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Middle East Fertility Society Journal (2013) 18, 135–141

Middle East Fertility Society

Middle East Fertility Society Journal www.mefsjournal.org www.sciencedirect.com

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 b

Obstetrics and Gynaecology Department, Ain Shams University, Cairo, Egypt 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 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

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: [email protected] (W.M. Abuelghar). Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier 1110-5690 Ó 2013 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

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W.M. Abuelghar et al. 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 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. Ó 2013 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 considered as the principal feature of this syndrome (2). Insulin resistance is an important feature of PCOS and impaired 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 women 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 clomiphene-induced ovulation rates (12,13), others have reported similar ovulation and pregnancy rates with clomiphene and metformin therapy (14,15). Obese women with PCOS treated with pioglitazone were found to have increased ovulation rates and improved hyperandrogenemia (16,17). When compared with metformin, pioglitazone 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 combination between CC and pioglitazone is better than CC alone or CC and metformin in induction of ovulation and achievement 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 overweight 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 General 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 transvaginal ultrasound, cycle day three serum FSH, LH, TSH, prolactin, 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/m2. 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 inclusion 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 retardÒ, Chemical Industries Development (CID), Giza, Egypt) twice daily at breakfast and dinner (Group 2) or in combination with pioglitazone 30 mg tablets (GlustinÒ, Lilly, Egypt) once daily at breakfast (Group 3). Randomization was performed 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 enrolled 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

Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy 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 occurrence 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 biochemical 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 Pearson v2-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 MedCalcÓ version 12.2.1.0 (MedCalcÓ Software, Mariakerke, Belgium). The D’Agostino-Pearson test was performed to test

Figure 1

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the normality of numerical data distribution; a statistically significant test denotes non-normally distributed data. Normally distributed numerical data are presented as mean and SD. Skewed numerical data are presented as median and interquartile range. Qualitative data are presented as number and percentage. Normally distributed numerical data are compared with one-way analysis of variance (ANOVA). Skewed numerical 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 factors that may affect the induction of ovulation as there was

Participant flow chart, CONSORT.

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W.M. Abuelghar et al.

no statistically significant difference between the studied groups regarding age, BMI, hirsutism score, medical comorbidities, 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 assays of FSH, LH, prolactin, TSH, total testosterone, free testosterone 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 succeeded to have mature follicles and the percentage of occurrence of adverse drug events (Table 3). 4. Discussion CC is currently considered as the first-line therapy for ovulation induction in women with infertility due to PCOS. It succeeded 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 College of Obstetricians & Gynecologists (ACOG) has recommended 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 withdrawn from the market due to its hepatotoxicity, rosiglitazone and pioglitazone appear to be safer in this aspect (26). Rosiglitazone, 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

Table 1

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 insulin 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 assessed. 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 results; 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 approach 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 metformin is more effective in body weight reduction. The authors advised that well-designed trials are still needed to build a good evidence (33).

Baseline characteristics of the studied groups.

Variable

Group 1 (n = 27)

Group 2 (n = 27)

Group 3 (n = 27)

P value

Age (year) BMI (kg/m2) Duration of marriage (years) Duration of infertility (year)

28.44 ± 4.48 28.09 ± 2.28 3 (2–4) 2.83 ± 1.06

27.63 ± 4.05 28.61 ± 2.34 3 (2.5–5) 3.15 ± 1.22

26.74 ± 3.32 28.42 ± 1.87 3 (2–5) 2.89 ± 1.09

0.296 0.676 0.817 0.548

Type of infertility (%) Primary Secondary

19 (70.4%) 8 (29.6%)

20 (74.1%) 7 (25.9%)

18 (66.7%) 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 (%) Hirsutism score PCO by ultrasound (%) Oligomenorrhea

12 (44.4%) 11.67 ± 1.56 25 (92.6%) 18 (66.7%)

18 (66.7%) 11.78 ± 1.96 25 (92.6%) 17 (63.0%)

13 (48.1%) 11.31 ± 1.97 24 (88.9%) 17 (63.0%)

0.215 0.780 1.000 0.948

Prior deliveries (%) Prior miscarriages (%) Prior live births (%)

6 (22.2%) 4 (14.8%) 5 (18.5%)

5 (18.5%) 3 (11.1%) 5 (18.5%)

7 (25.9%) 3 (11.1%) 6 (22.2%)

0.933 1.000 0.932

0.837

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.

Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy Table 2

139

Results of semen analysis and hormonal assays.

Variable

Group 1 (n = 27)

Group 2 (n = 27)

Group 3 (n = 27)

P value

Sperm count (million/ml) Total motility (%) Progressive motility (%) Abnormal morphology (%) FSH (mIU/ml) LH (mIU/ml) Prolactin (ng/ml) TSH (mIU/l) Total testosterone (ng/ml) Free testosterone (pg/ml) DHEAS (lg/dl)

60.04 ± 22.98 63.78 ± 9.84 43.37 ± 9.43 17.78 ± 7.22 6.35 ± 1.89 6.87 ± 2.41 11.12 ± 3.09 2.42 ± 0.90 0.77 ± 0.33 4.18 ± 2.40 216.63 ± 57.82

62.00 ± 24.06 64.52 ± 10.29 47.48 ± 8.10 16.81 ± 7.17 5.66 ± 1.76 6.64 ± 2.36 11.49 ± 3.52 2.47 ± 0.74 0.86 ± 0.41 4.05 ± 1.87 245.89 ± 56.84

64.33 ± 26.61 62.07 ± 9.34 44.37 ± 9.20 13.89 ± 5.33 5.62 ± 1.57 6.16 ± 2.03 10.76 ± 2.12 2.61 ± 0.74 0.79 ± 0.29 3.83 ± 2.18 234.11 ± 46.99

0.814 0.646 0.217 0.087 0.236 0.506 0.664 0.655 0.651 0.832 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

(n = 27)

(n = 27)

(n = 27)

Number of mature follicles None 1 follicle 2 follicles P3 follicles

7 (25.9%) 11 (40.7%) 7 (25.9%) 2 (7.4%)

7 (25.9%) 11 (40.7%) 7 (25.9%) 2 (7.4%)

5 (18.5%) 7 (25.9%) 11 (40.7%) 4 (14.8%)

Biochemical pregnancy No biochemical pregnancy Biochemical pregnancy

25 (92.6%) 2 (7.4%)

24 (88.9%) 3 (11.1%)

22 (81.5%) 5 (18.5%)

Side effects None Flushing GIT discomfort Diarrhea Flushing + GIT discomfort

21 (77.8%) 4 (14.8%) 2 (7.4%) 0 (0.0%) 0 (0.0%)

16 (59.3%) 2 (7.4%) 5 (18.5%) 3 (11.1%) 1 (3.7%)

22 (81.5%) 1 (3.7%) 3 (11.1%) 1 (3.7%) 0 (0.0%)

P value

0.726

0.588

0.285

GIT, gastrointestinal tract. Data are presented as number (%).

In 2008, one study investigated the role of pioglitazone as monotherapy in infertile women with PCOS who were resistant to ovulation induction by CC, dexamethasone, or metformin. 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 definition is wider, including more women; especially women without androgen excess (36). To the best of our knowledge, no published data are available 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 extended 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 assess other important outcomes like clinical pregnancies, miscarriages and fetal anomalies, the major strength points in Legro et al. study (20) are the relative large number of participants (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

140 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.

W.M. Abuelghar et al.

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Conflict of interest (14)

None.

Acknowledgments Special thanks to Dr. Mohamed Ibrahem Ellaithy for his valuable scientific advice and his kind assistance in manuscript revision.

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