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

 描述（由申请人提供）：使用雌激素（IMPROVE）减少阴道脱垂复发的研究盆腔器官脱垂是一种盆腔器官（膀胱、阴道、宫颈和子宫）通过阴道口疝出的疾病，是一种非常常见的盆底疾病，具有影响女性生活质量的重大社会和心理影响。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手术的终生风险为20%（仅脱垂手术的风险为13%）;预测到2050年，美国脱垂女性的数量将从330万增加到490万，增加46%，给我们的医疗保健系统带来更大的负担。复发性脱垂和再次手术也很常见;至少17%的手术修复患者在10年内接受了重复手术，更多的患者复发了令人烦恼的症状。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，迫切需要确定天然组织脱垂修复的方法，以预防或减少复发性疾病。我们在绝经后脱垂妇女中进行的术前阴道内雌激素治疗与安慰剂治疗的初步试验表明，厚度增加，组织良好的胶原蛋白含量增加（即，I型）的阴道壁肌层在雌激素治疗的妇女。I型胶原蛋白的上调伴随着几种蛋白酶的下调，表明绝经后脱垂妇女围手术期阴道雌激素可减轻几种降解酶的手术诱导，从而改善盆底结缔组织完整性的长期维持。在本申请中，我们提出了一个双盲随机试验阴道内雌激素（结合雌激素，0.625毫克/1克霜）与安慰剂在绝经后妇女（n=276）有症状的脱垂超出处女膜计划经阴道天然组织修复。术后1年将继续用药，即直至疤痕重塑完成。我们的目的是确定术前和术后阴道内雌激素治疗是否（i）导致盆腔器官支持的解剖学和患者报告的主观改善，以及（ii）影响其他盆底疾病（膀胱过度活动症和尿失禁，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阴道壁全层活检的组织学、结缔组织和组织学，确定局部雌激素治疗改变盆腔器官支持的潜在机制。 平滑肌合成和降解变化。我们希望这将突出其他新的目标，为未来的治疗脱垂修复和预防。

 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.