Human Reproduction, Vol.25, No.7 pp.

1675 1683, 2010

Advanced Access publication on April 30, 2010 doi:10.1093/humrep/deq100

ORIGINAL ARTICLE Infertility

PCOSMIC: a multi-centre randomized

trial in women with PolyCystic Ovary
Syndrome evaluating Metformin for
Infertility with Clomiphene
N.P. Johnson 1,2,3,*, A.W. Stewart 1, J. Falkiner 1,2,3, C.M. Farquhar 1,2,3,
S. Milsom 1,2, V.-P. Singh 4,5, Q.L. Okonkwo 1, and
K.L. Buckingham 2,3 on behalf of REACT-NZ (REproduction And

Downloaded from http://humrep.oxfordjournals.org/ by guest on November 14, 2015

Collaborative Trials in New Zealand), a multi-centre fertility
trials group
1
Department of Obstetrics & Gynaecology, University of Auckland, Level 12, Auckland Hospital, Auckland, New Zealand 2Fertility Plus,
Green Lane Clinical Centre, Auckland, New Zealand 3Repromed Auckland, 105 Remuera Road, Auckland, New Zealand 4Waikato Hospital,
Hamilton, New Zealand 5Fertility Associates, Hamilton, New Zealand

*Correspondence address. E-mail: n.johnson@auckland.ac.nz

Submitted on September 29, 2009; resubmitted on March 10, 2010; accepted on March 23, 2010

background: Ovulation induction treatment with metformin, either alone or in combination with clomiphene citrate (CC), remains
controversial even though previous randomized trials have examined this.
methods: A double blinded multi-centre randomized trial was undertaken including 171 women with anovulatory or oligo-ovulatory
polycystic ovary syndrome. Women with high body mass index (BMI) . 32 kg/m2 received placebo (standard care) or metformin;
women with BMI 32 kg/m2 received CC (standard care), metformin or both. Treatment continued for 6 months or until pregnancy
was conrmed. Primary outcomes were clinical pregnancy and live birth.
results: For women with BMI . 32 kg/m2, clinical pregnancy and live birth rates were 22% (7/32) and 16% (5/32) with metformin, 15%
(5/33) and 6% (2/33) with placebo. For women with BMI 32 kg/m2, clinical pregnancy and live birth rates were 40% (14/35) and 29%
(10/35) with metformin, 39% (14/36) and 36% (13/36) with CC, 54% (19/35) and 43% (15/35) with combination metformin plus CC.
conclusions: There is no evidence that adding metformin to standard care is benecial. Pregnancy and live birth rates are low in
women with BMI . 32 kg/m2 whatever treatment is used, with no evidence of benet of metformin over placebo. For women with
BMI 32 kg/m2 there is no evidence of signicant differences in outcomes whether treated with metformin, CC or both.
ClinicalTrials.gov number NCT00795808; trial protocol accepted for publication November 2005: Johnson, Aust N Z Journal Obstet Gynaecol
2006;46:141 145.

Key words: polycystic ovary syndrome / anovulation / metformin / clomiphene citrate / randomized controlled trial

however, these trials and systematic reviews were vastly underpow-

Introduction
Polycystic ovary syndrome (PCOS) is the usual etiology of anovulatory
infertility (Hull, 1987) and is associated with increased insulin resist-
ance. Treatment with the insulin sensitising agent metformin has
been proposed as an alternative to clomiphene citrate (CC), the
long established effective ovulation induction treatment for women
with anovulatory PCOS (Nestler et al., 1998). Early systematic
reviews of randomized controlled trials (RCTs) showed that metfor-
min was more effective than placebo for inducing ovulation,
ered to detect differences in clinically relevant outcomes such as preg-
nancy and live birth (Lord et al., 2005; Creanga et al., 2008). The
addition of metformin to CC in combination therapy was proven to
be more effective than CC alone only among women with known
CC resistance (Al-Inany and Johnson, 2006).
In New Zealand our standard treatment for anovulatory infertility in
women with PCOS has traditionally been lifestyle intervention (with
emphasis on exercise and weight-reducing diet) for women whose
BMI is greater than 32 kg/m2 and CC ovulation induction therapy

