting tumour
Mean age (SD) 27.2 (6.8), 28.6 (7.4)
Mean BMI (SD) 28.3 (3.18), 29.5 (4.75)
DROP OUTS - Not mentioned
Interventions
MAIN INTERVENTION: metformin 500mg tds, placebo

DURATION: 3 months
CO-INTERVENTIONS: nil
Outcomes
OVULATION: progesterone over 10ng/ml

METABOLIC MARKERS: cholesterol, triglycerides
OTHERS: pregnancy
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

bias)
Computer generated sequences that was

sealed in envelopes
Sequences sealed in envelopes and code

kept in the pharmacy department
Low risk

bias)
All outcomes
Double blinded

All outcomes
Unclear risk
Not stated
Unclear risk
57
Karimzadeh 2007
(Continued)
Other bias
Unclear risk
Inadequate information to assess other bias.

Sample size calculation not mentioned.
Unspecified recruitment period
Karimzadeh 2010
Methods
RANDOMISED TRIAL
SETTING: Iran
METHOD OF RANDOMISATION: not stated
BLINDING: not stated
Participants
SUMMARY: Non obese PCOS

INCLUSION CRITERIA: Rotterdam criteria 2003. Age between 19 and 35, BMI 2529, primary infertility, normal prolactin levels, TFT, liver and renal functions
EXCLUSION CRITERIA: male factor infertility
Mean age: clomifene only 27.47 metformin only 27.33, CC+Met 27.34, Lifestyle 27.
48
Mean BMI: clomifene only 27.2 metformin only 27.17, CC+Met 27.96 Lifestyle 27.92
DROP OUTS - none
Interventions
MAIN INTERVENTION: metformin 500mg tds, No placebo

DURATION: 3-6 months
CO-INTERVENTIONS: clomifene 100mg day 3-7; lifestyle group were advised to
increase daily excerise by 30 mins along with high carbohydrate diet
Outcomes
OVULATION: USS follicular tracking
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.
Risk of bias
Bias
Authors judgement

bias)
Unclear risk

bias)
All outcomes
58
Karimzadeh 2010
(Continued)

All outcomes
Unclear risk
Low risk
Not all the primary outcome measures

(endocrine parameters, lipid profile) data
available
Other bias
Low risk
A large sample size without any dropping

out.
Some of the women may have been included in the previous trial Karimzadeh
2007.
Khorram 2006
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: picking a card out of a box.
BLINDING: unblinded
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (less than 8 cycles in a year), PCO on
USS, clinical (acne, hirsutism, alopecia) or biochemical hyperandrogenism (elevated
testosterone level)
BMI over 29
EXCLUSION CRITERIA: pregnancy, hepatic or renal disease, heart disease, alcoholism,
pulmonary disorder, abnormal TFT, hyperprolactinemia, CAH or androgen secreting
tumour.
Mean age (SD) 28.2(3.12), 28(4.26)
Mean BMI (SD) 35.3(4.0), 38.8(6.2)
Mean fasting insulin mIU/L (SD) 17(11.2), 15.8(10.8)
Mean total testosterone nmol/L (SD) 1.79(0.79), 1.5(0.97)
DROP OUTS - none
Interventions
MAIN INTERCENTION: metformin 500mg t.d.s. Placebo was not used

DURATION: ywo weeks from the start of the menstrual cycle. One trial cycle only.
CO-INTERVENTIONS: clomifene 100mg for 5 days from day 5 of the cycle
Outcomes
OVULATION: method to detect ovulation was not stated

HORMONES: free testosterone, testosterone, SHBG
METABOLIC MARKERS: insulin, glucose
Notes
This study was designed to evaluate the effect of a shot course of metformin treatment
on the outcomes of clomifene ovulation induction therapy.
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

bias)
Picking a card out of a box
Unclear risk

bias)
All outcomes
Unblinded

All outcomes
Unclear risk
No missing data
Unclear risk
Other bias
Unclear risk
Insufficient information
Ladson 2011
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: computer generated random number
BLINDING: Double
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (less than 8 cycles in a year), biochemical
hyperandrogenism (elevated testosterone level over 50ng/dl or FAI over 1.5)
EXCLUSION CRITERIA:Hormonal medications
Mean age 29, 28.8
Mean BMI 38, 38.3
DROP OUTS - 60% in metformin, 73% in placebo
Interventions
MAIN INTERCENTION: metformin 500mg qds or Placebo

DURATION: 6 months
CO-INTERVENTIONS: lifestyle modification (reduced daily calorie intake by 500kcal,
increase exercise by at least 150 mins of walk
60
Ladson 2011
(Continued)
Outcomes
OVULATION: urinary progestin*

HORMONES: testosterone, SHBG*
METABOLIC MARKERS: insulin, glucose, lipid profile*
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

bias)
Computer generated
Identical metformin and placebo capsules.

Drug and placebo packaged and labelled
according to subject study number by the
investigational pharmacy
Low risk

bias)
All outcomes
Blinded to investigators and participants

All outcomes
High risk
Data of incomplete trial participants not

stated
Low risk
All primary outcome measures reported.

Detail of study protocol given
Other bias
Low risk
A large drop out rates (60% in metformin,

73% in placebo) in 6 months
All subjects were advised to take contraception throughout the trial period
61
Lam 2011
Methods
RANDOMISED TRIAL
SETTING: Hong Kong
METHOD OF RANDOMISATION: computer generated random number, block of
10
BLINDING: Double
Participants

INCLUSION CRITERIA: Rotterdam criteria,
EXCLUSION CRITERIA: CAH, Cushings syndrome, endometrial hyperplasia, diabetes, cardiovascular, hepatic or renal disease
Mean BMI 25.9, 23.5
Mean fasting insulin mIU/L 14.2,14.9
DROP OUTS - 11 in metformin, 5 in placebo
Interventions
MAIN INTERVENTION: rosiglitazone 4mg or placebo

DURATION: 6 months
CO-INTERVENTIONS:
Outcomes
Menstrual cycle frequency

Metabolic parameters: lipid profiles, testosterone, SHBG, glucose and insulin
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

bias)
Computer generated random number
Trial drug and placebo similar appearance,

and packaged according to the trial number. The code kept in the local pharmaceutical company and concealed from the research team until the end of the trial
Low risk

bias)
All outcomes
double blind

All outcomes
Unclear risk
Low risk
A clear detail study protocol and all primary

outcome measures reported
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
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (less than 8 periods per year), biochemical
hyperandrogenism (elevated testosterone level documented within the previous year on
the basis of local laboratory results).
Women should have at least one proven patent fallopian tube. Normal uterine cavity.
Normal semen analysis (sperm concentration >20million per ml)
EXCLUSION CRITERIA: hyperprolactinemia, CSH, thyroid disease, Cushingss syndrome, androgen secreting tumour
Mean age (SD) 28.3 (4.0), 27.9(4.0), 28.1(4)
Mean BMI (SD) 34.2(8.4), 36.0(8.9), 35.6(8.5)
Mean fasting insulin mIU/L (SD) 22.4(30), 22.6(20.7), 24(28.4)
Mean total testosterone mmol/L (SD) 2.21(0.98), 2.13(1.1), 2.13(0.87)
DROP OUTS - 49 (23.7%) in the metformin and clomiphene group, 55(26.3%) in
the placebo and clomiphene group, 72(34.6%) in the metformin group. The differences
were not significant
Interventions
MAIN INTERVENTION: two extended release metformin 500mg or two placebo

tablets twice daily
DURATION: up to six cycles or 30 weeks
CO-INTERVENTIONS: clomiphene 50mg or second matching placebo tablet was
commenced concurrently from day 3 to 7 of the cycle. When women had no or poor
response, the dose was increased by 50 mg or one additional placebo tablet with the
maximum dose of 150mg or three placebo tablets
Outcomes
OVULATION: progesterone over 5ng/ml

ARTHROPOMETRIC: BMI, WHR
HORMONES: testosterone, SHBG
METABOLIC MARKERS: insulin, proinsulin, glucose
OTHERS: pregnancy, live birth, miscarriage, side effects, serious adverse events in pregnancy
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)
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

bias)
Computer generated; participants were

randomised by means of an interactive
voice system and stratified based on study
site and previous exposure to study drugs
Each subject received a medication package on a monthly basis which consisted of

a bottle M (metformin or placebo) and a
bottle C(clomifene or placebo). Data coordinating centre at the clinical research institute Legro 2006b
Low risk

bias)
All outcomes
Double blind

All outcomes
DROP OUTS - 49 (23.7%) in the metformin and clomiphene group, 55(26.3%)

in the placebo and clomiphene group, 72
(34.6%) in the metformin group. A much
higher drop out rate at the metformin only
group. The differences were not significant.
Unclear risk
64
Legro 2007
(Continued)
Characteristics of the subjects who dropped

out were not given
Low risk
All primary and secondary outcome measures reported
Other bias
High risk
The original sample size was 678 to detect a

15% absolute difference in live birth rates.
However, due to drug supply logistics, the
sample size later reduced to 626 after the
data safety and monitoring board review
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
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (less than 6 periods per year), biochemical
hyperandrogenism (free androgen index >5.0)
Age between 18-40.
EXCLUSION CRITERIA: diabetes, thyroid disease, hyperprolactinaemia, CAH.
The use of ovulation induction agents or drugs that could affect insulin metabolism
within two months before the start of the trial
Mean age (SD) 27.76 (4.89), 30.63(4.84)
Mean BMI (SD) 33.74 (6.74),36.37 (7.46)
Mean fasting insulin mIU/L (SD) 21.57 (15.54), 18.85 (6.04)
Mean total testosterone mmol/L (SD) 2.60 (0.78), 2.74 (0.65)
DROP OUTS - three women in the metformin group and one in the placebo were
excluded after they were assigned to the group (did not meet the inclusion criteria).
Furthermore, three (2 due to pregnancy and 1 lost to follow up) in the metformin arm
and five (3 due to pregnancy and 2 lost to follow up) in the placebo arm did not complete
the study.
Overall, 6 (27.2%) in the metformin group and 6 (27.2%) in the placebo group withdrew
from the study after they have been randomised
Interventions

DURATION: 12 weeks
CO-INTERVENTIONS: general advice on diet and exercise.
Outcomes
OVULATION: progesterone >30nmol/l

ARTHROPOMETRIC: the distributions of subcutaneous and visceral fat were measured by areal planimetry (CT scan).
65
Lord 2006
(Continued)
Weight, BMI, waist circumference, WHR, blood pressure

HORMONES: testosterone, SHBG, DHEAS
METABOLIC MARKERS: insulin, glucose, cholesterol, LDL, HDL, triglyceride
OTHERS: menstrual pattern, pregnancy
Notes
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
Risk of bias
Bias
Authors judgement

bias)
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.
Low risk

bias)
All outcomes
Double blinded

All outcomes
Unclear risk
Overall, 6 (27.2%) in the metformin group

and 6 (27.2%) in the placebo group withdrew from the study after they have been
randomised. Details of drop out subjects
were not provided
Low risk
All outcome measures reported
Other bias
Unclear risk
66
Maciel 2004
Methods
RANDOMISED TRIAL
SETTING: Brazil
METHOD OF RANDOMISATION: computer generated random numbers.
BLINDING: Double
Participants

INCLUSION CRITERIA: amenorrhoea or oligomenorrhoea (less than 6 periods in a
year), clinical or biochemical hyperandrogenism. USS evident of PCO was not part of
the diagnostic criteria.
Age between 17 and 32.
EXCLUSION CRITERIA: other causes of amenorrhoea. Use of lipid-lowering drugs,
antidiabetic medications or hormonal contraception within three months of the recruitment.
Cushings syndrome, CAH, androgen secreting tumours, diabetes, renal or hepatic disease
Mean age (SD) 22.5(5), 19.9(1.1)
Mean BMI (SD) 25.3(5.5), 25.1(4.5)
DROP OUTS - The details of the drop outs were not available.
SUMMARY: obese PCOS
INCLUSION CRITERIA: amenorrhea or oligomenorrhea (less than 6 periods in a
year), clinical or biochemical hyperandrogenism. USS evident of PCO was not part of
the diagnostic criteria
Age between 17 and 32.
EXCLUSION CRITERIA: other causes of amenorrhoea. Use of lipid-lowering drugs,
antidiabetic medications or hormonal contraception within three months of the recruitment
Cushings syndrome, CAH, androgen secreting tumors, diabetes, renal or hepatic disease.
Mean age (SD) 20.5(5.4), 21.1(1.7)
Mean BMI (SD) 37.2(4.8), 35.8(3.7)
Mean fasting insulin mIU/L (SD) 22.6(11.6) 20.9(4.6)
Mean total testosterone nmol/L (SD) 4.1(0.8), 3.5(2.4))
DROP OUTS - the details of the drop outs were not available.
Interventions

DURATION: six months
Outcomes
ARTHROPOMETRIC: BMI, blood pressure.

HORMONES: testosterone, SHBG, free testosterone, androstenedione
METABOLIC MARKERS: insulin, glucose, AUC insulin, AUCglucose, cholesterol,
LDL, HDL and triglyceride
OTHERS: menstrual pattern, hirsutism
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

bias)
Computer generated random numbers.
Participants received a sealed envelope that

contained the study number. An independent clinician recorded side effects and clinical measurements
Low risk

bias)
All outcomes
Double blinded

All outcomes
Unclear risk
5 subjects were not evaluated because of

pregnancy. Details were not given
Unclear risk
All pre-specified outcome measures (androgens and metabolic parameters)
Other bias
Unclear risk
Although USS evidence of PCO was not

employed as part of the diagnostic criteria
for PCOS, the diagnostic criteria used in
this study would have met the Rotterdam
criteria
68
Malkawi 2002
Methods
RANDOMISED TRIAL
SETTING: Jordan
METHOD OF RANDOMISATION: centralised randomisation process with women
receiving a sequential number*
BLINDING: double blind*
Participants
SUMMARY: non-obese PCOS, clomiphene resistance

INCLUSION CRITERIA: ultrasound findings of polycystic ovaries together with three
of: oligomenorrhoea <6 cycles in preceding year, Ferriman-Gallwey score >7, hyperandrogaenemia [free testosterone, androstenedione, DHEAS], elevated LH or LH:FSH >
2. clomiphene resistance defined as failure to ovulate with 150mg day 5-9 for 3 months.
Normal uterine cavity and patent tubes on hysterosalpingography. Normal semen analysis
EXCLUSION CRITERIA: raised prolactin, adrenal hyperplasia, thyroid dysfunction,
Cushings syndrome
(7.3)
Mean BMI ( SD) 27.5(4.1), 27.8(3.3)
DROP OUTS: nil
Interventions

DURATION: 6 months
CO-INTERVENTIONS: clomiphene 50mg day 5-9 in the first cycle, increasing by
50mg up to 200mg in each subsequent cycle until ovulation achieved
Outcomes
OVULATION: serum progesterone on day 21 and 28 >15.9nmol/l.

OTHERS: pregnancy
Notes
Units of testosterone assumed to be ng/ml.

