Human Reproduction Vol.22, No.5 pp. 1200–1209, 2007 doi:10.

1093/humrep/dem005
Advance Access publication January 29, 2007

Metformin versus oral contraceptive pill in polycystic

ovary syndrome: a Cochrane review

Michael F.Costello1,2,3,6, Bhushan Shrestha1, John Eden1, Neil P.Johnson4 and Peter Sjoblom5
1
Division of Obstetrics and Gynaecology, School of Women’s and Children’s Health, University of New South Wales, Royal Hospital for
Women, Sydney, NSW, 2031, Australia, Department of Reproductive Medicine, Royal Hospital for Women, Sydney, NSW, Australia,
IVFAustralia, Sydney, NSW, Australia, 4National Women’s Department of Obstetrics and Gynaecology, University of Auckland,
Auckland, New Zealand and 5Fertility Centre Scandinavia, Stockholm Storangsvagen 10, Stockholm, Sweden

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6
To whom correspondence should be addressed at: Division of Obstetrics and Gynaecology, School of Women’s and Children’s Health,
Level 1 Women’s Health Institute, Royal Hospital for Women, Locked Bag 2000, Randwick, Sydney, NSW 2031, Australia. Fax: 61 2
9382 6444; E-mail: mfcostello@unsw.edu.au

BACKGROUND: The object of this review was to compare metformin versus oral contraceptive pill (OCP) treatment
in polycystic ovary syndrome. METHODS: A systematic review and meta-analysis employing the principles of the
Cochrane Menstrual Disorders and Subfertility Group was undertaken. RESULTS: Four randomized controlled
trials (RCTs) (104 subjects) were included. Limited data demonstrated no evidence of a difference in effect
between metformin and the OCP on hirsutism, acne or development of type 2 diabetes mellitus. There were no
trials assessing diagnosis of cardiovascular disease or endometrial cancer. Metformin, in comparison with the
OCP, was less effective in improving menstrual pattern [Peto odds ratio (OR) 0.08, 95% confidence interval (CI)
0.01–0.45) and in reducing the serum total testosterone level weighted mean difference (WMD) 0.54, 95% CI
0.22–0.86] but more effective in reducing fasting insulin (WMD 23.46, 95% CI25.39 to 21.52) and not increasing
fasting triglyceride (WMD 20.48, 95% CI20.86 to 20.09) levels. Limited data demonstrated no evidence of a differ-
ence in effect between the two therapies on reducing fasting glucose or total cholesterol levels and severe adverse
events. CONCLUSIONS: The limited RCT evidence to date does not show adverse metabolic risk with the use of
the OCP compared with metformin. Further long-term RCTs are required.

Key words: meta-analysis/metformin/oral contraceptive pill/polycystic ovary syndrome

Introduction infertility, hirsutism or acne (Balen and Michelmore, 2002).

Polycystic ovary syndrome (PCOS) is characterized by chronic
anovulation and hyperandrogenism and affects 5 – 10% of
women of reproductive age (Knochenhauer et al., 1998;
Diamanti-Kandarakis et al., 1999). PCOS is probably the
most prevalent endocrinopathy in women (Homburg, 1996).
PCOS is a heterogenous condition (clinically and biochemi-
cally) in affected women presenting in clinical practice
seeking treatment for reproductive disorders such as menstrual
cycle disturbances (oligomenorrhoea, amenorrhoea),
This paper is based on a Cochrane review to be published in The Cochrane
Library, 24 January 2007 (see www.thecochranelibrary.com for information)
with permission from The Cochrane Collaboration and John Wiley & Sons.
Cochrane reviews are regularly updated as new evidence emerges and in
response to feedback, and The Cochrane Library should be consulted for the
most recent version of the review. The results of a Cochrane review can be
interpreted differently, depending on people’s perspectives and circumstances.
Please consider the conclusions presented carefully. They are the opinions of
review authors and are not necessarily shared by The Cochrane Collaboration.
In addition, women with PCOS are thought to be at increased
risk for endometrial cancer through chronic anovulation with
consequent unopposed estrogen exposure (i.e. unopposed by
progesterone) of the endometrium (Hardiman et al., 2003).
However, it has recently become clear that PCOS is also
linked to a number of metabolic disturbances, including type
2 (non-insulin-dependent) diabetes mellitus (T2DM) and poss-
ibly cardiovascular disease (CVD) (Ovalle and Azziz, 2002;
Wild 2002).
The primary aetiology of PCOS is unknown (Balen, 2004).
However, insulin resistance with compensatory hyperinsuli-
naemia is a prominent feature of the syndrome and appears
to have a pathophysiological role in the hyperandrogenism
of the disorder for both lean and obese women with
PCOS (Dunaif et al., 1989). Hyperinsulinaemia stimulates
both ovarian and adrenal androgen secretion directly and
suppresses sex hormone-binding globulin synthesis from the
liver, resulting in an increase in free, biologically active

