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Clinical Endocrinology (2009) 70, 311–321 doi: 10.1111/j.1365-2265.2008.03369.

ORIGINAL ARTICLE

Clomiphene citrate, metformin or both as first-step approach


Blackwell Publishing Ltd

in treating anovulatory infertility in patients with polycystic


ovary syndrome (PCOS): a systematic review of head-to-head
randomized controlled studies and meta-analysis
Stefano Palomba*, Renato Pasquali†, Francesco Orio Jr‡ and John E. Nestler§

*Chair of Gynecology & Obstetrics, University ‘Magna Graecia’ of Catanzaro, Italy, †Chair of Endocrinology, University of
Bologna, Italy, ‡Endocrinology, Faculty of Exercise Sciences, University ‘Parthenope’ of Naples, Italy, §Division of Endocrinology
and Metabolism, Virginia Commonwealth University, Richmond, VA, USA

(Received 14 April 2008; returned for revision 27 April 2008; finally


Summary revised 2 May 2008; accepted 31 July 2008)

Background To date, no systematic review or meta-analysis has been


published of direct head-to-head studies comparing clomiphene
citrate (CC) vs. metformin, or the combination of both drugs as Introduction
first-line therapy in anovulatory polycystic ovary syndrome (PCOS)
patients seeking pregnancy. The aim of the current paper was to The polycystic ovary syndrome (PCOS) is a multifaceted disease
define, if possible, the best evidence-based recommendations regarding characterized by clinical or biochemical androgen excess and/or
the use of CC and/or metformin as the initial treatment of PCOS chronic anovulation and/or polycystic ovaries on ultrasonography.1
women with anovulatory infertility. PCOS is the most common cause of anovulatory infertility, affecting
2–4
Design Systematic review and meta-analysis of the head-to-head approximately 5–10% of women of reproductive age.
randomized controlled trials (RCTs) available in the literature. Administration of clomiphene citrate (CC) is the standard
Methods A bibliographic search was performed using the following treatment for PCOS patients with anovulatory infertility.5
bibliographic databases: Medline, EMBASE, Biological Abstracts, More recently, metformin, a biguanide and insulin-sensitizing
Cochrane Controlled Trials Register and Cochrane Database of drug used in the treatment of type 2 diabetes mellitus, has been
Systematic Reviews. Reference lists of included studies, other introduced for the treatment of chronic anovulation in PCOS.6
7–12
relevant review articles and textbooks were checked for additional Several systematic reviews and a meta-analyses have evaluated
citations of interest. the efficacy of metformin in the treatment of anovulation because
Results Four head-to-head RCTs were identified and qualified of PCOS. The unanimous conclusion of these reviews7–12 was that
for inclusion in the analysis. No difference in fertility improvement metformin monotherapy represents a safe and valid therapeutic
was observed comparing CC with metformin (OR = 1·22, 95% CI option for improving ovulation in PCOS patients. However, no
0·23– 6·55, P = 0·815), whereas a significant (P < 0·0001) heterogeneity significant effect on pregnancy or live birth was demonstrated, likely
was observed. Homogeneous data showed no difference in fertility because the studies were short-term, did not control for other causes
improvement between the combination treatment and CC monotherapy of infertility, and did not have pregnancy7–9 nor live birth10 as an
(OR = 0·99, 95% CI 0·70–1·40, P = 0·982), but a significant difference outcome measure.
in comparison with metformin monotherapy (OR = 0·23, 95% CI Metformin has been also administrated in association with CC to
0·14–0·37, P < 0·0001). improve the efficacy of CC alone in CC-resistant and not resistant
Conclusions In PCOS patients with anovulatory infertility and patients. Furthermore, although the combination of metformin with
not previously treated, the administration of metformin plus CC is CC resulted in a higher ovulation rate, the analysis was robust only
not better than monotherapy (metformin alone or CC alone), in those women who had been previously resistant to CC.7–9,11 In
whereas to date no specific recommendation can be given regarding particular, Siedert et al.10 confirmed the efficacy of metformin in
the use of CC or metformin as first-step drug. improving ovulation in a population of CC-resistant PCOS women
with an odds ratio (OR) of 6·82 [95% confidence interval (CI) of
3·59–12·96 (P < 0·00001)]. However, no satisfactory meta-analysis
Correspondence: Stefano Palomba, Chair of Gynecology & Obstetrics,
University ‘Magna Graecia’ of Catanzaro via Tommaso Campanella 182/I, has been reported evaluating the efficacy of combined metformin
88100 Catanzaro, Italy. Tel.: +39 3475880 503; Fax: +39 0961961 820; and CC in anovulatory PCOS women with CC sensitivity not
E-mail: stefanopalomba@tin.it defined and/or naïve for any treatment.

