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Metformin in polycystic ovary syndrome
Moll, E.
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Citation for published version (APA):Moll, E. (2013). Metformin in polycystic ovary syndrome.
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35
Chapter 3
The role of metformin in polycystic ovary syndrome. A systematic review.
Etelka Moll, Fulco van der Veen, Madelon van Wely
Human Reproduction Update 2007; 13(6):527-537
36
Abstract
This meta-analysis evaluated the effectiveness of metformin in subfertile
women with polycystic ovary syndrome (PCOS). Only randomised trials investigating
the effectiveness of metformin and PCOS definition consistent with the Rotterdam
consensus criteria were eligible. Primary outcome was live birth rate. A literature
search identified 27 trials. In therapy naive women, we found no evidence of a
difference in live birth rate when comparing metformin with clomifene citrate (CC)
[relative risk (RR) 0.73; 95% confidence interval (CI) 0.51 - 1.1] or comparing
metformin plus CC with CC (RR 1.0; 95% CI 0.82 - 1.3). In CC-resistant women,
metformin plus CC led to higher live birth rates than CC alone (RR 6.4; 95% CI 1.2 -
35); metformin also led to higher live birth rates than laparoscopic ovarian drilling
(LOD) (RR 1.6; 95% CI 1.1 - 2.5). We found no evidence for a positive effect of
metformin on live birth when added to LOD (RR 1.3; 95% CI 0.39 - 4.0) or FSH (RR
1.6; 95% CI 0.95 - 2.9), or when co-administered in IVF (RR 1.5; 95% CI 0.92 - 2.5).
In IVF, metformin led to fewer cases of ovarian hyperstimulation syndrome (OHSS)
(RR: 0.33; 95% CI: 0.13 - 0.80). This meta-analysis demonstrates that CC is still first
choice therapy for women with therapy naïve PCOS. In CC-resistant women, the
combination of CC plus metformin is the preferred treatment option before starting
with LOD or FSH. At present, there is no evidence of an improvement in live birth
when adding metformin to LOD or FSH. In IVF, metformin leads to a reduced risk of
OHSS.
37
Introduction
The polycystic ovary syndrome (PCOS) affects 5% to 10% of women of
reproductive age.1 PCOS is characterised by oligo-anovulation, clinical or
biochemical hyperandrogenism and / or polycystic ovaries.2-4 Insulin resistance
accompanied by compensatory hyperinsulinemia constitutes another major
biochemical feature of PCOS.
In 1994, more than 70 years after the first description of a patient with insulin
resistance and hyperandrogenism, the first study on the insulin sensitizer metformin
in women with PCOS was published.5 Originally, this trial was meant to study
metabolic and endocrinological parameters, but the authors noticed that some (12%)
of the women conceived spontaneously.
From that moment on many trials were set up to test insulin sensitizers (mainly
metformin) for ovulation induction in women with PCOS. These studies have been
summarized in several reviews and meta-analyses.6-11 These meta-analyses were
based on trials all consisting of a very small number of patients. In the analyses no
consistent distinction between therapy naïve and clomifene citrate (CC)-resistant
women was made. The reviews separately did not overview the total spectrum of
treatment possibilities.
In addition, two large trials were recently published.12;13 The total number of
patients in each separate trial exceeded the total number of patients in the existing
reviews. Both trials found - in contrast to the previously published trials - that
metformin does not lead to higher pregnancy rates when combined with CC and the
same was true for metformin alone when compared with CC.
In view of this, we felt that updating our knowledge on metformin in subfertility
and a critical appraisal of all existing studies might be helpful to guide clinical
practice. In this review, we will therefore concentrate on the effect of metformin on
live birth rate in women with PCOS for all comparisons studied so far.
38
Materials and Methods
Search Strategy
We searched the Cochrane Menstrual Disorders & Subfertility Group trials
register, the Cochrane Central Register of Controlled Trials (both searched February
2007), MEDLINE (January 1966 to February 2007), the website for registration of
controlled trials (controlled-trials.com) and several personal contacts with experts in
this field (Balen, Nestler, Palomba). All electronic databases were searched using the
following keywords: assisted reproduction, clomifene citrate, gonadotrophins, IVF,
IUI, metformin, ovulation induction, PCOS, pregnancy. We handsearched the
reference lists of selected trials and of recent reviews concerning this subject. No
restrictions were held concerning publication year or language. All retrieved articles
were of English language and published from 1996 till February 2007.
Study selection and data extraction
Studies were selected if the target population were women with PCOS. The
definition of PCOS had to follow the standards of the ESHRE/ASRM 2003
consensus, or the criteria used in the article had to be, in retrospect, in consensus
with the definition.4 If included patients did not meet the definition of ESHRE/ASRM,
the study was not included in this review. Furthermore, the studies had to be of
randomised design comparing the effect of metformin with placebo or no treatment,
metformin with another ovulation induction agent or method or comparing the effect
of metformin as co-treatment in IVF with no co-treatment.
The primary outcome of interest was live birth rate per randomised woman.