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androgens. This excess in local ovarian androgen production
augmented by hyperinsulinaemia causes premature follicular
atresia and anovulation along with the other clinical manifes-
tations of hyperandrogenism such as hirsutism and acne
(Utiger, 1996).
Oral contraceptive pills (OCPs) have been the traditional
medical therapy for the long-term treatment of PCOS in
order to provide endometrial protection, regularize menses
and to improve hirsutism and/or acne by reducing ovarian
androgen production. However, recent limited and contradic-
tory observational evidence has raised the concern that OCPs
may reduce insulin sensitivity and glucose tolerance in PCOS
women but there is no evidence that OCPs modify the risk of
T2DM or CVD either negatively or positively (Diamanti-
Kandarakis et al., 2003; Vrbikova and Cibula, 2005).
More recently, insulin-sensitizing drugs have been advo-
cated as another long-term medical treatment option. Given
the importance of hyperinsulinaemia in the development of
hyperandrogenism and anovulation, it seems possible that
insulin-sensitizing drugs may be useful in the restoration of
normal endocrinological and clinical parameters of PCOS by
lowering insulin secretion (Harborne et al., 2003a). Of
the insulin-sensitizing drugs, metformin has been the one
studied most widely and has the most reassuring safety
profile (Nestler et al., 2002), particularly since the withdrawal
of troglitazone from the US markets in 1999 by the Food and
Drug Administration (FDA) of USA owing to numerous
reports of fatal liver toxicity (Baillargeon et al., 2003;
Ehrmann and Rychlik, 2003). Metformin enhances insulin sen-
sitivity in both the liver, where it inhibits hepatic glucose pro-
duction, and the peripheral tissue, where it increases glucose
uptake and utilization into muscle tissue. By increasing
insulin sensitivity, metformin reduces insulin resistance,
insulin secretion and hyperinsulinaemia (Dunn and Peters,
1995).
Two recent systematic reviews have shown metformin to be
superior to placebo in regularizing menstrual cycles (Costello
and Eden, 2003; Kashyap et al., 2004). A third recent systema-
tic review and meta-analysis comparing metformin with either
placebo or no treatment demonstrated that metformin reduced
blood pressure, fasting insulin, fasting glucose and serum
androgens but there was insufficient evidence of an effect on
body weight or hirsutism scores. However, the data for
hirsutism scores were derived from a single small trial. The
effect of metformin on lipids was variable with evidence of
a reduction in serum low density lipoprotein cholesterol level
but no demonstrable effect on the levels of total cholesterol,
high density lipoprotein cholesterol or triglycerides (Lord
et al., 2004). In addition, there is speculation that metformin
may reduce long-term consequences of insulin resistance in
PCOS women, such as T2DM and CVD (Homburg, 2002).
Therefore, it is important to directly compare the use of
OCPs versus metformin in view of the above reservations con-
cerning the appropriateness of OCPs as a therapeutic agent for
PCOS and suggestions that metformin may be safer as well as a
more effective treatment alternative. The aim of this systematic
review is to compare the efficacy and safety of metformin
versus OCP in the treatment of women with PCOS.
Metformin versus OCP in PCOS
Materials and methods
The patient population were women with PCOS based on clinical
(ovulatory dysfunction, hirsutism, acne, androgen-dependent
alopecia), biochemical (hyperandrogenaemia) and/or ultrasound
(polycystic ovaries) evidence. Note was taken of whether any of the
participants had diabetes mellitus or were taking any other medi-
cations which may alter insulin sensitivity. Note was also taken as
to whether the subjects of the included studies met the new proposed
internationally agreed definition of PCOS (Fauser et al., 2004). The
interventions compared were metformin versus OCP in a direct
head-to-head fashion. Primary outcome measures were the clinical
parameters of hirsutism, acne, diagnosis of T2DM, CVD (stroke or
myocardial infarction) event and endometrial cancer event. Secondary
outcome measures were the clinical parameter of menstrual cyclicity
(i.e. an initiation of menses or significant shortening of cycles), hor-
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monal parameter of serum total testosterone, metabolic parameters
of fasting serum levels of insulin, glucose, total cholesterol and trigly-
cerides and severe (requiring stopping of medication) adverse events.
All randomized controlled trials (RCTs) comparing metformin with
the OCP were reviewed. Non-RCTs and quasi-randomized trials, in
which the method of allocation to different forms of treatment is not
truly random, were excluded. Crossover trials were not included
unless phase 1 (i.e. pre-crossover) data were available, in which
case only these data were used for the purpose of the review.
The literature search aimed to locate RCTs in both English and
foreign languages, with no language or other limitations imposed.
We searched the Cochrane Menstrual Disorders and Subfertility
Group’s (MDSG) trials register (September 2005) and the following
electronic databases: Cochrane Central Register of Controlled Trials
[CENTRAL (Ovid), 3rd Quarter 2005], MEDLINE (1966 to
