Oxytocin antagonist mechanism of action in ART – a prospective, randomized study of nolasiban effects on uterine contraction, perfusion and gene expression in healthy female volunteers

Abstract

Abstract Research Question To study the effects of oxytocin receptor antagonist (OTR antagonist) nolasiban on uterine contractions, endometrial perfusion and endometrial mRNA expression. Design Increased uterine contractions during embryo transfer (ET) are negatively correlated with pregnancy rates, and endometrial blood flow was shown to be an important predictor for endometrial receptivity. OTRs are expressed during human peri-implantation in myometrium, endometrium and uterine blood vessels, and several clinical studies demonstrated that OTR antagonists decrease uterine contractions, increase endometrial perfusion and improve pregnancy rates following ET. We conducted a randomized, double-blind, parallel-group mode-of-action study with nolasiban. Fourty-five healthy, pre-menopausal women were treated with placebo, 900 mg or 1800 mg nolasiban on the day corresponding to blastocyst transfer. We assessed ultrasonographic uterine contraction frequency and endometrial perfusion, and collected endometrial biopsies analyzed by Next-Generation-Sequencing. Results Both doses of nolasiban showed trends of decreased contraction frequency and increased endometrial perfusion. At 1800 mg, 10 endometrial genes (DPP4, CNTNAP3, CNTN4, CXCL12, TNXB, CTSE, OLFM4, KRT5, KRT6A, IDO2) were significantly differentially expressed (adjusted p Conclusions These data expand the understanding of the mechanism-of-action of nolasiban in increasing pregnancy rates following ET. The results suggest more marked effects of nolasiban 1800 mg compared to the 900 mg dose, supporting testing at higher doses in IVF patients.