Endometrial aging and female fertility: Molecular mechanisms, clinical consequences and therapeutic opportunities

Endometrial aging encompasses progressive structural, vascular, hormonal, cellular, and epigenetic changes that impair uterine receptivity and embryo implantation in both natural conception and assisted reproductive technology (ART). Although ovarian aging has historically been considered the principal determinant of female fertility decline, mounting clinical and molecular evidence demonstrates that the uterus itself is not age-invariant. This review summarizes the historical paradigm of the “ageless uterus,” the demographic and social context that has made endometrial aging a clinically urgent question, the cellular and molecular mechanisms underlying endometrial aging (including senescence, decidualization failure, transcriptomic remodeling, vascular decline, and epigenetic drift), the clinical evidence demonstrating its impact on implantation, pregnancy loss, live birth, and obstetric outcomes, the contemporary public narrative around late motherhood, the emerging regenerative strategies aimed at restoring endometrial function, and future directions including artificial intelligence-based endometrial assessment. A central clinical message is that although reproductive outcomes decline with age, they remain non-zero even into the fifth decade and beyond, supporting calibrated rather than dichotomous counseling.