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ORIGINAL ARTICLE
Clomiphene citrate alone, in combination with metformin
or in combination with pioglitazone as first line therapy
in induction of ovulation in infertile women with
polycystic ovary syndrome, a randomized controlled trial
Wessam Magdi Abuelghar
a,
*, Osama Saleh Elkady
a
,
Ahmed Abdelmohsen Khamees
b
a
Obstetrics and Gynaecology Department, Ain Shams University, Cairo, Egypt
b
Obstetrics and Gynaecology Department, Nasr City Insurance Hospital, Cairo, Egypt
Received 20 March 2013; accepted 7 May 2013
Available online 31 May 2013
KEYWORDS
Chemical pregnancy rate;
Clomiphene citrate;
Metformin;
Ovulation induction;
Pioglitazone;
Polycystic ovary syndrome
Abstract Study objective: To compare the efficacy of clomiphene citrate (CC) alone, combined
CC and metformin and combined CC and pioglitazone as first line therapy for induction of ovula-
tion and achievement of pregnancy in overweight and obese infertile women due to polycystic ovary
syndrome (PCOS).
Design: A randomized controlled trial.
Setting: The infertility clinic of Ain Shams University maternity hospital.
Materials and methods: 106 overweight and obese women complaining of infertility due to PCOS
were randomly assigned to receive ovulation induction using CC, 100 mg daily for 5 days beginning
on the third day of spontaneous or induced menses, either alone (Group 1) in combination with
metformin, 850 mg twice daily, (Group 2) or in combination with pioglitazone, 30 mg daily, (Group
Abbreviations: ACOG, the American college of obstetricians &
gynecologists; BMI, body mass index; CC, clomiphene citrate;
DHEAS, dehydroepiandrosterone sulfate; FSH, follicle stimulating
hormone; hCG, human chorionic gonadotrophin; LH, luteinizing
hormone; PCO, polycystic ovary; PCOS, polycystic ovary syndrome;
TSH, thyroid stimulating hormone
*Corresponding author. Address: Obstetrics and Gynaecology
Department, Ain Shams University Maternity Hospital, Abbasiya
Square, Cairo, Egypt. Tel.: +20 122 7460679.
E-mail address: dr.awessam@gmail.com (W.M. Abuelghar).
Peer review under responsibility of Middle East Fertility Society.
Production and hosting by Elsevier
Middle East Fertility Society Journal (2013) 18, 135–141
Middle East Fertility Society
Middle East Fertility Society Journal
www.mefsjournal.org
www.sciencedirect.com
1110-5690 Ó2013 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
http://dx.doi.org/10.1016/j.mefs.2013.05.002
3). Folliculometry was started from cycle day 9 and repeated every 2 days. hCG (10000 IU) was
given intramuscular when at least one follicle P18 mm was formed. Serum b-hCG was measured
16 days after hCG injection to diagnose pregnancy.
Main outcome measure: Biochemical pregnancy rate.
Results: There were no statistically significant differences between the three study groups regard-
ing the biochemical pregnancy rates (7.4% (2/27), 11.1% (3/27) and 18.5% (5/27) for groups 1, 2
and 3, respectively) and the number of women who succeeded to have mature follicles (74.1%
(20/27), 74.1% (20/27) and 81.5% (22/27) for groups 1, 2 and 3, respectively).
Conclusion: There is no potential benefit from adding pioglitazone or metformin to CC while
inducing ovulation in overweight and obese women complaining of infertility due to PCOS. Further
larger extended trials are needed to assess using insulin sensitizers for longer duration which could
give a better chance to evaluate the cumulative effect of these drugs.
Ó2013 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
1. Introduction
Polycystic ovary syndrome (PCOS) can be considered as the
most common endocrinological disorder in women with a
prevalence of 6–10% based on the National Institute of Health
criteria and 15% when the broader Rotterdam criteria are used
(1). Several definitions and diagnostic criteria have been used
to describe PCOS; however still oligo/anovulation is consid-
ered as the principal feature of this syndrome (2).
