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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

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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 ovulation 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 3). Folliculometry was started from cycle day 9 and repeated every 2 days. hCG (10000 IU) was given intramuscular when at least one follicle ⩾18 mm was formed. Serum β-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 regarding 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.
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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, 135141
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
... which is in conformance with Athar R et al. [37] reported 27.55±5.6, Abuelghar WM et al. [38] reported 27.63±4.05, Karimzadeh MA et al. [39] reported 27.4±2.38. ...
... Most of the patients (56.7%) suffered from primary infertility and 43.3% from secondary infertility. This finding is in accordance with the study of Abuelghar WM et al. [38,40] reported 66.7% and 33.3%, SF Majeedi et al. [36] reported 65% and 35%. Literature report says that the incidence of primary infertility is more than compared to secondary infertility. ...
... which is in conformance with Athar R et al. [37] reported 27.55±5.6, Abuelghar WM et al. [38] reported 27.63±4.05, Karimzadeh MA et al. [39] reported 27.4±2.38. ...
... Most of the patients (56.7%) suffered from primary infertility and 43.3% from secondary infertility. This finding is in accordance with the study of Abuelghar WM et al. [38,40] reported 66.7% and 33.3%, SF Majeedi et al. [36] reported 65% and 35%. Literature report says that the incidence of primary infertility is more than compared to secondary infertility. ...
Article
Full-text available
Background and objectives: Obesity represents a rapidly growing threat to the health of populations which has detrimental effect on fertility by disrupting the neuroendocrinal and ovulatory functions. The aim of the study was to evaluate the efficacy of Unani formulation in infertility among obese women. Methods: A single blind non-randomized pre and post observational study was carried out at National Institute of Unani Medicine Hospital, Bengaluru. Infertile women (n=30) in the age group of 18-40 years, with Body Mass Index 30-40 kg/m2 , menstrual irregularities, controlled thyroid dysfunction and spouse normal seminogram were included in the study. Patients with systemic illnesses and those on weight reduction in last 3 months were excluded. 12.5 gm of Unani formulation (Tukhme Karafs, Tukhme Anisoon, Tukhme Ajwain Desi, Tukhme Hulba, Asaroon) was administered orally twice daily in the form of decoction for two consecutive months. Primary outcome measures (weight reduction, menstrual regulation and conception) and secondary outcome measures (changes in BMI, lipid profile and fasting insulin) were assessed for improvement. Data were analyzed using paired Student ‘t’ test. Results: Weight loss (7% reduction of body weight) was achieved in 80% patients with significant reduction (P<0.001) in BMI and waist to hip ratio, Menstrual regulation was achieved in 66.7% with significant reduction (P=0.081) in duration of cycle. The conception rate was 0% during the study period, but 10% patients conceived after 2 months of completion of study. Changes in lipid profile (on fixing 5% reduction) were achieved in 40% patients clinically (P>0.05). Changes in fasting insulin were achieved in 20% patients (P=0.004). Interpretation and conclusion: Unani formulation may be used as an effective alternative in infertility among obese women with PCOD. Keywords: Infertility, Obesity, PCOD, Conception, Unani formulation
... Previous studies have evaluated the treatment with metformin and pioglitazone alone or in different combinations with other drugs for hormone modulation, ovulation induction and insulin resistance in women with PCOS (14,18,19,(35)(36)(37)(38). After metformin monotreatment, circulating testosterone, Δ-4-androstenedione and the hirsutism score in PCOS patients were significantly decreased, indicating that metformin treatment led to a reduction of hyperandrogenism (39). ...
... Clomifene citrate, metformin and pioglitazone, as common insulin sensitizers, were evaluated for their effectiveness in the treatment of PCOS. There were no statistically significant differences between clomifene citrate monotreatment or its combination with metformin/pioglitazone in the biochemical pregnancy rates and the number of mature follicles (38). The efficacy of combined treatment with letrozole, metformin and pioglitazone was similar to that of combined treatment with clomifene citrate, metformin and pioglitazone within a group of 100 women with PCOS resistant to clomifene citrate (14). ...
