Altered endometrial oestrogen-responsiveness and recurrent reproductive failure

GRAPHICAL ABSTRACT: [Image: see text] ABSTRACT: Recurrent reproductive failure (RRF) encompasses recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). These highly prevalent, distressing conditions have many unanswered questions regarding aetiology and management. Oestrogen receptor beta (ERβ) is the predominant oestrogen receptor expressed in the vascular endothelium of the endometrium during the window of implantation (WOI). The establishment of normal endometrial receptivity is integrally associated with progesterone receptor (PR). Therefore, we aimed to investigate whether women with RRF have clinical, type-specific endometrial aberrations of ERβ, PR and Ki-67 expression during the WOI. Thirty-eight endometrial biopsies were collected; 29 RRF (10 RIF, 9 recurrent loss of early pregnancy (RLEP) and 10 recurrent fetal loss (RFL)) and 9 fertile controls (FC). Within RIF, RLEP and RFL groups, the perivascular compartment showed significantly lower levels of ERβ vs FC (P = 0.02, P = 0.03 and P = 0.01, respectively). Vascular endothelium also displayed significantly lower levels of ERβ within RIF and RFL cohorts vs FC (P = 0.03 and P = 0.003). The expression of Ki-67 was significantly lower within vascular endothelium of all RRF; RIF (P = 0.02), RLEP (P = 0.02) and RFL (P <0.01). PR was significantly reduced (P <0.001) in the perivascular area of women with RIF. These findings provide novel insights into biological correlates of clinical subtypes of RRF. The endometrium of women with RRF display significantly altered levels of ERβ, PR and Ki-67 during the WOI, furthering our understanding of the defective endometrial phenotype of women suffering from RRF, with possible impaired glandular function, angiogenesis and decidualisation. LAY SUMMARY: Recurrent reproductive failure (RRF) refers to a group of devastating conditions with many unanswered questions regarding their causes and treatment options. The lining of the womb, the endometrium, is primed and suitable for successful embryo implantation for a short time during the menstrual cycle; the window of implantation (WOI). Oestrogen is a key hormone that plays an important role in regulating the endometrium and its effects are exerted via two oestrogen receptor subtypes. Oestrogen receptor beta (ERβ) is the main oestrogen receptor present during the WOI. Progesterone receptor allows the other main hormone, progesterone, to influence the endometrial activity and Ki-67 reflects the proliferative activity of the cells within the endometrium. We investigated the expression of these markers in endometrial samples collected from women with RRF and proven fertility. We found that the endometrium of women with RRF has significantly lower levels of ERβ and Ki-67 during the WOI, possibly leading to unsuccessful pregnancies.