Insulin resistance is an important feature of PCOS and im-
paired glucose tolerance, gestational diabetes mellitus (DM)
and type 2 DM are common association with this syndrome
(3–5). Insulin resistance is a common feature among PCOS
women of normal weight as well as overweight women (6).
10–37% of PCOS women are overweight but not obese while
61–76% of PCOS women in the USA and Australia are obese
(7,8).
Metformin and thiazolidinedione (Glitazones) have been
used to improve insulin sensitivity and reduce insulin resistance.
The first line ovulation induction agents for PCOS infertile wo-
men include clomiphene citrate (CC) (9), metformin (10) as well
as pioglitazone (11) either alone or in combination.
Although previous studies have revealed that metformin is
significantly associated with better spontaneous and clomi-
phene-induced ovulation rates (12,13), others have reported
similar ovulation and pregnancy rates with clomiphene and met-
formin therapy (14,15).
Obese women with PCOS treated with pioglitazone were
found to have increased ovulation rates and improved hyperan-
drogenemia (16,17). When compared with metformin, pioglitaz-
one was found to be less effective in improving ovulation rates,
whereas the effect of the two drugs on hyperandrogenemia and
insulin resistance was similar (18).
The aim of the current study was to decide whether the com-
bination between CC and pioglitazone is better than CC alone
or CC and metformin in induction of ovulation and achieve-
ment of pregnancy in infertile women due to PCOS.
2. Materials and methods
This randomized trial was carried out in the infertility clinic of
Ain Shams university maternity hospital from May 2012 to
January 2013 after being approved by the local institutional
ethics and research committee and it included overweight
and obese infertile women with PCOS to whom ovulation
induction using CC was performed as a first line treatment
for their anovulatory infertility.
Diagnosis of PCOS was made according to the Rotterdam’s
criteria (19) and body mass index was used to define the over-
weight and obese women.
All the procedures, in this research were carried out in
accordance with the ethical principles for medical research
involving human subjects of the World Medical Association
(Declaration of Helsinki), as last revised in 59th WMA Gen-
eral Assembly, Seoul, October 2008.
All recruited women were thoroughly evaluated via history
taking and physical examination; the routine investigations
performed for all enrolled women included baseline transvag-
inal ultrasound, cycle day three serum FSH, LH, TSH, prolac-
tin, total, free testosterone and DHEAS and husband semen
analysis. Normal husband’s semen analysis was defined
according to WHO 2010 criteria.
All participants were 635 year old with a body mass index
(BMI) P25 kg/m
2
. Women who had infertility due to causes
other than PCOS or due to combined factors as well as women
who were allergic to pioglitazone, metformin or CC were
excluded from the study. Women who fulfilled the study inclu-
sion and exclusion criteria and accepted to participate in the
study were randomly assigned to receive ovulation induction
using CC, 100 mg daily for 5 days starting on the third day
of spontaneous or induced menses, either alone (Group 1),
in combination with metformin 850 mg tablets (Cidophage re-
tard
Ò
, Chemical Industries Development (CID), Giza, Egypt)
twice daily at breakfast and dinner (Group 2) or in combina-
tion with pioglitazone 30 mg tablets (Glustin
Ò
, Lilly, Egypt)
once daily at breakfast (Group 3). Randomization was per-
formed using a computer-generated list of random numbers;
the allocation sequence was concealed from the researcher
enrolling and assessing participants in sequentially numbered,
opaque, sealed and stapled envelopes that were kept with the
infertility clinic nurse, envelopes were opened only after the en-
rolled participants completed all baseline assessments and it
was time to allocate the intervention.
Folliculometry was started from cycle day 9 and repeated
every 2 days. hCG (10000 IU) was given intramuscular when
at least one follicle P18 mm was formed. Women were advised
to have timed intercourse 24–36 h after hCG injection. Serum
b-hCG was measured 16 days after hCG injection to diagnose
pregnancy.
The main outcome measure was the biochemical pregnancy
rate, defined as having a positive serum pregnancy test 16 days
136 W.M. Abuelghar et al.
after hCG injection, while the secondary outcomes included
the percentage of women succeeded to have mature follicles
P18 mm in average dimension and the percentage of occur-
rence of prescribed drugs’ adverse events.
