The estrogen–ECM–integrin– cytoskeleton axis in pelvic organ prolapse: a mechanobiological framework linking matrix remodeling to repair failure

Pelvic organ prolapse (POP) is a common disorder of pelvic support, but its estimated prevalence depends strongly on ascertainment. A 2024 meta-analysis reported a pooled prevalence of 30.9%, increasing to 41.8% in examination-based studies. Altered collagen turnover and estrogen-responsive tissue remodeling are important features of POP, yet they do not fully explain how extracellular-matrix (ECM) abnormalities may become persistent defects in cellular force transmission and repair. This narrative Review develops an evidence-graded estrogen–ECM–integrin–cytoskeleton axis, organized around ECM mechanics and fibroblast mechanosensing. We distinguish ERα-, ERβ- and GPER-mediated signaling; indirect hormonal effects on the matrix presented to integrins; and the more limited evidence for direct hormonal control of integrin signaling in human POP. We examine LOX/LOXL-dependent matrix maturation while separating expression, catalytic activity and mature cross-link measurements. The integrin–talin–vinculin molecular clutch provides a candidate connection between abnormal matrix resistance, FAK/Src–RhoA/ROCK signaling, cytoskeletal function and YAP/TAZ-dependent transcription. However, POP-associated mechanics vary with tissue compartment, measurement scale and disease state. Reduced counter-resistance and clutch slippage therefore represent a testable scenario, not a universal disease sequence. We identify experiments that could distinguish matrix-mediated effects from intrinsic fibroblast dysfunction and connect these questions to biomaterial design, controlled loading and local pathway modulation. Clinical estrogen therapy and experimental mechanopharmacology must remain distinct: improved local tissue quality does not establish prevention of prolapse recurrence, and no YAP/TAZ-targeted drug is approved for POP.