Risk of bias
Bias
Authors judgement

bias)
Centralised randomisation process with

women receiving a sequential number
Centralised randomisation process with

women receiving a sequential number
Unclear risk

bias)
All outcomes
69
Malkawi 2002
(Continued)

All outcomes
Low risk
No drop outs
Unclear risk
Other bias
Unclear risk
Moghetti 2000
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: sequentially numbered, identical containers of
identical drugs*
Participants
SUMMARY: non obese PCOS

INCLUSION CRITERIA: PCOS (oligomenorrhoea <=6 cycles per year or anovulation
confirmed with luteal-phase progesterone, hyperandrogenaemia (either raised serum androgens, or clinical hyperandrogenaemia*). Exclusion of other endocrinopathy)
EXCLUSION CRITERIA: adrenal hyperplasia,
Cushings,
hyperprolactinaemia,
androgen secreting tumour,
concomitant disease,
taking any medication.
21.4(4.9)
Mean BMI ( SD) 27.1(5.0), 32.6(3.8)
Mean total testosterone nmol/L ( SD)* 2.9(0.6), 2.4(0.6)
DROP OUTS - nil*
Interventions

DURATION: 26 weeks
CO-INTERVENTIONS: no modification in usual eating habits
Outcomes
Waist-hip ratio
REPRODUCTIVE HORMONES: free testosterone
Androstenedione
DHEAS
SHBG
FSH
LH
fasting insulin
70
Moghetti 2000
(Continued)
120 minute insulin and glucose levels after GTT

Insulin sensitivity
Cholesterol
HDL
LDL
Triglycerides
Systolic blood pressure
Diastolic blood pressure
OTHERS: Menstrual pattern
17-alpha-hydroxyprogesterone response to buserelin
Notes
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
Risk of bias
Bias
Authors judgement

bias)
Not stated
Sequentially numbered, identical containers of identical drugs
Low risk

bias)
All outcomes
Double blind

All outcomes
Low risk
No drop outs
High risk
All primary outcome measures reported

(menstrual frequency and metabolic parameters)
Other bias
High risk
Placebo group had a significantly higher

BMI than the metformin group. It was assumed that the figures quoted in the publication are for standard errors
71
Moll 2006
Methods
RANDOMISED TRIAL
SETTING: Holland, Netherlands multicentre
METHOD OF RANDOMISATION: computer generated blocks of four.
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
Mean age (SD) 27.9 (3.7), 28.4(4.7)
Mean BMI (SD) 28.5(7.1), 27.8(6.7)
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
MAIN INTERVENTION: metformin 2000mg per day (increased from 500mg to

2000mg over a period of 7 days in order to limit the side effects) or placebo
DURATION: all women received metformin or placebo for one month before starting
clomiphene treatment (a maximum of 6 cycles for those who ovulated with clomiphene)
CO-INTERVENTIONS: clomiphene 50mg from day 3 (spontaneous menstruation)
or day 5 (progestogen induced menstruation) for a period of 5 days. If ovulation did not
occur with this dose, clomiphene was increased with steps of 50mg with a maximum of
150mg a day in the next cycles
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

bias)

Computer generated blocks of four
72
Moll 2006
(Continued)
Low risk
Randomisation was carried out in the coordinating centre (Armsterdam) and the list
was kept until inclusion was completed

bias)
All outcomes
Double blind. Each centre received blinded

numbered container

All outcomes
Unclear risk
DROP OUTS - no significant difference in

the drop rates, 28 (25%) in the metformin
arm, 21 (18%) in the placebo arm. Details
of the drop out subjects not mentioned; although number of drop outs in each group
were similar
Low risk
Primary outcome (ovulation) and secondary outcome (pregnancy, miscarriage

rates) measures reported
Other bias
Unclear risk
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
Participants

INCLUSION CRITERIA: PCOS (oligomenorrhoea <6 cycles per year, hyperandrogenaemia (elevated free testosterone), exclusion of other endocrinopathy, ultrasound finding of PCO),
BMI>28.
adrenal hyperplasia
hyperprolactinaemia
taking any medication for previous 2 months.
(5.1)
Mean BMI ( SD) 32.3(4.7), 32.2(5.1)
Mean fasting insulin mIU/L ( SD) 19(11.8), 22(30.6)
DROP OUTS - none
Interventions

DURATION: 34 days, then those who did not ovulate continued for a further 19 days
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
OVULATION: by serum progesterone (>=25.6nmol/L) measured on days 14, 28, 35

(and 44 & 53 in those that went on to receive clomiphene)
ANTHROPOMETRIC: BMI
Waist-hip ratio
Free testosterone
Androstenedione
DHEAS
SHBG
17-beta estradiol
fasting insulin
Notes
89% of participants were recruited in Venezuela.

Most of the outcome measures were only reported for those that failed to ovulate during
the metformin vs. placebo phase of the trial. These have not been included in the analysis
as a further analysis to include all participants was not possible
Risk of bias
Bias
Authors judgement

bias)
Centralised randomisation process
Unclear risk

bias)
All outcomes
Single blinded (participant only)

All outcomes
Low risk
No drop outs
Unclear risk
Other bias
High risk
Most of the outcome measures were only

reported for those that failed to ovulate during the metformin vs. placebo phase of the
trial
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.
Participants

INCLUSION CRITERIA: PCOS (oligomenorrhoea <=8 cycles per year, hyperandrogenaemia (elevated free testosterone)* or hirsutism (physician reported - subjective)*,
exclusion of other endocrinopathy),
BMI>28.
thyroid dysfunction
hyperprolactinaemia
taking any medication for previous 2 months.
BASELINE CHARACTERISTICS OF EACH GROUP: Mean age ( SD) 29(6), 26
(5)
Mean BMI ( SD) 31.3(2.4), 31.0(2.2)
Mean fasting insulin mIU/L ( SD) 35(40), 38(51)
Mean total testosterone mmol/l ( SD) 3.14(1.64), 2.79(1.50)
DROP OUTS - none
Interventions
MAIN INTERVENTION: one of: D-chiro inositol 1200mg od, placebo

DURATION: 6 weeks; those who ovulated continued for a further 2 weeks.
CO-INTERVENTIONS: no change in usual eating habits, physical activity or lifestyle
Outcomes
OVULATION: by serum progesterone (25nmol/l) weekly.

Waist-hip ratio
Free testosterone
Androstenedione
DHEAS
SHBG
17-beta estradiol
fasting insulin
Systolic blood pressure
Diastolic blood pressure
Cholesterol
HDL
LDL
Triglycerides
OTHERS: LH response to leuprolide
17-alpha-hydroxyprogesterone response to leuprolide
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).
Risk of bias
Bias
Authors judgement

bias)
Randomisation in blocks of four
Drug and placebo packaged at same time

and labelled according to subject number
Low risk

bias)
All outcomes
Double blind

All outcomes
Low risk
No drop outs
Unclear risk
Other bias
Unclear risk
Ng 2001
Methods
RANDOMISED TRIAL
SETTING: Hong Kong (Chinese women)
METHOD OF RANDOMISATION: computer generated list in sealed envelopes
Participants

INCLUSION CRITERIA: PCOS (irregular cycles of <=21 days or >=35 days and cycle-to-cycle variation of >4 days*, anovulation with mid-luteal progesterone<16nmol/
L whilst taking clomiphene 100mg for five days over three cycles, exclusion of other
endocrinopathy (raised prolactin, thyroid disorder*), ultrasound findings of PCO)
Age<40
Day 2 FSH<10
Bilateral patent tubes demonstrated by laparoscopy
Normal semen parameters.
EXCLUSION CRITERIA: taking any sex hormones in previous 3 months
smokers
renal impairment.
BASELINE CHARACTERISTICS OF EACH GROUP*: Mean age ( SD) 30.4(2.1)
, 31.2(2.6)
76
Ng 2001
(Continued)
Mean BMI ( SD) 25.5(4.6), 23.5(4.4)

Mean total testosterone mol/L ( SD) 2.0(0.9), 1.6(1.2)
DROP OUTS - 5(25%), 3 in placebo arm, 2 in metformin. Analysis on intention-totreat
Interventions

DURATION: 3 months. Those who did not ovulate continued for a further cycle
CO-INTERVENTIONS: clomiphene 100mg for five days was given after 3 months if
there was no ovulation
Outcomes
OVULATION: by serum progesterone (>16nmol/l) weekly.

ANTHROPOMETRIC: BMI
Androstenedione
DHEA
SHBG
FSH
LH
fasting insulin
120 minute glucose levels after GTT
fasting leptin
cholesterol
HDL
LDL
triglycerides
Other: live birth
Notes
The BMI was lower than in other trials.

In spite of the fact that anovulation and clomiphene resistance was an inclusion criteria,
7 out of 9 women taking placebo ovulated (3 with placebo alone, and 4 out of the 6
remaining in the trial who had clomiphene and placebo)
Risk of bias
Bias
Authors judgement

bias)
Computer generated list .
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

bias)
All outcomes
Double blind
77
Ng 2001
(Continued)

All outcomes
Unclear risk
DROP OUTS - 5(25%), 3 in placebo arm,

2 in metformin. Analysis on intention-totreat. Details not provided
Low risk
All primary outcome measures reported
Other bias
Unclear risk
In spite of the fact that anovulation and

clomiphene resistance was an inclusion criteria, 7 out of 9 women taking placebo
ovulated (3 with placebo alone, and 4 out
of the 6 remaining in the trial who had
clomiphene and placebo)
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

INCLUSION CRITERIA: oligomenorrhoea (less than 6 periods per year), clinical hyperandrogenism (Ferrriman-Gallwey score > 7) and or biochemical hyperandrogenism
(free testosterone >4ng/dl)
EXCLUSION CRITERIA: other causes of hyperandrogenism, Cushings syndrome,
CAH, hyperprolactinaemia, thyroid dysfunction
Mean age (SD) hyperinsulinemic lean 25.7(4.9), 24.2(4.7); hyperinsulinaemic overweight 27.5(5.7), 24.8(6.6); normoinsulinemic lean 26.4(4.1), 27.1(4.8); normoinsulinemic overweight 24.6(4.8), 27.3(4.4)
Mean BMI (SD) hyperinsulinemic lean 21.55(3.07), 21.8(1.76); hyperinsulinaemic
overweight 28.4(0.7), 28.4(0.9); normoinsulinemic lean 21.6(2.25), 21.96(1.52); normoinsulinemic overweight 28.1(1.0), 28.2(0.7)
Mean fasting insulin mIU/L (SD) hyperinsulinemic lean 20.5(0.68), 22.0(3.95); hyperinsulinaemic overweight 22.7(3.0), 23.1(6.0); normoinsulinemic lean 14.9(2.2), 15.6
(2.52); normoinsulinemic overweight 14.6(1.5), 13.8(1.6)
SUMMARY: obese PCOS
INCLUSION CRITERIA: oligomenorrhoea (less than 6 periods per year), clinical hyperandrogenism (Ferrriman-Gallwey score > 7) and or biochemical hyperandrogenism
(free testosterone >4ng/dl).
CAH, hyperprolactinaemia, thyroid dysfunction
78
Onalan 2005
(Continued)
Mean age (SD) hyperinsulinemic obese 25.1(3.6), 28.4(6.9); normoinsulinemic obese

31.8(4.0)
Mean BMI (SD) hyperinsulinemic obese 31.7(1.9), 34.9(3.5); normoinsulinemic obese
31.6(1.1), 32.2(3.2)
Mean fasting insulin mIU/L (SD) Hyperinsulinemic obese 27.8(10.3), 23.3(2.8); normoinsulinemic obese 18.8(2.3), 21.2(1.3)
DROP OUTS - 15 in total, mainly due to gastro-intestinal sideeffects. Further 8 subjects
were excluded in the analysis because of pregnancy*
DROP OUTS- 15 in total, mainly due to gastro-intestinal side effects.*
Interventions
MAIN INTERVENTION: metformin 850mg or placebo tablet twice daily

DURATION: 6 months
Outcomes
OVULATION: progesterone > 5ng/ml

ARTHROPOMETRIC: BMI, weight, WHR*
HORMONES: testosterone, free testosterone, androstenedione, DHEAS, cortisol.*
METABOLIC MARKERS: glucose, insulin, cholesterol, LDL, HDL, triglyceride.*
OTHERS: hirsutism*
Notes
The objective of this study is to investigate the effects of hyperinsulinemia (fasting

glucose/insulin ratio <4.5mg/10-4 U and obesity (BMI>30) on the responses to metformin treatment in women with PCOS. There were six subgroups, normoinsulinemic
lean (BMI <25), overweight (BMI 25-29.9) and obese (BMI?30); hyperinsulinemic lean
(BMI <25), overweight (BMI 25-29.9) and obese (BMI>30)
The results of the non-obese subgroups were entered separately from the obese subgroup
in the meta-analysis
We have written to the author regarding the details of randomisation and concealment.
Additionally, the author was also asked to provide further information of the arthropometric, hormonal and metabolic results at the end of the trial period.
*= No reply from author.
Risk of bias
Bias
Authors judgement

bias)
Computer generated blocks of four randomisation
Not stated
Unclear risk

bias)
All outcomes

All outcomes
DROP OUTS - 15 in total (11%), mainly

due to gastro-intestinal side effects.Missing outcome not addressed. Imbalance in
missing data between the intervention and
Unclear risk
79
Onalan 2005
(Continued)
placebo groups
Unclear risk
Primary outcome measures not stated. Inadequate study protocol reporting
Other bias
Unclear risk
Inadequate information to assess
Otta 2010
Methods
RANDOMISED TRIAL
SETTING: Argentina
METHOD OF RANDOMISATION: computer generated
BLINDING: Double
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: oligomenorrhoea (cycle length >35 days), biochemical hyperandrogenism (level not defined)
CAH, hyperprolactinaemia, thyroid dysfunction, abnormal renal, liver functions, diabetes, infection
Mean age 25, 24
Mean BMI 32.4, 31.5
DROP OUTS - 1 in metformin, poor compliance
Interventions
MAIN INTERVENTION: metformin 750mg or placebo tablet twice daily

DURATION: 4months
CO-INTERVENTIONS: lifestyle modification (high carbohydrate diet and increase
exercise with a minimum of 40 mins walk per day)
Outcomes
Ovulation: method of detecting ovulation not stated

ARTHROPOMETRIC: BMI, weight, WHR
Metabolic markers
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

bias)

Computer generated
80
Otta 2010
(Continued)
Unclear risk
Not stated

bias)
All outcomes
Not stated

All outcomes
High risk
Missing data not reported. One in metformin group and excluded from analysis
Unclear risk
Primary outcome measures were unclear
Other bias
Low risk
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.
Palomba 2005
Methods
RANDOMISED TRIAL
SETTING: Italy
METHOD OF RANDOMISATION: computer generated random allocation sequence
in double block
BLINDING: Double
Participants

INCLUSION CRITERIA: National Institutes of Health criteria, age 20-34 year old,
BMI<30kg/m2 , tubal patency confirmed by hysterosalpingogram, normal semen analysis
EXCLUSION CRITERIA: metabolic disorders, hepatic or renal dysfunction, thyroid
disease, hyperprolactinemia, Cushing?s syndrome, CAH, hormonal drugs, pelvic diseases, previous pelvic surgery
Mean age (SD) 26.4(2.9), 25.9(2.7)
Mean BMI (SD) 27.0(2.9), 26.7(2.8)
Mean fasting insulin mIU/L (SD) 19.5 (5.4), 20.4(5.6)
Mean total testosterone mol/L (SD) 3.12(1.04), 3.47(1.0)
DROP OUTS - 5 in the metformin group and 3 in the metformin/clomiphene group
Interventions
MAIN INTERVENTION: Metformin 850mg or matched placebo tables twice daily

DURATION: 6 months
CO-INTERVENTIONS: clomiphene 150mg or matched placebo tablets, Day 3 to 7
of the cycle and and timed intercourse
Outcomes

Pregnancy, ovulation
81
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

bias)
Computer generated random allocation sequence in double block
Allocation sequence concealed until the interventions were assigned
Unclear risk

bias)
All outcomes

All outcomes
Unclear risk
DROP OUTS - 5 in the metformin group

and 3 in the metformin/clomiphene group
Unclear risk
Other bias
Unclear risk
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
82
Pasquali 2000
(Continued)
Interventions
Main intervention: metformin 850mg bd or placebo

Duration: 6 months
Co-interventions: standardised hypercaloric diet one month prior to treatment and continue throughout the trial
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

bias)
Block of four, random table
Drug and placebo packaged and labelled

according to subject number
Low risk

bias)
All outcomes
Double blinded

All outcomes
High risk
Unclear risk
A clear protocol published with all primary

outcome measured reported
Other bias
Unclear risk
PCOSMIC 2010
Methods
A multicentre double blind parallel randomised trial
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
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

bias)
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

bias)
All outcomes
Blinding of all parties was maintained in

all cases ...until the end of the course of
treatment or in the event of pregnancy, until after the pregnancy

All outcomes
Low risk
Intention to treat analysis planned and protocol breach and losses to follow up were
reported in figure 3
Low risk
Protocol published and all outcomes reported
Other bias
Unclear risk
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*
84
Rautio 2006
(Continued)
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: PCOS was defined according to the Rotterdam consensus
2003. PCO on USS. Oligomenorrhoea or amenorrhoea, clinical (Ferriman-Gallwey
score >7) or biochemical (testosterone >2.7nmol/l) hyperandrogenism.
BMI>25
EXCLUSION CRITERIA: diabetes, abnormal liver function tests, smokers, history of
alcohol abuse, hormonal drugs or drugs known to affect lipid metabolism
Mean age (SD) 26.7(1.1), 30.1(2.1)
Mean BMI (SD) 33.1(5.8), 33.6(3.7)
DROP OUTS - three (20%) in the rosiglitazone group (2 due to pregnancy); one (6.
6%) in the placebo group (personal reasons)
Interventions
MAIN INTERVENTION: rosiglitazone 4 mg for two weeks followed by 4mg twice

daily for four months or placebo
DURATION: four months
Outcomes
ARTHROPOMETRIC: BMI, WHR*