Article
Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5’adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy demonstrated great efficacy in ameliorating PCOS through regulating the AMPK/PI3K/JNK pathway.
... Accumulating evidence have examined how insulin resistance in PCOS women could be managed by metformin, empagliflozin, either alone or in combination with other treatments. (Abuelghar et al., 2013;El Maghraby et al., 2015;El-khayat et al., 2016;Mhao et al., 2016). In accordance with our findings, study done on efficacy of canagliflozin versus metformin in women with PCOS revealed that both drugs can significantly improve HOMA-IR in women having PCOS with IR without significant difference between them (Cai et al., 2022). ...
Article
Full-text available
Polycystic ovary syndrome (PCOS) is a common endocrine, reproductive, and metabolic disorder affecting females. The management of PCOS is challenging and current interventions are not enough to deal with all consequences of this syndrome. We explored the beneficial effect of combined sodium glucose co transporter‐2 inhibitor (SGLT‐2i); (empagliflozin) and metformin on hormonal and metabolic parameters in an animal model of PCOS and insulin resistance (IR). Forty adult female Wistar rats divided into five groups: control, PCOS‐IR, PCOS‐IR treated with metformin, PCOS‐IR treated with empagliflozin, and PCOS‐IR treated with combined metformin and empagliflozin. Single modality treatment with metformin or empagliflozin yielded significant improvement in body mass index, insulin resistance, lipid profile, sex hormones, inflammatory markers, and ovarian cystic follicles. Combined metformin with empagliflozin expressed further significant improvement in sex hormones, inflammatory markers with disappearance of ovarian cystic follicles. The superior significant improvement with combined treatment over the single modality was in line with significant improvement in the ovarian AMPKα‐SIRT1 expression.
... IPD were available from 17 RCTs (shared IPD group) (Sahin et al., 2004;Palomba et al., 2005;Bayar et al., 2006;Lord et al., 2006;Moll et al., 2006;Legro et al., 2007;Johnson et al., 2010;Homburg et al., 2012;Kar, 2012;Morin-Papunen et al., 2012;Nazik and Kumtepe, 2012;Leanza et al., 2014;Legro et al., 2014;Kar and Sanchita, 2015;Amer et al., 2017;Liu et al., 2017;Wu et al., 2017). Twenty-eight trials were categorized as the non-shared IPD group due to no response (n ¼ 20) (Boostanfar et al., 2001;Lopez et al., 2004;Atay et al., 2006;Karimzadeh et al., 2007;Dasari and Pranahita, 2009;Dehbashi et al., 2009;Karimzadeh and Javedani, 2010;Zeinalzadeh et al., 2010;Sheikh-El-Arab Elsedeek and Elmaghraby, 2011;Banerjee Ray et al., 2012;Basirat et al., 2012;Roy et al., 2012;Selim and Borg, 2012;Seyedoshohadaei et al., 2012;Abuelghar et al., 2013;Ayaz et al., 2013;Maged et al., 2015;Sharief and Nafee, 2015;Chen et al., 2016;Hossein-Rashidi et al., 2016), data loss (n ¼ 7) (Fleming et al., 2002;Khorram et al., 2006;Tang et al., 2006;Badawy et al., 2009;Zain et al., 2009;Badawy and Gibreal, 2011;Mobusher, 2014) or legal reasons (n ¼ 1) (Moussa et al., 2016). ...