The required sample size has been estimated using the
Power Analysis and Sample Size software (PASSÓ) version
11 (NCSS, LLC. Kaysville, Utah, USA). Taking the biochem-
ical pregnancy rate as the primary outcome measure and
according to a previous study that indicated a conception rate
of 29.7% in women receiving CC (20), it has been estimated
that a sample size of 27 women in each study group would
achieve an 80% power (b-error = 0.2) to detect an effect size
(w) of 0.35. The test statistic used has been the two-sided Pear-
son v
2
-test with 2 degrees of freedom and significance has been
targeted at the 95% confidence level (a-error = 0.05).
Statistical analysis was done on a personal computer using
MedCalcÓversion 12.2.1.0 (MedCalcÓSoftware, Mariakerke,
Belgium). The D’Agostino-Pearson test was performed to test
the normality of numerical data distribution; a statistically sig-
nificant test denotes non-normally distributed data. Normally
distributed numerical data are presented as mean and SD.
Skewed numerical data are presented as median and interquar-
tile range. Qualitative data are presented as number and per-
centage. Normally distributed numerical data are compared
with one-way analysis of variance (ANOVA). Skewed numer-
ical data are compared non-parametrically with the Kruskal
Wallis test. Qualitative data are compared using the Pearson
chi square test.
3. Results
179 women were initially recruited to participate in this clinical
trial, however by the end of the study; only 81 participants
were included in the final statistical analysis (Fig. 1). Table 1
illustrates that the three groups were matched regarding fac-
tors that may affect the induction of ovulation as there was
Figure 1 Participant flow chart, CONSORT.
Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy 137
no statistically significant difference between the studied
groups regarding age, BMI, hirsutism score, medical comor-
bidities, past surgical, obstetric and gynecological history
and other baseline characteristics. Table 2 shows that there
was no statistically significant difference between the three
groups regarding semen characteristics and the hormonal as-
says of FSH, LH, prolactin, TSH, total testosterone, free tes-
tosterone and DHEAS.
As regards the outcome measures, there was no statistically
significant difference between the study groups concerning the
biochemical pregnancy rates, the percentage of women suc-
ceeded to have mature follicles and the percentage of occur-
rence of adverse drug events (Table 3).
4. Discussion
CC is currently considered as the first-line therapy for ovula-
tion induction in women with infertility due to PCOS. It suc-
ceeded to achieve ovulation in 70–85% of women, but only
33–45% got pregnant (21).
The leading experience with insulin sensitizers in treating
PCOS women has been with metformin. The American Col-
lege of Obstetricians & Gynecologists (ACOG) has recom-
mended the use of metformin as an insulin sensitizer with
CC, if CC does not result in ovulation, regardless of whether
insulin resistance is there or not (22). Insulin sensitizers from
the thiazolidenediones family have been used successfully in
women with PCOS, namely troglitazone, pioglitazone, and
rosiglitazone (16,23–25). Although troglitazone has been with-
drawn from the market due to its hepatotoxicity, rosiglitazone
and pioglitazone appear to be safer in this aspect (26). Rosig-
litazone, has been put under selling restrictions in the United
States and has been withdrawn from the market in Europe
due to the increased risk of cardiovascular events (27). This
is the cause behind selecting pioglitazone to be the member
of the thiazolidinedione family used in the current trial.
Most of the previous studies that addressed the use of insu-
lin sensitizers in women with PCO have been observational
and concentrated only on the hormonal profile and menstrual
pattern. The effects on the success of the different ovulation
induction protocols, especially with CC, have rarely been as-
sessed. In the current trial we enrolled a total of 81 overweight
and obese infertile women due to PCOS, relatively a large
number of participants as compared to other studies, insulin
sensitizers were found to increase the biochemical pregnancy
rates but this did not reach a significant significance.
The published placebo-controlled studies had conflicting re-
sults; some reported significant improvements in ovulation and
pregnancy rates after adding metformin to CC (28,29) while
the others did not support these findings (20,30). In 2008,
the same researcher concluded that although the initial trial
showed no significant benefit form adding metformin, this ap-
proach was effective in fatty women with PCOS (31).