& The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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1676
for women whose body mass index (BMI) is 32 kg/m2 or less. We
designed a randomized trial to ascertain whether the addition of met-
fomin to standard treatment provided any clinically relevant benet.
We also studied the relative efcacy of CC, metformin and both
among women with BMI 32 kg/m2; metformin versus placebo
among women with BMI . 32 kg/m2.
Since initiating our trial, further RCTs have been published with con-
icting results. The largest RCT, a high quality American multi-centre
trial, showed a signicant benet of CC over metformin (live birth rate
22.5 versus 7.2%; Legro et al., 2007). This was widely accepted as
denitive evidence that CC should remain the rst line treatment
for anovulatory PCOS, with apparently no place for metformin rst
line (Al-Inany and Johnson, 2006), results largely conrmed by the
most recent RCT from Malaysia (live birth rate 15.4% for CC versus
7.9% for metformin; Zain et al., 2008). However, a smaller Italian
RCT had suggested the live birth rate for metformin (52.0%) was
higher than that for CC (18.0%) for non-obese women with anovula-
tory PCOS (Palomba et al., 2005). A Dutch RCT has shown no benet
of combination therapy CC plus metformin versus CC alone as a rst
line ovulation induction treatment for women with PCOS (Moll et al.,
2006) and a British trial showed no signicant benet of metformin
for obese women (Tang et al., 2006). These RCT ndings were
assimilated into the Thessaloniki consensus recommendation that
appeared to close the door on metformin, stating use of metformin
should be restricted to those patients with glucose intolerance (The
Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Group, 2008; Thessaloniki ESHRE/ASRM-Sponsored PCOS Consen-
sus Workshop Group, 2008). Others, however, have questioned
whether metformin should continue to have a more prominent role,
especially where immediacy of achieving pregnancy is not paramount
(Nestler, 2008; Palomba et al., 2009). The recent updated Cochrane
review (Tang et al., 2010) included these RCTs and concluded that
the use of metformin in improvement of reproductive outcomes or
in reducing the risk of developing metabolic syndrome in women
with PCOS appears to be limited, but that some women with
PCOS may benet from using insulin sensitizers and that more
research is needed to improve patient selection. Thus a level of
uncertainty remains regarding the role of metformin in PCOS.
The aim of this trial was to assess whether metformin provides
benet when added to standard treatment and to assess the best rst
line treatment for women with ovulation dysfunction related to PCOS.
Materials and Methods
Study design
A multi-centre double-blind placebo-controlled parallel randomized trial
was conducted among women with oligo- or anovulatory infertility
owing to PCOS. Approval was granted by the New Zealand Multi-Region
Ethics Committee and all participants gave written informed consent. The
trial methodology meets CONSORT statement criteria and has previously
been described in detail (Johnson, 2006).
In brief, we included anovulatory or oligo-ovulatory women with PCOS
dened by the Rotterdam consensus criteria (The Rotterdam ESHRE/ASRM-
Sponsored PCOS Consensus Workshop Group, 2004; Rotterdam ESHRE/
ASRM-Sponsored PCOS Consensus Workshop Group, 2004) and excluded
couples who had undergone previous fertility treatment involving more than
5 months treatment with CC or metformin. We also excluded couples in
Johnson et al.
whom any other important infertility factor was known to be present, includ-
ing known tubal factor where at least one fallopian tube was blocked (although
a tubal patency test was not a prerequisite for trial entry). However, women
known to have stage 1 or 2 endometriosis and men with very mild oligosper-
mia, with sperm count 15 million per ml, were included. Women with
important medical disorders were also excluded (Johnson, 2006).
Our power calculation (Johnson, 2006) suggested a sample size of 160
women distributed between the ve treatment arms in the study would be
required to show an increase in the pregnancy rate from 30 to 55% by
adding metformin to standard therapy (to comfortably allow for attain-
ment of at least 122 participants required to have adequate power for
this primary comparison of standard care versus standard care plus met-
formin). The standard care group comprised women with BMI . 32 kg/m2
receiving placebo and women with BMI 32 kg/m2 receiving CC; the stan-
dard care plus metformin group comprised women with BMI . 32 kg/m2
receiving metformin and women with BMI 32 kg/m2 receiving CC plus
