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Reproductive BioMedicine Online (2016) 32, 4453

w w w. s c i e n c e d i r e c t . c o m
w w w. r b m o n l i n e . c o m

REVIEW

Twenty years of ovulation induction with


metformin for PCOS; what is the best available
evidence?
Hatem Abu Hashim *
Department of Obstetrics and Gynaecology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
* E-mail address: hatem_ah@hotmail.com.
Dr Hatem Abu Hashim is a Professor of Obstetrics and Gynaecology at Mansoura University, Egypt. He obtained
his MD at Mansoura University in 2001, and subsequently obtained his MRCOG in the UK in 2006. His major areas
of interest are reproductive endocrinology and infertility, especially polycystic ovary syndrome, the subject of
his PhD, which he obtained from the Free University of Brussels (the Vrije Universiteit Brussel, Belgium) in 2013.
Professor Abu Hashim is a member of several scientic societies, and peer-reviews for several international scientic journals. He has published several papers in reputed journals.

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.

Metformin in anovualtory infertile women with PCOS

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.

Figure 1 Insulin resistance as a signicant contributor to


polycystic ovary syndrome Rotterdam diagnostic criteria. IGF-1
= Insulin growth factor-1; PCO = polycystic ovary; SHBG = sex
hormone-binding-globulin. = Increase; = Decrease.

Materials and methods


A litereature search of English-language studies was conducted on PubMed (from January 1994 to January 2015) and
CENTRAL (Cochrane Central Register of Controlled Trials, Issue
1, 2015) using the terms metformin, PCOS, polycystic ovary
syndrome, and polycystic ovary disease. The search was
limited to high-quality evidence from randomized trials, systematic reviews and meta-analyses of RCT in which reproductive outcomes were reported, including ovulation, clinical
pregnancy, live birth and spontaneous abortion rates. A population, intervention, comparison, outcome (PICO) framework was established a priori to select the articles for the
question posed for each section in the review. RCT not addressing the specied outcomes to this evidence review, nonrandomized studies, editorials, letters to the editor, narrative
reviews, case series, reports as well as old versions of Cochrane systematic reviews, were excluded. For each comparison, individual RCT were excluded if their results were
previously included in a subsequent meta-analysis of RCT.
Those RCT published after the most recent meta-analysis addressing a specic comparison were included. Pertinent full
texts were selected and reviewed, and its reference lists were
manually searched to identify other important articles. A
search update to 20 May 2015 was carried out to identify newly
relevant citations. Overall, this search produced 947 articles, 18 of which met the selection criteria (four RCT and
14 meta-analyses of RCT) (Abu Hashim et al., 2015; Cassina
et al., 2014; Costello et al., 2006; Creanga et al., 2008; Hamed
et al., 2010; Hosseini et al., 2013; Johnson, 2011; Karimzadeh
and Javedani, 2010; Misso et al., 2013; Palomba et al., 2004,
2009a, 2009b, 2013, 2014; Siebert et al., 2006, 2012; Tang
et al., 2012; Tso et al., 2014). A ow diagram of the study is
presented in Figure 2. Examples of excluded studies and

H Abu Hashim

Identification

46

Records identified through


database searching
(n = 942)

Additional records identified


through other sources
(n = 5)

Screening

Records after duplicates removed


(n = 826)

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

Cochrane systematic reviews

Full-text articles assessed


for eligibility
(n = 91)

73 full-text articles of RCT


excluded because their
results were included in
subsequent meta-analyses
of RCT.

Studies included in the


evidence review
(n = 18)
Four RCT and 14 metaanalyses of RCT

Figure 2

The study ow diagram.

reasons for their exclusion are presented in Supplementary


Table S1.