Secondary outcomes were clinical pregnancy, multiple pregnancy and ovarian
hyperstimulation syndrome (OHSS). It appeared that if live birth rate was not given in
a manuscript, data on ongoing pregnancy were also not presented. Therefore,
clinical pregnancy rate was chosen as a secondary outcome.
The review was undertaken by two reviewers (E.M., M.v.W.). The search
strategy was employed to obtain titles and, where possible, abstracts of studies that
were potentially relevant to the review. Both reviewers independently assessed
whether the studies met the inclusion criteria, with disagreements resolved by
discussion and final arbitration by F.V.
For each included trial, information was collected regarding the location of the
study, methods of the study (as per quality assessment checklist), the participants
39
(age range, eligibility criteria), the nature of the interventions and data relating to the
outcomes specified above. When possible, missing data were sought from the
authors. The trial specific characteristics are expressed in Table 1.
We distinguished three indications: metformin as first-line treatment in therapy
naive women; metformin as second-line treatment in CC-resistant women and
metformin as co-treatment in women undergoing IVF. We subdivided first-line and
second-line treatment into metformin monotherapy or co-treatment in combination
with CC, FSH or laparoscopic ovarian drilling (LOD).
Statistical analysis
Relative risks (RR) with 95% confidence intervals (95% CI) were calculated for
every study. Pooled RR were calculated using fixed effects models.14 If there was
statistical heterogeneity, we performed a sensitivity analysis by pooling using a
‘random effects’-method.15
Statistical heterogeneity was assessed using forest plots, the I2 statistic and
chi-square test. Clinical heterogeneity was assessed by reviewing differences across
trials in characteristics of randomized patients.
Data from cross-over trials were only used from the first phase (i.e. before
crossover). Any such trials that did not provide results at this point were excluded
from the analysis. Review Manager-software (RevMan 4.2.7, Cochrane
Collaboration, Oxford, UK) was used for the statistical analysis. We analysed the
data on intention to treat basis.
Results of search
Our search selected 443 articles. After reading the titles, 296 articles did not
answer our question. From the remaining 147 articles, 94 articles were discarded
while they were non-original papers (reviews, letters). The 53 remaining articles were
read. Thirty articles did not meet our inclusion criteria for not having a proper control
group,5;16-24 for not using randomisation,25-27 for not providing clear information on live
birth or clinical pregnancy rates,28-40 for using a cross-over design without clear rates
of pregnancy before the cross-over,41-43 or because of selection bias.44 Furthermore,
in one trial women were included that did not intend to get pregnant and had been
advised to take contraception (J.Nestler, personal communication).45
40
By handsearching reference lists, we came across four articles we did not find
in the initial search.46-49 In total 27 studies were included in the analysis (Fig. 1).
Three studies compared metformin with placebo,46;50;51 two compared
metformin with CC,13;52 12 compared metformin plus CC with CC,12;13;41;47;49;53-59 one
compared metformin with LOD,60 one compared metformin plus LOD with LOD,61 one
compared metformin plus CC with HMG,62 four compared metformin plus FSH with
FSH48;63-65 and four compared metformin added in IVF versus IVF without
metformin.34;66-68
Results
The quality and the main characteristics of the 27 trials included in this review
are presented in Table 1. Most trials were of poor quality. Seventeen of 27 trials used
an appropriate method of randomization, with 17 out of 27 having adequate
concealment of allocation. A power calculation was only reported in eight trials. Trial
size varied from 17 to 626 women.
Eight studies excluded women over the age of 35 years. Most studies did not
have restrictions considering BMI. One study included women with BMI <25 kg/m2.
Two studies included women with BMI <30 and <35 kg/ m2, respectively. Two studies
included women with BMI >29 and 30 kg/m2, respectively.
Metformin in CC naïve women
Metformin monotherapy
We retrieved two randomised controlled trials in which metformin was
compared with placebo for as first line treatment in 185 therapy naïve infertile women
with PCOS (Table 1).46;51 None used HCG for triggering ovulation. Both trials
reported clinical pregnancy rate. The pooled RR was 3.3 (95% CI: 0.92-11) (Fig. 2a).
Visual examination of the forest plot and the I2 statistic (0%) suggested no
heterogeneity in treatment effect across trials.
Live birth rate was not reported, nor multiple pregnancy rates. One study gave
life style modification before starting drug therapy.51 The median weight loss was 2.8
versus 1.5%.
We found two double-blinded randomised controlled trials in which metformin
was directly compared with CC as first line treatment in 509 infertile women with
41
PCOS (Table 1).13;52 HCG was not used for triggering ovulation. The pooled clinical
pregnancy rate after six months of treatment was significantly lower after metformin
(RR: 0.72; 95% CI: 0.54-0.97) (Fig. 2a). The pooled RR for live birth was 0.73 (95%
CI: 0.51-1.1) (Fig. 2b). However, for both pregnancy outcomes there was significant
heterogeneity in treatment effect across the two trials. When the data were pooled
using a random effects model the RR was 0.88 (95% CI: 0.19 – 4.1) and 0.96 (95%
CI: 0.11-8.2) for clinical pregnancy rate and live birth rate respectively. Furthermore,
there was no evidence of a difference in multiple pregnancy rate between the two
groups (RR: 0.38; 95% CI: 0.02-7.1).
