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REVIEW
The potential reproductive benets of metformin, a drug endowed with the capacity to ameliorate insulin resistance in
polycystic ovary syndrome (PCOS), has garnered much interest over the past 2 decades. In this review, randomized-controlled trials
(RCT) and meta-analyses of RCT comparing metformin are critically appraised and summarized. PubMed and CENTRAL databases were
consulted. Evidence is insufcient to favour the use of metformin or metformin plus clomiphene citrate instead of clomiphene citrate
for ovulation induction in women with newly diagnosed PCOS. Evidence is also insufcient to recommend metformin as a primary
treatment for non-obese women with PCOS. Metformin plus clomiphene citrate should be considered as an effective option in clomiphene citrate-resistant PCOS. In women with PCOS undergoing gonadotrophin ovulation induction, metformin signicantly increased pregnancy and live birth rates (P < 0.0001 and P = 0.020, respectively) with reduced risk of cancelled cycles. A benecial
effect of metformin co-treatment in increasing clinical pregnancy rates and reducing the risk of OHSS in PCOS patients undergoing
assisted reproduction techniques has been shown. No evidence was found of reduced risk of spontaneous abortion or increased risk
of major anomalies in women with PCOS taking metformin during the rst trimester.
Abstract
2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: clomiphene citrate, infertility, metformin, polycystic ovary disease, polycystic ovary syndrome, pregnancy rate
http://dx.doi.org/10.1016/j.rbmo.2015.09.015
1472-6483/ 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
45
Introduction
Since its discovery 80 years ago (Stein and Leventhal, 1935),
polycystic ovary syndrome (PCOS) remains a challenging
metabolic disorder for gynaecologists and endocrinologists. It is the leading cause of World Health Organization type 2 anovulatory infertility, and is by far the most
common endocrinopathy of women in their reproductive
age (ESE PCOS Special Interest Group, 2014; ESHRE Capri
Workshop Group, 2012). Over the past 12 years, great
efforts have been made by the European Society of
Human Reproduction and Embryology and the American
Society for Reproductive Medicine to resolve three
consensuses to diagnose the syndrome, its infertility management as well as addressing various aspects of womens
health (ESHRE/ASRM, 2004, 2008, 2012). The Rotterdam diagnostic consensus for PCOS requires at least two of the
following three criteria to be met: oligo- or anovulation;
clinical, biochemical signs of hyperandrogenism, or both,
and polycystic ovaries on ultrasound; and absence of other
causes (ESHRE/ASRM, 2004). Recently, a prevalence rate of
around 20% has been reported based on the Rotterdam criteria compared with 610% according to the US National
Institute of Health criteria (March et al., 2010; Yildiz et al.,
2012).
An Australian study found that women with PCOS were
more proactive in seeking out treatment for infertility than
normal women (Herbert et al., 2009). Ovulation induction
remains a milestone in managing anovulatory infertile women
with PCOS, and clomiphene citrate is rst-line pharmacological treatment for ovulation induction in women with PCOS
(Abu Hashim, 2012; Brown et al., 2009; ESHRE/ASRM, 2008).
Resistance to clomiphene citrate has been shown in 1540%
of women with PCOS who did do not ovulate with a daily
treatment dose of 150 mg of clomiphene citrate for 5 days
in three successive cycles (Abu Hashim, 2012; Brown et al.,
2009).
Polycystic ovary syndrome is not merely an ovarian
disease, but rather a disorder of intermediary metabolism
often characterized by insulin resistance and hyperandrogenism. Insulin-sensitizing agents, especially metformin,
have therefore been used as a treatment option in women
with PCOS (Diamanti-Kandarakis and Dunaif, 2012; Fox and
Ryan, 2002). In fact, insulin resistance is a signicant contributor to the widely accepted Rotterdam criteria for
diagnosing PCOS by virtue of its direct and indirect effects
(Figure 1). The use of metformin as a treatment option for
PCOS was rst reported in a pilot study of 26 women with
PCOS by Velazquez et al. (1994). Reduction of insulin resistance and hyperandrogenism resulted in improvements of
hormonal and metabolic patterns, as well as reproductive
function. This appealing aspect of metformin opened up a
window of opportunity for extensive research, spanning 2
decades, on its potential for inducing ovulation in women
with PCOS. Within this context, and given that this is a
clinically important area to address, this review was conducted to critically appraise and summarize current research
on the effect of metformin on reproductive outcomes in
women with PCOS on the basis of the best available evidence from randomized controlled trials (RCT) and metaanalyses of RCT.