Metformin versus lifestyle intervention as rst-line


treatment in women with anovulatory PCOS
Optimization of body weight should be the rst line of treatment in all obese infertile women with PCOS (body mass
index [BMI] 30 kg/m2) before considering any further treatment. Weight loss alone through lifestyle management improves hyperandrogenism and insulin resistance. It may,
therefore, restore ovulation, improve response to ovulatory
drugs, in addition to successful pregnancy outcomes (Moran
et al., 2011; NCC-WCH/NICE, 2013). In a large randomized
double-blind study including 343 overweight infertile women
with PCOS, Karimzadeh and Javedani (2010) compared lifestyle modication (diet plus exercise) with three ovulationinduction protocols, including clomiphene citrate, metformin
and clomiphene citrate plus metformin. They reported a
higher, albeit non-signicant clinical pregnancy rate in the
lifestyle modication group (20%) compared with metformin
(14.4%), clomiphene citrate (12.2%) or combined treatment
(14.4%). No data were available on live birth rate. Consequently, the authors highlighted the importance of lifestyle
modication as rst-line treatment of infertile women with
PCOS before resorting to pharmacological ovulation induction (Table 1).

Metformin or clomiphene citrate as the rst-line


pharmacological therapy in women with
anovulatory PCOS
The use of metformin as rst-line pharmacological treatment option for ovulation induction in PCOS has sparked a
heated discussion. A recent Cochrane review reported that
metformin was better than placebo or no treatment for ovulation (odds ratio [OR] 1.81; 95% condence interval [CI] 1.13
to 2.93; 16 RCT; n = 1208) and clinical pregnancy (OR 2.31;
95% CI 1.52 to 3.51; eight RCT; n = 707) rates per patient but
not for live birth rate (OR 1.80; 95% CI 0.52 to 6.16; three RCT;
n = 115) (Tang et al., 2012) (Table 1). Compared with the gold
standard clomiphene citrate, potential advantages of
metformin include absence of anti-oestrogenic adverse effects,
reduced multiple pregnancies as well as the need for less intensive monitoring (Nestler, 2008). On the basis of these considerations, two systematic review and meta-analyses of RCTs
were conducted to evaluate the reproductive efcacy of
metformin compared with clomiphene citrate as rst-line pharmacological treatment in women with anovulatory PCOS
(Palomba et al., 2009a; Siebert et al., 2012) (Table 1).
In a meta-analysis, Palomba et al. (2009a) examined three
RCT, and found that metformin was no more effective than
clomiphene citrate in stimulating ovulation (OR 1.55; 95% CI
0.40 to 5.99), clinical pregnancy (OR 1.22; 95% CI 0.23 to 6.55),
or live birth (OR 1.17; 95% CI 0.16 to 8.61) rates; however,
signicant heterogeneity (P < 00001) was detected for all
three end-points. Subsequently, in a recent meta-analysis of

Metformin in anovualtory infertile women with PCOS


Table 1

47

Metformin as rst-line treatment in anovulatory women with PCOS.


Study design

Ovulation rate

Clinical pregnancy rate

RCT (n = 343)

62.5% versus 66.6%a

14.1% versus 20%

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

Siebert et al. (2012)

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

Siebert et al. (2012)

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)

Live birth rate

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.

14 RCT, Siebert et al. (2012) addressed the same question.


Clomiphene citrate alone performed signicantly better
than metformin alone in ovulation per cycle (OR 0.48;
95% CI 0.41 to 0.57; P < 0.00001; two RCT; number of cycles
= 2387) and live birth (OR 0.48; 95% CI 0.31 to 0.73; P = 0.0006;
four RCT; n = 612 women) rates but not for clinical pregnancy rate (OR 0.78; 95% CI 0.59 to 1.0; six RCT; n = 1396).
Heterogeneity was detected for all three outcomes.
On the basis of these two meta-analyses, evidence favouring the use of metformin instead of clomiphene citrate is insufcient, and clomiphene citrate still represents the gold
standard rst-line pharmacological treamtnet for ovulation
induction in anovulatory infertile women with PCOS (Abu
Hashim, 2012).