Metformin as co-treatment in combination with CC
Seven randomised controlled trials compared CC plus metformin with CC in
985 infertile women with PCOS (Table 1).12;13;47;49;53-55 Two studies used HCG to
trigger ovulation.47;55 After combining the data, there was a significantly higher clinical
pregnancy rate in the metformin plus CC group (RR 1.5; 95% CI 1.2 - 1.8) (Fig. 2a).
However, there was significant heterogeneity in treatment effect across the trials.
When the data were pooled using a random effects model the difference in clinical
pregnancy was still significant (RR 1.9; 95% CI: 1.2 – 3.3). The pooled RR for live
birth was 1.0 (95% CI 0.82 - 1.3; three trials with 664 women) (Fig. 2b). For live birth,
there was no indication for heterogeneity in treatment effect across trials.
Two studies reported multiple pregnancy rates.12;13 After combining these data
no significant difference was seen (RR 0.38; 95% CI 0.09 - 1.5; 193 women).
Metformin in CC-resistant women
Metformin monotherapy
We retrieved one randomised clinical trial in which metformin was compared
with placebo in 18 infertile women with CC-resistant PCOS (Table 1).50 In this small
number of women there was no evidence of a difference in clinical pregnancy or live
birth rate (both RR: 0.50; 95% CI: 0.05-4.6) (Fig. 3a and b). No data on multiple
pregnancy rates were given.
42
Metformin as co-treatment in combination with CC
We retrieved five randomised controlled trials in which CC plus metformin was
compared with CC alone in 210 infertile women with CC-resistant PCOS (Table
1).41;56-59 Two trials used HCG to trigger ovulation.56;57
Combining the results showed that metformin plus CC led to a significantly
higher clinical pregnancy rate than CC alone (RR: 5.6; 95% CI: 2.3-13) (Fig. 3a). Live
birth rate was also in favour of metformin plus CC compared with the CC group (RR:
6.4; 95% CI: 1.2-34; 2 trials with 107 women) (Fig. 3b). For both pregnancy
outcomes, visual examination of the forest plot and the I2 statistic (0%) suggested no
heterogeneity in treatment effect across trials.
In the only trial that reported on multiple pregnancy no multiple pregnancies
were observed in both groups.59
Metformin as opposed to LOD
Only one randomised trial was retrieved in which metformin treatment was
compared with LOD (Table 1).60 There was no evidence of a difference in clinical
pregnancy rate (RR: 1.3; 95% CI: 0.96-1.7) (Fig 3a). Live birth rate however was
higher in the metformin group (RR: 1.6; 95% CI: 1.1-2.5) (Fig 3b). Multiple
pregnancies were not observed.
Metformin as co-treatment in combination with LOD
One trial randomised 42 PCOS patients between LOD followed by metformin
or LOD alone (Table 1).61 There were no significant differences in clinical pregnancy
rate (RR: 2.3; 95% CI: 0.82-6.2) or live birth rate (RR: 1.3; 95% CI: 0.39-4.0) (Fig. 3a
and 3b).
Metformin plus CC compared with gonadotrophins
In one randomised clinical trial, metformin plus CC was compared with
gonadotrophins in 60 CC- resistant women (Table 1).62 Both groups were triggered
for ovulation with HCG. There was no evidence of a difference in clinical pregnancy
rate (RR: 0.71; 95% CI: 0.26-2.0) (Fig. 3a). There were no data on live birth, multiple
pregnancy or OHSS.
43
Metformin plus FSH compared with FSH alone
In four randomised controlled trials FSH plus metformin was compared with
FSH alone in 154 infertile women with PCOS (Table 1).48;63-65 All studies used HCG
to trigger ovulation. The pooled clinical pregnancy rate was significantly higher in the
FSH plus metformin group compared with FSH only group (RR: 1.7; 95% CI: 1.1-2.8)
(Fig. 3a). A difference in live birth rate could however not be proven (RR: 1.6; 95%
CI: 1.0-2.9) (Fig. 3b). For both pregnancy outcomes, visual examination of the forest
plot and the I2 statistic (0%) suggested no heterogeneity in treatment effect across
trials. Metformin led to less multiple pregnancies (RR: 0.26; 95% CI: 0.07-0.96).
There was no evidence of a difference in OHSS (RR: 0.59; 95% CI: 0.17-2.1).
Metformin as additional treatment in controlled ovarian hyperstimulation in IVF
Four trials studied the effect of metformin during ovarian hyperstimulation in
IVF/ICSI in 283 women with PCOS (Table 1)34;66-68 (T.Tang, personal
communication).