© 2009 The Authors


Journal compilation © 2009 Blackwell Publishing Ltd 311
312 S. Palomba et al.

A previous meta-analysis11 aimed to evaluate the effect on two reviewers were resolved by discussion and final decision by the
live-birth rate of metformin, CC or both drugs in therapy naïve first author (S.P).
PCOS patients was published. Furthermore, some studies included
in that meta-analysis did not evaluate the live birth rate,13–16 whereas
Study populations
in others16,17 metformin pretreatment was scheduled. In addition,
the conclusions on metformin vs. CC comparison were drawn using The population consisted of women with well defined diagnosis
data analysed with a fixed effects models,17 even if a significant data of PCOS based on the presence of chronic oligo-anovulation
heterogeneity was detected in both pregnancy and live-birth rates. and/or clinical/biochemical hyperandrogenism and/or ovarian
Recently, a RCT18 comparing CC, metformin or the combination morphology on ultrasonography [National Institute of Health
of both in Asian women with PCOS was published and that data has (NIH)19 and the European Society for Human Reproduction and
not been included in any of the previous meta-analyses.7–12 Embryology/American Society of Reproductive Medicine (ESHRE/
To date, no systematic review or meta-analysis was specifically ASRM)1] or other not validated criteria and who were treated for
aimed to evaluate the reproductive efficacy of CC, metformin, or anovulatory infertility.
the combination of both drugs as first-line therapy in anovulatory All selected studies included the following information:
PCOS patients seeking pregnancy using head-to-head comparisons. demographic characteristics [specifically, age and body mass index
Based on these considerations, the aim of the present report was to (BMI)], criteria used to diagnose PCOS (chronic oligo-anovulation,
search and review systematically all RCTs available in the literature oligo-amenorrhea, biochemical/clinical hyperandrogenism, polycystic
to define, if possible, the best evidence-based recommendations ovary at ultrasound), dosages and protocols used for administered
regarding the use of these drugs administered alone or in com- drugs, previous treatment(s) for inducing ovulation, presence of
bination as initial treatment of PCOS women with anovulatory glucose intolerance or diabetes mellitus, exclusion of male or tubal
infertility. factors of infertility and/or subfertility.

Materials and methods Interventions

Three different types of interventions were analysed: CC vs.


Ethics
metformin, CC plus metformin vs. CC, and CC plus metformin vs.
No institutional review board approval was required because only metformin. All dosages and schedules for CC and metformin admin-
published data were analysed. istration are included in the present review.

