Prospective randomized trial comparing the effects of letrazole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI).

Abstract

Objective: CC is commonly used to increase the number of pre-ovulatory follicles in ovulatory patients prior to IUI. However, pregnancy rates following induction with CC and IUI are lower than expected for the number of follicles produced. This is probably the result of the negative effect of CC on endometrial development. Recently, a report of a small cohort of anovulatory patients suggested that LE, a non-steroidal aromatase inhibitor, could result in a successful ovulation induction with a normally developed endometrium and high pregnancy rates when administered to patients who developed a thin endometrium when treated with CC. In this study we investigated whether treatment with LE offers an advantage over treatment with CC in patients with unexplained infertility undergoing IUI treatment. Design: Prospective randomized double blind trial. Materials/Methods: Patients with at least 12 months of unexplained infertility and the absence of ovarian cysts on ultrasound scan performed between day 1 and 3 of the menstrual cycle, were offered to participate in the study. The patients were randomized to receive either 100 mg of CC or 2.5 mg of LE for five days starting from cycle day 3. Ultrasound scans and blood tests were performed on cycle day 7, and as required thereafter, until the dominant follicle reached 18 mm in mean diameter. Ovulation was then triggered with 10,000 IU hCG and IUIs were performed 24 and 48 hours later. In subsequent cycles patients remained in their original study group. A maximum of three cycles were offered to each patient. Results: In the period between November 2000 and March 2001 a total of 49 patients were recruited into the study. Of these 25 received LE and 24 received CC. There was no difference between the two groups in age (30.7 years vs. 32.8 years p = .11), duration of infertility (26 vs. 24 months p = .82), semen characteristics or any other relevant parameters. On day 7 of the menstrual cycle the group receiving CC had significantly higher serum E2 (898 vs. 326 pmol/mL p < .0001) and FSH levels (7.0 vs. 6.2 IU/mL p = .03). Both groups had a similar number of measurable follicles (5.5 in CC vs. 6.0 in LE group p = .8) and endometrial thickness (5.4 mm in CC vs 5.5 mm in LE group p = .9). Patients in both groups required a similar period of time to satisfy the criteria for hCG administration (10 days in CC vs. 11 days in LE group p = .3). On the day of hCG administration the patients in the CC group had higher E2 levels (2322.5 vs. 605 pmol/mL p < .0001), more follicles 14 mm in the mean diameter (2 vs 1 p = .005), a thinner endometrium (6.9 vs 8.6 mm p = .03) and an increased uterine artery Pulsatility Index (3.6 vs. 3.1 p = .0005). A non-significant increase in pregnancy rate was observed in patients receiving the LE treatment (16.7% vs. 5.6% per patient p = .55). Conclusions: Patients with unexplained infertility, when treated with LE rather than CC develop less pre-ovulatory follicles but achieve a superior uterine environment. Due to its less detrimental effects on uterus LE could replace CC, at least in some patients, with unexplained infertility undergoing ovulation induction and IUI. Supported By: ‘Serono’ Canada.