Aromatase inhibitor letrozole improves implantation rate in poor responder IVF/ICSI patients

Abstract

Recent studies have shown that androgens in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental trophic role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. This mechanism may explain the frequent hyperresponse to ovarian stimulation of PCO patients. The objective of this pilot study is to assess if aromatase inhibition with letrozole improves ovarian response and cycle outcome in a low responder series undergoing controled ovarian hyperstimulation for IVF in comparison with a control group. Case-control study 147 patients with a previous poor response to standard long protocol (less than four follicles ≥16 mm and/or serum E2≤ 500 pg/ml on the day of hCG administration) were included and divided in two groups: 76 patients (control group) received high doses FSH/hMG stimulation protocol starting on day 3 of menstrual cycle. A GnRH antagonist was administered to avoid premature ovulation starting when leading follicles reached 14 mm in mean diameter. On the other hand 71 patients (study group) also received a similar protocol with GnRH antagonist but with the addition of letrozole 2.5 mg/day administered from stimulation days 1 through 5. Follicular fluid and blood samples were obtained for all patients the day of egg retrieval. Chi square and student‘s t test were used as appropiate and p≤ 0.05 was considered significant. Patients were comparable in terms of age (37.4 vs 36.5), body mass index (23.2 vs 22.5) and day 3 serum FSH, LH and estradiol levels. No significant differences among groups were found in terms of days of stimulation (8.9 vs 9.3), mean FSH/hMG dose administered (3804.6 vs 3627.4), mean serum E2 levels the day hCG (813.5 vs 770.04), endometrial thickness (9.8 vs 9.6) and cancelation rate (19.7 vs 15.5%). Despite no difference was found in the number of mature follicles (3.3 vs 3.7), the oocyte retrieved resulted significantly higher in the study group (4.3 vs 6.1, p : 0.033). Interestingly, we found a marked difference in the implantation rate resulting significantly higher in the letrozole group (9.4 vs 25%, p :0.009). There was a clinically relevant higher pregnancy rate in the letrozole group (41.6% vs 28.9%) but values did not reach statistical significance, probably due to sample size. We have shown that aromatase inhibition with letrozole significantly improves implantation rate in low responder patients undergoing IVF cycle in comparison with a control group. A randomized trial is mandatory to validate this hypothesis.