A recent Cochrane review, published in 2012, reviewed
insulin sensitizing drugs used for treating women with PCOS;
no well-designed trials were found assessing the efficacy of
combined CC and pioglitazone in inducting ovulation and
achieving pregnancy. Most of the available data were for some
outcomes, including menstrual frequency and anthropometric,
endocrine and metabolic outcomes but not for pregnancy rates
(32).
A recent systematic review and meta-analysis found that
pioglitazone is more effective in treating hyperinsulinemia
and insulin resistance among women with PCOS, while met-
formin is more effective in body weight reduction. The authors
advised that well-designed trials are still needed to build a
good evidence (33).
Table 1 Baseline characteristics of the studied groups.
Variable Group 1 (n= 27) Group 2 (n= 27) Group 3 (n= 27) Pvalue
Age (year) 28.44 ± 4.48 27.63 ± 4.05 26.74 ± 3.32 0.296
BMI (kg/m
2
) 28.09 ± 2.28 28.61 ± 2.34 28.42 ± 1.87 0.676
Duration of marriage (years) 3 (2–4) 3 (2.5–5) 3 (2–5) 0.817
Duration of infertility (year) 2.83 ± 1.06 3.15 ± 1.22 2.89 ± 1.09 0.548
Type of infertility (%) 0.837
Primary 19 (70.4%) 20 (74.1%) 18 (66.7%)
Secondary 8 (29.6%) 7 (25.9%) 9 (33.3%)
Duration of marriage (years) 3 (2–4) 3 (2.5–5) 3 (2–5) 0.817
Medical comorbidities (%) 4 (14.8%) 2 (7.4%) 4 (14.8%) 0.585
Prior pelvic surgery (%) 10 (37.0%) 8 (29.6%) 10 (37.0%) 0.313
Prior use of contraceptive use (%) 1 (3.7%) 0 (0.0%) 2 (7.4%) 0.769
Hirsutism (%) 12 (44.4%) 18 (66.7%) 13 (48.1%) 0.215
Hirsutism score 11.67 ± 1.56 11.78 ± 1.96 11.31 ± 1.97 0.780
PCO by ultrasound (%) 25 (92.6%) 25 (92.6%) 24 (88.9%) 1.000
Oligomenorrhea 18 (66.7%) 17 (63.0%) 17 (63.0%) 0.948
Prior deliveries (%) 6 (22.2%) 5 (18.5%) 7 (25.9%) 0.933
Prior miscarriages (%) 4 (14.8%) 3 (11.1%) 3 (11.1%) 1.000
Prior live births (%) 5 (18.5%) 5 (18.5%) 6 (22.2%) 0.932
BMI, body mass index; IQR, interquartile range; PCO, polycystic ovary syndrome; SD, standard deviation.
Data are presented as mean ± SD, median (IQR) or number (%) as appropriate.
138 W.M. Abuelghar et al.
In 2008, one study investigated the role of pioglitazone as
monotherapy in infertile women with PCOS who were resis-
tant to ovulation induction by CC, dexamethasone, or metfor-
min. The authors concluded that pioglitazone is effective in
infertile patients with resistant PCOS (34).
The criteria for the diagnosis of PCOS among the previous
studies (25,30,35) were variable. This study and another one
(30) used the Rotterdam 2003 criteria which has increased
the prevalence of PCOS from 4–8% to 18%. Rotterdam defi-
nition is wider, including more women; especially women with-
out androgen excess (36).