Metformin plus clomiphene citrate versus


clomiphene citrate as rst-line treatment in
women with anovulatory PCOS
In the above mentioned meta-analysis, Palomba et al. (2009a)
showed that combination therapy of metformin plus clomiphene citrate did not differ from clomiphene citrate alone
in rates of ovulation (OR 0.84; 95% CI 0.60 to 1.18), clinical
pregnancy (OR 0.85; 95% CI 0.62 to 1.15), or live birth (OR
0.99; 95% CI 070 to 140), with no signicant heterogeneity
among the three RCT. On the other hand, although Siebert
et al. (2012) reported signicant benets of combined therapy
over clomiphene citrate alone in terms of ovulation rate (OR
1.6; 95% CI 1.2 to 2.1; P = 0.0009; eight RCT) and a marginal

benet in clinical pregnancy rate (OR 1.3; 95% CI 1.0 to 1.6;


P = 0.05; 10 RCT), they did not recommend the combined
therapy as a primary method for ovulation induction in women
with PCOS owing to no evidence of benet for the live birth
rate (OR 1.1; 95% CI 0.78 to 1.5; four RCT) as well as the sideeffect prole of metformin (Table 1). Consequently, clomiphene citrate still represents the rst-line pharmacological
treatment for ovulation induction in women with newly diagnosed PCOS.

Metformin or clomiphene citrate for non-obese


anovulatory infertile women with PCOS
In a recent Cochrane review, subgroup analysis according to
BMI revealed that obese women with PCOS (BMI 30 kg/m2)
under clomiphene citrate had signicantly better ovulation
per cycle (OR 0.43; 95% CI 0.36 to 0.51; two RCT; number of
cycles = 2044; I2 = 0%), clinical pregnancy (OR 0.34; 95% CI
0.21 to 0.55; two RCT; n = 500; I2 = 0%) and live birth (OR
0.30; 95% CI 0.17 to 0.52; I2 = 0%) rates compared with
those who received metformin without heterogeneity
across the studies. On the other hand, non-obese women
(BMI <30 kg/m2 or 32 kg/m2) who received metformin had
a higher clinical pregnancy (OR 1.94; 95% CI 1.19 to 3.16;
three RCTs; n = 349; I2 = 44%), but not ovulation per
cycle (OR 0.87; 95% CI 0.60 to 1.26; two RCT, number of
cycles = 497; I2 = 0%) rate compared with those who received clomiphene citrate. Pooling of data on live birth rate
was not achieved owing to the heterogeneity observed in

48

H Abu Hashim

the non-obese subgroup. The authors pointed out that


metformin signicantly reduced fasting insulin concentrations in the non-obese group (mean difference 5.65 mIU/l;
95% CI 10.25 to 1.06) but not in obese women with PCOS
(mean difference 2.72 mIU/l; 95% CI 6.50 to 1.05), i.e.
metformin had limited effect on reducing serum insulin concentrations in the obese compared with the non-obese women
with PCOS (Tang et al., 2012).
The Cochrane review by Tang et al. (2012) did not include
data on the non-obese subgroup of women of a large RCT
(Legro et al., 2007). These important data were considered
in a subsequent meta-analysis of four RCT to compare the
effectiveness of metformin with clomiphene citrate for improving fertility outcomes in non-obese women with PCOS
(BMI <32 kg/m2) (Misso et al., 2013). The authors found no
signicant difference in ovulation rate per cycle (relative
risk [RR] 0.79 95%; CI 0.54 to 1.17; I2 = 78%; two RCT;
number of cycles = 909) or clinical pregnancy rate (RR 0.98;
95% CI 0.49 to 1.96; four RCT, I2 = 80%) or live birth rate (RR
0.84; 95% CI 0.22 to 3.26; three RCT; I2 = 90%) per patient
for metformin compared with clomiphene citrate given for
at least 3 months to non-obese anovulatory infertile women
with PCOS. Consequently, the authors concluded that the
available evidence is insufcient to recommend metformin
as a primary treatment of non-obese women with PCOS.
The ndings of this meta-analysis are in agreement
Table 2

with another meta-analysis of three RCT addressing this


subset (Johnson, 2011).