metformin. A sample size of 61 participants per group was required for 80%
power to detect an increase in pregnancy rate from 30% in the standard
care group to 55% in the standard care plus metformin group. Thus,
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122 analysed participants were required. A third intervention group (due
to receive metformin alone) was added to the BMI 32 kg/m2 subpopulation,
thus the target number of participants in this subpopulation was 92.
The target number of 153 analysed participants (92 BMI 32 kg/m2; 61
BMI . 32 kg/m2) was increased to 160 (97 BMI 32 kg/m2; 63 BMI .
32 kg/m2) to allow for losses to follow-up and the possibility of preferential
allocation to one treatment arm.
From four active recruiting centres, we randomly assigned 171 women
with PCOS from two a priori identied subpopulations, 65 women
with BMI . 32 kg/m2 (in blocks of 10) and 106 women with BMI
32 kg/m2 (in blocks of 15). Women with BMI . 32 kg/m2 received no
treatment other than advice and encouragement on lifestyle intervention
(that included advice on calorie restriction and on increasing aerobic exer-
cise to 30 min at least ve times per week with an opportunity to see a
dietician and an exercise therapist if required, i.e. standard care) or met-
formin (in addition to standard care) for 6 months (with the possibility of
CC treatment after 3 months if they remained anovulatory, in a protocol
similar to the RCT by Nestler et al. 1998). Women with BMI 32 kg/m2
received CC (standard care), metformin or both for 6 months. Allocation
concealment was strictly maintained by a telephone call from the recruiting
research nurse to pharmacy, the research pharmacist then executing the
assignment by dispensing preprepared drugs in a true third party ran-
domization. Blinding (masking) of all parties was maintained in all cases
by placebo control until the end of the course of treatment or, in the
event of pregnancy, until after the pregnancy.
Study drugs
Metformin 500 mg standard release tablets, CC 50 mg tablets with iden-
tical placebo tablets (to maintain blinding) for both metformin and CC
were purchased from Pacic Pharmaceuticals and packaged in our
research pharmacy in Auckland. Each patient received up to two
3-month treatment packages. Drugs were commenced concurrently and
standard monitoring as for a CC cycle was undertaken in each case,
with any required dose modications initiated as previously described
(Johnson, 2006). Briey, metformin 500 mg three times daily in a
gradual increasing dose over 2 weeks was given; for CC 50 mg was the
initial dose and 150 mg the highest dose used. All study drugs were
stopped once pregnancy was diagnosed.
Outcomes
The primary outcomes were clinical pregnancy (positive urine or serum
pregnancy test plus intrauterine gestation sac on ultrasound scan or
Multicentre RCT metformin and clomiphene in PCOS
histological evidence of trophoblastic tissue with spontaneous abortion or
ectopic pregnancy) that occurred within 6 months of randomization and
resultant live birth. Secondary outcomes were adverse events, ovulation
(conrmed if pregnancy occurred or if serum progesterone level was
25 nmol/l; strongly suggested if serum progesterone level was 15
25 nmol/l), spontaneous abortion, ectopic pregnancy, multiple pregnancy
and other adverse perinatal or obstetric complications.
All comparisons used the Pearson x2 test. For the combined data and
for the BMI . 32 kg/m2 subgroup, the comparison was between two pro-
portions; for the BMI 32 kg/m2 subgroup, the comparison was between
the three treatments; for adverse events, the comparison was between
the ve different treatment groups. This analysis was conducted on an
intention-to-treat basis using worst case assumptions that women lost
to follow-up did not become pregnant, or that they did not have a live
birth if pregnant at the time of loss to follow-up.
Results
Study population and ow
The important baseline variables were similar among the different
treatment groups in each BMI category (Table I).
Figure 1 shows the ow of participants through the trial. We
assessed 677 women for eligibility, of whom 349 did not meet the cri-
teria for inclusion (primarily couples with other causes for infertility or
where there were multiple causes for infertility including PCOS) and
157 were eligible but did not wish to proceed with involvement in
the study. Thus 171 women from four recruiting centres in New
Zealand were randomized and included in the trial after fully informed
written consent was obtained from the participants and their male
partners. Women were recruited between 21 August 2003 and
28 February 2007; the last baby was delivered by a participant on
28 November 2007.