HORMONES: testosterone, SHBG, androstenedione, DHEAS
METABOLIC MARKERS: insulin, glucose, AUC insulin, AUCglucose*, fasting Cpeptide, insulin resistance measured by euglycaemic hyperinsulinaemic clamp test
OTHERS: hirsutism, menstrual pattern
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
Risk of bias
Bias
Authors judgement

bias)

(block of 5)
Randomisation was conducted within the

department. Unclear concealment, carried
out by the departmental staff
Unclear risk

bias)
All outcomes
85
Rautio 2006
(Continued)

All outcomes
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
Other bias
Unclear risk
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
Participants

INCLUSION CRITERIA: Rotterdamconsensus 2003, normal weight
EXCLUSION CRITERIA: abnormal TFT, LFT
Mean age (SD):24.7(4.4), 27.2(2.3)
Mean BMI (SD): 22.2(2.2), 22.3(3.9)
Mean fasting insulin mIU/L (SD):
Mean total testosterone nmol/L (SD): 1.94, 1.9
DROP OUTS- 2 in metformin due to poor compliance; 3 in placebo group (lost in
follow-up)
Interventions
MAIN INTERVENTION: metformin 500mg or placebo tablets twice daily

DURATION: 6 months
CO-INTERVENTIONS: lifestyle modification
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
86
Romualdi 2010
(Continued)

bias)
Not stated
Blocks of 10 sealed opaque envelopes containing randomisation codes
Low risk

bias)
All outcomes
Double blind placebo-controlled

All outcomes
Unclear risk
DROP OUTS - 2 in metformin due to

poor compliance; 3 in placebo group (lost
in follow-up)
High risk
None identified
Other bias
Unclear risk
Sahin 2004
Methods
RANDOMISED TRIAL
SETTING: Turkey
METHOD OF RANDOMISATION: not stated*
BLINDING: not stated*
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: PCO on USS (10 or more cysts 2-10mm), oligomenorrhoea
(cycle length over 35 days) or amenorrhoea (no menstrual period > 6 months), clinical
or biochemical hyperandrogenism (testosterone over 2.7nmol/l)
For at least12 weeks before the study, none of the subjects had received any medication
known to affect pituitary-ovarian function or carbohydrate metabolism.
EXCLUSION CRITERIA: androgen secreting tumour, Cushings syndrome, thyroid
dysfunctions, CAH, hyperprolactinemia and diabetes.
Median age 27, 24.5
Median BMI 30.4, 25.7
DROP OUTS - none
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)
87
Sahin 2004
(Continued)
Outcomes
OVULATION: progesterone over 5.0 ng/ml.

ARTHROPOMETRIC: BMI
HORMONES: testosterone, free testosterone, androstenedione, SHBG, DHEAS, estradiol, prolactin
METABOLIC MARKERS: insulin, glucose, AUCinsulin, AUCglucose
OTHERS: pregnancy, live birth, miscarriage
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

bias)
Unclear risk

bias)
All outcomes

All outcomes
Unclear risk
Insufficient information to assess
Unclear risk
Other bias
Unclear risk
88
Siebert 2009
Methods
RANDOMISED TRIAL
SETTING: South Africa
METHOD OF RANDOMISATION: computer generated random numbers.
BLINDING: unblinded
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: PCOS (according to Rotterdamconsensus 2003), confirmed
tubal patency.
EXCLUSION CRITERIA: male factor subfertility
Median BMI: 30.48, 30.71
Median fasting insulin mIU/L: 17.20, 13.6
Median total testosterone nmol/L: 2.35, 2.00
DROP OUTS - no significant different in the drop out rates, 10 in metformin+ clomifene
group and 7 in clomifene only group
Interventions
MAIN INTERVENTION: metformin 850mg twice daily

DURATION: 6 weeks before and throughout ovulation induction with clomifene
CO-INTERVENTIONS: clomifene 50-150mg day 4 to 8 for 4 cycles + lifestyle modification
Outcomes
OVULATION: day 21 progesterone level (level not stated)
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

bias)
Not stated
Unclear risk

bias)
All outcomes
Unblinded

All outcomes
Unclear risk
DROP OUTS - no significant different

in the drop out rates, 10 in metformin+
clomifene group and 7 in clomifene only
group
Unclear risk
89
Siebert 2009
Other bias
(Continued)
Unclear risk
Sturrock 2002
Methods
RANDOMISED TRIAL
SETTING: UK
METHOD OF RANDOMISATION: performed by pharmacy*
Participants
SUMMARY: obese PCOS, clomiphene resistance

INCLUSION CRITERIA: oligomenorrhoea cycle >40 days for 6 months, anovulation
demonstrated by day 20-22 progesterone 10nmol/L, lack of response to clomiphene
100mg for 5 days with U/S showing endometrial thickness 5mm and no ovarian follicle
14mm Age 18-40
EXCLUSION CRITERIA: raised prolactin, adrenal hyperplasia, thyroid dysfunction,
medication known to affect insulin action*.
BASELINE CHARACTERISTICS OF EACH GROUP*: Mean age ( SD) 29.1(4.3)
, 31.1(3.7)
Mean BMI ( SD) 34.2(4.0), 35.0(3.6)
DROPOUTS: 4(40%) from metformin arm and 4(44%) from placebo arm*. Not included in analysis
Interventions

DURATION: 6 months
CO-INTERVENTIONS: first week of treatment at 500mg od, second at 500mg bd and
third at 500mg tds. Those that did not ovulate after 3 months had clomiphene 50mg
days 2-6, increased to 100mg for a total of three cycles
Outcomes
OVULATION: by monthly serum progesterone (>10nmol/L) and presence of follicle

>=14mm on ovarian ultrasound*
ANTHROPOMETRIC: weight, BMI, Waist:hip ratio
REPRODUCTIVE HORMONES: total testosterone, Free androgen index, SHBG
METABOLIC MARKERS: fasting glucose, fasting insulin, insulin resistance, Beta-cell
function, systolic blood pressure, diastolic blood pressure
OTHERS: pregnancy, menstrual cycle, Ferriman-Gallwey score
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*
90
Sturrock 2002
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Performed by pharmacy
Unclear risk
Performed by pharmacy

bias)
All outcomes

All outcomes
High risk
DROPOUTS: 4(40%) from metformin

arm and 4(44%) from placebo arm*. Not
included in analysis
Unclear risk
Other bias
Unclear risk
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
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: PCO on USS (> 10 cysts 2-8mm in diameter), oligomenorrhoea (cycle length >35 days) or amenorrhoea (no period in six months)
Age between 18 and 39
BMI >30
Normal semen analysis and the subject should have at least one proven patent fallopian
tube
EXCLUSION CRITERIA: Concurrent hormone therapy within previous 6 weeks,
metabolic or chronic disease, renal or liver disease, diabetes, CAH, androgen secreting
tumour
Mean age (SD) 29.7(3.7), 29.8(3.8)
Mean BMI (SD) 37.6(5.0), 38.9(9.5)
91
Tang 2006
(Continued)

DROP OUTS - 11 (15.9%) in the metformin arm, 6 (8.1%). The difference was not
significant
Interventions
MAIN INTERVENTION: metformin 850mg or placebo tablet once twice daily

DURATION: 6 months
CO-INTERVENTIONS: lifestyle modification (combination of diet and exercise) aiming to reduce 500kcal per day
Outcomes
ARTHROPOMETRIC: BMI, weight, WHR, blood pressure.

HORMONES: total testosterone, SHBG
METABOLIC MARKERS: insulin, glucose, total cholesterol, triglyceride
OTHERS: menstrual pattern, pregnancy
Notes
A large multi-centre randomised placebo controlled study was conducted to investigate

the combined effects of the life-style modification and the use of metformin in obese
women with PCOS (BMI>30). A total of 8 centres in UK took part in the recruitment
All the participants were recruited from the infertility clinics. The ethnic origin of the
participants was not recorded
Both the metformin and the placebo groups experienced improvement in weight loss
and in menstrual pattern. However, the differences between the two groups were not
significant. Participants in the metformin arm showed a greater reduction in total testosterone levels compared with women in the placebo arm
Risk of bias
Bias
Authors judgement

bias)
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
Low risk

bias)
All outcomes
Double blinded

All outcomes
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
92
Tang 2006
(Continued)
Low risk
Primary outcome measure (menstrual frequency) and secondary outcome measures

(metabolic parameters) were reported
Other bias
Unclear risk
Trolle 2007
Methods
RANDOMISED TRIAL
SETTING: Denmark
METHOD OF RANDOMISATION: random number table
BLINDING: Double, crossover
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: Rotterdam criteria, age between 18-45 years old
EXCLUSION CRITERIA: elevated serum gonadotropins levels, hyperprolactinaemia,
diabetes, abnormal thyroid, renal or liver functions, pregnancy, a wish for fertility treatment
Mean age 32 year old
Mean BMI 33.8 kg/m2
Mean fasting insulin 9.50 mIU/L
Mean total testosterone 2.89 mmol/L
DROP OUTS - two in each group.
Interventions
MAIN INTERVENTION: metformin 850mg or placebo twice daily

DURATION: 6 months
CO-INTERVENTIONS: no
Outcomes
ARTHROPOMETRIC: weight, systolic blood pressure*

HORMONES: testosterone*
METABOLIC MARKERS: insulin, glucose, HDL*
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

bias)

Random number table
93
Trolle 2007
(Continued)
Unclear risk
The randomisation code stored in a closed

envelope until the end of recruitment.
Identical trial drug and placebo tablet

bias)
All outcomes
Double blinded

All outcomes
Low risk
Two drop outs in each group. Similar drop

out rates. Baseline characteristics were comparable between the drop out and the completed groups
Low risk
A clear study protocol. Power calculation

reported. Primary outcome (menstrual frequency) reported
Other bias
High risk
Initial power calculation indicated minimum of 50 subjects in the trial. However,

due to an increased drop out rate, the number of recruitment subsequently increased
to 60
Vandermolen 2001
Methods
RANDOMISED TRIAL
SETTING: USA, multi-centre
METHOD OF RANDOMISATION: computer generation in blocks of 6
Participants
SUMMARY: obese PCOS, clomiphene resistance

INCLUSION CRITERIA: PCOS (oligomenorrhoea <6 cycles per year, anovulation
with clomiphene 150mg for 5 days confirmed by progesterone<4ng/ml or amenorrhoea
by day 35, hyperandrogaenemia [elevated androstenedione, free testosterone or total
testosterone]* or hirsutism, exclusion of other endocrinopathy, ultrasound findings of
PCO)
Age 18-35
Normal semen analysis
Tubal patency if previous pelvic surgery or infection
adrenal hyperplasia
thyroid dysfunction
hyperprolactinaemia
abnormal renal or liver function, medication known to affect insulin action*
(3.7)
Mean BMI ( SD) 37.6(14.3), 38.4(8.2)
94
Vandermolen 2001
(Continued)

Mean total testosterone nmol/L ( SD) 2.90(0.8), 3.04(1.42)
DROP OUTS - one from each arm (7%); one in the placebo arm ovulated in response
to clomiphene but was excluded owing to non-compliance. Not included in analysis
Interventions

DURATION: 7 weeks initially, then those who did not ovulate continued for a further
6 cycles
CO-INTERVENTIONS: those that did not ovulate after 7 weeks had clomiphene 50mg
for 5 days. If ovulation did not occur the dose was increased to 100mg then 150mg for
a total of 6 cycles
No change in usual eating habits, physical activity or lifestyle
Outcomes
OVULATION: serum progesterone>=12.7nmol/l on days 10, 20, 30 and 40 (and days

21 and 28 of subsequent cycles if received clomiphene)
ANTHROPOMETRIC: weight
BMI
Free testosterone
Androstenedione
DHEAS
SHBG
Estradiol
FSH
LH
17-alpha hydroxyprogesterone
fasting insulin
OTHERS: live birth, pregnancy
Notes
Although obesity was not an inclusion criteria, the mean BMI was high in this study
although similar in both arms
Risk of bias
Bias
Authors judgement

bias)
Computer generation in blocks of 6
Not stated
Unclear risk

bias)
All outcomes
Double blind
95
Vandermolen 2001
(Continued)

All outcomes
Unclear risk
DROP OUTS - one from each arm (7%);

one in the placebo arm ovulated in response
to clomiphene but was excluded owing to
non-compliance. Not included in analysis.
Details not provided
Unclear risk
Other bias
Unclear risk
Williams 2009
Methods
RANDOMISED TRIAL
SETTING: USA
METHOD OF RANDOMISATION: not stated
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
MAIN INTERVENTION: metformin 500mg or placebo TDS

DURATION: 6 cycels
CO-INTERVENTIONS: clomifene (dose unclear)
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

bias)
Unclear risk
96
Williams 2009
(Continued)

bias)
All outcomes

All outcomes
Unclear risk
Unclear risk
Other bias
Unclear risk
Yarali 2002
Methods
RANDOMISED TRIAL
SETTING: Turkey
METHOD OF RANDOMISATION: computer generated numbers. Centralised randomisation process*
Participants

INCLUSION CRITERIA: PCOS (oligomenorrhoea <6 cycles per year, anovulation
confirmed with progesterone <5ng/ml, testosterone >2.4nmol/l, exclusion of other endocrinopathy, ultrasound findings of PCO)
clomiphene resistance to 250mg for 5 days for up to 6 months
Normal semen analysis
Normal HSG or laparoscopy within 6 months
adrenal hyperplasia
Cushings
thyroid dysfunction
hyperprolactinaemia
medication known to alter insulin action
previous gonadotrophin treatment
Infertility other than that caused by PCOS
previous pelvic surgery
28.4(5.1)
Mean BMI ( SD) 28.6(4.0), 29.6(4.8)
Mean fasting insulin mIU/L ( SD) 15.5(21.4), 11(5.5)
DROP OUTS - 2(6%) from the metformin/placebo part of the trial owing to pregnancy.
They were excluded from analysis
Interventions

DURATION: 6 weeks initially, then those who did not ovulate continued for one cycle
CO-INTERVENTIONS: those that did not ovulate after 6 weeks had recombinant
FSH in a low dose step-up protocol
97
Yarali 2002
(Continued)
No change in usual eating habits.

Outcomes
OVULATION: serum progesterone>15.9nmol/l weekly

ANTHROPOMETRIC: BMI
Waist-hip ratio
Free testosterone
Androstenedione
DHEAS
Estradiol
FSH
LH
17-alpha hydroxyprogesterone
Insulin sensitivity
Leptin
OTHERS:
Live birth, pregnancy
duration of rFSH stimulation
total dose of FSH
Oestradiol on day of hCG
Monofollicular development
cycle cancellation rate
Notes
Free testosterone was significantly higher in the metformin group. Fasting insulin was
non-significantly higher with a wide SD compared with placebo
Risk of bias
Bias
Authors judgement

bias)
Computer generated numbers. Centralised

randomisation process*
Unclear risk

bias)
All outcomes

All outcomes
Unclear risk
DROP OUTS - 2(6%) from the metformin / placebo part of the trial owing to
pregnancy. They were excluded from analysis
Unclear risk
98
Yarali 2002
Other bias
(Continued)
Unclear risk
Zain 2009
Methods
RANDOMISED TRIAL
SETTING: Malaysia
METHOD OF RANDOMISATION: picking a card out of a box
BLINDING: no
Participants
SUMMARY: obese PCOS

INCLUSION CRITERIA: newly diagnosed with PCOS (Rotterdam criteria), age <40
year old.
EXCLUSION CRITERIA: diabetes, hepatic or renal dysfunction, heart disease, abnormal semen analysis (WHO criteria)
Mean age (SD) 27.8(3.6), 29.6(4.3), 29.3(4.9)
Mean BMI (SD) 33.9(3.6), 32.9(4.2), 33.0(4.1)
Mean total testosterone nmol/L (SD) 0.57(0.1), 0.41(0.45), 0.77 (0.14)
DROP OUTS - 4 (9.5%) in the metformin group, 2 (4.9%) in the clomiphene group
and 3 (7.3%) in the combined metformin and clomiphene group
Interventions
MAIN INTERVENTION: metformin 1500mg per day

DURATION: six months
CO-INTERVENTIONS: clomiphene 50mg from day 2 to 6 of the cycle. When women
not responded to the treatment, the dose increased by 50mg with the maximum dose of
200mg
All the women were offered dietary advice.
Outcomes

HORMONES: testosterone
OTHERS: live birth pregnancy, miscarriage
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

bias)

99
Zain 2009
(Continued)
Unclear risk

bias)
All outcomes
unblinded

All outcomes
High risk
DROP OUTS - 4 (9.5%) in the metformin

group, 2 (4.9%) in the clomiphene group
and 3 (7.3%) in the combined metformin
and clomiphene group. Analysis was based
on analysis per protocol, not ITT
Unclear risk
Other bias
Unclear risk
Baseline characteristics given in order of main intervention (drug, placebo).