Search strategy Endpoints

A bibliographic search was performed using the following search Our primary end-point was the live birth rate.20 Secondary end-points
terms: ‘anovulation’, ‘infertility’, ‘polycystic ovary syndrome’, ‘PCOS’, were the rates of ovulation, pregnancy, abortion and discontinuation
‘sterility’; exposure: ‘antiestrogens’, ‘clomiphene citrate’, ‘insulin- for adverse events.
sensitizing drug’, ‘metformin’, ‘ovulation induction’; and outcome of
interest ‘abortion’, ‘adverse events’, ‘compliance’, ‘live birth’, ‘menses’,
Studies’ quality
‘menstruation’, ‘ovulation’ and ‘pregnancy’. To eliminate bias, no
study filter or language limit was applied. Quality of the included trials was assessed using the Cochrane
21
The following bibliographic databases were searched: Medline guidelines. The following characteristics were assessed for each
(from January 1966 to January 2008), EMBASE (from January study: allocation concealment, blinding, intention-to-treat (ITT)
1980 to January 2008), Biological Abstracts, Cochrane Controlled analysis and follow-up. The allocation concealment was graded
Trials Register and Cochrane Database of Systematic Reviews. as adequate (A), unclear (B), or inadequate (C) according to criteria
Reference lists of included studies, other relevant review articles provided by the Cochrane Menstrual Disorders and Subfertility
and textbooks were checked for additional citations of interest. Group.22 Blinding was reported as yes/no/not reported for investi-
Titles and abstracts were screened and potential relevant articles gators, patients, outcome assessors, or data analysts. The use of ITT
were identified. Bibliographies of review and retrieved studies analysis was recorded and coded as yes/no. Finally, the follow-up
also were searched for candidate articles. Successively, identified period was also reported.
articles were reviewed for inclusion and exclusion criteria.
The search was run every 3 weeks between January 2008 and
Statistical analysis
March 2008 to identify new articles.
Only RCTs were identified and head-to-head studies were The outcome measures, defined as dichotomous data, were the pro-
selected for the analysis. Specifically, retrospective, case–control, portions of patients reporting ovulation, pregnancy, abortion, live
nonrandomized and quasi-randomized trials and case reports/series birth and discontinuation for adverse events, respectively. The analysis
were excluded. Two independent reviewers, not blinded at any point of treatment effect was performed on an ‘ITT basis’ considering
to the authors or sources of publication, identified and selected dropouts and missing data as treatment failures and ‘per-protocol
the RCTs that met the inclusion criteria. Disagreements between the basis’ considering the results from evaluated patients alone.

© 2009 The Authors


Journal compilation © 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 70, 311–321
First-step approach for anovulatory PCOS 313

Fig. 1 Trial flow chart.

13–15,18,24–26
Results for each study were expressed as OR with 95% CI Seven RCTs met the initial eligibility criteria. Given
and combined for meta-analysis to calculate a pooled estimate of our primary end-point,20 three studies13–15 were excluded, as the
treatment effect for each outcome across studies. treatment effectiveness on live-births was not analysed.
To measure the heterogeneity (the variation in study outcomes Thus, a total of four RCTs18,24–26 were included and analysed
between studies), we used Cochran Q-test, which is calculated as the in the present systematic review. Table 1 summarizes the quality of
weighted sum of squared differences among individual study effects the RCTs enclosed.
and the pooled effect across studies, with the weights being those All four articles18,24–26 were published in the English language
used in the pooling method. A Cochran Q-test P = 0·05 represents between 2005 and 2008 in international journals of very good
statistical homogeneity. quality, i.e. The Journal of Clinical Endocrinology and Metabolism,
For data with statistical homogeneity, the Mantel–Haenszel The British Medical Journal, The New England Journal of Medicine
method was used for calculating the weighted summary OR under and Fertility and Sterility, as defined by high impact factors and
the fixed effects model. On the other hand, the random-effects model their ranking in the Journal Citation Report (JCR). Two studies were
of meta-analysis was used in the presence of unexplained statistical performed in Europe,24,25 one in the United States (U.S),26 and one
heterogeneity. in Asia.18 The allocation concealment was adequately explained in
A P-value < 0·05 of 95% CI not containing 1·0 OR was considered all studies. Treatment was blinded to both patients and investigators
statistically significant. in three studies,24–26 whereas in one study18 neither investigators
The statistical analysis was performed by use of StatsDirect nor patients were blinded to the treatments. In only one study,26 data
software (release 2·6·2, 19 February 2007). analysis followed the ITT principle. Two studies24,26 had a six-month
follow-up period followed by nine-month extension in pregnant
patients to evaluate live births, whereas only a six-month follow-up
Results
was provided for the other two studies.18,25
The flow-chart of the study selection according to Quality of Report- The characteristics of the included populations are summarized
ing of Meta-analyses (QUOROM) guidelines23 is shown in Fig. 1. in Table 2. Whereas, the treatments received were shown in Table 3.

© 2009 The Authors


Journal compilation © 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 70, 311–321
314 S. Palomba et al.

Table 1. Quality assessment of the included RCTs

Study Year of publication Country Allocation concealment Blinding ITT Follow-up

A: Adequate A: Investigators
B: Unclear B: Patients
C: inadequate C: Outcome assessors
Palomba et al.24 2005 Italy A A: Yes No Six cycles plus 9-
B: Yes month extension for
C: Not reported pregnant patients
Moll et al.25 2006 The Netherlands A A: Yes No Six cycles
B: Yes
C: Not reported
Legro et al.26 2007 United States A A: Yes Yes Six cycles plus 9-
B: Yes month extension for
C: Yes pregnant patients
Zain et al.18 2008 Asia A A: No No Six cycles
B: No
C: No

ITT, intention-to-treat; RCTs, randomized controlled trials.

and metformin group, respectively). No drop-out because of


Outcomes
drug-related side-effects was observed in the study by Zain et al.18
The analysis of treatment effect was performed both on an ‘ITT basis’
and ‘per-protocol basis’, and no difference was detected. Therefore,
Meta-analysis
only the meta-analyses on a ‘per-protocol’ are shown.
18,24,26
When the data of these studies were combined, the effect
of metformin did not differ from CC with respect to cumulative
CC vs. metformin
ovulation rate (OR = 1·55, 95% CI 0·40–5·99, P = 0·527), pregnancy
18,24,26
Three RCTs evaluated the efficacy of CC vs. metformin. rate (OR = 1·22, 95% CI 0·23–6·55, P = 0·815), or live birth rate
(OR = 1·17, 95% CI 0·16–8·61, P = 0·881) (Fig. 2). However, significant
(P < 0·0001) heterogeneity was detected for all three end-points
Descriptive data
(Fig. 2).
In the study by Palomba et al.,24 the cumulative ovulation rate was Similarly, the effect of metformin did not differ from CC with
similar in women treated with CC or metformin (62·0% vs. 84·0%, respect to the rates of abortion (OR = 1·58, 95% CI 0·77–3·25,
respectively), whereas the pregnancy rate was higher (32·0% vs. P = 0·219) or of discontinuation for adverse events (OR = 0·71,
62·0%, respectively) and the abortion rate was lower (12·0% vs. 95% CI 0·22–2·25, P = 0·765) (Fig. 2). For these two parameters
6·0%, respectively) in women treated with metformin compared no significant heterogeneity (P = 0·219 and 0·765, respectively) was
with those treated with CC. There was no statistical difference in live detected (Fig. 2).
births (18·0% vs. 5·2%, respectively) in women treated with CC vs.
metformin although a trend (P = 0·07) favouring the metformin
Metformin plus CC vs. CC
group was present.
The subsequent study by Legro et al.26 reported markedly different Three RCTs evaluated the efficacy of metformin plus CC vs.
results. In this study, CC was markedly superior to metformin in CC.18,25,26
increasing cumulative ovulation rate (75·1% vs. 55·3, respectively),
pregnancy (29·7% vs. 12·0%, respectively) and live births (22·5% vs.
Descriptive data
7·2%, respectively). There was no significant difference in abortions
(22·5% vs. 7·2%, respectively) between CC and metformin. The combination of metformin plus CC was no more effective
Lastly, in the study by Zain et al.18 the cumulative ovulation rate than CC alone in inducing ovulation in the study by Moll et al.25
was higher in CC than metformin (59·0% vs. 23·7%, respectively), (64·0% vs. 71·9%, respectively) and by Zain et al.18 (68·4% vs. 59·0%,
whereas no differences between groups was reported in pregnancy respectively), whereas in the study by Legro et al.26 the combination
(15·4% vs. 7·9%, respectively) and live births (15·4% vs. 7·9%, was significantly (P = 0·041) more effective than CC alone (83·3%
respectively). No abortion was reported in any group. vs. 75·1%, respectively).
The rate of discontinuation for adverse events was similar Combination therapy was no better than CC alone with regard
between treatments in both studies by Palomba et al.24 (2·0% for to rates of pregnancy [(39·6% vs. 45·6%, respectively) and (38·3%
each treatment arm) and Legro et al.26 (1·9% vs. 2·9% for CC vs. 29·7%, respectively)], abortion [(11·7% vs. 10·5%, respectively)

© 2009 The Authors


Journal compilation © 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 70, 311–321
© 2009 The Authors
Fig. 2 Comparison CC vs. metformin.

Journal compilation © 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 70, 311–321
Table 2. Characteristics of the included populations

Previous infertility
2
Study Primary end-point Sample (n) Diagnosis of PCOS Age (years) BMI (kg/m ) Insulin resistance treatments Exclusion of other causes for infertility/sub-fertility

Palomba et al.24 Pregnancy rate 100 NIH criteria (1992) 20–34 < 30 Not excluded None – Exclusion of suspected peritoneal factor infertility
– Exclusion of tubal and male factor infertility or sub-fertility
Moll et al.25 Ovulation rate 225 ESHRE/ASRM (2004) < 40 No limit Not excluded Not excluded – Exclusion of male factor subfertility/infertility
No assessment of tubal patency
Legro et al.26 Live-birth rate 626 – Oligomenorrhea No limit No limit Not excluded Not excluded – Exclusion of uterine cavity diseases
– Hyperandrogenemia – Exclusion of tubal and male factor infertility or sub-fertility
Zain et al.18 Ovulation rate 115 ESHRE/ASRM (2004) < 40 No limit Not excluded Not excluded – Exclusion of male factor subfertility/infertility
No assessment of tubal patency

BMI, body mass index; ESHRE/ASRM, European Society for Human Reproduction and Embryology/American Society of Reproductive Medicine; NIH, National Institute of Health.
First-step approach for anovulatory PCOS 315
316 S. Palomba et al.

Table 3. Interventions

Study Comparisons Protocol Duration

Palomba et al.24 CC vs. metformin Metformin: 850 mg twice daily 6 months


CC: fixed dose, 150 mg daily (from 3rd to 8th day of the cycle)
Moll et al.25 CC plus metformin vs. CC Metformin: step-up dose (up to 2000 mg daily) 6 months
CC: incremental dose (starting with 50 mg daily up to 150 mg/daily)
Legro et al.26 Metformin vs. CC vs. metformin plus CC Metformin: extended release, step-up dose (up to 2000 mg daily) 6 months
CC: incremental dose (starting with 50 mg daily up to 150 mg/daily)
Zain et al.18 Metformin vs. CC vs. metformin plus CC Metformin: step-up dose (up to 1500 mg daily) 6 months
CC: incremental dose (starting with 50 mg daily up to 200 mg/daily)

CC, clomiphene citrate.

and (9·6% vs. 6·7%, respectively)] and live birth [(18·9% vs. 26·3%, Combination therapy was more effective than metformin alone
respectively) and (26·8% vs. 22·5%, respectively)] in the study by with regard of pregnancy (38·3% vs. 12·0%, respectively) and live
Moll et al.25 and Legro et al.26, respectively. Similar results in terms birth (26·8% vs. 7·2%, respectively) rates in the study by Legro
of pregnancy (21·1% vs. 15·4%, respectively), abortion (12·5% vs. 0·0%, et al.,26 whereas no differences in pregnancies (21·1% vs. 7·9%,
respectively) and live birth rates (18·4% vs. 15·4%, respectively) were respectively) and live births (18·4% vs. 7·9%, respectively) were
also reported by Zain et al.18 observed in the study by Zain et al.18 No differences in the abortion
Finally, no difference in rate of discontinuation for adverse events rate [(9·6% vs. 4·8%) and (12·5% vs. 0·0%)] were observed between
was recorded between treatments in the study by Legro et al.26 (3·3% the two treatments in the studies by Legro et al.26 and Zain et al.,18
vs. 1·9%, respectively) and by Zain et al.18 (none patients in both respectively. In the study by Legro et al.,26 no difference in rate of
groups), whereas the study by Moll et al.25 reported a significantly discontinuation for adverse events (3·3% vs. 1·9%, respectively)
(P < 0·05) higher adverse events rate in patients treated with was noted between patients treated with combined therapy and
combination therapy (16·2% vs. 5·3%, respectively). those treated with metformin alone. In no case, discontinuation for
drug-related adverse events was observed in the study by Zain et al.18

Meta-analysis
Meta-analysis
When the data from these three studies18,25,26 were combined, the
metformin plus CC association was no more effective than CC in When the data from these two studies18,26 were combined, the metformin
inducing ovulation (OR = 0·84, 95% CI 0·60–1·18, P = 0·360), and plus CC association was more effective than metformin alone in
no significant (P = 0·06) heterogeneity was detected (Fig. 3). inducing ovulation (OR = 0·23, 95% CI 0·15–0·34, P < 0·0001), and
Similarly, combination therapy did not differ from CC with no significant (P = 0·330) heterogeneity was detected (Fig. 4).
respect to rates of pregnancy (OR = 0·85, 95% CI 0·62–1·15, Similarly, combination therapy was better than metformin alone
P = 0·326), abortion (OR = 0·74, 95% CI 0·43–1·26, P = 0·273), or with respect to rates of pregnancy (OR = 0·23, 95% CI 0·14 to 0·37,
live birth (OR = 0·99, 95% CI 0·70–1·40, P = 0·982) (Fig. 3). No P < 0·0001) and live birth (OR = 0·23, 95% CI 0·13 to 0·40,
significant heterogeneity (P = 0·326, 0·982 and 0·273, respectively) P < 0·0001) (Fig. 4). No significant heterogeneity (P = 0·622 and
was detected for these three parameters (Fig. 3). 0·465, respectively) was detected for these two parameters (Fig. 4).
Finally, no significant effect of metformin plus CC in comparison Finally, no significant difference between metformin plus CC and
with CC in discontinuation for adverse events (OR = 0·23, 95% CI metformin alone was observed in abortion rate (OR = 0·47, 95% CI
0·04–1·24, P = 0·096) was observed (Fig. 3). However, a significant 0·22 to 1·0, P = 0·069) and discontinuation rate for adverse events
(P = 0·033) heterogeneity was detected (Fig. 3). (OR = 0·86, 95% CI 0·23 to 3·04, P = 0·993) without any significant
heterogeneity (P = 0·820 and 1·0 respectively) (Fig. 4). No significant
heterogeneity was detected.
Metformin plus CC vs. metformin

Two RCTs evaluated the efficacy of metformin plus CC vs.


Discussion
metformin.18,26
This systematic review and meta-analysis evaluated exclusively RCTs
which were head-to-head comparisons between CC, metformin, or
Descriptive data
both as first-line treatment for treating anovulatory infertility in
Both studies by Legro et al.26 and Zain et al.18 showed a clear advantage patients with PCOS having as primary end-point the live-birth rate.
of combination therapy over metformin alone in terms of ovulation Four head-to-head RCTs18,24–26 were identified and qualified for
rate (83·3% vs. 55·3% and 68·4% vs. 23·7%, respectively). inclusion; one study26 assessed about three-fold more women than the

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First-step approach for anovulatory PCOS 317

Fig. 4 Comparison metformin plus CC vs. metformin.

other three studies combined.18,24,25 The meta-analysis evaluated


Fig. 3 Comparison metformin plus CC vs. CC. separately the efficacy of mono- and combined therapies. Clear
results were obtained regarding the use of combined therapies as
first-step approach for treating anovulatory infertility in PCOS
patients, whereas the efficacy of monotherapies was uncertain.

© 2009 The Authors


Journal compilation © 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 70, 311–321
318 S. Palomba et al.

Three RCTs18,24,26 were head-to-head comparisons between Tubal patency was not evaluated in the studies by Moll et al.25 and
metformin and CC for treating therapy naive PCOS patients Zail et al.18 Women with only one patent fallopian tube and patients
with ovulatory infertility. The meta-analysis revealed that metformin having a partner with a sperm concentration of at least 20 million
and CC did not differ with respect to rates of cumulative ovulation, per millilitre one year before study entry, regardless of motility or
pregnancy, live birth and abortion. However, these findings are morphology, were included in the study by Legro et al.26 The
inconclusive, as significant heterogeneity existed among studies. presence of only one patent fallopian tube can be a potential feature of
Conversely, homogeneous data demonstrated that both drugs were a peritoneal factor of subfertility because of minimal endometriosis31,32
safe; rates of discontinuation for adverse events were low and did not or eventual controlateral hydrosalpinx.31,33 Abnormal sperm motility
differ between treatment groups. or morphology31,34 are potential factors of subfertility.
Although metformin is know to be effective in restoring ovulatory Although Moll et al.25 stated that PCOS was diagnosed using the
menstrual cycles in oligomenorrheic PCOS patients,7–12 two 2003 ESHRE/ASRM criteria,1 enrolment actually started prior to the
RCTs18,26 reveal that the combination of metformin plus CC was validation and publication of the criteria, and the investigators
more effective than metformin alone in terms of ovulation, performed a retrospective analysis on data prospectively collected.35
pregnancy and live birth rates; abortion and discontinuation rates This issue is pivotal, as the proportion of anovulatory patients with
for adverse events did not differ between the two treatment regimens. different PCOS phenotypes may be critical in terms of clinical
No significant heterogeneity was detected. efficacy, as most studies that had demonstrated metformin efficacy
On the other hand, when the data from RCTs18,25,26 comparing assessed PCOS women with biochemical androgen excess.
the metformin plus CC association with CC monotherapy were Another crucial point was the heterogeneity in BMI of the studied
combined, no significant heterogeneity for the main reproductive populations. The population studied by Palomba et al.24 was less
parameters was observed, and the combination therapy was no more representative of the typical PCOS population because obese subjects
effective than CC with respect to rates of ovulation, pregnancy, abortion were excluded and all patients were normal weight or overweight
and live birth. Significant heterogeneity was detected among studies after completion of enrolment. Obesity adversely affects reproduction
regarding abortion and discontinuation rates for adverse events in in PCOS patients36 and metformin may be more effective in
PCOS patients who received metformin with or without CC. nonobese than obese subjects;37 these factors may have contributed
A main drawback in the design of the RCTs that assessed the to metformin’s efficacy in this study.
efficacy of combined CC plus metformin vs. CC18,25,26 or metformin18,26 No limitation for BMI was defined in the other studies18,25,26 and
alone was that metformin was started either concurrently with18,26 the standard deviations of the BMI were wide, suggesting a highly
or after only one month25 of CC initiation rather than after three or heterogeneous population. In particular, the study population in the
more months of pretreatment with metformin. Metformin has a Pregnancy in Polycystic Ovary Syndrome (PPCOS) Trial26 consisted
slower onset of action than CC; hence, the studies as designed were primarily of obese patients; there was a low proportion of lean,
unintentionally biased against demonstrating a value of combining normal-weight or over-weight patients. Hence, the women were
CC with metformin. not representative of all countries. In Europe, particularly in the
The analysis of the studies comparing CC and metformin Mediterranean area, the prevalence of obesity in PCOS patients is
monotherapies27,28 reveals that CC resulted in ovulation more significantly lower than in the US, and there is about a 10-point
rapidly than metformin. This is not surprising, as CC is a fertility difference in BMI among PCOS populations.38 Furthermore, although
drug that acts directly to induce ovulation by provoking an LH surge a large number of severely obese patients were enrolled in the
through its central antiestrogenic action and can be effective in a PPCOS Trial,26,39 no comment was made regarding potential co-
matter of days. In contrast, metformin is a metabolic drug that acts treatments. Obese women are frequently treated with insulin-
indirectly by improving insulin dynamics. Studies27,28 indicate that sensitizing drugs, cholesterol lowering drugs, dietary treatments,
it may take up to 6 months for metformin to exert optimal improve- physical exercise programs, or bariatric surgery; many of these
ment of ovulation. Hence, one can draw the conclusion that if time therapies may influence reproductive outcomes.31,40–42
is of the essence, CC needs to be included in the ovulation induction Lastly, although the RCTs were designed to evaluate the best
regimen. first-step treatment in inducing ovulation in anovulatory PCOS
Alternatively, if time is not of the essence, as may be the case for patients,39 greater than 50% of the population studied by Legro et al.
many PCOS women, a six month trial of metformin remains a had been treated previously with CC, metformin or both.26 This is
reasonable option, and the value of such an approach may be critical because each specific treatment could influence response to
decreased multiparity.29,30 the subsequent one; for example, a single one-cycle treatment with
The most interesting findings of the head-to-head comparison oral contraceptives can improve the efficacy of a subsequent cycle of
between metformin and CC, was the significant heterogeneity CC.43 Also, previous treatment potentially results in the selection of
detected for ovulation, pregnancy and live birth.18,24,26 Why did well patients ‘resistant’ to the treatment or patients who ovulated under
conducted RCTs yield conflicting results? In addition to differences treatment but did not conceive (‘treatment failure’).
in study design, there were also substantive differences in the Given the above, the cycle-by-cycle data analysis performed
populations studied. according to previous treatment is surprising. When analysing the
First, the diagnosis of PCOS-related infertility was controversial. data according to previous CC treatment, no change was observed
Only in the study by Palomba et al.24 were tubal and male factors of in the results, despite the fact that the reported success rate of CC
fertility and subfertility formally excluded by appropriate testing. re-administration in patients with CC-resistance or CC-failure is