In the first study, reasons for IVF treatment were not specified.34 In the second
study, women received IVF or ICSI because of other fertility problems like tubal
pathology, endometriosis or male subfertility.66 In the third study women with PCOS
in whom conventional therapy had not lead to pregnancy, were included.67 In the
fourth study, reasons for IVF were failure of conventional therapy and other fertility
problems.68
All studies presented data in clinical pregnancy rate. Combining the results did
not show a significant difference between the women treated with metformin or
placebo (RR: 1.2; 95% CI: 0.85-1.6) (Fig. 4). Visual examination of the forest plot and
the I2 statistic (0%) suggested no heterogeneity in treatment effect across trials. Live
birth rate was reported in two studies.66;68 There was no evidence of a significant
difference between the two groups (RR: 1.5; 95% CI: 0.92-2.5) (Fig. 4). Pooling the
data of the two trials that reported multiple pregnancy gave no evidence of a
significant difference between the two groups on multiple pregnancy rate66;68 (RR:
0.93; 95% CI: 0.42-2.1). OHSS was reported in all studies. When combining the
results, there was a significant reduced risk in favour of metformin (RR: 0.33; 95% CI:
0.13-0.80).
44
Discussion
In this review, we evaluated whether metformin leads to a more effective
fertility treatment for women with PCOS.11;69-73 From the placebo controlled trials
performed in infertile women with therapy naïve PCOS it is clear that metformin can
induce ovulation and can lead to pregnancies. The important clinical question
however is not whether metformin “works”, but whether it is better than CC in terms
of live birth in CC naïve women or whether it has additional benefit in terms of live
birth when used as co-treatment in therapy naïve or CC-resistant women.
At present, there is no evidence of a difference between metformin and CC in
therapy naïve women in favour of metformin. The two trials that studied this
comparison had conflicting results. In the study by Palomba et a 52 the live birth rate
was three times higher in the metformin group. In contrast, in the study by Legro et
al13 with quadruple the number of patients, the live birth rate was three times lower in
the metformin group. Of interest is that in the Palomba study, live birth rate in the CC
group was unusually low due to a high miscarriage rate. Legro included patients
previously treated with CC or metformin. We presumed these patients not to be CC-
resistant. Through personal communication we were informed that it is not clear how
many of these patients were CC-resistant. (R. Legro, personal communication). Still,
this particular mixture of patients can explain the low live birth rate in this study.
Meta-analysis of the studies that compared co-treatment of metformin with CC
versus CC alone did not show any benefit of metformin for live birth rate. These data,
taken together, make it highly unlikely that metformin – as monotherapy or as co-
treatment in combination with CC - is beneficial over CC in CC naïve women.
The clinical pregnancy rate in the comparison metformin plus CC versus CC in
therapy naïve women was significantly higher in the metformin group. However, there
was significant heterogeneity between studies as the small studies all favoured
metformin plus CC above CC alone while this difference was not found in the larger
studies. This difference between the larger and smaller studies may be a result of
publication bias or low study quality bias.74;75 The sensitivity analysis using pooling
with a random effects method was not helpful here as a random effects meta-
analysis will award relatively more weight to smaller studies.
In CC-resistant women, two studies showed a clear benefit of adding
metformin to CC over CC alone in terms of live birth. One should interpret these
45
results with some caution as one study was not blinded and the total number of
patients in these two studies was only 107.
Metformin appears to be superior to LOD considering live birth rate in CC-
resistant women, but these data are also based on a small number of women and
from one monocenter study. This being so, metformin is quite a different treatment
strategy than LOD and avoids the considerable risks of laparoscopic surgery,
especially in obese patients.
No differences in live birth were detected when metformin was added to LOD
compared with LOD alone and when metformin was added to FSH compared with
FSH alone, but again few studies, including few patients, have been carried out so
far.
Up till now, there is no evidence for better results on live birth rates when
metformin is added during ovarian hyperstimulation in IVF. This is based on two
studies with a limited number of patients and with probably totally different
populations of women, as in one study a mix of women after failed ovulation
induction and with other indications was included, while in the other studies only
women with other fertility problems were included. Metformin may however, reduce
the risk of OHSS.
In general, duration of metformin therapy differed substantially over the studies
and we can only speculate which effects this will have on outcome parameters.
In summary, this meta-analysis demonstrates that CC is still first choice
therapy for women with therapy naïve PCOS. In CC-resistant women, the
combination of CC plus metformin is the preferred treatment option before starting
with LOD or FSH. At present, there is no evidence of an improvement in live birth
rates when adding metformin to LOD or FSH.
46
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56
Tab
le 1
. Cha
ract
eris
tics
of r
ando
mis
ed tr
ials
of m
etfo
rmin
ver
sus
plac
ebo
in fe
rtili
ty tr
eatm
ent
Tri
al
(n =
nu
mb
er o
f ra
nd
om
ised
p
atie
nts
)
Par
tici
pan
ts
Inte
rven
tio
n
Co
mp
aris
on
M
ain
O
utc
om
es
Qu
alit
y fe
atu
res
El B
iely
200
1 (n
=45
ver
sus
45)
CC
-nai
ve;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd;
Age
: 26
vers
us 2
6 B
MI:
29 v
ersu
s 27
Met
form
in 5
00m
g 3/
day
+ C
C 5
0-15
0mg
6 m
onth
s
Pla
cebo
+
CC
50-
150m
g 6
mon
ths
Ovu
latio
n P
regn
ancy
O
HS
S
Ran
dom
isat
ion
with
com
pute
r-ge
nera
ted
bloc
ks;
Sin
gle
blin
ded.