Of 33 women with BMI . 32 kg/m2 receiving placebo, 30 com-
pleted treatment and follow-up (two of whom were not fully adherent
to treatmentone experienced side effects so took a reduced dose,
one misunderstood the gradual increase in dose and did this every
month); three breached the protocol by stopping trial medications;
25 women who had not had conrmed ovulation 3 months into
the trial received CC thereafter. Among 32 women with BMI .
32 kg/m2 receiving metformin, 29 completed treatment and follow-up
(all of whom were fully adherent to treatment)two women were
lost to follow-up, one of whom was pregnant at the time of emigration
to Australia and one stopped trial medication; 22 women who had not
had conrmed ovulation 3 months into the trial received CC there-
after. Among 36 women with BMI 32 kg/m2 receiving CC, 32 com-
pleted treatment and follow-up (all of whom were fully adherent to
treatment)there was one loss to follow-up and three either
stopped or failed to start treatment. Of 35 women with BMI
32 kg/m2 receiving metformin, 32 completed treatment and follow-up
(all of whom were fully adherent)three breached the protocol by
stopping treatment early, one of whom failed to resume treatment
after a pregnancy miscarried. Of 35 women with BMI 32 kg/m2
receiving CC plus metformin, 34 completed treatment and follow-up
(one of whom was not fully adherent and took the trial drugs
erratically)one woman breached the protocol by failing to resume
treatment after a pregnancy miscarried. Of four women who
1677
stopped taking study drugs owing to gastrointestinal side effects,
only one was actually taking metformin.
Primary outcomes
Primary and secondary outcomes are expressed in Table II. For
women with BMI . 32 kg/m2, there were no signicant differences
in the live birth rate for metformin (5/32 16%) versus placebo
(2/33 6%) (P 0.21), nor for the clinical pregnancy rate for metfor-
min (7/32 22%) versus placebo (5/33 15%) (P 0.48). In the
metformin group, ve of the seven pregnancies occurred in the rst
3 months and two in the second 3 months of therapy in association
with adjunct CC treatment; in the placebo group, three of the ve
pregnancies occurred in the rst 3 months and two in the second
3 months of therapy in association with adjunct CC treatment.
For women with BMI 32 kg/m2, the live birth rates were not sig-
nicantly different among women treated with metformin (10/35
29%), CC (13/36 36%) or combination CC plus metformin (15/
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35 43%) (P 0.46). The clinical pregnancy rates for women
treated with metformin (14/35 40%), CC (14/36 39%) or com-
bination CC plus metformin (19/35 54%) were not signicantly
different (P 0.35).
Overall the live birth rate for standard care (15/69 22%) was
not signicantly different from the live birth rate for standard care
plus metformin (20/67 30%) (P 0.28). The clinical pregnancy
rate for standard care (19/69 28%) was not signicantly different
from the clinical pregnancy rate for standard care plus metformin
(26/67 39%) (P 0.16).
Secondary outcomes
There were no signicant differences in spontaneous abortion rates
(prior to 20 weeks) between women receiving different treatments;
there were no late pregnancy losses (after 20 weeks) and too few
ectopic pregnancies on the trial to yield useful comparisons. Four
women delivered twins, all from different treatment groups and two
of these women had not received CC treatment.
Although the ovulation rate appeared lower in women with BMI .
32 kg/m2, the ovulation rates were relatively similar in the respective
treatment groups within each BMI category (Table II).
The monitoring (undertaken to minimize the risk of high order mul-
tiple pregnancy in women taking clomiphene) revealed that seven
women had a serum estradiol level .2500 pmol/l, all of whom had
vaginal ultrasound scans, from whom three continued without the
need for further intervention, three were prescribed progestogen emer-
gency contraception and one was advised to avoid sexual intercourse for
1 week. All seven women with high serum estradiol were receiving CC
(three of whom were receiving combination CC/metformin).
Adverse events and pregnancy complications
Table III expresses adverse events and pregnancy complications. Other
than two ectopic pregnancies that occurred in a woman of BMI .
32 kg/m2 receiving placebo and a women of BMI 32 kg/m2 receiving
CC plus metformin and one termination of pregnancy undertaken at
gestation 23 weeks for fetal hypoplastic heart in a women of BMI
32 kg/m2 who had received CC treatment, there were no other
serious adverse events. The overall incidence of women with BMI .
32 kg/m2 experiencing side effects was 42% in those receiving
1678 Johnson et al.