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First-step approach for anovulatory PCOS 319

typically low (approximately 10%).44 It is also surprising that but could result in multiparity. If the woman is willing to wait for a
patients with a BMI of 36·0 ± 8·9 (mean ± standard deviation) had few months, metformin could be equally effective.
an ovulation rate of 43·1% using the lowest dose of CC (50 mg daily),
and that there was no significant improvement in reproductive References
outcomes by increasing the CC dosage.44,45 Hence, the women in the
1 The Rotterdam ESHRE/ASRM-Sponsored, PCOS consensus workshop
PPCOS Trial differed in responsiveness to CC from typical PCOS
group (2004) Revised 2003 consensus on diagnostic criteria and
women in the literature.
long-term health risks related to polycystic ovary syndrome (PCOS).
Finally, regarding previous treatments, both CC and metformin Human Reproduction, 19, 41– 47.
could exert sustained salutary effects after discontinuation. High 2 Hull, M.G. (1987) Epidemiology of infertility and polycystic ovarian
concentrations of CC persist for an extended time after treatment disease. Endocrinological and demographic studies. Gynecological
suspension in patients previously treated,46,47 exerting continued Endocrinology, 1, 235 –245.
antiestrogenic action. Similarly, previous metformin administration 3 Frank, S. (1995) Polycystic ovary syndrome. New England Journal of
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of metformin on ovulation can continue for several months after its 4 Azziz, R., Woods, K.S., Reyna, R. et al. (2004) The prevalence and
discontinuation. features of the polycystic ovary syndrome in an unselected popula-
Regarding primary endpoints, two RCTs18,25 were powered to tion. Journal of Clinical Endocrinology and Metabolism, 89, 2745–
2749.
demonstrate a difference only in ovulation rate. As emphasized in
5 Palomba, S., Orio, F. & Zullo, F. (2006) Ovulation induction in
the literature, trials should be designed on the most important
women with polycystic ovary syndrome. Fertility and Sterility, 86,
primary endpoint, which is live birth rate, or lacking that, pregnancy S26 –S27.
rate. This issue is an important consideration given the unexpectedly 6 Velazquez, E.M., Mendoza, S., Hamer, T. et al. (1994) Metformin
low pregnancy rate in anovulatory infertile patients who ovulate therapy in polycystic ovary syndrome reduces hyperinsulinemia,
using CC48,49 and the putative beneficial effects of metformin on insulin resistance, hyperandrogenemia, and systolic blood pressure,
endometrium and oocytes.50–52 while facilitating normal menses and pregnancy. Metabolism, 43,
Regarding treatment schedules and formulations, in the study 647–654.
by Palomba et al.24 both treatments were administered at fixed 7 Costello, M.F. & Eden, J.A. (2003) A systematic review of the reproductive
dosages to simplify the double-blind design. The administration of system effects of metformin in patients with polycystic ovary syndrome.
1700 mg/day metformin at fixed doses can increase the drug-related Fertility and Sterility, 79, 1–13.
8 Lord, J.M., Flight, I.H. & Norman, R.J. (2003) Metformin in polycystic
side-effects without altering the clinical response. Conversely,
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but also efficacy of the treatment.50,53 A subsequent study54 demonstrated as primary therapy for patients with polycystic ovarian syndrome.
the higher safety and effectiveness of CC treatment at incremental Human Reproduction, 19, 2474 –2483.
doses in a similar population. Thus, the study of Palomba et al.24 the 10 Siebert, T.I., Kruger, T.F., Steyn, D.W. et al. (2006) Is the addition of
design was biased in favour of metformin effectiveness because of metformin efficacious in the treatment of clomiphene citrate-resistant
the selection of only normal- and over-weight patients, and to use patients with polycystic ovary syndrome? A structured literature
of a fixed high-dose schedule of CC treatment. review. Fertility and Sterility, 86, 1432–1437.
With regard to formulation, all the RCTs18,24,25 utilized the 11 Moll, E., van der Veen, F. & van Wely, M. (2007) The role of metformin
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© 2009 The Authors


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