Effects of preoperative local estrogen in postmenopausal women with prolapse: a randomized trial

Abstract

Context: Pelvic organ prolapse (POP) increases in prevalence with age; recurrence after surgical repair is common.

Objective: The objective of the study was to determine the effects of local estrogen treatment on connective tissue synthesis and breakdown in the vaginal wall of postmenopausal women planning surgical repair of POP.

Design: This was a randomized trial.

Setting: The study was conducted at an academic tertiary medical center.

Patients or other participants: Postmenopausal women with a uterus and symptomatic anterior and/or apical prolapse at stage 2 or greater participated in the study.

Intervention: Estrogen (Premarin) or placebo cream for 6 weeks preoperatively was the intervention.

Main outcome measures: Full-thickness anterior apical vaginal wall biopsies were obtained at the time of hysterectomy and analyzed for mucosa and muscularis thickness, connective tissue synthesis, and degradation. Serum levels of estrone and 17β-estradiol were analyzed at baseline and the day of surgery using highly sensitive liquid chromatography-tandem mass spectrometry.

Results: Fifteen women per group (n = 30 total) were randomized; 13 per group underwent surgery. Among drug-adherent participants (n = 8 estrogen, n = 13 placebo), epithelial and muscularis thickness was increased 1.8- and 2.7-fold (P = .002 and P =.088, respectively) by estrogen. Collagen types 1α1 and 1α2 mRNA increased 6.0- and 1.8-fold in the vaginal muscularis (P < .05 for both); collagen type Ia protein increased 9-fold in the muscularis (P = .012), whereas collagen III was not changed significantly. MMP-12 (human macrophage elastase) mRNA was suppressed in the vaginal mucosa from estrogen-treated participants (P = .011), and matrix metalloprotease-9 activity was decreased 6-fold in the mucosa and 4-fold in the muscularis (P = .02). Consistent with menopausal norms, serum estrone and 17β-estradiol were low and did not differ among the two groups.

Conclusions: Vaginal estrogen application for 6 weeks preoperatively increased synthesis of mature collagen, decreased degradative enzyme activity, and increased thickness of the vaginal wall, suggesting this intervention improves both the substrate for suture placement at the time of surgical repair and maintenance of connective tissue integrity of the pelvic floor.

Trial registration: ClinicalTrials.gov NCT01778985.

Figures

Figure 1.

Study recruitment and follow-up. *, Number available for intention-to-treat analysis.

Figure 2.

Effect of vaginal estrogen on synthesis activity in the vaginal wall. Hematoxylin and eosin stains are shown; a representative cross-section of vaginal wall from postmenopausal women with prolapse treated with placebo (A) or vaginal estrogen (B) is also shown. Epi, epithelium; l.p., lamina propria; Musc, muscularis. Bar, 1 mm. C, Thickness (micrometers) of epithelium, lamina propria, and muscularis of vaginal tissues from women treated with placebo or estrogen. Data represent mean ± SEM of 12 placebo and eight estrogen. *, P = .002; δ, P = .088. D, Levels of Col1α1, Col 1α2, and Col 3α mRNA in tissues from women treated with placebo (n = 12) or estrogen (n = 8). Data represent mean ± SEM. *, P < .05 compared with the same gene in the placebo group. Immunoblot analysis (E) and densitometry (F) of collagen types I and III (n = 4 per group). Monomeric (140 kDa), dimeric (270 kDa), and trimeric (∼400 kDa) forms of collagen I or collagen III are indicated by arrows. The human fetal lung represents positive control. **, P = .012.

Figure 3.

Effect of vaginal estrogen on degradative activity in the vaginal wall. A, In the vaginal mucosa, MMP12 (human macrophage elastase) was increased in 5 of 12 placebo (greater than 95% confidence interval of normal premenopausal controls) but within normal limits in eight of eight women treated with estrogen (5.8 ± 1.5, P = .035). Dashed line represents 95% confidence interval of data from 15 premenopausal controls without prolapse. B, MMP1 mRNA was suppressed in six of seven mucosal samples from estrogen but more variable in women treated with placebo. Dashed line represents 75th percentile of placebo controls. Representative gelatin zymograms of vaginal mucosa (C) and muscularis (D) from women treated with placebo or estrogen are shown. Quantitative analysis of MMP9 activity in mucosa (E) (n = 8, placebo; n = 7 estrogen) or muscularis (F) (n = 5, placebo; n = 7, estrogen) is also shown. Bars represent mean ± SEM.