Where the trial protocol included a statement such as, all patients had ultrasound features of PCOS then this has been included as
an inclusion criteria (unless the authors specifically state that it was not in which case it is recorded under notes).
ABBREVIATIONSTable 1:
BMI - Body mass index
CI - Confidence interval
CT - Computerised tomography scan
DHEAS - Dehydroepiandrosterone sulphate
FSH - Follicle stimulating hormone
GTT - Glucose tolerance test
HbA1C - Glycosylated haemoglobin
HDL - High density lipoprotein cholesterol
IGFBP-1 - Insulin growth factor binding protein 1
LDL - Low density lipoprotein cholesterol
LH - Luteinising hormone
rFSH - Recombinant follicle stimulating hormone
SD - Standard deviation
SE - Standard error of the mean
SHBG - Sex hormone binding globulin
VLDL - Very low density lipoprotein cholesterol
Characteristics of excluded studies [ordered by study ID]
100
Study
Reason for exclusion
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
Randomised double blind trial comparing metformin 850mg bd with placebo

Participants were women with hirsutism and obesity but not necessarily anovulation. 67% had regular
menses. 63% had polycystic ovaries on ultrasound
The results indicated that weight loss induced by a hypo calorific diet led to improvements in insulin and
androgen levels, but that metformin gave no additional benefit over diet
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
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
102
(Continued)
It was unclear whether the study was randomised. We are currently still waiting for a response from the
author
Characteristics of studies awaiting assessment [ordered by study ID]

Chaudhury 2008
Methods
RCT
Participants
27 non-obese women with PCOS
Interventions
Metformin versus placebo (folic acid)
Outcomes
Ovulation
Notes
Used high dose folic acid as placebo.

Women with PCOS known to have a higher level of serum homocysteine and lower Vit B12 concentration than
women with normal ovaries. Folic acid supplement has previously been used to treatment PCOS women with hyperhomocysteine. Hence, folic acid may have a role in treating women with PCOS and is not appropriate being used as
a placebo in a
Costantino 2009
Methods
RCT
Participants
42 women with PCOS
Interventions
Myo-inisitol with folic acid or folic acid alone
Outcomes
Metabolic outcomes, including ovulation
Notes
Farzadi 2006
Methods
RCT
Participants
50 women with clomiphene-resistant PCOS
Interventions
Metformin versus placebo (vitamin B)
Outcomes
Ovulation and pregnancy rates and correction of metabolic disorders
Notes
Attempts to contact author not successful.
103
Morin-Papunen 2010
Methods
RCT
Participants
324 PCOS undergoing ART
Interventions
clomifene, ovulation induction, IUI or IVF, co-treatment with metformin or placebo
Outcomes
Primary: miscarriage rates

Secondary: pregnancy and live birth rates
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
Metformin with clomiphene citrate (CC) versus cc alone
Outcomes
Reproductive and metabolic functions
Notes
Attempts to contact author not successful.
104
DATA AND ANALYSES
Comparison 1. Metformin versus placebo or no treatment
Outcome or subgroup title

1 Live birth rate
2 Adverse events (gastrointestinal
side effects)
2.1 Nausea and vomiting
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
30kg/m2
30kg/m2
5 Menstrual frequency
<30 kg/m2
30kg/m2
6 Miscarriage rate
7 Body Mass Index (kg/m2)
30kg/m2
30kg/m2
8 Waist-hip ratio
30kg/m2
30kg/m2
9 Blood pressure - systolic (mm
Hg)
<30kg/m2
30kg/m2
10 Blood pressure - diastolic (mm
Hg)
No. of
studies
No. of
participants
3
6
115
Odds Ratio (M-H, Fixed, 95% CI)

1.80 [0.52, 6.16]

Subtotals only
3
5
73
318

3.91 [0.98, 15.64]

4.27 [2.40, 7.59]
8
4
707
413

2.31 [1.52, 3.51]

2.35 [1.44, 3.82]
294
2.21 [0.98, 4.98]
15
5
1208
441
Odds Ratio (M-H, Random, 95% CI)

1.81 [1.13, 2.93]

2.94 [0.81, 10.61]
11
767
1.50 [0.95, 2.37]
7
1
427
23

1.72 [1.14, 2.61]

21.15 [1.01, 445.00]
404
1.57 [1.03, 2.41]
3
16
6
279
630
166

Mean Difference (IV, Fixed, 95% CI)
0.36 [0.09, 1.47]

-0.05 [-0.31, 0.20]
-0.04 [-0.31, 0.23]
11
464
-0.15 [-0.86, 0.55]
10
4
449
136

-0.01 [-0.01, -0.00]

-0.01 [-0.01, -0.00]
313
-0.01 [-0.02, 0.01]
379
-3.59 [-5.13, -2.04]
96
-3.52 [-5.29, -1.76]
283
-3.80 [-5.00, -0.60]
292
-0.14 [-1.35, 1.07]
Statistical method
Effect size
105

30kg/m2
30kg/m2
11 Serum testosterone (nmol/L)
30kg/m2
30kg/m2
12 Serum sex hormone-binding
globulin (nmol/L)
30kg/m2
30kg/m2
13 Fasting glucose (mmol/L)
30kg/m2
30kg/m2
14 Fasting insulin (mIU/L)
30kg/m2
30kg/m2
15 Total cholesterol (mmol/l)
15.1 Participants with BMI<
30kg/m2
30kg/m2
16 Triglyceride levels (mmol/L)
30kg/m2
30kg/m2
96
-0.21 [-1.55, 1.13]
196
0.18 [-2.65, 3.02]
14
6
610
166

-0.60 [-0.73, -0.48]

-1.68 [-1.95, -1.42]
444
-0.29 [-0.44, -0.15]
15
626
-0.05 [-2.33, 2.24]
134
-5.23 [-14.34, 3.87]
11
492
0.30 [-2.06, 2.66]
14
4
596
111

-0.15 [-0.25, -0.06]

-0.13 [-0.31, 0.05]
11
485
-0.16 [-0.27, -0.05]
14
4
573
85
Mean Difference (IV, Random, 95% CI)

-3.51 [-6.50, -0.53]

-5.65 [-10.25, -1.06]
11
488
-2.72 [-6.50, 1.05]
10
5
562
276

-0.14 [-0.31, 0.02]

-0.02 [-0.26, 0.22]
286
-0.26 [-0.48, -0.03]
7
3
309
53

0.14 [-0.05, 0.32]

0.00 [-0.33, 0.34]
256
0.20 [-0.02, 0.42]
Comparison 2. Metformin combined with ovulation induction agent clomifene versus clomifene alone
No. of
studies
No. of
participants
1 Live birth rate

30kg/m2 or 32kg/m2
30kg/m2
7
3
907
359

1.16 [0.85, 1.56]

1.00 [0.62, 1.59]
548
1.28 [0.86, 1.91]
2 Adverse events
2.1 Nausea and vomiting
2
1
489
418

3.31 [2.11, 5.20]

3.40 [2.08, 5.54]
Statistical method
Effect size
106
2.2 Gastrointestinal
disturbance (other than nausea
and vomiting)
30kg/m2
30kg/m2
4 Ovulation rate (grouped by
sensitivity to clomiphene)
4.1 PCOS and clomifene
sensitive
resistant
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
2.84 [0.87, 9.28]
11
4
1208
513

1.51 [1.17, 1.96]

1.19 [0.79, 1.80]
695
1.76 [1.26, 2.47]
18
3265
1.73 [1.50, 2.00]
56
3.55 [0.65, 19.37]
179
4.86 [2.43, 9.74]
12
3030
1.64 [1.41, 1.90]
17
3078
1.77 [1.53, 2.05]
8
9
7
6
691
2387
837
916

1.75 [1.27, 2.39]

1.78 [1.51, 2.10]
1.61 [1.00, 2.60]
0.56 [0.18, 1.68]
Comparison 3. Metformin versus clomiphene citrate
No. of
studies
1 Live birth: Participants with

BMI < 30kg/m2 or 32kg/m2
2 Live birth: Participants with
BMI 30kg/m2
2
2

30kg/m2 or 32kg/m2
30kg/m2
4 Ovulation rate
30kg/m2
30kg/m2
5 Miscarriage rate
6 Multiple pregnancy
No. of
participants
Statistical method
Effect size
Subtotals only
500
0.30 [0.17, 0.52]
5
3
349

Subtotals only
1.94 [1.19, 3.16]
500
0.34 [0.21, 0.55]
4
2
497

Subtotals only
0.87 [0.60, 1.26]
2044
0.43 [0.36, 0.51]
4
5
173
403

1.24 [0.60, 2.58]

0.41 [0.08, 2.08]
107
Comparison 4. D-chiro-inositol versus placebo or no treatment

1 Ovulation
3 Waist-hip ratio
4 Blood pressure - systolic (mm
Hg)
5 Blood pressure - Diastolic (mm
Hg)
globulin (nmol/L)
10 Cholesterol (mmol/L)
11 Triglyceride levels (mmol/L)
No. of
studies
No. of
participants
2
1
1
1
327
44
44
44

5.38 [0.70, 41.31]

0.5 [-0.86, 1.86]
-0.01 [-0.05, 0.03]
-2.0 [-5.85, 1.85]
44
-4.0 [-7.26, -0.74]
1
1
44
44

1
1
1
1
44
44
44
44

-0.63 [-1.37, 0.11]

69.44 [34.97, 103.
91]
-0.28 [-0.99, 0.43]
-20.0 [-43.43, 3.43]
-0.23 [-0.99, 0.53]
-2.20 [-6.23, 1.83]
Statistical method
Effect size
Comparison 5. Rosiglitazone versus placebo or no treatment

1 Ovulation rate
4 Waist-hip ratio
5 Blood pressure-systolic (mm Hg)
6 Blood pressure-diastolic (mm
Hg)
7 Testoserone (nmo/l)
8 serum sex hormone-binding
globulin (nmol/L)
11 Cholesterol
12 Triglyceride levels
No. of
studies
No. of
participants
1
2
3
3
1
1
64
100
132
132
52
52

1.91 [0.70, 5.22]

5.59 [2.20, 14.19]
0.68 [0.40, 0.96]
-0.01 [-0.02, -0.00]
-2.0 [-3.95, -0.05]
-0.20 [-1.72, 1.32]
1
3
54
132

3
2
2
1
132
80
80
26

0.20 [-0.34, 0.74]

-6.92 [-27.96, 14.
12]
-0.21 [-0.39, -0.04]
-3.98 [-9.38, 1.42]
-0.20 [-0.21, -0.19]
1.0 [0.89, 1.11]
Statistical method
Effect size
108
Comparison 6. Pioglitazone versus placebo or no treatment

3 Waist-hip ratio
globulin (nmol/L)
No. of
studies
No. of
participants
2
2
1
2
2
70
63
28
63
63

8.88 [2.35, 33.61]

0.91 [-1.88, 3.70]
0.02 [-0.02, 0.06]
-0.12 [-0.53, 0.29]
2.75 [-5.26, 10.77]
63
-1.46 [-3.97, 1.06]
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
Comparison: 1 Metformin versus placebo or no treatment

Outcome: 1 Live birth rate
Study or subgroup
Metformin
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
1/9
2/9
45.6 %
0.44 [ 0.03, 5.93 ]
PCOSMIC 2010 (1)
5/32
2/33
42.7 %
2.87 [ 0.51, 16.01 ]
Yarali 2002
1/16
0/16
11.7 %
3.19 [ 0.12, 84.43 ]
57
58
100.0 %
1.80 [ 0.52, 6.16 ]
Ng 2001
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 7 (Metformin), 4 (Control)

Heterogeneity: Chi2 = 1.53, df = 2 (P = 0.46); I2 =0.0%
Test for overall effect: Z = 0.93 (P = 0.35)
Test for subgroup differences: Not applicable
0.001 0.01 0.1

Favours control
10 100 1000
Favours metformin
(1) All patients had BMI > 32
109
Analysis 1.2. Comparison 1 Metformin versus placebo or no treatment, Outcome 2 Adverse events
(gastrointestinal side effects).
Review:

Outcome: 2 Adverse events (gastrointestinal side effects)
Study or subgroup
Metformin
Control
n/N
n/N
Odds Ratio
Weight
5/11
2/12
48.2 %
4.17 [ 0.61, 28.62 ]
3/9
1/9
30.8 %
4.00 [ 0.33, 48.66 ]
1/16
0/16
21.0 %
3.19 [ 0.12, 84.43 ]
36
37
100.0 %
3.91 [ 0.98, 15.64 ]
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
1 Nausea and vomiting

Moghetti 2000
Ng 2001
Yarali 2002
Subtotal (95% CI)


2 Gastrointestinal disturbance (other than nausea and vomiting)
Fleming 2002
15/45
5/47
26.1 %
4.20 [ 1.38, 12.81 ]
Moghetti 2000
2/11
0/12
3.0 %
6.58 [ 0.28, 153.74 ]
2/9
0/9
3.0 %
6.33 [ 0.26, 152.86 ]
PCOSMIC 2010
10/32
11/33
59.6 %
0.91 [ 0.32, 2.57 ]
Trolle 2007
29/60
2/60
8.3 %
27.13 [ 6.07, 121.31 ]
157
161
100.0 %
4.27 [ 2.40, 7.59 ]
Ng 2001
Subtotal (95% CI)

Heterogeneity: Chi2 = 14.48, df = 4 (P = 0.01); I2 =72%
Test for overall effect: Z = 4.95 (P < 0.00001)
0.001 0.01 0.1

Favours metformin
10 100 1000
Favours control
110
Analysis 1.3. Comparison 1 Metformin versus placebo or no treatment, Outcome 3 Clinical pregnancy rate.
Review:

Outcome: 3 Clinical pregnancy rate
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 %
5.69 [ 0.25, 128.50 ]
1/9
2/9
5.9 %
0.44 [ 0.03, 5.93 ]
Karimzadeh 2007
40/100
11/100
21.9 %
5.39 [ 2.57, 11.34 ]
Karimzadeh 2010
17/88
15/75
43.4 %
0.96 [ 0.44, 2.08 ]
Subtotal (95% CI)
213
200
72.6 %
2.35 [ 1.44, 3.82 ]
M-H,Fixed,95% CI
1 Participants with BMI < 30kg/m2

Yarali 2002
Ng 2001

2 Participants with BMI 30kg/m2
Fleming 2002
4/23
1/19
3.0 %
3.79 [ 0.39, 37.20 ]
Lord 2006
3/22
2/22
5.7 %
1.58 [ 0.24, 10.52 ]
Tang 2006
6/69
2/74
5.9 %
3.43 [ 0.67, 17.60 ]
PCOSMIC 2010 (1)
7/32
5/33
12.8 %
1.57 [ 0.44, 5.57 ]
Subtotal (95% CI)
146
148
27.4 %
2.21 [ 0.98, 4.98 ]
348
100.0 %
2.31 [ 1.52, 3.51 ]

Total (95% CI)
359

Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.90), I2 =0.0%
0.001 0.01 0.1

Favours control
10 100 1000
Favours metformin
(1) All patients had BMI >32
111
Analysis 1.4. Comparison 1 Metformin versus placebo or no treatment, Outcome 4 Ovulation rate.
Review:

Outcome: 4 Ovulation rate
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 %
10.31 [ 3.10, 34.27 ]
7/12
3/12
5.0 %
4.20 [ 0.74, 23.91 ]
3/9
3/9
4.2 %
1.00 [ 0.14, 7.10 ]
17/153
20/150
11.1 %
0.81 [ 0.41, 1.62 ]
6/16
1/16
3.4 %
9.00 [ 0.94, 86.52 ]
222
219
31.3 %
2.94 [ 0.81, 10.61 ]

Baillargeon 2004
Carmina 2004
Ng 2001
Onalan 2005
Yarali 2002
Subtotal (95% CI)

Heterogeneity: Tau2 = 1.51; Chi2 = 16.48, df = 4 (P = 0.002); I2 =76%
Fleming 2002
37/45
30/47
9.1 %
2.62 [ 0.99, 6.90 ]
Hoeger 2004
4/9
3/9
4.4 %
1.60 [ 0.24, 10.81 ]
Hoeger 2004
3/9
6/11
4.7 %
0.42 [ 0.07, 2.58 ]
8/28
0/28
2.3 %
23.63 [ 1.29, 433.02 ]
18/111
15/104
10.7 %
1.15 [ 0.55, 2.42 ]
9/22
9/22
7.6 %
1.00 [ 0.30, 3.33 ]
Nestler 1998
12/35
1/26
3.8 %
13.04 [ 1.57, 108.36 ]
Onalan 2005
5/63
5/51
7.0 %
0.79 [ 0.22, 2.91 ]
Otta 2010
7/14
6/15
6.1 %
1.50 [ 0.34, 6.53 ]
17/32
13/33
9.0 %
1.74 [ 0.65, 4.67 ]
Sturrock 2002
0/12
1/14
1.8 %
0.36 [ 0.01, 9.68 ]
Vandermolen 2001
1/12
1/15
2.3 %
1.27 [ 0.07, 22.72 ]
Subtotal (95% CI)
392
375
68.7 %
1.50 [ 0.95, 2.37 ]
100.0 %
1.81 [ 1.13, 2.93 ]
Jakubowicz 2001
Ladson 2011
Lord 2006
PCOSMIC 2010 (1)

Total (95% CI)
614
594
0.001 0.01 0.1
Favours control
10 100 1000
Favours metformin
(Continued . . . )
112
(. . .
Study or subgroup
Metformin
Control
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Continued)
Odds Ratio
MH,Random,95%
CI

0.001 0.01 0.1
Favours control
10 100 1000
Favours metformin
Analysis 1.5. Comparison 1 Metformin versus placebo or no treatment, Outcome 5 Menstrual frequency.
Review:

Outcome: 5 Menstrual frequency
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 %
21.15 [ 1.01, 445.00 ]
11
12
0.8 %
21.15 [ 1.01, 445.00 ]
14/15
8/17
1.5 %
15.75 [ 1.67, 148.12 ]
8/22
2/23
3.6 %
6.00 [ 1.11, 32.54 ]
Hoeger 2004
2/9
2/11
4.1 %
1.29 [ 0.14, 11.54 ]
Hoeger 2004
2/9
0/9
1.1 %
6.33 [ 0.26, 152.86 ]
Sturrock 2002
5/12
6/14
9.4 %
0.95 [ 0.20, 4.54 ]
Tang 2006
36/69
43/74
57.7 %
0.79 [ 0.41, 1.52 ]
Trolle 2007
19/60
11/60
21.9 %
2.06 [ 0.88, 4.83 ]
M-H,Fixed,95% CI
1 Participants with BMI <30 kg/m2

Moghetti 2000
Subtotal (95% CI)

Heterogeneity: not applicable

Chou 2003
Eisenhardt 2006
0.002
0.1
Favours control
10
500
Favours metformin
(Continued . . . )
113
(. . .
Study or subgroup
Metformin
Subtotal (95% CI)
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
196
Continued)
Weight
Odds Ratio
208
99.2 %
1.57 [ 1.03, 2.41 ]
220
100.0 %
1.72 [ 1.14, 2.61 ]
M-H,Fixed,95% CI

Total (95% CI)
207

Test for subgroup differences: Chi2 = 2.74, df = 1 (P = 0.10), I2 =64%
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:

Outcome: 6 Miscarriage rate
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
PCOSMIC 2010 (1)
1/32
2/33
31.1 %
0.50 [ 0.04, 5.80 ]
160
119
100.0 %
0.36 [ 0.09, 1.47 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
68.9 %
0.30 [ 0.06, 1.59 ]

Not estimable

0.01
0.1
Favours Metformin
10
100
Favours control
114
Analysis 1.7. Comparison 1 Metformin versus placebo or no treatment, Outcome 7 Body Mass Index
(kg/m2).
Review:

Outcome: 7 Body Mass Index (kg/m2)
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 %
0.0 [ -0.28, 0.28 ]
24.9 (7.1)
25.3 (5.1)
0.2 %
-0.40 [ -6.74, 5.94 ]
11
26 (4.64)
12
31.9 (3.81)
0.5 %
-5.90 [ -9.39, -2.41 ]
24.4 (4.3)
22.7 (3.5)
0.4 %
1.70 [ -2.25, 5.65 ]
Romualdi 2010
13
22.1 (2.52)
10
23.2 (4.1)
0.8 %
-1.10 [ -3.99, 1.79 ]
Yarali 2002
16
29.8 (3.4)
16
29.8 (4.9)
0.8 %
0.0 [ -2.92, 2.92 ]
87.0 %
-0.04 [ -0.31, 0.23 ]

Baillargeon 2004
Maciel 2004
Moghetti 2000
Ng 2001
Subtotal (95% CI)
83
83

Chou 2003
14
34.9 (5)
16
37.2 (6.4)
0.4 %
-2.30 [ -6.39, 1.79 ]
Fleming 2002
25
35.2 (8.9)
39
35.3 (8.6)
0.3 %
-0.10 [ -4.51, 4.31 ]
Hoeger 2004
41.7 (9.2)
40.6 (8)
0.1 %
1.10 [ -8.51, 10.71 ]
Hoeger 2004
36.1 (5.3)
36.4 (5.1)
0.2 %
-0.30 [ -6.29, 5.69 ]
Jakubowicz 2001
26
31.8 (1.52)
22
31.7 (1.52)
8.7 %
0.10 [ -0.76, 0.96 ]
Ladson 2011
31
37.18 (5.86)
25
35.99 (7.96)
0.5 %
1.19 [ -2.55, 4.93 ]
Lord 2006
16
34.6 (9.1)
16
35.3 (6.5)
0.2 %
-0.70 [ -6.18, 4.78 ]
36.5 (6.8)
36.2 (3.4)
0.2 %
0.30 [ -5.14, 5.74 ]
Otta 2010
14
31.53 (4.93)
15
34.16 (4.95)
0.5 %
-2.63 [ -6.23, 0.97 ]
Pasquali 2000
10
36.4 (7.4)
38 (6.2)
0.2 %
-1.60 [ -7.88, 4.68 ]
Tang 2006
56
37.1 (5.1)
66
37.4 (6.3)
1.6 %
-0.30 [ -2.32, 1.72 ]
Vandermolen 2001
11
35.4 (10.28)
14
38.4 (7.43)
0.1 %
-3.00 [ -10.21, 4.21 ]
243
13.0 %
-0.15 [ -0.86, 0.55 ]
326
100.0 %
-0.05 [ -0.31, 0.20 ]
Maciel 2004
Subtotal (95% CI)
221

Total (95% CI)
304
-10
-5
Favours metformin
10
Favours control
(Continued . . . )
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:

Outcome: 8 Waist-hip ratio
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 %
-0.01 [ -0.02, 0.00 ]
Moghetti 2000
11
0.82 (0.07)
12
0.82 (0.07)
0.7 %
0.0 [ -0.06, 0.06 ]
Romualdi 2010
13
0.75 (0.1)
10
0.76 (0.1)
0.4 %
-0.01 [ -0.09, 0.07 ]
Yarali 2002
16
0.8 (0.1)
16
0.8 (0.1)
0.5 %
0.0 [ -0.07, 0.07 ]
93.2 %
-0.01 [ -0.01, 0.00 ]
Subtotal (95% CI)
68
68

Chou 2003
14
0.95 (0.07)
16
0.93 (0.07)
1.0 %
0.02 [ -0.03, 0.07 ]
Fleming 2002
26
0.88 (0.07)
38
0.88 (0.07)
2.0 %
0.0 [ -0.03, 0.03 ]
Jakubowicz 2001
26
0.84 (1.02)
22
0.85 (0.05)
0.0 %
-0.01 [ -0.40, 0.38 ]
Lord 2006
16
0.83 (0.06)
15
0.88 (0.07)
1.1 %
-0.05 [ -0.10, 0.00 ]
Pasquali 2000
10
0.86 (0.07)
0.88 (0.05)
0.8 %
-0.02 [ -0.08, 0.04 ]
-0.2
-0.1
Favours metformin
0.1
0.2
Favours control
(Continued . . . )
116
(. . .
Study or subgroup
Metformin
Tang 2006
Subtotal (95% CI)
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 %
0.01 [ -0.03, 0.05 ]
165
6.8 %
-0.01 [ -0.02, 0.01 ]
233
100.0 %
-0.01 [ -0.01, 0.00 ]

Total (95% CI)
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:

Outcome: 9 Blood pressure - systolic (mm Hg)
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 %
-3.20 [ -5.01, -1.39 ]
101.4 (10.6)
106.3 (13)
1.7 %
-4.90 [ -16.85, 7.05 ]
11
119.1 (12.93)
12
133 (13.51)
2.0 %
-13.90 [ -24.71, -3.09 ]
76.7 %
-3.52 [ -5.29, -1.76 ]
1 Participants with BMI <30kg/m2

Baillargeon 2004
Maciel 2004
Moghetti 2000
Subtotal (95% CI)
46
50

Chou 2003
14
121.6 (10.5)
16
126.1 (18.4)
2.1 %
-4.50 [ -15.06, 6.06 ]
Lord 2006
16
122.7 (13.5)
15
138.4 (11.3)
3.1 %
-15.70 [ -24.44, -6.96 ]
-20
-10
Favours metformin
10
20
Favours control
(Continued . . . )
117
(. . .
Study or subgroup
Metformin
Mean
Difference
Control
Mean
Difference
Weight
Mean(SD)
Mean(SD)
110 (17)
125 (13.7)
0.9 %
-15.00 [ -31.09, 1.09 ]
Tang 2006
56
121.7 (12.5)
66
121.4 (12.1)
12.4 %
0.30 [ -4.09, 4.69 ]
Trolle 2007
42
126 (17)
44
130.2 (16.5)
4.8 %
-4.20 [ -11.29, 2.89 ]
147
23.3 %
-3.80 [ -7.00, -0.60 ]
197
100.0 %
-3.59 [ -5.13, -2.04 ]
Maciel 2004
Subtotal (95% CI)
136
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI

Total (95% CI)
182

-20
-10
Favours metformin
10
20
Favours control
118
Analysis 1.10. Comparison 1 Metformin versus placebo or no treatment, Outcome 10 Blood pressure diastolic (mm Hg).
Review:

Outcome: 10 Blood pressure - diastolic (mm Hg)
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 %
-0.10 [ -1.46, 1.26 ]
71.4 (10.6)
67.5 (8.8)
1.5 %
3.90 [ -6.04, 13.84 ]
11
76.7 (10.96)
12
85.5 (11.78)
1.7 %
-8.80 [ -18.09, 0.49 ]
81.8 %
-0.21 [ -1.55, 1.13 ]

Baillargeon 2004
Maciel 2004
Moghetti 2000
Subtotal (95% CI)
46
50

Chou 2003
14
84.6 (10)
16
84.8 (10.4)
2.7 %
-0.20 [ -7.51, 7.11 ]
Lord 2006
15
76.7 (10.9)
15
79.5 (13)
2.0 %
-2.80 [ -11.39, 5.79 ]
73.8 (7.3)
81.6 (11)
1.4 %
-7.80 [ -17.95, 2.35 ]
56
77.2 (10)
66
75.5 (9.5)
12.1 %
1.70 [ -1.78, 5.18 ]
103
18.2 %
0.18 [ -2.65, 3.02 ]
153
100.0 %
-0.14 [ -1.35, 1.07 ]
Maciel 2004
Tang 2006
Subtotal (95% CI)
93

Total (95% CI)
139

-20
-10
Favours metformin
10
20
Favours control
119
Analysis 1.11. Comparison 1 Metformin versus placebo or no treatment, Outcome 11 Serum testosterone
(nmol/L).
Review:

Outcome: 11 Serum testosterone (nmol/L)
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 %
0.0 [ -0.89, 0.89 ]
Baillargeon 2004
28
1.28 (0.7)
30
4.15 (0.76)
11.1 %
-2.87 [ -3.25, -2.49 ]
Yarali 2002
16
5.83 (1.56)
16
5.15 (2.74)
0.7 %
0.68 [ -0.86, 2.22 ]
Ng 2001
1.3 (0.5)
1.7 (0.7)
4.0 %
-0.40 [ -1.02, 0.22 ]
Maciel 2004
2.25 (0.69)
3.57 (0.83)
2.6 %
-1.32 [ -2.09, -0.55 ]
13
1.52 (0.5)
10
2 (1.42)
1.8 %
-0.48 [ -1.40, 0.44 ]
22.2 %
-1.68 [ -1.95, -1.42 ]
Romualdi 2010
Subtotal (95% CI)
83
83
Heterogeneity: Chi2 = 84.67, df = 5 (P<0.00001); I2 =94%

Lord 2006
16
2.51 (0.64)
15
2.26 (0.61)
8.1 %
0.25 [ -0.19, 0.69 ]
Tang 2006
56
1.9 (0.6)
66
2.3 (0.7)
29.4 %
-0.40 [ -0.63, -0.17 ]
Jakubowicz 2001
26
1.33 (1.78)
22
3.73 (1.92)
1.4 %
-2.40 [ -3.45, -1.35 ]
Chou 2003
14
1.6 (0.67)
16
2.27 (0.87)
5.1 %
-0.67 [ -1.22, -0.12 ]
1.57 (0.58)
2.36 (0.66)
3.1 %
-0.79 [ -1.50, -0.08 ]
Vandermolen 2001
11
2.46 (0.81)
14
2.67 (0.65)
4.5 %
-0.21 [ -0.80, 0.38 ]
Trolle 2007
42
2.3 (0.89)
45
2.54 (0.6)
15.2 %
-0.24 [ -0.56, 0.08 ]
Fleming 2002
25
2.74 (1.07)
36
2.81 (0.94)
5.8 %
-0.07 [ -0.59, 0.45 ]
Hoeger 2004
2.1 (0.34)
1.89 (0.8)
4.3 %
0.21 [ -0.39, 0.81 ]
Maciel 2004
3.73 (0.79)
3.52 (1.55)
0.9 %
0.21 [ -1.15, 1.57 ]
236
77.8 %
-0.29 [ -0.44, -0.15 ]
319
100.0 %
-0.60 [ -0.73, -0.48 ]
Hoeger 2004
Subtotal (95% CI)
208

Total (95% CI)
291
Heterogeneity: Chi2 = 196.00, df = 15 (P<0.00001); I2 =92%

-4
-2
Favours metformin
Favours control
120
Analysis 1.12. Comparison 1 Metformin versus placebo or no treatment, Outcome 12 Serum sex hormonebinding globulin (nmol/L).
Review:

Outcome: 12 Serum sex hormone-binding globulin (nmol/L)
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 %
-6.10 [ -20.58, 8.38 ]
Maciel 2004
169.5 (67)
274.3 (74.1)
0.1 %
-104.80 [ -176.21, -33.39 ]
Romualdi 2010
13
45.1 (15.5)
10
49.6 (18.8)
2.5 %
-4.50 [ -18.88, 9.88 ]
Moghetti 2000
11
44.6 (35.16)
12
34.4 (18.91)
1.0 %
10.20 [ -13.17, 33.57 ]
Baillargeon 2004
28
208 (91.8)
30
232 (95)
0.2 %
-24.00 [ -72.08, 24.08 ]
6.3 %
-5.23 [ -14.34, 3.87 ]
Subtotal (95% CI)
67
67

