Proteolytic Imbalance of the MMP/E-Cadherin Axis in Genitourinary Syndrome of Menopause: A Cross-Sectional Study

Purpose: To investigate the hypothesis that an imbalance between the epithelial adhesion molecule E-cadherin and matrix metalloproteinases (MMPs) underlies the vaginal atrophy associated with menopause. Methods: This cross-sectional study included 90 women undergoing hysterectomy for benign conditions, stratified into premenopausal (n=30), early postmenopausal (1– 5 years, n=30), and late postmenopausal (> 5 years, n=30) groups. Expression of E-cadherin, MMP-1, MMP-7, and MMP-9 in vaginal tissue was assessed by immunohistochemistry and RT-qPCR. Soluble protein levels in vaginal lavage fluid were quantified by ELISA. Results: Compared to premenopausal women, postmenopausal groups showed a significant decrease in E-cadherin protein expression without changes in CDH1 mRNA. Conversely, protein and mRNA expression of MMP-1, − 7, and − 9 were significantly upregulated. Levels of soluble E-cadherin (sE-cad), MMP-7, and MMP-9 were also significantly elevated in vaginal lavage fluid. Importantly, MMP-9 expression demonstrated a strong inverse correlation with tissue E-cadherin (r = − 0.552, P < 0.001) and a moderate positive correlation with lavage sE-cad (r = 0.448, P = 0.009). Conclusion: Menopause is associated with a proteolytic imbalance in the vagina, characterized by post-transcriptional downregulation of E-cadherin and upregulation of MMPs. Our findings support a model where increased MMP-9 activity is associated with the cleavage of E-cadherin, leading to compromised epithelial barrier integrity. This MMP/E-cadherin axis provides a key molecular mechanism for the atrophic changes underlying the Genitourinary Syndrome of Menopause (GSM). Furthermore, this study provides the first direct human evidence of post-transcriptional E-cadherin degradation, identifying soluble E-cadherin as a promising non-invasive biomarker for the objective clinical assessment of GSM.