MARKERS OF CONNECTIVE TISSUE REMODELING IN GENITAL PROLAPSE

Purpose: to expand the conception of molecular and biochemical changes in genital prolapse (GP) based on the study of morphological and immunohistochemical features in connective tissue structures of the ligamentous apparatus of the pelvic floor and their dependence on genetic polymorphisms MMP / TIMP.

Materials and Methods: the study involved 178 women aged 35 to 65, 134 of them with GP relapses (after hysterectomy by vaginal access because of a total and partial uterus and vaginal walls prolapse). Patients were randomized into the following groups: I – with manifestations of undifferentiated connective tissue dysplasia (CTD) (11.7 points on average) (n = 86); II – with no CTD signs (n = 48). Control group lll consisted of healthy women without any GP signs (among 15 patients abdominal hysterectomy was performed in connection with uterus hyperplastic processes) (n = 44). Used: morphological method of studies, immunohistochemical  (to assess tissue biopsies of sacrum-uterine  and round  uterine  ligaments), the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), genotyping by polymerase chain reaction of MMP / TIMP polymorphisms.

Results: the morphological study of women’s ligamentous apparatus in cases with GP revealed significant fibrosis, coarser collagen septa among bundles of smooth muscle fibers and degenerative changes in individual smooth muscle cells. The group with GP and CTD features showed diffuse atrophy, hyaline or mucinous degeneration of smooth muscle tissue and evident edema of extracellular matrix in 65% of samples. Pathobiochemical disorders in cases of pelvic descencia were determined by an imbalance in collagen type I and III content, with the predominance of the latter, less durable; a decrease in elastin levels and its considerable fragmentation. The greatest expression of tissue degradation was observed among women with GP and CTD manifestations on account of increased MMP-1 and -2 levels; TIMP-1 content was lowest in the group. Associations with GP development have been established among women with CTD signs for genetic polymorphisms: rs3918242 СT gene MMP9 (0,54) (p = 0,007; OR = 3,2; 95% CI 1,3-7,6), rs17576 AG gene MMP9 (0.62 vs. 0,32, p = 0,01; OR = 2,9; 95% CI 1,2-7,0); rs3025058 5A6A gene MMP3 (0.52 vs. 0.45, p = 0.009; OR = 3.7; 95% CI 1,3-10,1); rs2285053 (rs2285052) CT gene MMP2 (0.44 vs. 0.27, p = 0,007; OR = 3,2; 95% CI 1,3-7,5). Statistical significance for the groups was preserved after the correction for multiple comparisons.

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