Table I Baseline characteristics of the populations.

BMI > 32 BMI 32

...................................... ...........................................................................
Placebo Metformin Clomiphene Metformin Clomiphene
(n 5 33) (n 5 32) citrate (n 5 35) citrate 1 metformin
(n 5 36) (n 5 35)
.............................................................................................................................................................................................
Mean age in years (SD) 29.2 (4.2) 29.5 (4.3) 28.2 (4.0) 28.9 (4.4) 29.2 (4.7)
Ethnicity (%)
Maori 6 (18) 7 (22) 3 (8) 4 (11) 7 (20)
Pacic 8 (24) 5 (16) 2 (6) 1 (3) 2 (6)
European 16 (48) 16 (50) 21 (58) 19 (54) 15 (43)
Chinese 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Indian 2 (6) 2 (6) 8 (22) 7 (20) 8 (23)
Other Asian 0 (0) 0 (0) 1 (3) 4 (11) 2 (6)
Other 1 (3) 1 (3) 1 (3) 0 (0) 1 (3)
Mean body mass index (SD) (kg/m2)

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37.6 (3.2) 38.0 (3.9) 26.2 (3.4) 26.5 (3.5) 26.9 (4.1)
Smoking status (%)
Ex-smoker 7 (21) 11 (34) 5 (14) 5 (14) 3 (9)
Current smoker 6 (18) 5 (16) 4 (11) 4 (11) 5 (14)
Ovarian ultrasound showing PCO (%) 26 (79) 25 (78) 28 (78) 31 (89) 29 (83)
Biochemical androgen excess* (%) 24 (75) 22 (73) 25 (71) 23 (66) 25 (71)
Hyperandrogenism (%) 30 (91) 29 (94) 34 (94) 31 (89) 32 (91)
Both PCO and hyperandrogenism (%) 24 (73) 23 (72) 26 (72) 28 (80) 24 (69)
Mean total testosterone (SD) (nmol/l) 2.76 (1.19) 2.62 (1.06) 2.97 (1.29) 2.92 (1.53) 2.89 (1.39)
Mean free testosterone (SD) (pmol/l) 70.6 (34.3) 63.0 (30.3) 70.0 (41.4) 66.3 (40.5) 65.2 (39.5)
Mean fasting insulin (SD) (pmol/l) 18.3 (10.8) 18.0 (12.7) 10.7 (6.0) 10.4 (6.5) 10.3 (6.5)
Mean FSH (SD) (IU/l) 4.70 (1.66) 5.21 (1.42) 5.16 (1.53) 4.80 (1.86) 5.29 (2.05)
Previous tubal patency test (%)
Laparoscopy 29 (88) 27 (84) 30 (83) 34 (97) 31 (89)
HSG 1 (3) 5 (15) 4 (11) 1 (3) 1 (3)
Both laparoscopy and HSG 2 (6) 0 0 0 3 (9)
Other 1 (3) 0 2 (6) 0 0
Minimal or mild endometriosis 1 0 3 1 0
Partners mean sperm count geometric mean (95% CI) 76 (16, 357) 67 (17, 263) 55 (15, 197) 77 (20, 294) 79 (23, 272)
(million/ml)
Nulligravid (%) 18 (55) 23 (72) 28 (78) 22 (63) 23 (66)
Nulliparous (%) 24 (73) 27 (84) 33 (92) 27 (77) 28 (80)
Months infertility-overall median (IQR) 41 (2460) 39 (2972) 24 (12 36) 18 (12 48) 24 (1860)
Fertility delay less than 12 months 1 0 1 3 1
Previous treatment with study drug (%)
Clomiphene citrate 8 (24) 4 (13) 2 (6) 7 (20) 5 (14)
Metformin 8 (24) 3 (9) 3 (8) 3 (9) 4 (11)

*Biochemical androgen excess included women with total testosterone .2.5 nmol/l or free testosterone .50 pmol/l.