5
23.8 (8.2)
30.3 (12.1)
4.0 %
-6.50 [ -17.99, 4.99 ]
Lord 2006
16
27.41 (10)
15
30.3 (9.4)
11.2 %
-2.89 [ -9.72, 3.94 ]
Tang 2006
56
24.7 (12.1)
66
24.4 (12.9)
26.5 %
0.30 [ -4.14, 4.74 ]
Jakubowicz 2001
26
196 (66.29)
22
120 (42.21)
0.5 %
76.00 [ 45.01, 106.99 ]
Fleming 2002
25
29.2 (12.3)
36
28.6 (16.8)
9.8 %
0.60 [ -6.71, 7.91 ]
Nestler 1998
35
93 (59.16)
26
124 (86.68)
0.3 %
-31.00 [ -69.66, 7.66 ]
Vandermolen 2001
11
61 (39.8)
14
71 (36.67)
0.6 %
-10.00 [ -40.37, 20.37 ]
Chou 2003
14
24.3 (11)
16
23.9 (10.8)
8.5 %
0.40 [ -7.42, 8.22 ]
Pasquali 2000
10
16.7 (8.1)
13.8 (2.1)
19.1 %
2.90 [ -2.33, 8.13 ]
Ladson 2011
31
28.23 (11.82)
25
30.83 (16.7)
8.7 %
-2.60 [ -10.36, 5.16 ]
Hoeger 2004
37.2 (4.8)
34.4 (15.2)
4.5 %
2.80 [ -7.98, 13.58 ]
Maciel 2004
194.2 (110.9)
236.5 (134)
0.0 %
-42.30 [ -174.22, 89.62 ]
Hoeger 2004
-100
-50
Favours control
50
100
Favours metformin
(Continued . . . )
121
(. . .
Study or subgroup
Treatment
N
Subtotal (95% CI)
Mean
Difference
Control
Mean(SD)
242
Mean(SD)
Mean
Difference
Weight
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI
250
93.7 %
0.30 [ -2.06, 2.66 ]
317
100.0 %
-0.05 [ -2.33, 2.24 ]

Total (95% CI)
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:

Outcome: 13 Fasting glucose (mmol/L)
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 %
0.20 [ -0.16, 0.56 ]
Ng 2001
5.1 (0.3)
5.1 (0.5)
4.9 %
0.0 [ -0.42, 0.42 ]
Maciel 2004
4.59 (0.62)
4.34 (0.24)
3.7 %
0.25 [ -0.24, 0.74 ]
11
4.4 (0.33)
12
4.9 (0.35)
11.4 %
-0.50 [ -0.78, -0.22 ]
26.8 %
-0.13 [ -0.31, 0.05 ]

Baillargeon 2004
Moghetti 2000
Subtotal (95% CI)
54
57

Pasquali 2000
10
5.04 (0.952)
5.32 (0.616)
1.7 %
-0.28 [ -1.01, 0.45 ]
Fleming 2002
25
5.05 (0.64)
38
4.95 (0.45)
10.6 %
0.10 [ -0.19, 0.39 ]
-4
-2
Favours metformin
Favours control
(Continued . . . )
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 %
-0.62 [ -1.22, -0.02 ]
Trolle 2007
38
5.17 (0.42)
41
5.4 (0.5)
21.4 %
-0.23 [ -0.43, -0.03 ]
Otta 2010
14
4.77 (0.62)
15
4.98 (0.61)
4.4 %
-0.21 [ -0.66, 0.24 ]
Lord 2006
16
5.03 (0.53)
15
5.05 (0.48)
7.0 %
-0.02 [ -0.38, 0.34 ]
Chou 2003
14
5.06 (0.69)
16
5.12 (0.61)
4.0 %
-0.06 [ -0.53, 0.41 ]
Jakubowicz 2001
26
4.3 (1.02)
22
5 (0.94)
2.9 %
-0.70 [ -1.25, -0.15 ]
5.11 (0.57)
5.22 (0.49)
2.3 %
-0.11 [ -0.73, 0.51 ]
56
4.87 (0.65)
66
4.95 (0.85)
12.4 %
-0.08 [ -0.35, 0.19 ]
Hoeger 2004
4.97 (0.59)
5.53 (0.36)
2.7 %
-0.56 [ -1.13, 0.01 ]
Maciel 2004
4.74 (0.73)
4.73 (0.78)
1.4 %
0.01 [ -0.79, 0.81 ]
257
73.2 %
-0.16 [ -0.27, -0.05 ]
314
100.0 %
-0.15 [ -0.25, -0.06 ]
Hoeger 2004
Tang 2006
Subtotal (95% CI)
228
IV,Fixed,95% CI
Continued)
IV,Fixed,95% CI

Total (95% CI)
282

-4
-2
Favours metformin
Favours control
123
Analysis 1.14. Comparison 1 Metformin versus placebo or no treatment, Outcome 14 Fasting insulin
(mIU/L).
Review:

Outcome: 14 Fasting insulin (mIU/L)
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 %
-7.80 [ -10.79, -4.81 ]
11
10.2 (7.3)
12
21.3 (13.51)
6.0 %
-11.10 [ -19.88, -2.32 ]
7.1 (1.9)
9.3 (5.7)
9.7 %
-2.20 [ -6.62, 2.22 ]
16
16.4 (32.71)
16
12.2 (7)
2.6 %
4.20 [ -12.19, 20.59 ]
29.3 %
-5.65 [ -10.25, -1.06 ]

Maciel 2004
Moghetti 2000
Ng 2001
Yarali 2002
Subtotal (95% CI)
42
43

Chou 2003
14
39.4 (14.6)
16
36.9 (24.3)
3.3 %
2.50 [ -11.65, 16.65 ]
Fleming 2002
25
16.8 (9.7)
37
18.4 (12.3)
8.7 %
-1.60 [ -7.09, 3.89 ]
Hoeger 2004
16.7 (10.6)
17.5 (6)
5.0 %
-0.80 [ -11.10, 9.50 ]
Hoeger 2004
17.9 (6.5)
21.1 (10.8)
5.8 %
-3.20 [ -12.27, 5.87 ]
Jakubowicz 2001
26
13.17 (11.9)
22
46.01 (30.49)
3.5 %
-32.84 [ -46.38, -19.30 ]
Lord 2006
16
17.35 (8.9)
15
15.4 (6.3)
8.8 %
1.95 [ -3.45, 7.35 ]
21.1 (9.33)
23.2 (12.3)
4.2 %
-2.10 [ -13.88, 9.68 ]
Otta 2010
14
9.42 (5.13)
15
15.31 (5.36)
10.3 %
-5.89 [ -9.71, -2.07 ]
Pasquali 2000
10
21.6 (31.2)
19 (14.4)
1.6 %
2.60 [ -19.16, 24.36 ]
Tang 2006
56
24.2 (39)
66
18.9 (17.1)
4.6 %
5.30 [ -5.72, 16.32 ]
Trolle 2007
45
13.5 (12.8)
38
13.5 (9.8)
9.3 %
0.0 [ -4.87, 4.87 ]
Vandermolen 2001
11
10.4 (6.97)
14
14.4 (15.71)
5.7 %
-4.00 [ -13.20, 5.20 ]
70.7 %
-2.72 [ -6.50, 1.05 ]
100.0 %
-3.51 [ -6.50, -0.53 ]
Maciel 2004
Subtotal (95% CI)
235
253

Total (95% CI)
277
296

-100
-50
Favours metformin
50
100
Favours control
124
Analysis 1.15. Comparison 1 Metformin versus placebo or no treatment, Outcome 15 Total cholesterol
(mmol/l).
Review:

Outcome: 15 Total cholesterol (mmol/l)
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 %
-0.30 [ -0.67, 0.07 ]
4.35 (0.79)
3.82 (0.85)
3.9 %
0.53 [ -0.30, 1.36 ]
11
4.61 (0.4)
12
4.42 (0.69)
13.0 %
0.19 [ -0.27, 0.65 ]
4.5 (0.9)
5.2 (1.6)
1.5 %
-0.70 [ -2.04, 0.64 ]
13
3.93 (0.58)
10
3.73 (0.75)
8.6 %
0.20 [ -0.36, 0.76 ]
46.9 %
-0.02 [ -0.26, 0.22 ]
1 Participants with BMI< 30kg/m2

Karimzadeh 2007
Maciel 2004
Moghetti 2000
Ng 2001
Romualdi 2010
Subtotal (95% CI)
139
137

Chou 2003
14
4.18 (0.52)
16
5.11 (1.4)
5.0 %
-0.93 [ -1.67, -0.19 ]
Fleming 2002
26
4.61 (0.82)
34
4.93 (0.96)
13.3 %
-0.32 [ -0.77, 0.13 ]
Lord 2006
16
4.78 (0.82)
15
5.65 (1.15)
5.4 %
-0.87 [ -1.58, -0.16 ]
4.88 (0.77)
4.3 (1.13)
2.5 %
0.58 [ -0.47, 1.63 ]
Otta 2010
14
4.12 (0.77)
15
4.81 (0.75)
8.8 %
-0.69 [ -1.24, -0.14 ]
Tang 2006
56
5.14 (1.03)
66
4.88 (1.15)
18.1 %
0.26 [ -0.13, 0.65 ]
152
53.1 %
-0.26 [ -0.48, -0.03 ]
289
100.0 %
-0.14 [ -0.31, 0.02 ]
Maciel 2004
Subtotal (95% CI)
134

Total (95% CI)
273

-2
-1
Favours metformin
Favours control
125
Analysis 1.16. Comparison 1 Metformin versus placebo or no treatment, Outcome 16 Triglyceride levels
(mmol/L).
Review:

Outcome: 16 Triglyceride levels (mmol/L)
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 %
0.69 [ 0.00, 1.38 ]
11
0.98 (0.37)
12
1.12 (0.8)
13.5 %
-0.14 [ -0.64, 0.36 ]
0.9 (0.4)
1.2 (0.7)
9.9 %
-0.30 [ -0.89, 0.29 ]
30.6 %
0.00 [ -0.33, 0.34 ]

Maciel 2004
Moghetti 2000
Ng 2001
Subtotal (95% CI)
26
27

Chou 2003
14
1.69 (1.24)
16
1.64 (0.64)
6.6 %
0.05 [ -0.67, 0.77 ]
Fleming 2002
26
1.62 (0.97)
34
1.4 (0.49)
20.6 %
0.22 [ -0.19, 0.63 ]
Lord 2006
16
1.44 (0.71)
14
1.34 (0.62)
15.1 %
0.10 [ -0.38, 0.58 ]
1.63 (1.05)
1.29 (0.48)
5.1 %
0.34 [ -0.48, 1.16 ]
56
2.04 (1.01)
66
1.78 (1.21)
22.1 %
0.26 [ -0.13, 0.65 ]
136
69.4 %
0.20 [ -0.02, 0.42 ]
163
100.0 %
0.14 [ -0.05, 0.32 ]
Maciel 2004
Tang 2006
Subtotal (95% CI)
120

Total (95% CI)
146

-1
-0.5
Favours metformin
0.5
Favours control
126
Analysis 2.1. Comparison 2 Metformin combined with ovulation induction agent clomifene versus
clomifene alone, Outcome 1 Live birth rate.
Review:
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
1 Participants with BMI < 30kg/m2 or 32kg/m2

Boudhraa 2010
11/32
4/31
3.4 %
3.54 [ 0.98, 12.70 ]
21/111
31/114
31.8 %
0.62 [ 0.33, 1.17 ]
PCOSMIC 2010 (1)
15/35
13/36
9.4 %
1.33 [ 0.51, 3.45 ]
Subtotal (95% CI)
178
181
44.7 %
1.00 [ 0.62, 1.59 ]
Moll 2006
Total events: 47 (Met + clomifene), 48 (clomifene)

Legro 2007
56/209
47/209
44.2 %
1.26 [ 0.81, 1.97 ]
Sahin 2004
3/11
3/10
2.9 %
0.88 [ 0.13, 5.82 ]
Vandermolen 2001
4/12
1/15
0.8 %
7.00 [ 0.66, 73.93 ]
Zain 2009
7/41
7/41
7.5 %
1.00 [ 0.32, 3.16 ]
273
275
55.3 %
1.28 [ 0.86, 1.91 ]
456
100.0 %
1.16 [ 0.85, 1.56 ]
Subtotal (95% CI)

Total (95% CI)
451

0.01
0.1
Favours clomifene
10
100
Favours met+clomifene
(1) Ovulation induction with CC. All patients had BMI <33
127
clomifene alone, Outcome 2 Adverse events.
Review:
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 %
3.40 [ 2.08, 5.54 ]
209
209
84.4 %
3.40 [ 2.08, 5.54 ]
11/35
5/36
15.6 %
2.84 [ 0.87, 9.28 ]
35
36
15.6 %
2.84 [ 0.87, 9.28 ]
245
100.0 %
3.31 [ 2.11, 5.20 ]
M-H,Fixed,95% CI
1 Nausea and vomiting

Moll 2006
Subtotal (95% CI)
Total events: 72 (MF + clomifene), 28 (clomifene)

2 Gastrointestinal disturbance (other than nausea and vomiting)
PCOSMIC 2010
Subtotal (95% CI)

Total (95% CI)
244

0.001 0.01 0.1

Favours MF + clomifene
10 100 1000
Favours clomifene
128
clomifene alone, Outcome 3 Clinical pregnancy rate.
Review:
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 %
15.26 [ 0.83, 280.72 ]
13/90
11/90
10.1 %
1.21 [ 0.51, 2.87 ]
9/16
2/12
1.1 %
6.43 [ 1.05, 39.33 ]
57/111
64/114
32.8 %
0.82 [ 0.49, 1.39 ]
257
256
44.4 %
1.19 [ 0.79, 1.80 ]
13/45
4/45
3.0 %
4.16 [ 1.24, 14.00 ]
5/16
0/15
0.4 %
14.83 [ 0.74, 295.97 ]
Legro 2007
80/209
62/209
40.9 %
1.47 [ 0.98, 2.21 ]
Sahin 2004
5/11
3/10
1.8 %
1.94 [ 0.32, 11.76 ]
Sturrock 2002
3/12
4/14
3.0 %
0.83 [ 0.15, 4.78 ]
Vandermolen 2001
6/12
1/15
0.5 %
14.00 [ 1.37, 142.89 ]
Zain 2009
8/41
7/41
6.0 %
1.18 [ 0.38, 3.62 ]
346
349
55.6 %
1.76 [ 1.26, 2.47 ]
605
100.0 %
1.51 [ 1.17, 1.96 ]
M-H,Fixed,95% CI

Hwu 2005
Karimzadeh 2010
Malkawi 2002
Moll 2006
Subtotal (95% CI)

El-Biely 2001
Khorram 2006
Subtotal (95% CI)

Total (95% CI)
603

0.002
0.1
Favours clomifene
10
500
129
clomifene alone, Outcome 4 Ovulation rate (grouped by sensitivity to clomiphene).
Review:
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 %
3.55 [ 0.65, 19.37 ]
28
28
0.5 %
3.55 [ 0.65, 19.37 ]
M-H,Fixed,95% CI
1 PCOS and clomifene sensitive

Jakubowicz 2001
Subtotal (95% CI)
Total events: 26 (MF+ clomifene), 22 (clomifene)

2 PCOS and clomifene resistant
Hwu 2005
17/40
5/40
1.0 %
5.17 [ 1.68, 15.98 ]
Malkawi 2002
11/16
3/12
0.4 %
6.60 [ 1.23, 35.44 ]
4/9
1/9
0.2 %
6.40 [ 0.55, 74.89 ]
Sturrock 2002
5/12
4/14
0.8 %
1.79 [ 0.35, 9.13 ]
Vandermolen 2001
9/12
4/15
0.3 %
8.25 [ 1.45, 46.86 ]
Subtotal (95% CI)
89
90
2.6 %
4.86 [ 2.43, 9.74 ]
Ng 2001

