Endometrial receptivity defects during IVF cycles with and without letrozole

Abstract

Background: Our aim was to study ways to improve IVF success rates in women with suspected endometrial receptivity defects.

Methods: We conducted a retrospective cohort study examining the effect of letrozole (aromatase inhibitor) on integrin expression as a marker of endometrial receptivity. We compared IVF outcomes in 97 infertile women who had undergone ανβ3 integrin assessment by immunohistochemistry in mid-luteal endometrial biopsies. Of 79 women undergoing standard IVF, 29 (36.7%) lacked normal integrin expression. Eighteen other women with low integrin were studied after receiving letrozole during early IVF stimulation. An independent set of ανβ3 integrin-negative patients (n = 15) who had undergone repeat endometrial biopsy for integrin testing while taking letrozole were re-evaluated.

Results: Clinical pregnancy and delivery rates were higher in women with normal ανβ3 integrin expression compared with those who were integrin negative [20/50 (40%) versus 4/29 (13.8%); P = 0.02 and 19/50 (38%) versus 2/29 (7%); P < 0.01, respectively]. In 18 women who received letrozole early in IVF, 11 conceived (61.1%; P < 0.001) compared with integrin-negative patients who did not receive letrozole. In integrin-negative women who were rebiopsied on letrozole, 66.7% reverted to normal integrin expression. Positive endometrial aromatase immunostaining using a polyclonal antibody was a common finding in infertile patients compared with controls.

Conclusions: Lack of endometrial ανβ3 integrin expression is associated with a poor prognosis for IVF that might be improved with letrozole co-treatment. Prospective studies are needed to confirm and extend these findings but the data suggest that aromatase expression may contribute to implantation failure in some women.

Figures

Figure 1

(A) The effect of oral letrozole on endometrial integrin expression was studied in women with a negative HSCORE for the ανβ3 integrin. Integrin assessment was compared in the tissue of women before or after taking 5 mg of letrozole on cycle Days 5–9. A HSCORE cut-off for a negative test is shown by the dotted line (≤0.7) based on earlier analysis (Lessey et al., 1994b). (B) Reproducibility of integrin testing was examined in mid-luteal endometrial biopsies in normal controls in two separate menstrual cycles. HSCORE (0–4) was compared in the first and second biopsies performed at the same time in the proliferative or secretory phase in the same fertile volunteer.

Figure 2

Ongoing pregnancy rate in women undergoing IVF with positive (black) or negative integrins (white). In standard IVF protocols women with a negative integrin test had a significantly worse outcome than those who tested positive (P < 0.02). In integrin-negative women who underwent IVF with letrozole (2.5–5 mg/day on Days 2–6), outcomes were similar to integrin-positive women in non-letrozole cycles.

Figure 3

The level of p450 aromatase expression was studied in women with and without endometriosis using immunohistochemistry as described in the Materials and methods section. Placenta served as a positive control (A). In women without endometriosis, aromatase expression was low (B), while in those with endometriosis it is generally increased (C), independent of IVF outcome or integrin status. Women without endometriosis (D, controls) did not exhibit detectable aromatase expression, compared with the IVF patients in this study.