Hyperandrogenism included either biochemical androgen excess or symptoms of hyperandrogenaemia (including hirsutism and acne).

placebo and 41% in those receiving metformin; among women with
BMI 32 kg/m2, 31% with CC, 43% with metformin and 54% with
CC plus metformin. The overall number of women experiencing side
effects did not differ signicantly between the ve different treatment
groups (P 0.51) and this was also true for gastrointestinal side
effects (P 0.23). Only two women reported vasomotor side
effects. Of the 45 women having a live birth, one developed gestational
diabetes, three developed a hypertensive disorder of pregnancy and
three had a preterm delivery (ranging from gestation 3236 weeks).
Discussion
Our trial did not demonstrate any additional benet from metformin
added to standard treatment for ovulation dysfunction in PCOS-
Multicentre RCT metformin and clomiphene in PCOS
Figure 1 Flow of participants through the trial.
related infertility. There was no evidence of differences in adverse
events between treatment groups. Another nding (although based
only on pilot data of small numbers) was the very similar clinical preg-
nancy and live birth rate among women with BMI 32 kg/m2 treated
with CC compared with those treated with metformin.
The strengths of this trial are that it was a multi-centre RCT with a
highly secure method of allocation concealment (third party computer
randomization by a telephone call to the pharmacy) and a placebo-
controlled maintenance of blinding of all parties. Although it may
have been possible for participants to guess what treatment they
were receiving based on medication side effects, it was interesting
to note that more women taking placebo stopped treatment owing
to gastrointestinal side effects than those taking metformin. A
further strength was the categorization according to BMI, as there is
a suggestion that these ovulation induction treatments have differential
effectiveness in women of different BMIin the case of this trial the
cut-off was BMI 32 kg/m2, the threshold below which New Zealand
women qualify for government funded fertility treatment (Farquhar
1679
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and Gillett, 2006; Gillett et al., 2006) rather than the World Health
Organization-dened BMI 30 kg/m2 cut-off, above which an individual
is dened as obese. The main weakness was that the trial was insuf-
ciently powered to detect what many would regard as a clinically
meaningful differencein order to detect an increase in live birth
from 20 to 30% by adding metformin to standard care (80% power
at 95% condence level), 590 participants would have been required
for this comparison (as opposed to the 136 participants contributing
to this comparison in our trial, which exceeded the power to detect
an increase in pregnancy rate from 30 to 55%, established a priori
by Johnson, 2006). Other points that may be considered weaknesses
include the BMI dichotomy of BMI 32 kg/m2 arising from a local policy
thus potentially limiting generalizability, the absence of data linking
outcomes to womens weight loss whereas on the trial and the fact
that the metformin only treatment arm in the BMI 32 kg/m2 sub-
population can provide only pilot data that need to be combined
with data from other trials to give sufcient power for meaningful
comparisons.
1680
Table II Outcomes in each treatment group.
BMI > 32
...........................................
Placebo Metformin
(n 5 33) (n 5 32)
.............................................................................................................................................................................................
Clinical Pregnancy 5 7
Live birth 2 5
Spontaneous abortion , 20 weeks 2 1
Fetal loss 20 weeks 0 0
Ectopic pregnancy 1 0
Termination 0 0
Multiple pregnancy 1 0
Ovulation conrmed (+suggestive) 13 (+4) 17 (+2)
*Termination of pregnancy for fetal hypoplastic heart at gestation 23 weeks.
One patient was lost to follow-up while pregnant, so does not appear as a live birth, as the pregnancy outcome was unknown.
Ovulation was dened as conrmed based either on pregnancy or a serum progesterone level .25 nmol/l (and suggestive of ovulation if serum progesterone was 15 25 nmol/l). Note
that the outcome ovulation (conrmed and suggestive) was collected per randomized participant and the actual number of ovulatory and anovulatory cycles were not collected as
outcome data.
Our results are in keeping with other RCTs that have not shown sig-
nicant benet from use of combination CC plus metformin versus CC
alone (Moll et al., 2006; Legro et al., 2007; Zain et al., 2008). It is worthy
of debate whether detection smaller differences is important, as all