3 PCOS and clomifene sensitivity not defined
Ben Ayed 2009
10/16
6/16
0.8 %
2.78 [ 0.66, 11.62 ]
Boudhraa 2010
17/32
10/31
1.7 %
2.38 [ 0.85, 6.63 ]
El-Biely 2001
35/45
29/45
2.2 %
1.93 [ 0.76, 4.90 ]
7/16
1/15
0.2 %
10.89 [ 1.14, 103.98 ]
Legro 2007
582/964
462/942
64.7 %
1.58 [ 1.32, 1.90 ]
Moll 2006
84/141
98/168
12.6 %
1.05 [ 0.67, 1.66 ]
Nestler 1998
19/21
2/25
0.1 %
109.25 [ 14.04, 850.33 ]
PCOSMIC 2010
27/35
23/36
1.8 %
1.91 [ 0.67, 5.41 ]
Sahin 2004
38/51
34/55
2.9 %
1.81 [ 0.79, 4.15 ]
Siebert 2009
34/52
36/55
4.2 %
1.00 [ 0.45, 2.21 ]
Williams 2009
20/99
17/88
5.0 %
1.06 [ 0.51, 2.18 ]
Khorram 2006
0.05
0.2
Favours clomifene
20
Favours MF+ clomifene
(Continued . . . )
130
(. . .
Study or subgroup
Zain 2009
Subtotal (95% CI)
MF+ clomifene
clomifene
Odds Ratio
M-H,Fixed,95% CI
Weight
Continued)
Odds Ratio
n/N
n/N
38/41
24/41
0.6 %
8.97 [ 2.37, 33.91 ]
M-H,Fixed,95% CI
1513
1517
96.8 %
1.64 [ 1.41, 1.90 ]
1635
100.0 %
1.73 [ 1.50, 2.00 ]

Total (95% CI)
1630

0.05
0.2
Favours clomifene
20
clomifene alone, Outcome 5 Ovulation rate (grouped by BMI).
Review:
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
Ben Ayed 2009
10/16
6/16
0.8 %
2.78 [ 0.66, 11.62 ]
Boudhraa 2010
17/32
10/31
1.8 %
2.38 [ 0.85, 6.63 ]
El-Biely 2001
35/45
29/45
2.4 %
1.93 [ 0.76, 4.90 ]
Hwu 2005
17/40
5/40
1.1 %
5.17 [ 1.68, 15.98 ]
Malkawi 2002
11/16
3/12
0.4 %
6.60 [ 1.23, 35.44 ]
84/141
98/168
13.3 %
1.05 [ 0.67, 1.66 ]
4/9
1/9
0.2 %
6.40 [ 0.55, 74.89 ]
M-H,Fixed,95% CI
1 BMI <30 kg/m2
Moll 2006
Ng 2001
0.002
0.1
Favours clomifene
10
500
(Continued . . . )
131
(. . .
Study or subgroup
MF+ clomifene
clomifene
Odds Ratio
M-H,Fixed,95% CI
Weight
Continued)
Odds Ratio
n/N
n/N
PCOSMIC 2010 (1)
27/35
23/36
1.9 %
M-H,Fixed,95% CI
1.91 [ 0.67, 5.41 ]
Subtotal (95% CI)
334
357
21.8 %
1.75 [ 1.27, 2.39 ]
26/28
22/28
0.6 %
3.55 [ 0.65, 19.37 ]
7/16
1/15
0.2 %
10.89 [ 1.14, 103.98 ]
582/964
462/942
68.1 %
1.58 [ 1.32, 1.90 ]
Nestler 1998
19/21
2/25
0.1 %
109.25 [ 14.04, 850.33 ]
Sahin 2004
38/51
34/55
3.1 %
1.81 [ 0.79, 4.15 ]
Siebert 2009
34/52
36/55
4.5 %
1.00 [ 0.45, 2.21 ]
Sturrock 2002
5/12
4/14
0.8 %
1.79 [ 0.35, 9.13 ]
Vandermolen 2001
9/12
4/15
0.3 %
8.25 [ 1.45, 46.86 ]
38/41
24/41
0.6 %
8.97 [ 2.37, 33.91 ]
1197
1190
78.2 %
1.78 [ 1.51, 2.10 ]
1547
100.0 %
1.77 [ 1.53, 2.05 ]

2 BMI 30kg/m2
Jakubowicz 2001
Khorram 2006
Legro 2007
Zain 2009
Subtotal (95% CI)

Total (95% CI)
1531

0.002
0.1
Favours clomifene
10
500
(1) BMI < 33
132
clomifene alone, Outcome 6 Miscarriage rate.
Review:
Study or subgroup
MF + clomifene
clomifene
n/N
n/N
2/40
0/40
1.7 %
5.26 [ 0.24, 113.11 ]
Legro 2007
24/209
16/209
52.6 %
1.56 [ 0.81, 3.04 ]
Moll 2006
13/111
12/114
38.8 %
1.13 [ 0.49, 2.59 ]
PCOSMIC 2010
3/35
0/36
1.7 %
7.86 [ 0.39, 158.01 ]
Sahin 2004
1/11
0/10
1.7 %
3.00 [ 0.11, 82.40 ]
Vandermolen 2001
2/6
0/1
1.9 %
1.67 [ 0.05, 58.28 ]
Zain 2009
1/8
0/7
1.6 %
3.00 [ 0.10, 86.09 ]
420
417
100.0 %
1.61 [ 1.00, 2.60 ]
Hwu 2005
Total (95% CI)
Odds Ratio
Weight
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI

0.001 0.01 0.1

10 100 1000
Favours clomifene
133
clomifene alone, Outcome 7 Multiple pregnancy rate.
Review:
Outcome: 7 Multiple pregnancy rate
Study or subgroup
MF + clomifene
clomifene
n/N
n/N
1/90
2/90
22.4 %
0.49 [ 0.04, 5.55 ]
Legro 2007
2/209
3/209
33.6 %
0.66 [ 0.11, 4.01 ]
Moll 2006
1/111
3/114
33.2 %
0.34 [ 0.03, 3.28 ]
1/35
1/36
10.8 %
1.03 [ 0.06, 17.13 ]
Vandermolen 2001
0/6
0/1
Not estimable
Zain 2009
0/8
0/7
Not estimable
459
457
Karimzadeh 2010
PCOSMIC 2010
Total (95% CI)
Odds Ratio
Weight
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
100.0 %
0.56 [ 0.18, 1.68 ]

0.001 0.01 0.1

10 100 1000
Favours clomifene
134
Analysis 3.1. Comparison 3 Metformin versus clomiphene citrate, Outcome 1 Live birth: Participants with
BMI < 30kg/m2 or 32kg/m2.
Review:
Comparison: 3 Metformin versus clomiphene citrate

Outcome: 1 Live birth: Participants with BMI < 30kg/m2 or 32kg/m2
Study or subgroup
metformin
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Palomba 2005
26/50
9/50
4.94 [ 1.99, 12.26 ]
PCOSMIC 2010
10/35
19/35
0.34 [ 0.13, 0.91 ]
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 36 (metformin), 28 (clomifene)

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
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:

Outcome: 2 Live birth: Participants with BMI 30kg/m2
Study or subgroup
Legro 2007
Zain 2009
Total (95% CI)
metformin
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
15/208
47/209
87.2 %
0.27 [ 0.14, 0.50 ]
4/42
7/41
12.8 %
0.51 [ 0.14, 1.90 ]
250
250
100.0 %
0.30 [ 0.17, 0.52 ]
M-H,Fixed,95% CI

0.01
0.1
Favours clomiphene
10
100
Favours metformin
135
Analysis 3.3. Comparison 3 Metformin versus clomiphene citrate, Outcome 3 Clinical pregnancy rate.
Review:

Study or subgroup
metformin
clomifene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
M-H,Fixed,95% CI
1 Participants with BMI < 30kg/m2 or 32kg/m2

Karimzadeh 2010
17/88
11/90
37.9 %
1.72 [ 0.75, 3.92 ]
Palomba 2005
31/50
16/50
26.3 %
3.47 [ 1.52, 7.90 ]
PCOSMIC 2010 (1)
14/35
14/36
35.8 %
1.05 [ 0.40, 2.71 ]
Subtotal (95% CI)
173
176
100.0 %
1.94 [ 1.19, 3.16 ]
25/208
62/209
89.5 %
0.32 [ 0.19, 0.54 ]
4/42
7/41
10.5 %
0.51 [ 0.14, 1.90 ]
250
250
100.0 %
0.34 [ 0.21, 0.55 ]

Legro 2007
Zain 2009
Subtotal (95% CI)

0.02
0.1
Favours clomiphene
10
50
Favours metformin
(1) BMI < 33
136
Analysis 3.4. Comparison 3 Metformin versus clomiphene citrate, Outcome 4 Ovulation rate.
Review:

Study or subgroup
Metformin
Clomifene
n/N
n/N
Odds Ratio
Weight
129/205
148/221
87.2 %
0.84 [ 0.56, 1.25 ]
PCOSMIC 2010 (1)
23/35
23/36
12.8 %
1.08 [ 0.41, 2.87 ]
Subtotal (95% CI)
240
257
100.0 %
0.87 [ 0.60, 1.26 ]
296/1019
462/942
98.2 %
0.43 [ 0.35, 0.51 ]
4/42
7/41
1.8 %
0.51 [ 0.14, 1.90 ]
1061
983
100.0 %
0.43 [ 0.36, 0.51 ]
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI

Palomba 2005
Total events: 152 (Metformin), 171 (Clomifene)

Legro 2007
Zain 2009
Subtotal (95% CI)
Total events: 300 (Metformin), 469 (Clomifene)

0.01
0.1
Favours clomiphene
10
100
Favours metformin
(1) BMI < 33
137
Analysis 3.5. Comparison 3 Metformin versus clomiphene citrate, Outcome 5 Miscarriage rate.
Review:

Study or subgroup
Metformin
Clomiphene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
10/25
16/62
42.4 %
1.92 [ 0.72, 5.12 ]
Palomba 2005
3/31
6/16
54.9 %
0.18 [ 0.04, 0.85 ]
PCOSMIC 2010
4/14
0/14
2.7 %
12.43 [ 0.60, 256.66 ]
0/4
0/7
74
99
Legro 2007
Zain 2009
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Not estimable
100.0 %
1.24 [ 0.60, 2.58 ]
Total events: 17 (Metformin), 22 (Clomiphene)

0.01
0.1
Favours metformin
10
100
Favours clomiphene
138
Analysis 3.6. Comparison 3 Metformin versus clomiphene citrate, Outcome 6 Multiple pregnancy.
Review:

Outcome: 6 Multiple pregnancy
Study or subgroup
Metformin
Clomiphene
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Karimzadeh 2010
0/88
2/99
44.1 %
0.22 [ 0.01, 4.65 ]
Legro 2007
0/25
3/62
37.8 %
0.33 [ 0.02, 6.69 ]
Palomba 2005
0/31
0/16
PCOSMIC 2010
1/35
1/36
0/4
0/7
183
220
Zain 2009
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Not estimable
18.1 %
1.03 [ 0.06, 17.13 ]

Not estimable
100.0 %
0.41 [ 0.08, 2.08 ]
Total events: 1 (Metformin), 6 (Clomiphene)

0.01
0.1
Favours metformin
10
100
Favours clomiphene
139
Analysis 4.1. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 1 Ovulation.

Review:
Comparison: 4 D-chiro-inositol versus placebo or no treatment

Outcome: 1 Ovulation
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 %
2.09 [ 0.87, 5.02 ]
Nestler 1999
19/22
6/22
45.2 %
16.89 [ 3.63, 78.56 ]
Total (95% CI)
158
169
100.0 %
5.38 [ 0.70, 41.31 ]
Gerli 2003
Total events: 147 (D-chiro-inositol), 136 (Control)

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:

Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
31.5 (2.4)
22
31 (2.2)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
0.50 [ -0.86, 1.86 ]
100.0 %
0.50 [ -0.86, 1.86 ]

-10
-5
10
Favours control
140
Analysis 4.3. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 3 Waist-hip ratio.
Review:

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)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
-0.01 [ -0.05, 0.03 ]
100.0 %
-0.01 [ -0.05, 0.03 ]

-0.5
-0.25
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:

Outcome: 4 Blood pressure - systolic (mm Hg)
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
126 (7)
22
128 (6)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
-2.00 [ -5.85, 1.85 ]
100.0 %
-2.00 [ -5.85, 1.85 ]

-10
-5
10
Favours control
141
Analysis 4.5. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 5 Blood pressure Diastolic (mm Hg).
Review:

Outcome: 5 Blood pressure - Diastolic (mm Hg)
Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
85 (6)
22
89 (5)
Total (95% CI)
22
Weight
Mean
Difference
100.0 %
-4.00 [ -7.26, -0.74 ]
100.0 %
-4.00 [ -7.26, -0.74 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
22

-10
-5
Favours treatment
10
Favours control
Analysis 4.6. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 6 Serum

testosterone (nmol/L).
Review:

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)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
-0.63 [ -1.37, 0.11 ]
100.0 %
-0.63 [ -1.37, 0.11 ]

-10
-5
10
Favours control
142
Analysis 4.7. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 7 Serum sex
hormone-binding globulin (nmol/L).
Review:

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)
Total (95% CI)
22
Weight
Mean
Difference
100.0 %
69.44 [ 34.97, 103.91 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 % 69.44 [ 34.97, 103.91 ]

-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:

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)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
-0.28 [ -0.99, 0.43 ]
100.0 %
-0.28 [ -0.99, 0.43 ]

-10
-5
10
Favours control
143
Analysis 4.9. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 9 Fasting insulin
(mIU/L).
Review:

Study or subgroup
D-chiro-inositol
Mean
Difference
Control
Mean(SD)
Mean(SD)
Nestler 1999
22
22 (21)
22
42 (52)
Total (95% CI)
22
Weight
Mean
Difference
100.0 %
-20.00 [ -43.43, 3.43 ]
100.0 %
-20.00 [ -43.43, 3.43 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
22

-100
-50
50
100
Favours control
Analysis 4.10. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 10 Cholesterol

(mmol/L).
Review:

Outcome: 10 Cholesterol (mmol/L)
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)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
-0.23 [ -0.99, 0.53 ]
100.0 %
-0.23 [ -0.99, 0.53 ]

-10
-5
10
Favours control
144
Analysis 4.11. Comparison 4 D-chiro-inositol versus placebo or no treatment, Outcome 11 Triglyceride

levels (mmol/L).
Review:

Outcome: 11 Triglyceride levels (mmol/L)
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)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
22
100.0 %
-2.20 [ -6.23, 1.83 ]
100.0 %
-2.20 [ -6.23, 1.83 ]

-10
-5
10
Favours control
Analysis 5.1. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 1 Ovulation rate.
Review:
Comparison: 5 Rosiglitazone versus placebo or no treatment

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 %
1.91 [ 0.70, 5.22 ]
Total (95% CI)
32
32
100.0 %
1.91 [ 0.70, 5.22 ]
M-H,Fixed,95% CI
Total events: 16 (Rosiglitazone), 11 (Control)

0.1 0.2
0.5
Favours control
10
Favours Rosiglitazone
145
Analysis 5.2. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 2 Menstrual frequency.
Review:

Study or subgroup
Rosiglitazone
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Lam 2011
16/35
6/35
83.0 %
4.07 [ 1.35, 12.26 ]
Rautio 2006
10/15
2/15
17.0 %
13.00 [ 2.07, 81.48 ]
50
50
100.0 %
5.59 [ 2.20, 14.19 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 26 (Rosiglitazone), 8 (Control)

0.01
0.1
10
100
Favours control
Analysis 5.3. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 3 Body Mass Index
(kg/m2).
Review:

Mean
Difference
Weight
Mean
Difference
24.3 (0.55)
98.8 %
0.70 [ 0.42, 0.98 ]
30
26 (6.9)
0.7 %
-1.80 [ -5.03, 1.43 ]
14
34 (4.5)
0.4 %
0.10 [ -4.13, 4.33 ]
100.0 %
0.68 [ 0.40, 0.96 ]
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)
Total (95% CI)
Control
58
IV,Fixed,95% CI
IV,Fixed,95% CI
74

-10
-5
10
Favours control
146
Analysis 5.4. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 4 Waist-hip ratio.
Review:

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 %
-0.01 [ -0.02, 0.00 ]
Lam 2011
24
0.8 (0.05)
30
0.81 (0.08)
2.4 %
-0.01 [ -0.04, 0.02 ]
Rautio 2006
12
0.8 (0.2)
14
0.88 (0.07)
0.2 %
-0.08 [ -0.20, 0.04 ]
100.0 %
-0.01 [ -0.02, 0.00 ]
Total (95% CI)
58
IV,Fixed,95% CI
IV,Fixed,95% CI
74

-10
-5
10
Favours control
147
Analysis 5.5. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 5 Blood pressuresystolic (mm Hg).
Review:

Outcome: 5 Blood pressure-systolic (mm Hg)
Study or subgroup
Rosiglitazone
Mean
Difference
Control
Mean(SD)
Mean(SD)
Baillargeon 2004
22
120.7 (3.7)
30
122.7 (3.3)
Total (95% CI)
22
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
30
100.0 %
-2.00 [ -3.95, -0.05 ]
100.0 %
-2.00 [ -3.95, -0.05 ]

-10
-5
10
Favours control
Analysis 5.6. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 6 Blood pressurediastolic (mm Hg).
Review:

Outcome: 6 Blood pressure-diastolic (mm Hg)
Mean
Difference
Study or subgroup
Rosiglitazone
Control
Mean(SD)
Mean(SD)
Baillargeon 2004
22
81.3 (2.8)
30
81.5 (2.7)
Total (95% CI)
22
Weight
Mean
Difference
100.0 %
-0.20 [ -1.72, 1.32 ]
100.0 %
-0.20 [ -1.72, 1.32 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
30

-10
-5
10
Favours control
148
Analysis 5.7. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 7 Testoserone (nmo/l).
Review:

Outcome: 7 Testoserone (nmo/l)
Study or subgroup
Experimental
Lam 2011
Total (95% CI)
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 %
0.20 [ -0.34, 0.74 ]
100.0 %
0.20 [ -0.34, 0.74 ]

-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:

Outcome: 8 serum sex hormone-binding globulin (nmol/L)
Mean
Difference
Weight
Mean
Difference
232 (95)
12.2 %
-69.00 [ -122.09, -15.91 ]
30
38.2 (28.7)
43.5 %
2.70 [ -11.55, 16.95 ]
14
36.2 (17.2)
44.3 %
0.70 [ -12.90, 14.30 ]
100.0 %
-6.92 [ -27.96, 14.12 ]
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)
Total (95% CI)
Control
58
IV,Random,95% CI
IV,Random,95% CI
74

-100
-50
50
100
Favours control
149
Analysis 5.9. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 9 Fasting glucose
(mmol/L).
Review:

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 %
0.0 [ -0.39, 0.39 ]
Lam 2011
24
4.29 (0.37)
30
4.53 (0.67)
38.9 %
-0.24 [ -0.52, 0.04 ]
Rautio 2006
12
5.2 (0.35)
14
5.5 (0.37)
40.2 %
-0.30 [ -0.58, -0.02 ]
100.0 %
-0.21 [ -0.39, -0.04 ]
Total (95% CI)
58
IV,Fixed,95% CI
IV,Fixed,95% CI
74

-4
-2
Favours control
150
Analysis 5.10. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 10 Fasting insulin
(mIU/L).
Review:

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 %
-2.90 [ -9.55, 3.75 ]
Rautio 2006
12
14.56 (11.94)
14
20.62 (12.04)
34.1 %
-6.06 [ -15.30, 3.18 ]
100.0 %
-3.98 [ -9.38, 1.42 ]
Total (95% CI)
36
IV,Fixed,95% CI
IV,Fixed,95% CI
44

-20
-10
10
20
Favours control
Analysis 5.11. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 11 Cholesterol.

Review:

Outcome: 11 Cholesterol
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 %
-0.03 [ -0.51, 0.45 ]
Rautio 2006
12
5.23 (0.016)
14
5.43 (0.02)
99.9 %
-0.20 [ -0.21, -0.19 ]
100.0 %
-0.20 [ -0.21, -0.19 ]
Total (95% CI)
36
IV,Fixed,95% CI
IV,Fixed,95% CI
44

-100
-50
50
100
Favours control
151
Analysis 5.12. Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 12 Triglyceride levels.
Review:

Outcome: 12 Triglyceride levels
Study or subgroup
Rosiglitazone
Rautio 2006
Total (95% CI)
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 %
1.00 [ 0.89, 1.11 ]
100.0 %
1.00 [ 0.89, 1.11 ]

-100
-50
50
100
Favours control
152
Analysis 6.1. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 1 Menstrual frequency.
Review:
Comparison: 6 Pioglitazone versus placebo or no treatment

Study or subgroup
Pioglitazone
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
7/20
1/20
39.4 %
10.23 [ 1.12, 93.34 ]
12/15
5/15
60.6 %
8.00 [ 1.52, 42.04 ]
35
35
100.0 %
8.88 [ 2.35, 33.61 ]
Brettenthaler 2004
Glintborg 2005
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 19 (Pioglitazone), 6 (Control)

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:

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 %
2.40 [ -1.68, 6.48 ]
Glintborg 2005
14
33.8 (4.35)
14
34.2 (5.85)
53.3 %
-0.40 [ -4.22, 3.42 ]
Total (95% CI)
31
100.0 %
0.91 [ -1.88, 3.70 ]
32

-10
-5
10
Favours control
153
Analysis 6.3. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 3 Waist-hip ratio.
Review:

Study or subgroup
Pioglitazone
Mean
Difference
Control
Mean(SD)
Mean(SD)
Glintborg 2005
14
0.88 (0.06)
14
0.86 (0.06)
Total (95% CI)
14
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
14
100.0 %
0.02 [ -0.02, 0.06 ]
100.0 %
0.02 [ -0.02, 0.06 ]

-10
-5
10
Favours control
154
Analysis 6.4. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 4 Serum testosterone
(nmol/L).
Review:

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 %
-0.40 [ -0.93, 0.13 ]
Glintborg 2005
14
2.11 (0.67)
14
1.83 (1.02)
40.8 %
0.28 [ -0.36, 0.92 ]
Total (95% CI)
31
100.0 %
-0.12 [ -0.53, 0.29 ]
32

-10
-5
10
Favours control
Analysis 6.5. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 5 Serum sex hormonebinding globulin (nmol/L).
Review:

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 %
5.00 [ -5.14, 15.14 ]
Glintborg 2005
14
31 (19.2)
14
32 (16)
37.5 %
-1.00 [ -14.09, 12.09 ]
Total (95% CI)
31
100.0 %
2.75 [ -5.26, 10.77 ]
32

-10
-5
10
Favours control
155
Analysis 6.6. Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 6 Fasting insulin
(mIU/L).
Review:

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 %
-1.43 [ -4.65, 1.79 ]
IV,Fixed,95% CI
Glintborg 2005
14
9 (6.25)
14
10.5 (4.46)
39.0 %
-1.50 [ -5.52, 2.52 ]
Total (95% CI)
31
100.0 %
-1.46 [ -3.97, 1.06 ]
32

-10
-5
10
Favours control
ADDITIONAL TABLES
Table 1. Abbreviations used
Abbreviation
Definition
BMI
Body mass index
CI
Confidence interval
CT
Computerised tomography scan
DHEAS
Dehydroepiandrosterone sulphate
FSH
Follicle stimulating hormone
GTT
Glucose tolerance test
156
Table 1. Abbreviations used
(Continued)
HbA1C
Glycosylated haemoglobin
HDL
High density lipoprotein cholesterol
IGFBP-1
Insulin growth factor binding protein 1
LDL
Low density lipoprotein cholesterol
LH
Luteinising hormone
NIDDM
Non insulin dependent diabetes mellitus
PAI-1
Plasminogen activator inhibitor 1
PCOS
Polycystic ovary syndrome
RCT
Randomised controlled trial
rFSH
Recombinant follicle stimulating hormone
SD
Standard deviation
SE
Standard error of the mean
SHBG
Sex hormone binding globulin
VLDL
Very low density lipoprotein cholesterol
vs
Versus
MD
mean difference
Table 2. Conversion factors

Convert from
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
157
Table 2. Conversion factors
(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
Sex hormone binding globulin
microg/dl
nmol/L
34.7
Standard deviation
Standard error
Standard deviation
Sqrt n
Confidence Intervals
Confidence Intervals
Standard error
(upper limit - lower limit) / 3.92
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)
158
26 Hyperandrogenism/dt [Drug Therapy] (42)

27 Hyperinsulinism/dt [Drug Therapy] (45)
28 or/8-27 (11206)
29 7 and 28 (407)
Appendix 2. EMBASE search strategy

1 exp ovary polycystic disease/ (12308)
2 PCOS.tw. (5198)
3 polycystic ovar$.tw. (9461)
4 PCOD.tw. (289)
7 or/1-6 (13817)
8 Metformin/ (20078)
9 metformin.tw. (7634)
11 exp antidiabetic agent/ (245085)
12 exp 2,4 thiazolidinedione derivative/ (7335)
13 Thiazolidinedione$.tw. (4364)
17 exp INOSITOL/ (6997)
24 exp hyperinsulinism/dt [Drug Therapy] (999)
25 or/8-24 (259594)
26 7 and 25 (3784)
27 Clinical Trial/ (817984)
28 Randomized Controlled Trial/ (285130)
29 exp randomization/ (53000)
30 Single Blind Procedure/ (13540)
31 Double Blind Procedure/ (100142)
32 Crossover Procedure/ (29664)
33 Placebo/ (170876)
34 Randomi?ed controlled trial$.tw. (57788)
35 Rct.tw. (6158)
36 random allocation.tw. (1001)
37 randomly allocated.tw. (14902)
38 allocated randomly.tw. (1680)
39 (allocated adj2 random).tw. (679)
40 Single blind$.tw. (10534)
41 Double blind$.tw. (114459)
42 ((treble or triple) adj blind$).tw. (227)
43 placebo$.tw. (152616)
44 prospective study/ (159162)
45 or/27-44 (1101210)
159
46 case study/ (10642)

47 case report.tw. (193591)
48 abstract report/ or letter/ (760819)
49 or/46-48 (961460)
50 45 not 49 (1069247)
51 26 and 50 (1110)
52 2010$.em. (1068697)
53 51 and 52 (155)
Appendix 3. MEDLINE search strategy

1 Polycystic Ovary Syndrome/ (8235)
2 PCOS.ti,ab,sh. (4163)
3 polycystic ovar$.ti,ab,sh. (9950)
4 PCOD.ti,ab,sh. (252)
7 or/1-6 (10268)
8 Metformin/ (4720)
9 metformin.ti,ab,sh. (6627)
11 exp Hypoglycemic Agents/ (168875)
12 Thiazolidinediones/ (7217)
17 exp Inositol/ (20020)
22 exp Biguanides/ (14052)
24 Plasminogen Activator Inhibitor 1/ (6407)
26 Hyperandrogenism/dt [Drug Therapy] (170)
27 Hyperinsulinism/dt [Drug Therapy] (391)
28 or/8-27 (208975)
29 7 and 28 (2024)
30 randomized controlled trial.pt. (306481)
31 controlled clinical trial.pt. (83425)
32 randomized.ab. (219505)
33 placebo.tw. (131900)
34 clinical trials as topic.sh. (153118)
35 randomly.ab. (162298)
36 trial.ti. (94585)
37 (crossover or cross-over or cross over).tw. (50533)
38 or/30-37 (744791)
39 exp animals/ not humans.sh. (3601895)
40 38 not 39 (688742)
41 (200809$ or 200810$ or 200811$ or 200812$).ed. (280178)
160
42 (2009$ or 2010$).ed. (1770865)

43 41 or 42 (2051043)
44 29 and 40 and 43 (111)
Appendix 4. CINAHL search strategy

1 exp Endocrine Sexual Disorders/ (714)
2 PCOS.tw. (89)
3 polycystic ovar$.tw. (170)
4 PCOD.tw. (5)
7 or/1-6 (1047)
8 metformin.tw. (91)
10 Hypoglycemic Agent$.tw. (34)
11 Thiazolidinedione$.tw. (30)
16 Inositol.tw. (696)
22 Plasminogen Activator Inhibitor 1.tw. (42)
23 or/8-22 (1022)
24 7 and 23 (2)
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
New search has been performed
New studies added: Ben Ayed 2009; Boudhraa 2010;

Brettenthaler 2004; Carmina 2004; Karimzadeh 2010;
Khorram 2006; Ladson 2011; Lam 2011; Otta 2010;
Pasquali 2000; Romualdi 2010; Sahin 2004; Siebert
2009; Williams 2009
Re-classified publications Rautio 2006a; Rautio 2006b
into a single study Rautio 2006
Protocol changes: removed secondary outcomes of hirsutism, waist circumference and HDL cholesterol; Removed Kelly 2002,
161
(Continued)
Re-classification of risk of bias in included studies according to the CRG recommendations
HISTORY
Protocol first published: Issue 2, 2001
Review first published: Issue 3, 2003
Date
Event
Description
6 December 2010
New search has been performed
New Studies added: PCOSMIC 2010
1 March 2010
Amended
Error in abstract corrected
12 June 2008
New citation required and conclusions have changed
Converted to new review format. Twenty-one new

RCTs were added to the review: Baillargeon 2004, Chou
2003, Eisenhardt 2006, Gerli 2003, Glintborg 2005,
Hoeger 2004 and b, Karimzadeh 2007, Legro 2007,
Lord 2006, Maciel 2004 and b, Moll 2006 Onalan 2005
and b, Palomba 2005, Rautio 2006, Rautio 2006b, Tang
2006, Trolle 2007 and Zain 2009.
Some changes to the methodology were made in accordance with Revman 5 and one new comparison was
added (Metformin versus Clomifene)
Studies using troglitazone were removed as this drug
has been removed from the market because of safety
concerns
7 December 2006
New citation required and conclusions have changed
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)
162
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
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In the updated review, the title was changed from Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol)
for polycystic ovary syndrome to Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with
polycystic ovary syndrome, oligo amenorrhoea and subfertility.
The outcome measures were restructured. One new comparison was added (metformin versus clomiphene).
Studies using troglitazone were excluded.
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]
MeSH check words

Female; Humans; Pregnancy
163

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Insulin-sensitising drugs (metformin, rosiglitazone,

pioglitazone, D-chiro-inositol) for women with polycystic

Insulin-sensitising drugs (metformin, rosiglitazone,

Editorial group: Cochrane Menstrual Disorders and Subfertility Group.

PLAIN LANGUAGE SUMMARY

Illustrative comparative risks* (95% CI)

Quality of the evidence

Placebo or no treatment Metformin

118 per 1000

Clinical pregnancy rate

109 per 1000

221 per 1000

215 per 1000

332 per 1000

Description of the condition

with normal ovaries (Dunaif 1995; Morles 1996). Obesity, and

ulation (43% versus 24%) (Apridonidze 2005). The prevalence

Description of the intervention

Why it is important to do this review

Criteria for considering studies for this review

How the intervention might work

1) Metformin, rosiglitazone or pioglitazone versus placebo or no

Types of outcome measures

1. Live birth rate

See Appendix 1; Appendix 2; Appendix 3; Appendix 4.

3. Clinical pregnancy rate

Search methods for identification of studies

We also handsearched the reference sections of all trials obtained.

Data collection and analysis

1. Type of insulin-sensitising drug

unclear risk (insufficient information in the study or from

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Sensitivity analysis was performed after excluding studies with

See: Characteristics of included studies; Characteristics of excluded

Figure 3. Study flow diagram

except (Ben Ayed 2009; Boudhraa 2010; Carmina 2004; El-Biely

Specific advice on lifestyle modification was included in the

Primary outcome measures

Risk of bias in included studies

Incomplete outcome data

Other potential sources of bias

syndrome, oligo amenorrhoea and subfertility; Summary of

1. Metformin versus placebo or no treatment

1.1 Live birth rate (Analysis 1.1, Figure 4)

1.2 Adverse events (Analysis 1.2, Figure 5)

Consistent with the previous review, participants in the metformin

Data were not available for this outcome.

2.1 Live birth rate (Analysis 2.1, Figure 6)

There was no evidence that metformin in combination with

Participants in the metformin group experienced a significantly

Four RCTs reported this outcome (Legro 2007; PCOSMIC 2010;

4 D-chiro-inositol versus placebo or no treatment

5 Rosiglitazone versus placebo or no treatment

Three trials were included in the current review. Not surprisingly,

drug used in the trials was either rosiglitazone or pioglitazone.

6 Pioglitazone versus placebo or no treatment

Illustrative comparative risks* (95% CI)

Quality of the evidence

placebo or no treatment D-chiro-inositol

805 per 1000

957 per 1000

Illustrative comparative risks* (95% CI)