Three-year outcomes of a randomized clinical trial of perioperative vaginal estrogen as adjunct to native tissue vaginal apical prolapse repair

Background As the muscular and connective tissue components of the vagina are estrogen-responsive, clinicians may recommend vaginal estrogen to optimize tissues preoperatively and as a possible means to reduce prolapse recurrence, but long-term effects of perioperative intravaginal estrogen on surgical prolapse management are uncertain. Objective To compare the efficacy of perioperative vaginal estrogen vs. placebo cream in reducing composite surgical treatment failure 36 months following native tissue transvaginal prolapse repair. Study Design This is the extended follow-up of a randomized superiority trial conducted at 3 tertiary US sites. Postmenopausal patients with bothersome anterior/apical vaginal prolapse were randomized 1:1 to 1g conjugated estrogen cream (0.625mg/g) or placebo, inserted vaginally twice-weekly for ≥5wk preoperatively and continued twice-weekly for 12mo postoperatively. All participants underwent a vaginal hysterectomy (if uterus present) and standardized uterosacral or sacrospinous ligament suspension at surgeon discretion. The primary report's outcome was time-to-failure by 12mo postoperatively defined by a composite outcome of objective prolapse of the anterior or posterior walls beyond the hymen or the vaginal apex descending below one-third the total vaginal length; subjective bulge symptoms; and/or retreatment. After 12mo, participants could choose to use—or not use—vaginal estrogen for atrophy symptom bother. Secondary outcomes included pelvic organ prolapse quantification (POP-Q) points, subjective prolapse symptom severity using the Patient Global Impression of Severity (PGI-S), Patient Global Impression of Improvement (PGI-I), and prolapse-specific subscales of the Pelvic Floor Distress Inventory (PFDI-20) and Pelvic Floor Impact Questionnaire (PFIQ-7). Data were analyzed as intent-to-treat and "per-protocol" (i.e., ≥50% of expected cream use per medication diary). Results Of 206 postmenopausal patients, 199 were randomized and 186 underwent surgery; 164 (88.2%) provided 36-month data. Mean (SD) age was 65 (6.7) years; characteristics were similar at baseline between groups. Composite surgical failure rates were not significantly different for the estrogen vs. placebo groups through 36 months with model-estimated failure rates of 32.6% (95% CI: 21.6-42.0%) vs. 26.8% (95% CI: 15.8-36.3%), respectively, adjusted hazard ratio, 1.55 (95% CI: 0.90-2.66), P=0.11. Results were similar for the per-protocol analysis. Objective/anatomic failures were more common than subjective/symptomatic failures, combined objective and subjective failures, or retreatment. Using the PGI-I, 75 of 80 (94%) estrogen and 72 of 76 (95%) placebo participants providing 36-month data reported they were much- or very much better 36 months after surgery, P>0.99; these data include reporting from 51 of the 55 "surgical failures". POP-Q measurements, PGI-S scores, and prolapse subscale scores of the PFDI-20 and PFIQ-7 all significantly improved for both estrogen and placebo groups from baseline to 36 months postoperatively without differences between groups. Of the 160 providing data on vaginal estrogen usage at 36 months postoperatively, 40 of 82 (49%) originally assigned to estrogen were using prescribed vaginal estrogen, and 47 of 78 (60%) assigned to placebo were using vaginal estrogen, P=0.15. Conclusions Adjunctive perioperative vaginal estrogen applied ≥5wk preoperatively and 12mo postoperatively did not improve surgical success rates 36 months after uterosacral or sacrospinous ligament suspension prolapse repair. Patient perception of improvement remained very high at 36 months.