H Abu Hashim
Identification
46
Screening
Records screened
(n = 826)
Records excluded
(n =735)
Randomized controlled trials
(RCT) not addressing the
specified outcomes, nonRCT, case series, editorials,
letter to the editors, narrative
reviews, meta-analysis of non
RCT, old versions of
Included
Eligibility
Figure 2
47
Ovulation rate
RCT (n = 343)
A Cochrane
meta-analysis of RCT
OR 1.81;
95% CI 1.13 to 2.93b
OR 2.31;
95% CI 1.52 to 3.51b
OR: 1.80;
95% CI 0.52 to 6.16
Metformin versus
clomiphene citrate
Palomba et al. (2009a)
Meta-analysis of RCT
Meta-analysis of RCT
OR 1.55;
95% CI 0.40 to 5.99
OR 0.48;
95% CI 0.41 to 0.57b
OR 1.22;
95% CI 0.23 to 6.55
OR 0.78;
95% CI 0.59 to 1.0
OR 1.17;
95% CI 0.16 to 8.61
OR 0.48;
95% CI 0.31 to 0.73b
Metformin plus
clomiphene citrate
versus clomiphene
citrate
Palomba et al. (2009a)
Meta-analysis of RCT
Meta-analysis of RCT
OR 0.84;
95% CI 0.60 to 1.18
OR 1.6;
95% CI 1.2 to 2.1b
OR 0.85;
95% CI 0.62 to 1.15
OR 1.3;
95% CI 1.0 to 1.6
OR 0.99;
95% CI 070 to 140
OR 1.1;
95% CI 0.78 to 1.5
Comparison/references
Metformin versus
lifestyle intervention
Karimzadeh and
Javedani (2010)
Metformin versus
placebo/no treatment
Tang et al. (2012)
CI = condence interval; n = number of patients; OR = odds ratio; RCT = randomized controlled trial.
a
Expressed as resumption of regular menstrual cycles.
b
P < 0.05.
48
H Abu Hashim
Comparison/references
Metformin plus
clomiphene citrate
versus clomiphene
citrate with or
without placebo
Siebert et al. (2006)
Creanga et al. (2008)
Metformin plus
clomiphene citrate
versus other secondline treatments
Abu Hashim et al.
(2015)
Study design
Ovulation rate
Meta-analysis
of RCT
Meta-analysis
of RCT
CI = condence interval; LOD = laparoscopic ovarian diathermy; NAC = N-acetyl-cysteine; NNT = number-needed-to-treat; OR = odds ratio;
RCT = randomized controlled trial.
a
P< 0.05.
49
Figure 3 Evidence-based decision making for clomipheneresistant infertile women with polycystic ovary syndrome. LOD,
laparoscopic ovarian diathermy; PCOS, polycystic ovary syndrome.
50
Table 3
H Abu Hashim
Metformin as third-line treatment in women with PCOS undergoing assisted reproduction techniques.
Study design
OHSS rate
Meta-analysis of RCT
A Cochrane
meta-analysis of RCT
OR 1.20;
95% CI 0.90 to 1.61
OR 1.52;
95% CI 1.07 to 2.15a
OR 1.69;
95% CI 0.85 to 3.34
OR 1.39,
95% CI 0.81 to 2.40
OR 0.27;
95% CI 0.16 to 0.46a
OR 0.29;
95% CI 0.18 to 0.49a
References
CI = condence interval; OHSS = ovarian hyperstimulation syndrome; OR = odds ratio; RCT = randomized controlled trial.
a
P < 0.05.
(OHSS) and multiple pregnancy unless low-dose step-up protocol is used (ESHRE/ASRM, 2008). In addition, the presence
of insulin resistance in those patients was found to be associated with increased dosage and duration of gonadotrophin
treatment, increase cancellation rate and a lower conception rate (Dale et al., 1998). The use of metformin in women
with PCOS undergoing gonadotrophin ovulation induction was
therefore examined in RCT to evaluate possible improvement in treatment outcomes as well as reduction of adverse
effects. In a meta-analysis of RCT, Costello et al. (2006) reported no signicant improvement in either ovulation (OR 3.27;
95% CI 0.31 to 34.72; one RCT) or clinical pregnancy (OR 3.46;
95% CI 0.98 to 12.2; three RCT) rates with addition of
metformin in CCR-PCOS women undergoing gonadotrophin ovulation induction. No data on live birth rate were available.
The authors admitted the inability to afrmatively exclude
a benecial clinical treatment effect owing to the limited
power of their meta-analysis attributed to the limited number
of included trials with very few patients in each.