Metformin plus clomiphene citrate versus


clomiphene citrate plus placebo in clomiphene
citrate resistant-PCOS
Handling of anovulatory infertile women with clomiphene
citrate resistant-PCOS (CCR-PCOS) has witnessed a dramatic revolution in its current ideologies, goals, practice and
results. The examination of the potential benets of combined metformin plus clomiphene citrate had gained the
maximum interest of researchers rather than the use of
metformin monotherapy in this subset of patients. In a metaanalysis of six RCT, Siebert et al. (2006) reported that
metformin plus clomiphene citrate signicantly increased the
likelihood of ovulation compared with clomiphene citrate with
or without placebo in CCR-PCOS patients (OR 6.82; 95% CI 3.59
to 12.96; P < 0.0001). In a subsequent meta-analysis of 12 RCT,
Creanga et al. (2008) conrmed these ndings (OR 4.39; 95%
CI 1.94 to 9.96; number-needed-to-treat 3.7 for ovulation).
In addition, they demonstrated the superiority of combined
treatment in terms of clinical pregnancy (OR 2.67; 95% CI 1.45
to 4.94, number-needed-to-treat 4.6), but not live birth (OR
1.74; 95% CI 0.79 to 3.86) (Table 2). Different mechanisms

Metformin plus clomiphene in clomiphene-resistant polycystic ovary syndrome.

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

Clinical pregnancy rate

Live birth rate

Meta-analysis
of RCT
Meta-analysis
of RCT

OR 6.82; 95% CI 3.59 to


12.96a
OR 4.39; 95% CI 1.94 to
9.96;a NNT 3.7

OR 2.67; 95% CI 1.45 to


4.94;a NNT 4.6

OR 1.74; 95% CI 0.79 to 3.86

OR 0.45; 95% CI 0.27 to 0.75a


(versus gondotrophins)
OR 0.96; 95% CI 0.60 to 1.54
(versus LOD)
OR 0.85; 95% CI 0.53 to 1.36
(versus aromatase
inhibitors)
OR 5.28; 95% CI 1.9114.62a
(versus NAC plus clomiphene
citrate)
OR 0.39; 95% CI 0.20 to 0.75a
(versus other insulin
sensitizers plus clomiphene
citrate)

OR 0.33; 95% CI 0.13 to 0.85a


(versus gondotrophins)
OR 0.85; 95% CI 0.28 to 2.58
(versus LOD)
OR 0.21; 95% CI 0.05 to 0.87a
(versus aromatase
inhibitors)

Meta-analysis OR 0.25; 95% CI 0.15 to 0.41a


of RCT
(versus gondotrophins)
OR 0.88; 95% CI 0.53 to 1.47
(versus LOD)
OR 0.88; 95% CI 0.58 to 1.34
(versus aromatase
inhibitors)
OR 8.93; 95% CI 4.61 to
17.32a (versus NAC plus
clomiphene citrate)
OR 0.30; 95% CI 0.03 to 3.41
(versus other insulin
sensitizers plus clomiphene
citrate)

OR 0.62; 95% CI 0.12 to 3.22


(versus other insulin
sensitizers plus clomiphene
citrate)

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.

Metformin in anovualtory infertile women with PCOS

49

underpinning the benecial effects of adding metformin to


clomiphene citrate in treatment of women with clomiphene
citrate-resistant PCOS were suggested, including an intrinsic
alteration of follicle steroidogenesis through the insulin growth
factor-1 pathway in granulosa cells (Kocak et al., 2002), direct
inhibition of androgen production in ovarian thecal cells (Attia
et al., 2001), reduction of the adrenal steroidogenesis response to adrenocorticotropic hormone (la Marca et al., 1999)
and, its central action on the pituitary gland with LH lowering
and prolactin effects in women with PCOS (Billa et al., 2009).

