Abstract
PURPOSE: Preclinical evidence suggests that metformin may mitigate pelvic organ prolapse (POP) by altering the gene expression of human vaginal fibroblasts in a beneficial direction, but clinical validation is lacking. This study aimed to explore the association between metformin use and POP risk. METHODS: A cross-sectional analysis was conducted using the National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2012. POP was defined by self-reported vaginal bulging. Multivariable logistic regression models were used to assess associations between metformin use and POP in high-risk subgroups (hypertension or smoking), with adjustments for demographic, comorbidity, and obstetric/gynecologic factors. Associations between inflammatory and oxidative stress biomarkers and POP were also analyzed. RESULTS: Three hundred and thirty of 9344 included women reported POP. Among 668 metformin users (630 with diabetes, 36 with prediabetes), 37 had POP. (Pre)diabetes was a risk factor for POP (OR = 1.52, P = 0.007). POP prevalence was lower in metformin-treated (pre)diabetes subgroups with hypertension (OR = 0.32, P = 0.045) or smoking (OR = 0.09, P = 0.022), independent of glycemic control, while thiazolidinediones, sulfonylureas, and insulin did not show the effect. C-reactive protein was higher in POP individuals (0.56 ± 0.98 mg/dL vs. 0.44 ± 0.73 mg/dL) and associated with POP (OR = 1.30, P = 0.020), especially in smokers (OR = 1.50, P = 0.002), but not in metformin users. Other biomarkers (systemic immune-inflammation index, ferritin, alkaline phosphatase, bilirubin, albumin, iron, γ-glutamyl transferase, and uric acid) showed no significant associations. CONCLUSION: This is the first clinical study that suggests metformin may reduce POP risk in specific high-inflammatory subgroups, potentially via anti-inflammatory pathways. The findings warrant further prospective studies and mechanistic validation.