Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome

Abstract

STUDY QUESTIONWould letrozole as a primary ovulation induction agent generate better pregnancy rates than clomiphene citrate (CC) in subfertile women with anovulatory polycystic ovarian syndrome (PCOS)?SUMMARY ANSWERParticipants receiving letrozole as a primary treatment achieved a significantly (P = 0.022) higher clinical pregnancy rate per patient (61.2%) compared to CC (43.0%).WHAT IS KNOWN ALREADYAccording to a recent Cochrane systematic review (2014), letrozole appears to improve live-birth (LB) and pregnancy rates in anovulatory women with PCOS, compared to CC. However, the review concluded that the quality of evidence was low due to poor reporting of study methods and possible publication bias.STUDY DESIGN, SIZE, DURATIONThis double-blind randomized controlled trial (RCT) included 159 participants between April 2007 and June 2014. Subjects were randomly allocated to either CC (n = 79) or letrozole (n = 80) in a 1:1 ratio. Both drugs were encapsulated to look identical. Randomization was performed in mixed blocks and stratified by patients’ BMI (<30 and 30–35 kg/m2).PARTICIPANTS/MATERIALS, SETTING, METHODSThe trial included subfertile women diagnosed with PCOS. Treatment started with one tablet (CC 50 mg, letrozole 2.5 mg) increasing to two in non-responders and continuing until pregnancy or for up to six ovulatory cycles. Non-responders were crossed over to the other treatment after a 6-week break. Cycles were initially monitored with ultrasound follicle tracking then mid-luteal serum progesterone measurement in subsequent cycles.MAIN RESULTS AND THE ROLE OF CHANCEAmongst the 159 participants included in the intention-to-treat analysis, four women conceived before treatment and six were lost-to-follow-up. The remaining 149 participants (74 on CC and 75 on letrozole) completed at least the first treatment. Women receiving letrozole achieved a significantly (P = 0.022; absolute difference [95% confidence interval] 18% [3–33%]) higher pregnancy rate (61.%) than those on CC (43%). The median number of treatment cycles received until pregnancy was significantly (log rank P = 0.038) smaller with letrozole (4[3–5] cycles) compared to CC (6[4–7] cycles). LB rates were not statistically (P = 0.089) different between the two groups, although there was a trend towards higher rates on letrozole (48.8%) compared to CC (35.4%). After the crossover, pregnancy and LB rates on letrozole (n = 45; 28.9 and 24.4%, respectively) were not statistically (P = 0.539 and P = 0.601) different from CC (n = 31; 22.6 and 19.4%).LIMITATIONS, REASONS FOR CAUTIONOne possible limitation of this trial may be the exclusion of PCOS women with BMI > 35 kg/m2, which would limit the applicability of the results in this subgroup of PCOS. However, this group of women are generally excluded from treatment in the majority of fertility centres, especially in Europe, due to the associated challenges and risks.WIDER IMPLICATIONS OF THE FINDINGSThe results of this trial are consistent with the recent Cochrane systematic review. However, with its...

Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis

“…Fifty six publications reporting on 57 trials fulfilled the eligibility criteria, as one study 56 included two individual trials (appendices 2 and 3).Five studies 35 36 47 52 67 were crossover studies and eight studies 35 44 54 61 66 77 86 87 were reported in conference abstracts. Publication dates ranged from 1966 to 2015, with 45 trials published in the last 10 years.…”

Transvaginal sonographic assessment of follicular development and endometrial thickness in letrozole stimulated cycles of PCOS and non-PCOS infertile women

“…Despite evidence of effectiveness and safety in well designed large randomised controlled trials (RCTs), letrozole is still used off label for ovulation induction, since it has not been approved by the US Food and Drug Administration (FDA) for this indication. 6 A 2005 study 7 , including 150 babies, raised some concerns about the teratogenicity of letrozole, but there were major methodological flaws in this study as the intervention group was not well controlled. Two other large studies, including 911 and 470 infants respectively, compared the use of letrozole to CC and spontaneously conceiving women.…”

Predictors for Response to Letrozole as an Ovulation Induction in Anovulatory Infertile Polycystic Ovarian Syndrome Women

“…The primary outcome measure for letrozole as an OI in the study shows that the overall clinical response in the form of ovulation and pregnancy was 64.2% and 32.8%, respectively, and these results were lower than those seen in other studies (Alizzi FJ [11] , Amer, et al [22] , Palomba, et al [23] ). The lower ovulation and pregnancy rate seen could be due to the and clomiphene resistant (37.3).…”