In a recent meta-analysis of seven RCT, Palomba et al. (2014)
demonstrated that adding metformin resulted in signicant
improvement in rates of clinical pregnancy (OR 2.25; 95% CI
1.50 to 3.38; P < 0.0001; seven RCT; n = 942; I2 = 0%; number
needed to treat = 5.7) and live birth (OR 1.94; 95% CI 1.10 to
3.44; P = 0.020; two RCT; n = 661; I2 = 30%; number needed
to treat = 14), in addition to a signicant reduction of the cancellation rate (OR 0.41; 95% CI 0.24 to 0.72; P = 0.002; I2 =
0%; seven RCT; n = 942). No signicant differences were found
in multiple pregnancy, spontaneous abortion and OHSS rates.
Although signicantly lower gonadotrophin doses and duration of stimulation were observed under metformin (MD
306.62 IU; 95% CI 500.02 to 113.22; P = 0.002; and
MD 3.28 days; 95% CI 6.23 to 0.32; P = 0.03, respectively)
as well as a signicant effect on serum oestradiol levels (MD
194.43 pg/ml; 95% CI 313.46 to 75.40; P = 0.001), signicant heterogeneity across the studies were highlighted. In conclusion, the authors attributed the two-fold increase in
pregnancy and live birth rates with metformin administration to the 60% reduction in cancellation rate in CCR-PCOS
patients who had ovulation induction with gonadotrophins.
Importantly, they admitted suboptimal quality of the included studies and highlighted the need for further welldesigned and adequately powered RCT to conrm their ndings.
In a recent RCT, Hosseini et al. (2013) studied the effectiveness of metformin on ovulation and clinical pregnancy rates
51
Metformin side-effects
The most commonly encountered side-effects of metformin
are gastrointestinal symptoms, including nausea, vomiting,
abdominal pain, atulence, diarrhoea, and indigestion. In the
above-mentioned recent Cochrane systematic review and
meta-analysis, patients with PCOS who received metformin
experienced a higher albeit non-signicant incidence of nausea
and vomiting compared with the placebo group (OR 3.91; 95%
CI 0.98 to 15.64; three RCT; n = 73; I2 = 0%). A signicantly
higher incidence of other gastrointestinal side-effects occurred in the metformin group (OR 4.27; 95% CI 2.4 to 7.59;
P < 0.00001; ve RCT; n = 318; I2 = 72%). Additionally, a signicantly higher incidence of gastrointestinal side-effects, including nausea and vomiting, were found when metformin plus
clomiphene citrate were compared with the clomiphene
citrate only group (OR 3.31; 95% CI 2.11 to 5.20; P < 0.00001;
two RCT; n = 489; I2 = 0%) (Tang et al., 2012). Furthermore,
Tso et al. (2014) reported signicantly higher side-effects
(mostly gastrointestinal) with metformin treatment before and
during IVFICSI cycles in women with PCOS compared with
placebo (OR 4.49; 95% CI 1.88 to 10.72; P = 0.00074; four RCT;
n = 431; I2 = 57%).
Metformin safety
In view of the US Food and Drug Administration pregnancy classication, metformin is classied as a category B drug, meaning
that animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and wellcontrolled studies in pregnant women. In view of the current
best clinical evidence, metformin safety during the rst trimester of pregnancy is reassuring. In a recent meta-analysis
of nine controlled studies, Cassina et al. (2014) showed no
evidence of increased risk of major birth defects in women
with PCOS undergoing metformin treatment during the rst
trimester (OR 0.86; 95% CI 0.18 to 4.08; I2 = 0%). Six out of
the nine studies selected for the meta-analysis, however, were
RCT, and no increased risk of congenital malformations in the
exposed group was found compared with the control group
in each of them. The authors admitted that the studies were
designed primarily to evaluate the ovulation, pregnancy and
spontaneous abortion rates; however, the live birth rate was
reported with continuous follow-up until delivery, when information about the presence of birth defects were available.
Conclusion
In conclusion, examining the potential reproductive benets of metformin, a drug endowed with the capacity to ameliorate insulin resistance in women with PCOS, has gained a
great deal of interest from researchers in the past 2 decades.
Importantly, lifestyle modication represents the best rststep treatment for obese anovulatory infertile women with
PCOS before resorting to pharmacological ovulation induction.
The evidence favouring either the use of metformin alone,
or combined with clomiphene citrate instead of clomiphene
citrate for ovulation induction in women with newly diagnosed PCOS, is insufcient. Consequently clomiphene citrate
52
Table 4
H Abu Hashim
Clinical summary and key messages.
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