To the best of our knowledge, no published data are avail-
able to determine which insulin sensitizer is better in achieving
pregnancy in overweight and obese women with PCOS. This
study is unique as it is the first study to compare the efficacy
of pioglitazone and CC, metformin and CC with CC alone
as first-line therapy in induction of ovulation in overweight
and obese infertile women due to PCOS. However, our study
is limited by three main issues: First, the duration of the as-
signed treatment was given only for one cycle; prior studies ex-
tended the duration of the treatment for 6 months (20),
3 months (35) and 2 months (25) which could give a better
chance to evaluate the cumulative effect of used drugs. Second,
the main outcome measures were not extended to include the
clinical pregnancies. Lastly the study was not extended to as-
sess other important outcomes like clinical pregnancies, mis-
carriages and fetal anomalies, the major strength points in
Legro et al. study (20) are the relative large number of partic-
ipants (626 women) and using the live birth rate as the main
outcome measure rather than the biochemical pregnancy rate
which enabled them to evaluate pregnancy loss and multifetal
pregnancy rates.
5. Conclusions
Finally it can be concluded, that there is no potential benefit
from adding pioglitazone or metformin to CC while inducing
Table 2 Results of semen analysis and hormonal assays.
Variable Group 1 (n= 27) Group 2 (n= 27) Group 3 (n= 27) Pvalue
Sperm count (million/ml) 60.04 ± 22.98 62.00 ± 24.06 64.33 ± 26.61 0.814
Total motility (%) 63.78 ± 9.84 64.52 ± 10.29 62.07 ± 9.34 0.646
Progressive motility (%) 43.37 ± 9.43 47.48 ± 8.10 44.37 ± 9.20 0.217
Abnormal morphology (%) 17.78 ± 7.22 16.81 ± 7.17 13.89 ± 5.33 0.087
FSH (mIU/ml) 6.35 ± 1.89 5.66 ± 1.76 5.62 ± 1.57 0.236
LH (mIU/ml) 6.87 ± 2.41 6.64 ± 2.36 6.16 ± 2.03 0.506
Prolactin (ng/ml) 11.12 ± 3.09 11.49 ± 3.52 10.76 ± 2.12 0.664
TSH (mIU/l) 2.42 ± 0.90 2.47 ± 0.74 2.61 ± 0.74 0.655
Total testosterone (ng/ml) 0.77 ± 0.33 0.86 ± 0.41 0.79 ± 0.29 0.651
Free testosterone (pg/ml) 4.18 ± 2.40 4.05 ± 1.87 3.83 ± 2.18 0.832
DHEAS (lg/dl) 216.63 ± 57.82 245.89 ± 56.84 234.11 ± 46.99 0.142
DHEAS, Dehydroepiandrosterone sulfate; FSH, Follicle stimulating hormone; LH, Luteinizing hormone; TSH, Thyroid stimulating hormone.
Data are presented as mean ± SD.
Table 3 Outcome measures.
Variable Group 1 Group 2 Group 3 Pvalue
(n= 27) (n= 27) (n= 27)
Number of mature follicles 0.726
None 7 (25.9%) 7 (25.9%) 5 (18.5%)
1 follicle 11 (40.7%) 11 (40.7%) 7 (25.9%)
2 follicles 7 (25.9%) 7 (25.9%) 11 (40.7%)
P3 follicles 2 (7.4%) 2 (7.4%) 4 (14.8%)
Biochemical pregnancy 0.588
No biochemical pregnancy 25 (92.6%) 24 (88.9%) 22 (81.5%)
Biochemical pregnancy 2 (7.4%) 3 (11.1%) 5 (18.5%)
Side effects 0.285
None 21 (77.8%) 16 (59.3%) 22 (81.5%)
Flushing 4 (14.8%) 2 (7.4%) 1 (3.7%)
GIT discomfort 2 (7.4%) 5 (18.5%) 3 (11.1%)
Diarrhea 0 (0.0%) 3 (11.1%) 1 (3.7%)
Flushing + GIT discomfort 0 (0.0%) 1 (3.7%) 0 (0.0%)
GIT, gastrointestinal tract.
Data are presented as number (%).
Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy 139
ovulation in overweight and obese women complaining of
infertility due to PCOS. Further larger extended trials are
needed to assess using insulin sensitizers for longer duration
which could give a better chance to evaluate the cumulative ef-
fect of these drugs.
Conflict of interest
None.
Acknowledgments
Special thanks to Dr. Mohamed Ibrahem Ellaithy for his valu-
able scientific advice and his kind assistance in manuscript
revision.
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Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy 141