Fed
orc
sak
2003
(n
=9
vers
us 8
)
PC
O u
ltras
ound
+ 2
ou
t of
hype
rand
roge
nism
, hi
rsut
ism
; In
sulin
res
ista
nce
Age
and
BM
I: no
t av
aila
ble
Met
form
in 5
00m
g 3/
day
+ IV
F/IC
SI
5 w
eeks
IVF
/ICS
I 5
wee
ks
Pre
gnan
cy
Fle
min
g 2
002
(n=
45 v
ersu
s 47
)
CC
-nai
ve;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd;
Age
: 29
vers
us 2
9 B
MI:
34 v
ersu
s 35
Met
form
in 8
50m
g 2/
day
16 w
eeks
Pla
cebo
16
wee
ks
Ovu
latio
n R
ando
mis
atio
n w
ith c
ompu
ter-
gene
rate
d bl
ocks
; D
oubl
e bl
inde
d.
Geo
rge
2003
(n
=30
ver
sus
30)
CC
-res
ista
nt;
Olig
omen
orro
ea +
hy
pera
ndro
geni
sm +
1
out o
f PC
O
ultr
asou
nd, L
H-F
SH
-ra
tio >
2;
Age
: 25
vers
us 2
6 B
MI:
26 v
ersu
s 26
Met
form
in 5
00m
g 3/
day
+ C
C 1
50-2
00m
g 6
mon
ths
+ 3
cyc
les
(CC
was
sta
rted
af
ter
6 m
onth
s tr
eatm
ent)
hMG
, ste
p-up
3
cycl
es
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n w
ith c
ompu
ter-
gene
rate
d bl
ocks
; N
ot b
linde
d.
56
57
Hw
u 2
005
(n=
40 v
ersu
s 40
)
CC
-res
ista
nt;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd +
hy
pera
ndro
geni
sm;
Age
: 29
vers
us 2
8 B
MI:
25 v
ersu
s 24
Met
form
in 5
00m
g 3/
day
+ C
C 1
50m
g 1
cycl
e
CC
150
mg
1 cy
cle
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n no
t cl
ear;
N
ot b
linde
d.
Kh
orr
am 2
006
(n=
16 v
ersu
s 15
)
CC
-nai
ve;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd +
hy
pera
ndro
geni
sm +
B
MI >
29;
A
ge: 2
8 ve
rsus
28
BM
I: 35
ver
sus
39
Met
form
in 5
00m
g 3/
day
+ C
C 1
00m
g 2
wee
ks
CC
100
mg
2 w
eeks
O
vula
tion
Car
d ou
t of b
ox
with
trea
tmen
t; N
ot b
linde
d.
Kjo
tro
d 2
004
(n=
37 v
ersu
s 36
)
Mix
ed fe
rtili
ty
prob
lem
s;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd+
te
stos
tero
ne >
2
nmol
/l +
one
of
LH-
FS
H-r
atio
> 2
, hi
rsut
ism
, SH
BG
< 3
0 nm
ol/l,
bas
elin
e in
sulin
> 1
nm
ol/l;
A
ge: 2
9 ve
rsus
30
BM
I: st
ratif
ied
< o
r �
28
Met
form
in 1
000m
g 2/
day
+ IV
F/IC
SI
trea
tmen
t 16
wee
ks
Pla
cebo
+
IVF
/ICS
I tr
eatm
ent
16 w
eeks
Pre
gnan
cy
Live
birt
h O
HS
S
Ran
dom
isat
ion
with
pha
rmac
y-ge
nera
ted
bloc
ks;
Dou
ble
blin
ded.
57
58
Ko
cak,
I 20
06
(n=
21 v
ersu
s 21
)
CC
-fai
lure
; 3
or m
ore
of:
olig
omen
orro
ea, P
CO
ul
tras
ound
, hy
pera
ndro
geni
sm,
anov
ulat
ion,
infe
rtili
ty,
hirs
utis
m, o
besi
ty;
Age
: 27
vers
us 2
8 B
MI:
27 v
ersu
s 32
LOD
+
Met
form
in 8
50m
g 2/
day
6 m
onth
s
LOD
6
mon
ths
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n no
t cl
ear;
N
ot b
linde
d.
Ko
cak,
M 2
002
(n=
28 v
ersu
s 28
)
CC
-res
ista
nt;
Olig
omen
orro
ea +
1
or m
ore
of P
CO
ul
tras
ound
, hy
pera
ndro
geni
sm;
Age
: 26
vers
us 2
7 B
MI:
32 v
ersu
s 31
Met
form
in 8
50m
g 2/
day
+ C
C 1
00m
g 2
cycl
es (
CC
was
ad
ded
if no
ov
ulat
ion
afte
r 1
cycl
e)
Pla
cebo
850
mg
bid
+ C
C 1
00m
g 2
cycl
es (
CC
was
ad
ded
if no
ov
ulat
ion
afte
r 1
cycl
e)
Ovu
latio
n P
regn
ancy
S
eale
d en
velo
pes;
D
oubl
e bl
inde
d.