Metformin plus clomiphene citrate versus other


second-line treatments in CCR-PCOS
Second-line treatments for infertile women with CCR-PCOS
include gonadotrophins, laparoscopic ovarian diathermy (LOD)
and other oral agents, such as aromatase inhibitors, N-acetylcysteine (NAC), and other insulin sensitizers (Abu Hashim et al.,
2013; ESHRE/ASRM, 2008; Franik et al., 2014; Saha et al., 2013;
Tang et al., 2012). Although many RCT have investigated the
efcacy of metformin plus different second-line treatment
options in CCR-PCOS patients, only two RCT compared
metformin monotherapy with LOD with conicting results. One
study (n = 120 overweight primary infertile anovulatory clomiphene citrate-resistant women), demonstrated the superiority of metformin over LOD in clinical pregnancy (21.8% versus
13.4%; P < 0.05) and live birth (86.0% versus 64.5%;
P < 0.05), but not ovulation rates (54.8 versus 53.2%) (Palomba
et al., 2004). Meanwhile, another RCT of 110 clomiphene
citrate-resistant women with PCOS showed that LOD achieved
signicantly higher rates of ovulation (50.8% versus 33.5%;
P < 0.001) and clinical pregnancy (38.2% versus 20.0%; P < 0.03).
No data on live birth rate were available (Hamed et al., 2010).
Recently, we conducted a systematic review and metaanalysis to provide pooled estimates of RCT comparing the
reproductive outcomes (mainly ovulation and clinical pregnancy rates) of metformin plus clomiphene citrate with different second-line treatments in CCR-PCOS (Table 2). We
reported the superiority of gonadotrophins over metformin
plus clomiphene citrate in terms of ovulation (OR 0.25; 95%
CI 0.15 to 0.41; P < 0.00001; three trials; I2 = 85%; n = 323)
and clinical pregnancy (OR 0.45; 95% CI 0.27 to 0.75; P = 0.002,
three trials, I2 = 0%, n = 323). Meanwhile, no signicant differences were found when metformin plus clomiphene citrate
was compared with LOD (OR 0.88; 95% CI 0.53 to 1.47; one
trial; n = 282; OR 0.96; 95% CI 0.60 to 1.54; two trials;
I2 = 0%; n = 332; for ovulation and clinical pregnancy rates respectively) or with aromatase inhibitors (OR 0.88; 95% CI 0.58
to 1.34; three trials; I2 = 3%; n = 409; OR 0.85; 95% CI 0.53
to 1.36; two trials; n = 309; for ovulation and clinical pregnancy rates, respectively). Additionally, we demonstrated the
superiority of metformin plus clomiphene citrate over NAC
plus clomiphene citrate in terms of ovulation (OR 8.93; 95%
CI 4.61 to 17.32; P < 0.00001; one trial; n = 192) and clinical
pregnancy (OR 5.28; 95% CI 1.91 to 14.62; P = 0.001; one trial;
n = 192). Meanwhile, meta-analysis of three small trials
(n = 155) revealed signicantly fewer clinical pregnancies following metformin plus clomiphene citrate compared with other
insulin sensitizers plus clomiphene citrate (OR 0.39; 95% CI
0.20 to 0.75; P = 0.005; I2 = 0%), albeit no difference in

Figure 3 Evidence-based decision making for clomipheneresistant infertile women with polycystic ovary syndrome. LOD,
laparoscopic ovarian diathermy; PCOS, polycystic ovary syndrome.

ovulation rates in a small trial (OR 0.30; 95% CI 0.03 to 3.41;


n = 25) (Abu Hashim et al., 2015).
For live birth rate, the outcome of most interest for infertile patients with PCOS, we demonstrated the superiority of gonadotrophins over metformin plus clomiphene citrate
(OR 0.33; 95% CI 0.13 to 0.85; P = 0.02; two trials; I2 = 0%;
n = 170). No differences were found when metformin plus clomiphene were compared with LOD in one small trial (OR 0.85;
95% CI 0.28 to 2.58; n = 50) or to other insulin sensitizers plus
clomiphene in another small trial (OR 0.62; 95% CI 0.12 to 3.22;
n = 25). Meanwhile, we observed a signicantly lower live birth
rate when combined treatment was compared with an
aromatase inhibitor in one small trial (OR 0.21; 95% CI 0.05
to 0.87; P = 0.03; n = 59). No data were available on live birth
rate when metformin plus clomiphene citrate was compared with NAC plus clomiphene citrate (Table 2) (Abu Hashim
et al., 2015).
With this background in mind, we concluded that metformin
plus clomiphene citrate could be considered in the management protocol of patients with CCR-PCOS, and that more attempts with metformin plus clomiphene citrate are warranted
when access to gonadotrophins is limited (Abu Hashim et al.,
2015). It is also important to ensure that, from the available list of choices, the nal decision should be tailored to
each woman, taking into account her own personal values and
circumstances, e.g. economics, side-effects, in addition to
what is available in a country or clinic (Figure 3). This is consistent with the fundamental principle of evidence-based medicine as the conscientious, explicit and judicious use of current
best evidence in making decisions about the care of individual patients (Sackett et al., 2000).

Metformin and gonadotrophins for ovulation


induction in CCR-PCOS
Ovulation induction with gonadotrophins in CCR-PCOS requires extensive monitoring, and is also associated with signicantly increased risk for ovarian hyperstimulation syndrome

50
Table 3

H Abu Hashim
Metformin as third-line treatment in women with PCOS undergoing assisted reproduction techniques.
Study design

Clinical pregnancy rate

Live birth rate

OHSS rate

Palomba et al. (2013)

Meta-analysis of RCT

Tso et al. (2014)

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.

PCOS during IVF or intracytoplasmic sperm injection (ICSI)


cycles, has been encouraged to optimize the efcacy of ovarian
stimulation with gonadotrophins. A recent meta-analysis of
10 RCT including 845 women with PCOS, showed no evidence that metformin treatment before or during assisted reproductive technique cycles improved clinical pregnancy (OR
1.20; 95% CI 0.90 to 1.61; nine RCT; I2 = 21.4%), or live birth
rates (OR 1.69; 95% CI 0.85 to 3.34; seven RCT; I2 = 72.4%),
but it reduces signicantly the risk of OHSS (OR 0.27; 95% CI
0.16 to 0.46) (Table 3). Additional signicant benets of increased implantation rate (OR 1.42; 95% CI 1.24 to 2.75; six
RCT; I2 = 31.3%) and decreased spontaneous abortion rate (OR
0.50; 95% CI 0.30 to 0.83; eight RCT; I2 = 20.3%) were demonstrated and seem to be inuenced by higher metformin
doses and longer duration of metformin treatment. In conclusion, the authors highlighted that metformin should be regarded as a preventive strategy for OHSS in women with PCOS
who receive gonadotrophins during IVF or ICSI cycles, and admitted the need for more RCT to be conducted with specic
identication of PCOS phenotypes to evaluate the reproductive effect of metformin (Palomba et al., 2013).
A 2014 updated version of a Cochrane review including
nine RCT re-evaluated the effects of metformin administration in 816 infertile patients with PCOS who had ovarian stimulation with gonadotrophins for IVF and ICSI cycles (Table 3).
Metformin increased the clinical pregnancy rates signicantly (OR 1.52; 95% CI 1.07 to 2.15; eight RCT; n = 775;
I2 = 18%), but no benecial effect on the live birth rate was
reported (OR 1.39; 95% CI 0.81 to 2.40; ve RCT; n = 551;
I2 = 52%). The authors demonstrated the signicantly reduced
risk of OHSS in the metformin group (OR 0.29; 95% CI 0.18 to
0.49; six RCT; n = 798; I2 = 11%) and highlighted that a 27%
risk of OHSS without metformin would be expected to be
615% if metformin treatment is used. No effect on spontaneous abortion rate was reported (OR 0.76; 95% CI 0.43 to
1.37; six RCT; n = 521; I2 = 0%). The authors admitted imprecision and inconsistency as main limitations in the available
evidence, and recommended further large, well-designed RCT
to answer denitively the question of whether the use of
metformin in women with PCOS undergoing assisted reproduction techniques improves the live birth rate (Tso et al.,
2014).

