Investigation to Minimize Prolapse Recurrence Of the Vagina using Estrogen (IMPROVE)

 描述(申请人提供)：使用雌激素减少阴道脱垂复发的研究(改善)盆腔器官脱垂是一种盆腔器官(膀胱、阴道、宫颈和子宫)通过阴道开口突出的情况，是一种非常常见的盆底疾病，具有重大的社会和心理影响，影响女性的生活质量。年龄增长是脱垂和尿失禁的已知危险因素。脱垂或压力性尿失禁接受手术的终生风险为20%(仅脱垂手术的风险为13%)；2050年的预测是，美国脱垂女性的数量将从330万增加到490万，这将给我们的医疗体系带来更大的负担。复发性脱垂和再次手术也很常见；在接受手术修复的患者中，至少有17%的患者在10年内再次手术，更多的患者出现令人烦恼的症状复发。为了解决这些高失败率和再手术率--特别是在老年或绝经后妇女中--迫切需要确定天然组织脱垂修复的辅助手段，以防止或减少复发疾病。我们对绝经后脱垂妇女进行的术前阴道内雌激素治疗与安慰剂对照的先导性试验显示，接受雌激素治疗的妇女阴道壁肌层厚度增加，组织良好的胶原蛋白(即I型胶原)含量增加。I型胶原的上调伴随着几种蛋白水解酶的下调，这表明绝经后脱垂女性围手术期的阴道雌激素可能会减少手术诱导的几种降解酶，从而改善盆底结缔组织的长期维持。在这项应用中，我们提出了一项阴道内雌激素(结合雌激素，0.625 mg/1g乳膏)与安慰剂的双盲随机试验，用于绝经后妇女(共276人)的症状性脱垂，这些脱垂超过了计划经阴道自然组织修复的处女膜。术后1年继续用药，直到瘢痕重塑完成。我们的目标是确定阴道内雌激素治疗(I)是否导致解剖学和患者报告的盆腔器官支持的主观改善，以及(Ii)是否影响其他盆底疾病(过度活跃的膀胱和大小便失禁、性功能和疼痛、术后膀胱炎)、满意度、生活质量和阴道伤口愈合。最后，(Iii)我们将通过检查手术时采集的全层阴道壁活检的组织学、结缔组织学检查来确定局部雌激素治疗改变盆腔器官支持的潜在机制。 平滑肌合成和降解性改变。我们预计这将突出未来脱垂修复和预防治疗的其他新靶点。

 DESCRIPTION (provided by applicant): Investigation to Minimize Prolapse Recurrence Of the Vagina using Estrogen (IMPROVE) Pelvic organ prolapse, a condition in which the pelvic organs (bladder, vagina, cervix and uterus) herniate through the vaginal opening, is a very common pelvic floor disorder with substantial social and psychological implications that affect the quality of life for women. Increasing age is a known risk factor for prolapse and urinary incontinence. The lifetime risk of surgery for prolapse or stress urinary incontinence is 20% (and 13% for prolapse surgery alone); projections for 2050 are that the number of US women with prolapse will increase 46% from 3.3 to 4.9 million, placing an even greater burden on our healthcare system. Recurrent prolapse and reoperation are also common; at least 17% of patients who have surgical repairs undergo repeat operations within 10 years, and a greater number have recurrence of bothersome symptoms. To address these high failure and reoperation rates-particularly in aging or post-menopausal women-there is an urgent need to identify adjuncts to native tissue prolapse repairs that may prevent or minimize recurrent disease. Our pilot trial of preoperative intravaginal estrogen treatment vs. placebo in postmenopausal women with prolapse demonstrated increased thickness and greater content of well-organized collagen (i.e., type I) of the vaginal wall muscularis in estrogen-treated women. Up-regulation of collagen type I was accompanied by down- regulation of several proteases, suggesting perioperative vaginal estrogen in postmenopausal women with prolapse may mitigate surgical induction of several degradative enzymes and thereby improve long-term maintenance of connective tissue integrity of the pelvic floor. In this application, we propose a double-blind randomized trial of intravaginal estrogen (conjugated estrogens, 0.625mg/1g cream) vs. placebo in postmenopausal women (n=276 total) with symptomatic prolapse beyond the hymen planning transvaginal native tissue repairs. Medication will be continued 1 year postoperatively, i.e. until scar remodeling is complete. We aim to determine if pre- and postoperative intravaginal estrogen therapy (i) results in anatomic and patient-reported subjective improvement in pelvic organ support, and (ii) impacts other pelvic floor disorders (overactive bladder and incontinence, sexual function and pain, postoperative cystitis), satisfaction, quality of life, and vaginal wound healing. Finally, (iii) we will determine the potetial mechanisms by which local estrogen treatment alters pelvic organ support by examining full-thickness vaginal wall biopsies taken at the time of surgery for histologic, connective tissue, and smooth muscle synthesis and degradative changes. We expect this will highlight other novel targets for future therapies in prolapse repair and prevention.