Involvement of Oxidative Stress and Mitochondrial Apoptosis in the Pathogenesis of Pelvic Organ Prolapse

Abstract

Purpose: Biomechanical weakness of the pelvic supportive structures has been proposed to be a cause of pelvic organ prolapse. However, the molecular mechanism involved in these changes is not completely understood. In this investigation we evaluated oxidative stress biomarkers in the uterosacral ligaments of women with pelvic organ prolapse and compared them with those of women with normal support. In addition, mitochondrial apoptosis was examined. Materials and Methods: Samples were collected from 26 women with advanced stage pelvic organ prolapse and 29 age matched controls. The expression levels of 8-OHdG and 4-hydroxy-2-nonenal in the uterosacral ligaments were measured using immunohistochemistry. To assess mitochondrial apoptosis we performed TUNEL assay, immunohistochemistry for cleaved caspase-3 and cytochrome c, and Western blot analyses for cleaved caspase-3 and caspase-9. Results: The mean percentage of cells immunopositive for 8-OHdG, 4-hydroxy-2-nonenal, TUNEL, cleaved caspase-3 and cytochrome c in the uterosacral ligaments was significantly higher in patients with pelvic organ prolapse than in controls. Similarly, Western blot analysis revealed increased expression of cleaved caspase-3 and caspase-9 in patients with pelvic organ prolapse. Correlation analyses revealed significant positive correlations between the percentage of cells immunopositive for 8-OHdG or 4-hydroxy-2-nonenal and markers of mitochondrial apoptosis. Analyzing by pelvic organ prolapse quantification system stage according to C point, the mean percentage of cells immunopositive for 8-OHdG, 4-hydroxy-2-nonenal and cytochrome c was significantly higher in patients with pelvic organ prolapse compared to controls, regardless of stage. However, the mean percentage of TUNEL and cleaved caspase-3 positive cells was significantly higher only in patients with stage III or IV pelvic organ prolapse. Conclusions: Oxidative stress and increased mitochondrial apoptosis may contribute to the pathological process of pelvic organ prolapse.