Metformin as third-line treatment in women with


PCOS undergoing assisted reproductive techniques

Metformin treatment in different phenotypes of


PCOS

On the basis of the concept of a reduction of hyperinsulinaemia


and hyperandrogenism, the use of metformin, in women with

In a recent RCT, Hosseini et al. (2013) studied the effectiveness of metformin on ovulation and clinical pregnancy rates

Metformin in anovualtory infertile women with PCOS


among 359 women with PCOS who were divided into four
different PCOS phenotypes from AD. In phenotype A, patients fullled all of the three Rotterdam criteria (n = 147).
Phenotype B included patients with oligo ovulation and
hyperandrogenism without polycystic ovary morphology
(n = 26). Phenotype C comprised patients showing hyperandrogenism and polycystic ovaries without oligo ovulation
(n = 50) and lastly phenotype D with oligo ovulation and polycystic ovaries on ultrasonography without clinical or biochemical hyperandrogenism (n = 109). In each phenotype,
patients were allocated to have 1500 mg of metformin plus
1 mg of folic acid per day or 1 mg of folic acid only for 2 months
followed by ovulation induction with letrozole (5 mg/day) for
5 days and intrauterine insemination.
No signicant differences in ovulation or clinical pregnancy rates were found in different phenotypes in both
metformin and non-metformin groups except for the ovulation rate in patients with phenotype A (62% versus 81.1%;
P = 0.04 for metformin versus non-metformin, respectively).
No data on live birth rate were available. The authors concluded that metformin treatment does not add benecial
effects to ovulation and clinical pregnancy rates in different phenotypes of PCOS. They recognized, however, the small
sample size for B (n = 26) and C (n = 50) phenotypes as well
as the lack of blinding as important limitations for their study,
and recommended more adequately powered RCT to evaluate their ndings (Hosseini et al., 2013).

Metformin and spontaneous abortion risk


A 2009 systematic review and meta-analysis of 17 RCT reported no signicant benecial effect of pregestational metformin
administration on the spontaneous abortion risk in women with
PCOS who received the drug either alone or combined with
other ovulatory drugs (OR 0.89; 95% CI 0.65 to 1.21) (Palomba
et al., 2009b). The same ndings were reported in the recent
Cochrane review when metformin was compared with placebo
or no treatment (OR 0.36; 95% CI 0.09 to 1.47; I2 = 0%; three
RCT; n = 279) or to clomiphene citrate (OR 1.24; 95% CI 0.60
to 2.58; I2 = 78%; four RCT; n = 173) and when metformin plus
clomiphene citrate was compared with clomiphene citrate
alone (OR 1.61; 95% CI 1.00 to 2.60; I2 = 0%; seven RCT; n = 937)
(Tang et al., 2012). Similarly, no evidence of benecial effects
of metformin administration on spontaneous abortion rate were
observed in infertile patients with PCOS who had gonadotrophins for ovulation induction (OR 0.47; 95% CI 0.14 to 1.54; P
= 0.210; I2 = 0%; ve RCT, n = 292) (Palomba et al., 2014), or
in IVFICSI cycles (OR 0.76; 95% CI 0.43 to 1.37; six RCT; n = 521;
I2 = 0%) (Tso et al., 2014).
Our systematic review and meta-analysis of RCT also demonstrated no signicant benet of metformin plus clomiphene citrate on spontaneous abortion risk in CCR-PCOS patients
who received metformin plus clomiphene citrate compared
with other second-line treatments such as LOD (OR 0.94; 95%
CI 0.39 to 2.27; I2 = 0%; two RCT; n = 332), gonadotrophins
(OR 0.70; 95% CI 0.26 to 1.89; I2 = 0%; three RCT; n = 323),
armoatase inhibitors (OR 1.41; 95% CI 0.42 to 4.79; two RCT;
n = 309), other insulin sensitizers plus clomiphene citrate (OR
0.97; 95% CI 0.19 to 5.04; I2 = 0%; two RCT; n = 125) and NAC
plus clomiphene citrate in one trial (OR 1.32; 95% CI 0.29 to
6.06; one RCT; n = 192) (Abu Hashim et al., 2015).