RCTs undertaken thus far have been underpowered to detect less
than a 15% difference in live birth rate, yet other second line treatments
(such as gonadotrophin injections) substantially increase costs and inva-
siveness. We did not explore, in the lower BMI group, whether pre-
treatment with metformin might improve fertility outcomessome
authors have suggested that the optimal effect of metformin is achieved
after 46 months pretreatment (Baillargeon et al., 2004; Palomba et al.,
2005). It remains true that current RCT evidence suggests that CC is a
superior treatment to metformin for obese women (Legro et al., 2007;
Zain et al., 2008), although our RCT did not specically examine this
comparison in the BMI . 32 kg/m2 group, but many authorities have
questioned the appropriateness of administering ovulation induction
treatment to women with obesity (Balen et al., 2006; Lord and
Norman, 2006), the obstetric risks (both maternal and fetal) being par-
ticularly relevant in the context of gross obesity (Stotland, 2008).
However, it is unclear why the results of our New Zealand multi-centre
RCT, the American multi-centre RCT data for the non-obese subpopu-
lation of women (Table 1 of Supplementary Appendix of Legro et al.,
2007, available at www.nejm.org that showed a signicant advantage
of CC) and the Italian RCT that showed a signicant advantage of met-
formin (Palomba et al., 2005) were so heterogeneous in the comparison
metformin versus CC for non-obese women. Whether these dramati-
cally different results could relate to dose of metformin used, the failure
to adjust metformin dose according to BMI, the preparation used (for
example, a sustained release metformin was used in the American
trial; Legro et al., 2007), where the outcomes from metformin treat-
ment were particularly poor or fundamental differences in the popu-
lations studied in terms of their response to metformin, remains
unclear.
Our results for early pregnancy loss for women with BMI 32 kg/m2
(four from 14 metformin pregnancies versus none from 14 CC
Johnson et al.
BMI 32
.....................................................................................
Clomiphene Metformin Clomiphene
citrate (n 5 36) (n 5 35) citrate 1 metformin
(n 5 35)
14 14 19
13 10 15
0 4 3
0 0 0
0 0 1
1* 0 0
1 1 1
23 (+2) 23 (+0) 27 (+1)
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pregnancies) are noteworthy, although based on small numbers.
Legro et al. (2007) had similarly higher results for rst trimester losses
with metformin (40.0%) than CC (22.6%), but Palomba et al. (2005)
had a lower rate of pregnancy loss in women treated with metformin
(9.7%) than CC (37.5%). All these trials had a policy of stopping metfor-
min once pregnancy was diagnosed. Whether continuation of metfor-
min through the rst trimester might lower the pregnancy loss rate
among women becoming pregnant with metformin treatment is merit-
worthy of further investigation in robust RCTs.
There is perhaps a paradox that metformin is known to give poor
results for women with PCOS-related anovulatory infertility and
obesity (Tang et al., 2006), where insulin resistance tends to be more
pronounced, yet we have found that the results for women with
PCOS and BMI 32 kg/m2 are as good for metformin as for CC.
Our results challenge the consensus statement that metformin should
be restricted to women with known glucose intolerance (The
Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Group, 2008; Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus
Workshop Group, 2008). The main disadvantage of metformin appears
to be a high incidence of gastrointestinal side effects, but other studies
have shown numerous potential advantages of metformin over CC.
These include no known adverse endometrial effect whereas endo-
metrial thinning could reduce embryo receptivity for some women
using CC (Gonen and Casper, 1990; Wu et al., 2007), no known
increase in multiple pregnancy rate unlike that associated with CC and
thus no requirement for inconvenient and costly monitoring of ovulation
induction cycles that many fertility clinics insist upon for CC, no concern
over long-term adverse effects on the ovaries such as the lingering
concern over increased risk of ovarian cancer seen in some cohort
studies of women using CC, particularly serous ovarian cancer (Jensen
et al., 2009) and among those using long treatment courses (Rossing
et al., 1994). Nonetheless CC has had remarkable longevity as the rst
line treatment for anovulatory PCOS and doubtless will continue to
have an important place (Homburg, 2005). Such considerations
suggest that metformin is a perfectly reasonable alternative choice to
 Multicentre RCT metformin and clomiphene in PCOS
Table III Women experiencing adverse events.

BMI > 32 BMI 32

.................................................................... .................................................................................................................................................
Placebo (n 5 33) Metformin (n 5 32) Clomiphene citrate Metformin (n 5 35) Clomiphene citrate 1 metformin (n 5 35)
(n 5 36)
..........................................................................................................................................................................................................................................................
Women experiencing:
Serious adverse 1 0 1 0 1
events*
Moderate adverse 1 3 4 2 (1 woman had 3 events) 3
events
Mild adverse events 13 (4 women had 3; 5 12 (1 woman had 3; 3 9 (3 women had 3; 2 14 (1 woman had 4; 5 women 17 (3 women had 3; 3 women had 2 events)
women had 2 events) women had 2 events) women had 2 events) had 3; 1 woman had 2 events)
Between severity A woman with 3 mild events 1 woman had 1 moderate 2 women had 3 mild and 1 1 woman had 1 moderate and 1 1 woman had 2 mild and 1 moderate event; the woman
category combinations also had a moderate event and 1 mild event moderate event mild event with the severe event also had a moderate event
Women experiencing no 19 19 24 20 16
adverse events
Women having specic side effects:
GI 11 10 5 13 11
Vasomotor 0 0 0 1 1
Women having pregnancy-related complications
Ectopic pregnancy 1 0 0 0 1
Major fetal 0 0 1 0 0
abnormality
Gestational 0 0 2 0 1
hypertension
Gestational diabetes 0 0 0 0 1
Preterm labour or 1 0 1 0 1
PPROM

*Women appearing in the table with severe side effects may also appear in the table as having moderate and mild side effects.

1681
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1682
CC as rst line for ovulation induction for women with ovulation dysfunc-
tion related to PCOS in the absence of obesity and this debate should
not be closed.
Conclusion
There is no evidence that adding metformin to standard care is ben-
ecial in improving pregnancy and live birth rates for women with ano-
vulatory PCOS.
Authors roles
N.J. designed the study, took principal investigator responsibility
throughout, wrote the manuscript and is the guarantor of the
research. A.S. was the trial statistician and was responsible for data
analysis. J.F. was the co-ordinating research nurse for the study.
C.F., S.M., V.P.S. and K.B. commented on study design and were
involved in patient recruitment. Q.O. designed the trial database
and assisted with data monitoring. All authors commented on the
nal manuscript.
Acknowledgements
We thank all staff at Fertility Plus, Auckland and the following individ-
uals for their contribution: Marian Carter, Nichola Giblet, Guy Gudex,
Sonya Jessup, John Hutton, Deidre Jones, Megan Ogilvie, Ingrid Quick-
fall, Greg Phillipson, Bruno Radesic, Debbie Richards, Leanne Ryan,
Andrew Shelling.
Conict of interest. N.P.J. reports receiving travel support from
Serono, Organon, Bayer-Schering, Device Technologies New
Zealand and funding for a research meeting from Serono. V.P.S.
reports receiving travel support from Serono.
Funding
Supported by grants from Auckland Medical Research Foundation,
Mercia Barnes Trust and University of Auckland Research Committee.
The funders played no role in the design, the conduct of the research
or the decision to publish. The researchers maintained complete inde-
pendence from the funders. The Data Safety Monitoring Committee
of the Health Research Council of New Zealand provided data moni-
toring support.
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