Hormones and Female Urinary Incontinence

激素与女性尿失禁

• 批准号: 6858358
• 负责人: TOM F LUE
• 金额: $ 31.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858358
• 关键词: estrogen receptors; estrogens; female; hormone regulation /control mechanism; hormone therapy; laboratory rat; molecular pathology; muscle pharmacology; myosins; progesterone; pyrrolidines; raloxifene; somatotropin; urinary incontinence; urinary tract pharmacology; vascular endothelial growth factors

DESCRIPTION (provided by applicant): It is estimated that 100 million men and women are affected by urinary incontinence (UI). The prevalence of UI is generally higher in women than in men, women being between two (older age groups) and four times (younger and middle-aged) more likely to be incontinent than men. Hormone replacement has been the mainstay of medical therapy for women with urinary incontinence for several decades. However, two recently published long-term studies involving thousands of women showed that estrogen/progesterone therapy increased the incontinence rate. We have developed a rat model of stress urinary incontinence (SUI) and have since been actively involved in the study of female SUI. To investigate the hormonal effect on urinary incontinence, we treated our rat SUI models with placebo versus estrogen pellet. Consistent with the results of human studies mentioned above, our pilot study showed that estrogen treatment increased the rate of SUI. We went on to study the possible mechanism of this phenomenon and found that estrogen has differential effects on the vagina and urethra. We hypothesize that the relaxant effect of estrogen on the urethra contributes to the increase incontinence rate particularly in those women who already have "compromised" continence mechanism. We also hypothesize that better treatment options can be identified by studying the effect of selective estrogen receptor modulators (SERMs) as well as several known trophic factors for muscle and nerve. The hypotheses will be tested by completing the following specific aims. Our long term goal is to find better preventive and therapeutic measures for women with urinary incontinence. Specific Aim 1. To identify the effect of sex hormones and SERMs on female urinary continence. This will be accomplished by treating our established incontinence rat model with estrogen, progesterone, raloxifene, levormeloxifene, and growth hormone, followed by cystometrical analysis. Specific Aim 2. To elucidate the molecular mechanism associated with estrogen/progesterone induced incontinence. This will be accomplished by examining the urethra, bladder, vagina, and pelvic floor muscles for possible changes in myosin light chain phosphorylation, rho kinase expression, and VEGF promoter activity. Specific Aim 3. To identify better preventive and therapeutic options for stress urinary incontinence. This will be accomplished first by establishing primary urethra smooth muscle cell cultures and paracervical ganglion neurons from various groups of rats as in Specific Aim 1. The cell and ganglial cultures will be treated with estradiol, raloxifene, testosterone, and various growth factors, and analyzed for cell proliferation and neurite growth. Specific Aim 4. To identify the molecular mechanism through which estrogen modulates the expression of a1A adrenoceptor. This will be accomplished by analyzing various promoter constructs of the rat a1A adrenoceptor gene in the presence of estrogen and SERMs.

描述（由申请人提供）：据估计，有 1 亿男性和女性受到尿失禁 (UI) 的影响。女性尿失禁的患病率通常高于男性，女性失禁的可能性是男性的两倍（老年群体）到四倍（青年和中年）。几十年来，激素替代疗法一直是女性尿失禁的主要药物治疗方法。然而，最近发表的两项涉及数千名女性的长期研究表明，雌激素/黄体酮治疗会增加失禁率。我们开发了压力性尿失禁（SUI）大鼠模型，并积极参与女性 SUI 的研究。为了研究激素对尿失禁的影响，我们用安慰剂与雌激素颗粒治疗大鼠 SUI 模型。与上述人体研究结果一致，我们的初步研究表明雌激素治疗会增加 SUI 的发生率。我们继续研究这种现象的可能机制，发现雌激素对阴道和尿道有不同的影响。我们假设雌激素对尿道的松弛作用导致失禁率增加，特别是对于那些已经“受损”失禁机制的女性。我们还假设，通过研究选择性雌激素受体调节剂（SERM）以及几种已知的肌肉和神经营养因子的作用，可以找到更好的治疗方案。将通过完成以下具体目标来检验假设。我们的长期目标是为女性尿失禁找到更好的预防和治疗措施。具体目标 1. 确定性激素和 SERM 对女性尿失禁的影响。这将通过用雌激素、黄体酮、雷洛昔芬、左美洛昔芬和生长激素治疗我们建立的失禁大鼠模型，然后进行膀胱测压分析来实现。具体目标 2. 阐明与雌激素/孕激素引起的尿失禁相关的分子机制。这将通过检查尿道、膀胱、阴道和盆底肌肉的肌球蛋白轻链磷酸化、rho 激酶表达和 VEGF 启动子活性可能发生的变化来实现。具体目标 3. 确定压力性尿失禁更好的预防和治疗方案。这将首先通过建立来自各组大鼠的原代尿道平滑肌细胞培养物和宫颈旁神经节神经元来完成，如具体目标 1 中所示。细胞和神经节培养物将用雌二醇、雷洛昔芬、睾酮和各种生长因子处理，并进行分析用于细胞增殖和神经突生长。具体目标 4. 确定雌激素调节 a1A 肾上腺素受体表达的分子机制。这将通过在雌激素和 SERM 存在的情况下分析大鼠 a1A 肾上腺素受体基因的各种启动子构建体来实现。