Article
Background: In our recent individual participant data (IPD) meta-analysis evaluating the effectiveness of first-line ovulation induction for polycystic ovary syndrome (PCOS), IPD were only available from 20 studies of 53 randomized controlled trials (RCTs). We noticed that the summary effect sizes of meta-analyses of RCTs without IPD sharing were different from those of RCTs with IPD sharing. Granting access to IPD for secondary analysis has implications for promoting fair and transparent conduct of RCTs. It is, however, still common for authors to choose to withhold IPD, limiting the impact of and confidence in the results of RCTs and systematic reviews based on aggregate data. Objective and rationale: We performed a meta-epidemiologic study to elucidate if RCTs without IPD sharing have lower quality and more methodological issues than those with IPD sharing in an IPD meta-analysis evaluating first-line ovulation induction for PCOS. Search methods: We included RCTs identified for the IPD meta-analysis. We dichotomized RCTs according to whether they provided IPD (shared group) or not (non-shared group) in the IPD meta-analysis. We restricted RCTs to full-text published trials written in English.We assessed and compared RCTs in the shared and non-shared groups on the following criteria: Risk of Bias (RoB 2.0), GRADE approach, adequacy of trial registration; description of statistical methods and reproducibility of univariable statistical analysis; excessive similarity or difference in baseline characteristics that is not compatible with chance; and other miscellaneous methodological issues. Outcomes: In total, 45 trials (8697 women) were included in this study. IPD were available from 17 RCTs and 28 trials were categorized as the non-shared IPD group. Pooled risk rates obtained from the shared and non-shared groups were different. Overall low risk of bias was associated with 13/17 (76%) of shared RCTs versus 7/28 (25%) of non-shared RCTs. For RCTs that started recruitment after 1 July 2005, adequate trial registration was found in 3/9 (33%) of shared IPD RCTs versus 0/16 (0%) in non-shared RCTs. In total, 7/17 (41%) of shared RCTs and 19/28 (68%) of non-shared RCTs had issues with the statistical methods described. The median (range) of inconsistency rate per study, between reported and reproduced analyses for baseline variables, was 0% (0-92%) (6 RCTs applicable) in the shared group and 54% (0-100%) (13 RCTs applicable) in the non-shared group. The median (range) of inconsistency rate of univariable statistical results for the outcome(s) per study was 0% (0-63%) (14 RCTs applicable) in the shared group and 44% (0-100%) (24 RCTs applicable) in the non-shared group. The distributions of simulation-generated P-values from comparisons of baseline continuous variables between intervention and control arms suggested that RCTs in the shared group are likely to be consistent with properly conducted randomization (P = 0.163), whereas this was not the case for the RCTs in the non-shared group (P = 4.535 × 10-8). Wider implications: IPD meta-analysis on evaluating first-line ovulation induction for PCOS preserves validity and generates more accurate estimates of risk than meta-analyses using aggregate data, which enables more transparent assessments of benefits and risks. The availability of IPD and the willingness to share these data may be a good indicator of quality, methodological soundness and integrity of RCTs when they are being considered for inclusion in systematic reviews and meta-analyses.
... For the remaining 54 studies (8781 women), the primary investigators were contacted to share IPD of the primary studies. IPD from 34 studies (4819 women) were not available, due to no response (n = 23; 3258 women) (Abuelghar et al., 2013;Atay et al., 2006;Ayaz et al., 2013;Banerjee Ray et al., 2012;Basirat et al., 2012;Boostanfar et al., 2001;Chen et al., 2016;Dasari and Pranahita, 2009;Dehbashi et al., 2009;Hossein-Rashidi et al., 2016;Jahan, 2015;Karimzadeh et al., 2007;Karimzadeh and Javedani, 2010;Lopez et al., 2004;Lorzadeh et al., 2011;Maged et al., 2015;Robinson et al., 2003;Roy et al., 2012;Selim and Borg, 2012;Seyedoshohadaei et al., 2012;Sharief and Nafee, 2015;Sheikh-El-Arab Elsedeek and Elmaghraby, 2011;Zeinalzadeh et al., 2010), data loss (n = 10; 1411 women) (Aygen et al., 2007;Badawy et al., 2009;Badawy and Gibreal, 2011;Fleming et al., 2002;Keikha and Shahraki, 2011;Khorram et al., 2006;Mobusher, 2014;Santonocito et al., 2009;Tang et al., 2006;Zain et al., 2009) or legal reasons (n = 1; 150 women) (Moussa et al., 2016). These studies are listed in Supplementary Table S1. ...
Article
Background: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. Objective and rationale: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. Search methods: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. Outcomes: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). Wider implications: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.
