Randomized controlled trial of Letrozole versus Clomiphene citrate for induction of ovulation in polycystic ovarian syndrome (PCOS): A Malaysian experience ()
1. INTRODUCTION
Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy, affecting 6% of women within of reproductive age [1]. The overall prevalence of PCOS among reproductive-age women in the United States (US) was 4% [2].
Clomiphene citrate has been the first-line and standard drug treatment for PCOS for the last 40 years. Early studies proved that up to 80% of anovulatory patients responded well to Clomiphene citrate as assessed by achievement of ovulation, with about half of those who were ovulatory achieving pregnancy. However, approximately 20% of patients required a high dose of Clomiphene citrate (200 mg daily taken for 5 days early in the cycle), which may be a result of anti-estrogenic activities on the endometrium and cervical mucus.
Letrozole was proposed as an alternative to clomiphene citrate as a highly selective aromatase inhibitor that prevents androgen-to-estrogen conversion. This aromatase inhibitor has a short half-life (45 hours); thus it is rapidly eliminated from the body. No adverse effects on estrogen target tissues or down regulation of estrogen receptor (ER) is seen with Letrozole due to this short half-life, unlike Clomiphene citrate [3].
The aim of aromatase inhibitor was to avoid the peripheral anti-estrogenic effects of Clomiphene citrate, especially thinning of the endometrial lining [4]. Hence, a prospective open-labeled randomized controlled trial was conducted to determine which regime, Clomiphene citrate or Letrozole, was the best ovulation induction agent in infertile women with PCOS.
2. METHODS
This study consists of 150 participants enrolled in the infertility clinics at Hospital Sultanah Bahiyah (HSB), Alor Star, Kedah; Hospital Universiti Sains Malaysia (HUSM), Kelantan and Hospital Tengku Ampuan Afzan (HTAA), Kuantan, Pahang between May 2008 and May 2009 (Figure 1).
Inclusion criteria were an age between 18 years and 40 years old, diagnosed with PCOS by the Rotterdam criteria (2003) and normal seminal fluid analysis (SFA) [5]. Patients were not illiterate and consented to participate in the study. Exclusion criteria were having medical problems such as renal disease, thyroid disorder, hyperprolactinemia, liver disease or having other causes of anovulatory infertility Power calculations were performed to determine the sample size. Based on prior data, ovulation rate among patients treated with clomiphene citrate was approximately 60% [6]. If a 25% higher rate in ovulation among patients in the intervention (Letrozole) group is assumed to be clinically relevant, with a power of 90% and statistical significance (α) of 0.05, we would need a minimum of 64 patients in each arm. Taking into account a dropout rate of 20%, 150 patients were recruited. They were assigned to either the Letrozole or Clomiphene citrate group via computer block randomization and identified based on their identification card number.
2.1. Letrozole Group
Patients in this group were given Letrozole 5.0 mg daily from Day 5-Day 9 of menstruation. Base line transvaginal ultrasound (TVS) on the second day of menstruation was performed, following spontaneous menses by induction with medroxyprogesterone acetate (MPA) 10 mg daily for five days with serial TVS to document ovulation. If a dominant follicle (DF) was present (DF > 12 mm), a repeat TVS was performed every 2 days. Ovulation was diagnosed when the mature DF was approximately 18 to 22 mm followed by evidence of rupture approximately 3 to 4 days later. If a dominant follicle (DF) was absent (DF < 12 mm), a repeat TVS was performed every 3 - 4 days later. Endometrial thickness (ET) was measured at every follow-up. If there was absence of a dominant follicle (DF < 12 mm) up to Day 20, the patient was considered to be anovulatory.
2.2. Clomiphene Citrate Group
Patients were given Clomiphene citrate 100 mg daily from Day 5-Day 9 of menses. Those patients who had spontaneous menstruation following induction with MPA 10 mg daily for 5 days were reviewed on the second day (baseline TVS) of their menstruation and baseline ultrasound (TVS) was performed to measure the number, size and location of the follicles on each ovary, as well as endometrial thickness (ET). TVS was repeated on the tenth day of menstruation, where the presence, number and size of the dominant follicles (DF) were evaluated. DFs were defined as follicles measuring at least 12 mm on the tenth day of menstruation. Serial transvaginal scans were performed to document the evidence of ovulation. If a dominant follicle (DF) was present (DF > 12 mm), a repeat TVS was performed every 2 days. Ovulation was diagnosed when the mature DF was approximately 18 to 22 mm followed by evidence of rupture approximately 3 to 4 days later. If the dominant follicle (DF) was absent (DF < 12 mm), a repeat TVS was performed every 3 - 4 days later. The absence of a dominant follicle (DF < 12 mm) by Day 20 was considered as a failed induction or anovulation.
The investigator and the subject could choose to cease the study treatment or withdraw at any time, respectively.
All patients had a urine-based pregnancy test at 3 weeks after documented ovulation and continued amenorrhea. They were followed-up with until an ultrasound could document the viability of pregnancy. Primary outcome measures were ovulation rate, single follicle formation and endometrial thickness, while secondary outcome measure was pregnancy rate. The patients were given only one cycle of treatment for the study.
2.3. Statistical Analysis
Data entry and statistical analyses were performed using SPSS version 18. Means and standard deviations for numerical variables and frequency and proportion for categorical variables are reported. Two-tailed independent t-test was used to compare means and proportion was compared with the Chi-Square test or Fisher’s exact test. A p value of <0.05 was considered significant. Multiple logistic regression analysis was performed to assess the association of Letrozole and Clomiphene citrate with the ovulation rate after controlling for confounders.
Simple logistic regression was used in univariate analysis as a screening in the selection of variables for further analysis. All variables with a p value less than 0.25 were selected for inclusion in multiple logistic regression analysis.
Multiple logistic regression was chosen as the dependent variable of the binary outcome. Level of significance was 5% and results had 95% confidence intervals. The independent variables were a mix of numerical and categorical variables. Backward and forward stepwise procedure was used for variable selection. Interactions between pairs of variables from all variables in the main effect model were checked. Findings in the final model were presented as an adjusted odds ratio (OR), its 95% confidence interval (CI) and corresponding p value.
2.4. Approval by the Research and Ethics Committee
The protocol was approved by the Research and Ethical Committee, School of Medical Sciences, Universiti Sains Malaysia (ref: USMKK/PPP/JEPeM [(213.3.(11)], National Institutes of Health Approval For Conducting Research in The Ministry of Health Malaysia (NMRR-09- 893-3579) and Research and Ethical Committee, International Islamic University (ref: IIUM/ 305/ 20/4/10).
Written informed consent was obtained from the participants of this study. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
3. RESULT
Table 1 shows the characteristics of the 150 women who participated in the study. There were no significant differences noted with regard to socio-demographics, anthropometrics and duration of infertility between the studied groups, suggesting that they were homogenously distributed. The data were normally distributed.