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.

Lifestyle modication should be the rst-line treatment in


infertile PCOS patients before resorting to pharmacological
ovulation induction.
On the basis of current evidence, metformin cannot be
recommended as rst-line pharmacological treatment for
anovulatory infertile women with PCOS.
Clomiphene citrate still represents the gold standard rstline pharmacological therapy for ovulation induction in
anovulatory infertile women with PCOS.
Metformin does not improve the efcacy of clomiphene
citrate as a rst-step treatment for ovulation induction in
anovulatory infertile women with PCOS.
Available evidence is insufcient to recommend metformin
as a primary treatment in non-obese PCOS subgroup.
Metformin plus clomiphene citrate could be considered an
effective option in patients with CCR-PCOS. More attempts
with metformin plus clomiphene citrate are warranted when
there is limited access to gonadotrophins.
In patients with CCR-PCOS undergoing ovulation induction
with gonadotrophins, the addition of metformin increases
the rates of clinical pregnancy and live birth and reduces the
cancellation rate.
In patients with PCOS undergoing assisted reproduction
technniques, metformin co-treatment reduces the OHSS risk
and increases the pregnancy rate.
No evidence exists of reduced spontaneous abortion risk in
women with PCOS who have undergone pre-gestational
metformin tretment.
No evidence exists of increased risk of major anomalies in
women with PCOS undergoing metformin treamtent during
the rst trimester.
Adequately powered RCT are needed to evaluate the efcacy
of metformin treatment in different PCOS phenotypes.
CCR = clompihene-citrate-resistant; OHSS = ovarian hyperstimulation syndrome; PCOS = polycystic ovary syndrome; RCT = randomized controlled trial.

still represents the gold standard rst-line pharmacological


treatment for ovulation induction in anovulatory infertile
women with PCOS. It is also important to highlight that the
available evidence is insufcient to recommend metformin
as a primary treatment in non-obese women with PCOS. On
the other hand, metformin plus clomiphene citrate should be
considered as an effective option in CCR-PCOS patients. On
the basis of the best available clinical evidence, the use of
metformin in women with PCOS undergoing gonadotrophin ovulation induction signicantly increased the rates of clinical
pregnancy and live birth with reduced risk of cancelled cycles.
A benecial effect of metformin co-treatment in increasing
the clinical pregnancy rates and reducing the OHSS risk in infertile women with PCOS undergoing assisted reproduction
techniques has been shown. A clear evidence-based role for
metformin in reducing the spontaneous abortion risk in women
with PCOS who received the drug, either alone or combined
with other ovulatory drugs, remains unjustiable. Overall, gastrointestinal symptoms represent the most commonly
encountered side-effects of metformin. Finally, it is impor-

tant to highlight that no evidence of increased risk of major


birth defects has been found in women with PCOS undergoing metformin treatment during the rst trimester. Future adequately powered RCT are warranted to evaluate the efcacy
of metformin treatment in different PCOS phenotypes. Clinical summary and key messages are shown in Table 4.

Appendix: Supplementary material


Supplementary data to this article can be found online at
doi:10.1016/j.rbmo.2015.09.015.

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Declaration: The author reports no nancial or commercial conicts of interest.

Received 15 June 2015; refereed 21 September 2015; accepted 22 September 2015.