Oestradiol and reproductive outcomes in ART: when too much of a good thing hurts

Oestradiol plays a crucial role in reproduction, particularly in assisted reproductive technology (ART), where it can reach supraphysiological concentrations. These fluctuations occur during ovarian stimulation in fresh embryo transfer cycles and during endometrial preparation for frozen embryo transfer, potentially impacting implantation and perinatal outcomes. Oestradiol influences endometrial proliferation, receptivity, implantation and placentation, with the sensitivity of the endometrium to systemic oestrogen emerging as a key determinant of reproductive success. In fresh embryo transfer cycles, ovarian stimulation induces histological, immunological and genetic changes in the endometrium, correlating with elevated oestradiol concentrations and possibly disrupting implantation. However, this adverse effect appears time-limited, as endometrial receptivity is restored in subsequent cycles. In FET cycles, both the duration and intensity of oestradiol exposure are critical, as excessive or prolonged exposure to exogenous oestradiol may impair reproductive outcomes. Despite these potential effects, strategies to regulate oestradiol concentrations in ART remain underexplored. This review examines the physiological and pathological roles of oestradiol in natural and ART cycles, emphasizing its impact on endometrial function, implantation and pregnancy outcomes. It highlights the need for further research to define optimal oestradiol thresholds and develop personalized ART protocols that consider both oestradiol concentrations and endometrial sensitivity to improve reproductive success and obstetric outcomes. Finally, it highlights strategies aimed at modulating oestradiol exposure to optimize reproductive success.