Leg
ro 2
007
(n=
208
vers
us
209
vers
us 2
09)
CC
-naï
ve /
appr
oxim
atel
y 50
%
used
CC
or
met
form
in o
r co
mbi
natio
n pr
ior
to
stud
y;
Olig
omen
orro
ea +
el
evat
ed
test
oste
rone
; A
ge: 2
8 ve
rsus
28
BM
I: 36
ver
sus
36
Met
form
in 1
000m
g 2/
day
+ p
lace
bo
30 w
eeks
Pla
cebo
+
CC
50-
150m
g 30
wee
ks
Thi
rd g
roup
: M
etfo
rmin
10
00m
g bi
d +
CC
50
-150
mg
Live
birt
h In
tera
ctiv
e vo
ice
syst
em; s
trat
ified
ba
sed
on s
tudy
si
te a
nd p
revi
ous
expo
sure
to e
ither
of
the
stud
y dr
ugs;
D
oubl
e bl
inde
d.
58
59
Mal
kaw
i 200
2 (n
=16
ver
sus
12)
CC
-res
ista
nt o
r fa
ilure
; P
CO
ultr
asou
nd +
3
or m
ore
of
olig
omen
orro
ea,
hype
rand
roge
nism
, LH
-FS
H-r
atio
>2,
el
evat
ed L
H,
Fer
riman
-Gal
lwey
sc
ore
> 7
; A
ge: 2
9 ve
rsus
29
BM
I: 28
ver
sus
28
Met
form
in 8
50m
g 2/
day
+ C
C 5
0-20
0mg
6 cy
cles
Pla
cebo
+
CC
50-
200m
g 6
cycl
es
Ovu
latio
n P
regn
ancy
C
entr
alis
ed
rand
omis
atio
n pr
oces
s;
Dou
ble
blin
ded
Mo
ll 20
06
(n=
111
vers
us
114)
CC
-nai
ve;
Def
initi
on c
onfo
rm
ES
HR
E 2
003;
A
ge: 2
8 ve
rsus
28
BM
I: 29
ver
sus
28
Met
form
in 5
00m
g 4/
day
+ C
C 5
0-15
0mg
6 cy
cles
Pla
cebo
+
CC
50-
150m
g 6
cycl
es
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n w
ith c
ompu
ter-
gene
rate
d bl
ocks
; D
oubl
e bl
inde
d.
Ng
200
1 (n
=9
vers
us 9
)
CC
-res
ista
nt;
PC
O u
ltras
ound
; A
ge: 3
1 ve
rsus
32
BM
I: 24
ver
sus
24
Met
form
in 5
00m
g 3/
day
+ C
C 1
00m
g 3
mon
ths
and
1 cy
cle
(CC
was
ad
ded
if no
ov
ulat
ion
afte
r 3
mon
ths)
Pla
cebo
500
mg
3/da
y +
CC
100
mg
3 m
onth
s an
d 1
cycl
e (C
C w
as
adde
d if
no
ovul
atio
n af
ter
3 m
onth
s)
Ovu
latio
n R
ando
mis
atio
n w
ith c
ompu
ter-
gene
rate
d lis
t in
enve
lope
s;
Dou
ble
blin
ded.
On
alan
200
5 (n
=53
ver
sus
55)
Last
fert
ility
tr
eatm
ent;
O
ligom
enor
roea
+
hype
rand
roge
nism
; A
ge: 2
9 ve
rsus
30
BM
I: 25
ver
sus
24
Met
form
in 8
50m
g 2-
3/da
y (d
epen
ding
on
BM
I < o
r �
28)
+ IV
F/IC
SI
trea
tmen
t 12
wee
ks
Pla
cebo
+
IVF
/ICS
I tr
eatm
ent
12 w
eeks
Pre
gnan
cy
Abo
rtio
n O
HS
S
Ran
dom
isat
ion
with
com
pute
r-ge
nera
ted
bloc
ks;
Dou
ble
blin
ded.
59
60
Pal
om
ba
2004
(n
=54
ver
sus
55)
CC
-res
ista
nt;
Olig
omen
orro
ea +
el
evat
ed
test
oste
rone
; A
ge: 2
7 ve
rsus
28
BM
I: 28
ver
sus
28
Dia
gnos
tic
lapa
rosc
opy
+ M
etfo
rmin
850
mg
2/da
y 6
mon
ths
LOD
+
pla
cebo
6
mon
ths
Ovu
latio
n P
regn
ancy
Li
ve b
irth
Ran
dom
isat
ion
with
com
pute
r-ge
nera
ted
bloc
ks;
Dou
ble
blin
ded.
Pal
om
ba
2005
(n
=50
ver
sus
50)
CC
-nai
ve;
Olig
omen
orro
ea +
el
evat
ed
test
oste
rone
; A
ge: 2
6 ve
rsus
26
BM
I: 27
ver
sus
27
Met
form
in 8
50m
g 2/
day
+ p
lace
bo
6 m
onth
s
Pla
cebo
+
CC
150
mg
6 m
onth
s
Ovu
latio
n P
regn
ancy
Li
ve b
irth
Ran
dom
isat
ion
with
com
pute
r-ge
nera
ted
bloc
ks;
Dou
ble
blin
ded.
Pal
om
ba
2005
(n
=35
ver
sus
35)
CC
-res
ista
nt;
Olig
omen
orro
ea +
el
evat
ed
test
oste
rone
; A
ge: 2
6 ve
rsus
27
BM
I: 27
ver
sus
26
Met
form
in 8
50m
g 2/
day
+ F
SH
ste
p up
3
mon
ths
+ 3
cyc
les
(FS
H w
as s
tart
ed
afte
r 8
wee
ks
trea
tmen
t)
Pla
cebo
+
FS
H s
tep
up
3 m
onth
s +
3
cycl
es (
FS
H w
as
star
ted
afte
r 8
wee
ks tr
eatm
ent)
Pre
gnan
cy
Live
birt
h M
ultip
le
preg
nanc
y O
HS
S
Ran
dom
isat
ion
with
com
pute
r-ge
nera
ted
bloc
ks;
Dou
ble
blin
ded.
Raj
a 20
05
(n=
50 v
ersu
s 50
)
CC
-nai
ve;
PC
O u
ltras
ound
+ 2
or
mor
e of
: ol
igom
enor
roea
, hy
pera
ndro
geni
sm,
LH-F
SH
-rat
io >
2,
hirs
utis
m, e
leva
ted
LH;
Age
: 27
vers
us 2
7 B
MI:
not a
vaila
ble
Met
form
in 5
00m
g 3/
day
+ C
C 5
0mg
6 cy
cles
CC
50m
g 6
cycl
es
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n no
t cl
ear;
N
ot b
linde
d.
60
61
Sah
in 2
004
(n=
11 v
ersu
s 10
)
CC
-nai
ve;
3 or
mor
e of
ol
igom
enor
roea
, PC
O
ultr
asou
nd,
hype
rand
roge
nism
, LH
-FS
H-r
atio
>2,
hi
rsut
ism
; A
ge: 2
7 ve
rsus
25
BM
I: 30
ver
sus
26
Met
form
in 8
50m
g 2/
day
+ C
C 1
00m
g 3
mon
ths
CC
100
mg
3 m
onth
s O
vula
tion
Pre
gnan
cy
Ran
dom
isat
ion
not
clea
r;
Not
blin
ded.
Sin
gh
200
1 (n
=53
ver
sus
47)
CC
-nai
ve;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd +
LH
-FS
H-r
atio
> 2
; A
ge: 2
6 ve
rsus
28
BM
I: no
t ava
ilabl
e
Met
form
in 5
00m
g 2/
day
+ C
C 5
0mg
4 m
onth
s
CC
50m
g 4
mon
ths
Pre
gnan
cy
Ran
dom
isat
ion
not
clea
r;
Pre
sum
ed n
ot
blin
ded.
O
nly
abst
ract
av
aila
ble.
S
turr
ock
200
2 (n
=54
ver
sus
55)
CC
-res
ista
nt;
Olig
omen
orro
ea;
Age
: 29
vers
us 3
1 B
MI:
34 v
ersu
s 35
Met
form
in 5
00m
g 3/
day
+ C
C 5
0-15
0mg
3 m
onth
s +
3 c
ycle
s
Pla
cebo
+
CC
50-
150m
g 3
mon
ths
+ 3
cy
cles
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n pe
rfor
med
by
phar
mac
y;
Cro
ss-o
ver
(onl
y da
ta b
efor
e cr
oss-
over
are
use
d)
Dou
ble
blin
ded.
T
ang
200
6 (n
=56
ver
sus
66)
CC
-nai
ve;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd +
B
MI >
30;
Age
: 30
vers
us 3
0 B
MI:
38 v
ersu
s 39
Met
form
in 8
50m
g 2/
day
6 m
onth
s
Pla
cebo
6
mon
ths
Pre
gnan
cy
R
ando
mis
atio
n w
ith c
ompu
ter-
gene
rate
d bl
ocks
; D
oubl
e bl
inde
d.
61
62
Tan
g 2
006b
(n
=51
ver
sus
47);
4
patie
nts
ente
red
twic
e
Def
initi
on c
onfo
rm
ES
HR
E 2
003;
A
ge: 3
1 ve
rsus
31
BM
I: 28
ver
sus
27
Met
form
in 8
50m
g 2/
day
+ IV
F/IC
SI
trea
tmen
t 28
day
s
Pla
cebo
+
IVF
/ICS
I tr
eatm
ent
28 d
ays
Pre
gnan
cy
Live
birt
h O
HS
S
Ran
dom
isat
ion
with
com
pute
r-ge
nera
ted
bloc
ks;
Dou
ble
blin
ded.