Article
Background: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with an increased biochemical risk profile for cardiovascular disease and an increased prevalence of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. This is an update of Morley 2017 and only includes studies on metformin. Objectives: To evaluate the effectiveness and safety of metformin in combination with or in comparison to clomiphene citrate (CC), letrozole and laparoscopic ovarian drilling (LOD) in improving reproductive outcomes and associated gastrointestinal side effects for women with PCOS undergoing ovulation induction. Search methods: We searched the following databases from inception to December 2018: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. Selection criteria: We included randomised controlled trials of metformin compared with placebo, no treatment, or in combination with or compared with CC, letrozole and LOD for women with PCOS subfertility. Data collection and analysis: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes and ovulation. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes and reproductive outcomes using GRADE methodology. Main results: We included 41 studies (4552 women). Evidence quality ranged from very low to moderate based on GRADE assessment. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatment The evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51; I2 = 0%; 4 studies, 435 women; low-quality evidence). For a live birth rate of 19% following placebo, the live birth rate following metformin would be between 19% and 37%. The metformin group probably experiences more gastrointestinal side effects (OR 4.00, 95% CI 2.63 to 6.09; I2 = 39%; 7 studies, 713 women; moderate-quality evidence). With placebo, the risk of gastrointestinal side effects is 10% whereas with metformin this risk is between 22% and 40%. There are probably higher rates of clinical pregnancy (OR 1.98, 95% CI 1.47 to 2.65; I2 = 30%; 11 studies, 1213 women; moderate-quality evidence). There may be higher rates of ovulation with metformin (OR 2.64, 95% CI 1.85 to 3.75; I2 = 61%; 13 studies, 684 women; low-quality evidence). We are uncertain about the effect on miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35; I2 = 0%; 4 studies, 748 women; low-quality evidence). Metformin plus CC versus CC alone We are uncertain if metformin plus CC improves live birth rates compared to CC alone (OR 1.27, 95% CI 0.98 to 1.65; I2 = 28%; 10 studies, 1219 women; low-quality evidence), but gastrointestinal side effects are probably more common with combined therapy (OR 4.26, 95% CI 2.83 to 6.40; I2 = 8%; 6 studies, 852 women; moderate quality evidence). The live birth rate with CC alone is 24%, which may change to between 23% to 34% with combined therapy. With CC alone, the risk of gastrointestinal side effects is 9%, which increases to between 21% to 37% with combined therapy. The combined therapy group probably has higher rates of clinical pregnancy (OR 1.62, 95% CI 1.32 to 1.99; I2 = 31%; 19 studies, 1790 women; moderate-quality evidence). The combined group may have higher rates of ovulation (OR 1.65, 95% CI 1.35 to 2.03; I2 = 63%;21 studies, 1568 women; low-quality evidence). There was no clear evidence of an effect on miscarriage (OR 1.35, 95% CI 0.91 to 2.00; I2 = 0%; 10 studies, 1206 women; low-quality evidence). Metformin versus CC When all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01; I2 = 86%; 5 studies, 741 women; very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52; 2 studies, 500 women), while the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94; I2 = 78%, 3 studies, 241 women; very low-quality evidence). However, due to the very low quality of the evidence we cannot draw any conclusions. Among obese women taking metformin there may be lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55; I2 = 0%; 2 studies, 500 women; low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43; I2 = 0%; 2 studies, 500 women; low-quality evidence) while among non-obese women, the metformin group may have more pregnancies (OR 1.56, 95% CI 1.06 to 2.29; I2 = 26%; 6 studies, 530 women; low-quality evidence) and no clear difference in ovulation rates (OR 0.80, 95% CI 0.52 to 1.25; I2 = 0%; 5 studies, 352 women; low-quality evidence). We are uncertain whether there is a difference in miscarriage rates between the groups (overall: OR 0.92, 95% CI 0.51 to 1.66; I2 = 36%; 6 studies, 781 women; low-quality evidence) and no studies reported gastrointestinal side effects. Authors' conclusions: Our updated review suggests that metformin may be beneficial over placebo for live birth however, more women probably experience gastrointestinal side effects. We are uncertain if metformin plus CC improves live birth rates compared to CC alone, but gastrointestinal side effects are probably increased with combined therapy. When metformin was compared with CC, data for live birth were inconclusive, and the findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. No studies reported gastrointestinal side effects in this comparison. Due to the low quality of the evidence, we are uncertain of the effect of metformin on miscarriage in all three comparisons.