September 2005), CINAHL (1982 to September 2005) and
EMBASE (1988 to September 2005). Reference lists of included
studies, other relevant review articles and textbooks were checked
for additional relevant citations. Pharmaceutical companies were con-
tacted to locate any prospective registered clinical trials. Experts and
specialists in the field were also contacted to identify further reported
trials.
Study selection
All eligible studies were assessed for relevance to the review objec-
tives and their methodological quality. Study selection was undertaken
by two reviewers (M.F.C. and B.S.). Reviewers extracted data
independently and assessed whether the studies met the inclusion
criteria. Any disagreements were resolved in consensus with J.E. If
papers contained insufficient information to make a decision about
eligibility, the authors of those papers were contacted in order to
seek further information.
The quality of allocation concealment was graded as adequate (A),
unclear (B) or inadequate (C), following the detailed descriptions of
these categories provided by the MDSG.
Four RCTs comparing metformin with the OCP were identified.
(Morin-Papunen et al., 2000, 2003; Harborne et al., 2003b; Rautio
et al., 2005) (Figure 1). Three of the four trials comparing metformin
with the OCP were conducted by the same investigator centre (Morin-
Papunen et al., 2000, 2003; Rautio et al., 2005). The patients in one of
these studies (Rautio et al., 2005) included the combined patients of
two of the other studies (Morin-Papunen et al., 2000, 2003). The
study by Rautio et al. (2005) examined only the metabolic parameters
of lipid levels as outcomes, whereas the two studies by Morin-Papunen
et al. (2000) (recruited obese women with PCOS) and Morin-Papunen
et al. (2003) (recruited non-obese women with PCOS) assessed
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M.F.Costello et al.
Figure 1. Flow diagram showing the number of publications identified in the literature search. RCTs, randomized controlled trials; OCP, oral
contraceptive pill.
clinical, hormonal and metabolic (insulin sensitivity and glucose tol-
erance) parameters.
Description and quality assessment of included studies
Table I summarizes the characteristics of the four included RCTs.
The diagnosis of PCOS in all four trials required at least two of the
following three features: (i) oligomenorrhoea or amenorrhoea, (ii)
clinical or biochemical hyperandrogenism and (iii) polycystic
ovaries on ultrasound (Morin-Papunen et al., 2000, 2003; Harborne
et al., 2003b; Rautio et al., 2005). Subjects in three (Morin-Papunen
et al., 2000, 2003; Rautio et al., 2005) of the four included studies
did not meet the new proposed internationally agreed definition of
PCOS (Fauser et al., 2004) due to failure to exclude other causes of
hyperandrogenism such as hyperprolactinaemia and congenital
adrenal hyperplasia.
The main inclusion criteria were: PCOS in one of the trials (Rautio
et al., 2005); PCOS whose primary complaint was hirsutism in one of
the trials (Harborne et al., 2003b); obese PCOS in one of the trials
(Morin-Papunen et al., 2000) and non-obese PCOS in one of the
trials (Morin-Papunen et al., 2003). Exclusion criteria included
T2DM for all four trials (Morin-Papunen et al., 2000, 2003; Harborne
et al., 2003b; Rautio et al., 2005), sex hormones or drugs known to
affect carbohydrate metabolism for one of the trials (Harborne
et al., 2003b) and sex hormones or drugs known to affect lipid metab-
olism for all four trials (Morin-Papunen et al., 2000, 2003; Harborne
et al., 2003b; Rautio et al., 2005).
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The duration of the trials ranged from 4 to 12 months. The dropout
rate for the studies ranged from 15% to 44%. The number of with-
drawals was similar for both the treatment and control arms in all
of the studies. The dose of metformin was 500 mg three times
daily for one of the trials (Harborne et al., 2003b) and 500 mg
twice daily for the first 3 months increasing to 1000 mg twice
daily for the next 3 months for three of the trials (Morin-Papunen
et al., 2000, 2003; Rautio et al., 2005). The OCP type was ethinyl
estradiol (EE) 35 mg combined with cyproterone acetate (CPA)
2 mg (EE35/CPA2) in all four trials (Morin-Papunen et al., 2000,
2003; Harborne et al., 2003b; Rautio et al., 2005). None of the
trials actively changed the subject’s lifestyle in terms of diet and
exercise.
The included studies randomized a total of 156 (104 excluding
duplication of participants as discussed in ‘study selection’ above)
women (range for individual trials 20 –52). Two (50%) of the four
studies randomized fewer than 50 participants. All four trials were
graded ‘A—clear’ for allocation concealment performed by on-site
computer system utilizing locked files or third party with the
random allocation sequence generated by computer generation or
random numbers table. All four studies were unblinded and data
analysed by available case analyses (trial participants analysed in
the groups to which they were randomized and only participants
who completed the trial were included) rather than on the preferred
intention-to-treat basis (trial participants analysed in the groups to
which they were randomized and all participants included). One
trial (Rautio et al., 2005) had sample size justification.
 Metformin versus OCP in PCOS

Additional information was sought and supplied from all four trials

Recruited non-obese women with

syndrome (PCOS) women whose
primary complaint was hirsutism

patients of Morin-Papunen et al.

with the lead author responding for two trials (Morin-Papunen et al.,

patients included the combined

Assessed lipid levels only. The
Recruited obese women with
2000, 2003) and the second (Harborne et al., 2003b) and fourth

Recruited polycystic ovary

(Rautio et al., 2005) authors for the remaining trials.

Statistical analysis

(2000; 2003)
Statistical analyses were performed in accordance with the guidelines
for statistical analysis developed by the Cochrane Collaboration. For

PCOS

PCOS
dichotomous data, results for each study were expressed as an odds
Notes

ratio (OR) with 95% confidence intervals (CIs) and combined for
meta-analysis with Review Manager (RevMan) software using the
fixed-effect model (Peto method). For continuous data, the mean post-
contraceptive
Total daily metformin Type of oral

treatment/intervention values and standard deviation for each

Diane 35

Diane 35

Diane 35

Diane 35
group were measured and the weighted mean differences (WMDs)
with 95% CI were calculated. Where different scales measured the

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pill

same continuous data outcome, the mean post-treatment/intervention

values and standard deviation for each group were measured and the
2000 after 3 months

2000 after 3 months

2000 after 3 months

standardized mean difference (SMD) with 95% CI was calculated.
1000 increasing to

1000 increasing to

1000 increasing to

ACA, available case analysis; Allocation concealment: A, clear; BMI, body mass index; Diane 35, 35 mg ethinyl estradiol plus 2 mg cyproterone acetate.
Heterogeneity (variations) between the results of different studies
was examined by inspecting the scatter in the data points on the
treatment (months) dose (mg)

graph and the overlap in their CIs and, more formally, by checking
the results of the chi-squared tests where P  0.05 represents statisti-
1500

cal homogeneity. P ,0.05 or 95% CIs not containing 1.00 (OR) or 0

(WMD) were considered statistically significant.
Duration of

Results
12

Primary outcome measures

Hirsutism
Mean age Mean BMI
(kg m22)

Three trials comparing metformin versus OCP with a combined

total of 69 participants analysed (104 particpants randomized)
32

35

22

29

reported on hirsutism using either Ferriman – Gallway (FG)

scoring system (Morin-Papunen et al., 2000, 2003) or a
(years)

subjective (patient self-assessed) visual analogue scale from

31

30

28

29

0 to 10 (Harborne et al., 2003b). Meta-analysis demonstrated

no difference in effect on hirsutism between metformin and
Number analysed
(type of analysis)

OCP (SMD 20.18, P ¼ 0.48, 95% CI -0.67 to 0.32)

(Figure 2). The SMD statistic is used when pooling continuous
34 (ACA)

18 (ACA)

17 (ACA)

35 (ACA)

data on outcomes measured by different scales (Statistical

Analysis). Statistical heterogeneity (variability in the treatment
effects being evaluated in the different trials) was present.
randomized
Blinding Number

Acne
There was a single trial comparing metformin versus OCP with
52

32

20

52

34 participants analysed (52 participants randomized) reporting

acne subjectively (patient self-assessed) using a visual ana-
No

No

No

No

logue scale ranging from 0 to 10 (Harborne et al., 2003b).

Table I. Characteristics of included studies

This trial demonstrated no significant difference in acne

concealment

scores between metformin and the OCP (WMD 0.90,

Allocation

P ¼ 0.18, 95% CI -0.40 to 2.20 (Figure 3).

A

Type 2 diabetes mellitus

One trial comparing metformin versus OCP with 18 partici-
Morin-Papunen et al.

Morin-Papunen et al.

Rautio et al. (2005),

(2003b), Scotland

pants analysed (32 participants randomized) reported diagnosis

(2000), Finland

(2003), Finland
Harborne et al.

of T2DM (Morin-Papunen et al., 2000). No significant

difference was seen in the development of T2DM between
Finland

the metformin and OCP groups (Peto OR 0.17, P ¼ 0.37,

Study

95% CI 0.00 to 8.54) (Figure 4).

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M.F.Costello et al.

Figure 2. Comparison of metformin versus oral contraceptive pill with outcome of hirsutism.

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Figure 3. Comparison of metformin versus oral contraceptive pill with outcome of acne.

Figure 4. Comparison of metformin versus oral contraceptive pill with outcome of type 2 diabetes mellitus.

Cardiovascular disease reported menstrual pattern in terms of days between menses

There were no trials comparing metformin versus OCP report- and metformin was significantly less effective in improving
ing the outcome measure of CVD (stroke or myocardial menstrual pattern (Peto OR 0.08, P ¼ 0.004, 95% CI 0.01–
infarction). 0.45) (Figure 5).

Endometrial cancer Hormonal: serum total testosterone (nmol l21)

There were no trials comparing metformin versus OCP report-
ing endometrial cancer as an outcome.
Secondary outcomes measures
Improved menstrual pattern
There were two trials comparing metformin versus OCP with a
total of 35 participants analysed (52 participants randomized)
reporting on improvement in menstrual cyclicity (Morin-
Papunen et al., 2000, 2003). Eighteen of 21 participants on
metformin and 20 of 24 participants on the OCP had either
oligomenorrhoea or amenorrhoea at baseline. Both trials
1204
There were three trials comparing metformin versus OCP with
a total of 69 participants analysed (104 participants random-
ized) reporting on total serum testosterone (Morin-Papunen
et al., 2000, 2003; Harborne et al., 2003b). Meta-analysis
demonstrated a significantly higher serum total testosterone
with metformin compared with the OCP (WMD 0.54,
P ¼ 0.001, 95% CI 0.22– 0.86) (Figure 6).
Metabolic: fasting insulin (mIU l21)
There were three trials comparing metformin versus OCP
with a total of 69 participants analysed (104 participants

Figure 5. Comparison of metformin versus oral contraceptive pill with outcome of improved menstrual pattern.
Figure 6. Comparison of metformin versus oral contraceptive pill with outcome of serum total testosterone.
randomized) reporting on fasting insulin levels (Morin-
Papunen et al., 2000, 2003; Harborne et al., 2003b).
Meta-analysis showed significantly lower fasting insulin
levels in favour of metformin (WMD 23.46, P ¼ 0.0005,
95% CI 25.39 to 21.52) (Figure 7). The fasting insulin
levels did not change with OCP treatment in any of the three
individual trials.
Metabolic: fasting glucose (mmol l21)
Three trials comparing metformin versus OCP with a total of
69 participants analysed (104 participants randomized)
reported on fasting glucose levels (Morin-Papunen et al.,
2000, 2003; Harborne et al., 2003b). There was no significant
difference in fasting glucose levels between the two
interventions (WMD 0.13, P ¼ 0.25, 95% CI -0.09 to 0.35)
(Figure 8). The fasting glucose levels did not change with
OCP treatment in any of the three individual trials.
Metabolic: fasting total cholesterol (mmol l21)
There were two trials comparing metformin versus OCP with a
total of 69 participants analysed (104 participants randomized)
reporting on total cholesterol levels (Harborne et al., 2003b;
Rautio et al., 2005). Meta-analysis demonstrated no significant
difference in total cholesterol levels between metformin and
the OCP (WMD 20.11, P ¼ 0.60, 95% CI 20.53 to 0.30)
(Figure 9).
Metabolic: fasting triglycerides (mmol l21)
Two trials comparing metformin versus OCP with a total of 69
participants analysed (104 participants randomized) reported
Metformin versus OCP in PCOS
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on triglyceride levels (Harborne et al., 2003b; Rautio et al.,
2005). Metformin resulted in a significantly lower triglyceride
level than the OCP (WMD 20.48, P ¼ 0.01, 95% CI 20.86 to
20.09) (Figure 10).
Severe adverse events (requiring stopping of medication)
(gastrointestinal and others)
There were three trials comparing metformin versus OCP with
a total of 104 participants randomized and analysed reporting
on severe (requiring stopping of medication) adverse
events (Morin-Papunen et al., 2000, 2003; Harborne et al.,
2003b). Metformin caused a significantly higher incidence of
severe gastrointestinal side effects (i.e. nausea, diarrhoea)
(Peto OR 7.75, P ¼ 0.02, 95% CI 1.32 – 45.71) and a
significantly lower incidence of other severe adverse events
(i.e. weight gain, high blood pressure, depression, chest pain,
headache) (Peto OR 0.11, P ¼ 0.0008, 95% CI 0.03 – 0.39)
compared with the OCP. However, overall, there was no sig-
nificant difference between metformin and the OCP when
taking into account all severe adverse events (Peto OR 0.48,
P ¼ 0.18, 95% CI 0.17– 1.39) (Figure 11). Not surprisingly,
there was significant heterogeneity in the overall severe
adverse events meta-analysis due to the different side-effect
profiles of metformin and the OCP.
Discussion
The OCP is the traditional therapy for the chronic treatment
of PCOS, exerting a number of beneficial effects including
regularization of menses, amelioration of hirsutism and acne
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M.F.Costello et al.

Figure 7. Comparison of metformin versus oral contraceptive pill with outcome of fasting insulin.

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Figure 8. Comparison of metformin versus oral contraceptive pill with outcome of fasting glucose.

Figure 9. Comparison of metformin versus oral contraceptive pill with outcome of fasting total cholesterol.

Figure 10. Comparison of metformin versus oral contraceptive pill with outcome of fasting triglycerides.

and protection from the development of endometrial cancer
(Diamanti-Kandarakis et al., 2003). However, limited but con-
tradictory observational evidence based on non-randomized
studies raises the issue that OCPs may worsen insulin resist-
ance, glucose tolerance and lipid levels in PCOS women and
consequently possibly enhance the long-term risk for T2DM
1206
and CVD leading to speculation that the insulin-sensitizing
agent metformin may be a safer treatment alternative
(Diamanti-Kandarakis et al., 2003, Vrbikova and Cibula,
2005).
This is the first systematic review and meta-analysis of RCTs
comparing metformin versus OCP treatment in women with

Figure 11. Comparison of metformin versus oral contraceptive pill with outcome of severe adverse events (requiring stopping of medication).
PCOS. This review has found that up to 12 months treatment
with the OCP compared with metformin in PCOS is associated
with an improvement in menstrual pattern and serum testoster-
one levels with the OCP and a reduction in fasting insulin
and lower fasting triglyceride levels with metformin. Severe
side-effect profiles differ between the two therapies. There
were either extremely limited or no data on important clinical
outcomes such as the development of T2DM, CVD or endo-
metrial cancer. There was no evidence of a difference in
effect between metformin and the OCP on hirsutism, acne
and fasting glucose or total cholesterol levels.
The OCP was superior to metformin in improving menstrual
pattern with all OCP subjects and 10/16 (62.5%) of metformin
subjects reporting such an outcome (Figure 5). This finding
was not surprising and consistent with that of a recent systematic
review which showed that metformin results in the restoration of
regular menses in only 60% of PCOS women with
oligomenorrhea or amenorrhea (Costello and Eden, 2003).
Unfortunately, there were no trials assessing whether this more
favourable OCP effect leads to a reduction in the long-term
risk of endometrial cancer compared with metformin.
The hirsutism score data from the three trials were con-
flicting, thus there is insufficient evidence of relative benefit
of either metformin or OCP. Statistical heterogeneity was
present with the results for the trial by Harborne et al.
(2003b) differing from the trials by Morin-Papunen et al.
(2000, 2003) with the former trial demonstrating a significant
reduction in hirsutism with metformin, whereas the other
two trials showing a trend in the opposite direction (conflicting
evidence) (Figure 2). The reasons for this are unclear but may
be due to differences in the selection criteria for the PCOS par-
ticipants, assessment method for hirsutism (described in
Results) and the duration of treatment as outlined below.
All 52 participants in the trial by Harborne et al. (2003b) and
18 of 52 participants in the trials by Morin-Papunen et al.
Metformin versus OCP in PCOS
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(2000, 2003) were clinically hirsute. Hirsutism was assessed
by a patient self-assessed visual analogue scale in the Harborne
et al. (2003b) trial and by the FG scoring system for the trials
by Morin-Papunen et al. (2000, 2003). The duration of treat-
ment was 12 months for Harborne et al. (2003b) and
6 months for Morin-Papunen et al. (2000, 2003) (Table I).
There was no evidence of benefit with either metformin or
OCP for acne based on 34 women in a single trial (Harborne
et al., 2003b) (Figure 3). The OCP was superior to metformin
in reducing serum total testosterone levels by 0.5 nmol l21
(Figure 6). Therefore, the OCP results in a greater reduction
in total testosterone levels when compared with metformin,
but there are insufficient studies to date assessing whether
this more favourable biochemical androgen profile with the
OCP leads to a more favourable clinical androgen effect in
terms of hirsutism or acne.
The meta-analysis demonstrated significantly lower fasting
insulin levels by 3.5 mIU l21 with metformin treatment
when compared with the OCP (Figure 7). All three individual
RCTs demonstrated a reduction in fasting insulin levels with
metformin and no change in fasting insulin levels with OCP
treatment (Morin-Papunen et al., 2000, 2003; Harborne et al.,
2003b). There was no evidence of a difference in effect
between metformin and the OCP on fasting glucose levels
(Figure 8). When one examines the data on fasting glucose
levels from the individual three trials, there was no change
seen with OCP treatment in all three trials comparing with
no change in two (Harborne et al., 2003b; Morin-Papunen
et al., 2003) of the three trials and a significant decrease by
0.2 mmol l21 in the third RCT (Morin-Papunen et al., 2000)
with metformin treatment.
The meta-analysis showed no evidence of a difference in
effect between metformin and the OCP on fasting total choles-
terol levels (Figure 9). Fasting total cholesterol levels did not
change with either metformin or OCP therapy in each of the
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M.F.Costello et al.
two trials (Harborne et al., 2003b; Rautio et al., 2005).
However, a significantly lower fasting triglyceride level by
0.5 mmol l21 was seen with metformin treatment when com-
pared with the OCP (Figure 10). The fasting triglyceride level
did not change in both individual RCTs with metformin treat-
ment. However, OCP treatment resulted in either no change
(Harborne et al., 2003b) or an increase (Rautio et al., 2005)
in fasting triglyceride levels. In the trial by Rautio et al.
(2005), the mean fasting triglyceride levels increased from
1.3 to 1.9 mmol l21 with OCP treatment. The current
recommended upper limit for fasting triglyceride levels in
the authors’ countries of Australia and New Zealand is
2.0 mmol l21 (Anonymous, 2001), although other international
cut-off levels of 1.7 mmol l21 do exist (Bloomgarden, 2004).
Overall, the meta-analysis showed no evidence of a differ-
ence in severe adverse events requiring stopping of medication
between the two treatments (Figure 11). However, metformin
caused a significantly higher incidence of severe gastrointesti-
nal side effects (i.e. nausea, diarrhoea), whereas those treated
with the OCP experienced a significantly higher incidence
of severe other (other than gastrointestinal) adverse events
(i.e. weight gain, high blood pressure, depression, chest pain,
headache).
Limitations
There are a number of limitations to this review. The value of
any meta-analysis is totally dependent on the quality and lack
of bias in its component primary studies. The careful assess-
ment of study validity and heterogeneity of the individual
studies is essential in minimizing the risk of inappropriately
combining biased and disparate studies leading to misleading
systematic reviews (Hughes, 1996). Although, all the included
studies were randomized with adequate allocation concealment
to reduce selection bias, none were blinded to outcome assess-
ment or analysed by intention-to-treat analysis, placing these
trials at risk of ascertainment and attrition biases, respectively
(Guyatt et al., 1993).
Although the inclusion of unpublished studies is controver-
sial (Cook, et al., 1993), reliance upon published studies
alone may distort the results of a meta-analysis because
positive studies (statistically significant) are more likely to be
published than negative ones (non-significant) with the attend-
ant risk for the review to overestimate treatment efficacy
(Dickersin et al., 1987). Funnel plot analysis for the identifi-
cation of publication bias in this review was not performed
due to the limited number of studies.
There were a limited number of RCTs (n ¼ 4) comparing
metformin versus OCP. A number of results are constrained
by small numbers and wide CIs that limit the precision and con-
fidence of conclusions. In addition, the ‘lack of evidence of
difference’ for a number of outcomes is not synonymous
with ‘evidence of a lack of difference’. Meta-analysis was
not possible for a number of important clinical primary out-
comes due to either an absence of trials (CVD, endometrial
cancer) or the presence of a single trial only (acne, T2DM).
All of the data in this review are from women with PCOS
recruited from European centres and three of the four trials
1208
were conducted by the same investigator group. This may
limit the potential applicability of the results of this review if
ethnic variation in baseline risk of adverse outcomes (clinical
or metabolic) or response to metformin or the OCP exists.
Differences between trial populations, assessment methods,
study duration and drug side-effect profiles have resulted in
heterogeneity within some of the analyses as discussed
above. The mean age of the subjects in the trials ranged from
28 to 31 years, limiting the applicability of the results of this
review to not include adolescent women with PCOS. All the
trials were of short duration, and therefore, long-term data on
the comparison effects between metformin and OCPs are
lacking in terms of important clinical outcomes such as
hirsutism, acne and development of T2DM, CVD or endo-
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metrial cancer.
Conclusions
From the studies included in this review, there is limited evi-
dence to support that the OCP is more effective than metformin
in improving menstrual pattern and reducing serum total testos-
terone levels. There is also limited evidence to show that met-
formin is more effective than the OCP in reducing fasting
insulin and not increasing triglyceride levels and that metfor-
min causes a higher incidence of severe gastrointestinal
adverse effects, whereas the OCP results in a higher incidence
of severe non-gastrointestinal adverse effects. However, there
is insufficient evidence to show that either metformin or the
OCP is more effective in terms of treating hirsutism and
acne, preventing the development of T2DM and reducing
fasting glucose or total cholesterol levels. There are no data
(or evidence) on which to make clinical decisions in terms of
development of CVD or endometrial cancer when comparing
metformin with the OCP.
The limited RCT evidence to date does not show adverse
metabolic risk with the use of the OCP compared with metfor-
min in terms of both clinical (T2DM, CVD) and surrogate
(fasting glucose, insulin and total cholesterol levels) metabolic
outcomes. However, it should be re-emphasized that all
available trials are limited in the duration of metformin or
OCP treatment and therefore long-term effects are not known.
The limited number of RCTs comparing metformin versus
OCP treatment highlights the need for more long-term, well-
designed and executed RCTs directly comparing the efficacy
(in terms of both clinical and surrogate hormonal and metabolic
outcomes) and safety of these therapies in order to help clarify
the preferred long-term medical treatment option for women
with PCOS, including adolescents. There is a striking lack
of data concerning long-term outcomes, including T2DM,
CVD and endometrial cancer, and this should be addressed in
longer-term trials.
Acknowledgement
The authors wish to thank the Cochrane Menstrual Disorders and
Subfertility Review Group in Auckland, New Zealand, for their help
and support in the conduct and preparation of this review.

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Submitted on November 29, 2006; accepted on January 3, 2007
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