Tas
dem
ir 2
004
(n=
16 v
ersu
s 16
)
CC
- re
sist
ant;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd +
hy
pera
ndro
geni
sm;
Age
: 32
vers
us 3
1 B
MI:
29 v
ersu
s 29
Met
form
in 8
50m
g 2/
day
+ F
SH
8
wee
ks +
1 c
ycle
(F
SH
was
sta
rted
af
ter
8 w
eeks
tr
eatm
ent)
FS
H
8 w
eeks
+ 1
cyc
le
(FS
H w
as s
tart
ed
afte
r 8
wee
ks
trea
tmen
t)
Pre
gnan
cy
Ova
rian
resp
onse
Ran
dom
isat
ion
not
clea
r;
Not
blin
ded.
van
San
tbri
nk
2005
(n
=11
ver
sus
7)
CC
-res
ista
nt o
r C
C-
failu
re;
Olig
omen
orro
ea +
in
sulin
res
ista
nce;
A
ge: 2
8 ve
rsus
28
BM
I: 38
ver
sus
34
Met
form
in 8
50m
g 2/
day
+ F
SH
ste
p-up
35
day
s an
d 1
cycl
e (F
SH
was
add
ed if
no
ovu
latio
n af
ter
35
days
)
Pla
cebo
850
mg
bid
+ F
SH
ste
p-up
35
day
s an
d 1
cycl
e (F
SH
was
ad
ded
if no
ov
ulat
ion
afte
r 35
da
ys)
Ova
rian
resp
onse
S
eale
d en
velo
pes;
D
oubl
e bl
inde
d.
Van
der
mo
len
20
01
(n=
12 v
ersu
s 15
)
CC
-res
ista
nt;
Olig
omen
orro
ea +
hy
pera
ndro
geni
sm;
Age
: 29
vers
us 3
0 B
MI:
38 v
ersu
s 38
Met
form
in 5
00m
g 3/
day
+ C
C 5
0-15
0mg
6 w
eeks
and
6
cycl
es (
CC
was
ad
ded
if no
ov
ulat
ion
afte
r 6
wee
ks)
Pla
cebo
+
CC
50-
150m
g 6
wee
ks a
nd 6
cy
cles
(C
C w
as
adde
d if
no
ovul
atio
n af
ter
6 w
eeks
)
Ovu
latio
n P
regn
ancy
R
ando
mis
atio
n w
ith c
ompu
ter-
gene
rate
d bl
ocks
; D
oubl
e bl
inde
d.
62
63
Yar
ali 2
002
(n=
16 v
ersu
s 16
)
CC
-res
ista
nt;
Olig
omen
orro
ea +
P
CO
ultr
asou
nd +
te
stos
tero
ne >
2.4
nm
ol/l;
A
ge: 3
0 ve
rsus
28
BM
I: 29
ver
sus
30
Met
form
in 8
50m
g 2/
day
+ F
SH
ste
p-up
6
wee
ks a
nd 1
cyc
le
(FS
H w
as a
dded
if
no o
vula
tion
afte
r 6
wee
ks)
Pla
cebo
850
mg
bid
+ F
SH
ste
p-up
6
wee
ks a
nd 1
cy
cle
(FS
H w
as
adde
d if
no
ovul
atio
n af
ter
6 w
eeks
)
Ova
rian
resp
onse
S
eale
d en
velo
pes;
D
oubl
e bl
inde
d.
63
64
Figure 1. Trial flow
Trials extra found in reference lists; n=4
Trials included in meta-analysis;
n=27
Potentially relevant trials; n=443
Trials retrieved for evaluation; n=147
Potentially appropriate trials; n=53
Articles excluded not meeting inclusion criteria by title;
n=296
Articles excluded not meeting inclusion criteria by abstract;
n=94
Trials withdrawn not meeting inclusion criteria; n=30 -10 no control group -3 no randomisation
-13 no pregnancy rates -3 cross-over design
-1 selection bias
F (Fig
ure
2. F
ore
(A)
Clin
ical
prees
t plo
ts fo
r cl
o
egna
ncy
rate
iomife
ne c
itrat
e
in c
lom
ifene
cie
naïv
e w
ome
itrat
e na
ïve
won om
en
65
65
6( 66
(B)
Live
birt
h rra
te in
clo
mife
ne c
itrat
e na
ïvve
wom
en
66
Figure
(A) Clin
3. Forest
nical pregn
plots for cl
nancy rate
lomifene c
in clomifen
itrate resis
ne citrate r
stant wome
resistant w
en
women
67
6 ( 68
(B)
Live
birt
h rra
te in
clo
mife
ne c
itrat
e re
sisst
ant w
omen
68
F Fig
ure
4. F
orees
t plo
ts fo
r cl
inic
al p
regn
ancy
rat
e an
d livv
e bi
rth
rate
in w
omen
trea
teed
with
IVF
.
69
69