Article
Full-text available
Background: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. Objectives: To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. Search methods: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. Selection criteria: We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. Data collection and analysis: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology. Main results: We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I2 = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I2 = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I2 = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I2 = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I2 = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I2 = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I2 = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I2 = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I2 = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I2 = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I2 = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I2 = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I2 = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I2 = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I2 = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I2 = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I2 = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I2=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I2 = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes. Authors' conclusions: Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.
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Objective To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive. Design Systematic review and network meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016. Study selection Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes. Results Of 2631 titles and abstracts initially identified, 57 trials reporting on 8082 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively). Conclusions In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of ovulation and pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth. Systematic review registration PROSPERO CRD42015027579.
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females with a high prevalence. The etiology of this heterogeneous condition remains obscure and its phenotype expression varies. Two, widely cited, previous ESHRE/ASRM-sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008). The present third PCOS consensus paper summarizes current knowledge and identifies knowledge gaps regarding various womens health aspects of PCOS. Relevant topics addressedall dealt with in a systematic fashioninclude adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication.
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Polycystic ovary syndrome (PCOS) is a medical condition that has brought multiple specialists together. Gynecologists, endocrinologists, cardiologists, pediatricians, and dermatologists are all concerned with PCOS patients and share research data and design clinical trials to learn more about the syndrome. Insulin resistance is a common feature of PCOS and is more marked in obese women, suggesting that PCOS and obesity have a synergistic effect on the magnitude of the insulin disorder. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism, and metabolic disturbances. Women with PCOS should be evaluated for cardiovascular risk factors, such as lipid profile and blood pressure. Modification of diet and lifestyle should be suggested to those who are obese. Several insulin-lowering agents have been tested in the management of PCOS. In particular, metformin is the only drug currently in widespread clinical use for treatment of PCOS. In a high percentage of patients, treatment with metformin is followed by regularization of menstrual cycle, reduction in hyperandrogenism and in cardiovascular risk factors, and improvement in response to therapies for induction of ovulation.
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Evidence indicates that metformin and pioglitazone both improve insulin resistance and hirsutism among patient with polycystic ovarian syndrome (PCOS). However, the effectiveness of pioglitazone versus metformin in the treatment of PCOS remains controversial. To summarize the relative efficacy of pioglitazone and metformin in PCOS patients, a systematic review and meta-analysis of randomized controlled trials (RCTs) was performed. The authors searched MEDLINE, EMBASE, CNKI and WANFANG DATA for articles published up to November 2011 to identify those comparing pioglitazone versus metformin as a treatment for PCOS. Of the 161 studies retrieved, six trials were included in this analysis, including a total of 278 women with PCOS. Pioglitazone was found to be significantly more effective than metformin at reducing fasting insulin level (P = 0.002, standardized mean differences [SMD] = -0.37, 95% confidence interval [CI] [-0.61, -0.13]). Similarly, pioglitazone was found to be significantly more effective than metformin at improving the HOMA-IR index (P = 0.014, SMD = -0.32, 95% CI [-0.57, -0.06]). However, pioglitazone was significantly less effective than metformin at reducing body mass index (BMI; P = 0.038, SMD = 0.25, 95% CI [0.01, 0.49]). The effect of pioglitazone on fasting glucose levels, testosterone levels, and Ferriman-Gallwey scores was not significantly different from that of metformin (P greater than 0.05 for all). This systematic review and meta-analysis suggests that pioglitazone was more suitable for treating hyperinsulinemia and insulin resistance among PCOS patients, while metformin was more effective in reducing body weight. Well designed RCTs are needed to provide better evidence.
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females, with a high prevalence. The etiology of this heterogeneous condition remains obscure, and its phenotype expression varies. Two widely cited previous ESHRE/ASRM sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008), respectively. The present third PCOS consensus report summarizes current knowledge and identifies knowledge gaps regarding various women's health aspects of PCOS. Relevant topics addressed-all dealt with in a systematic fashion-include adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health, and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication.