Hormones and Female Urinary Incontinence

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。尿失禁在女性中的患病率一般高于男性，女性大小便失禁的可能性是男性的两到四倍(年龄较大的年龄组)到四倍(中青年)。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/黄体酮疗法增加了大小便失禁的发生率。我们已经建立了压力性尿失禁(SUI)的大鼠模型，并一直积极参与女性SUI的研究。为了研究激素对尿失禁的影响，我们用安慰剂和雌激素颗粒治疗我们的大鼠SUI模型。与上述人类研究的结果一致，我们的初步研究表明雌激素治疗增加了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路有不同的影响。我们假设雌激素对尿路的松弛作用是导致大小便失禁发生率增加的原因之一，尤其是在那些已经“受损”的大小便失禁机制的女性中。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效果，可以确定更好的治疗方案。这些假设将通过完成以下具体目标来检验。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。具体目的1.确认性激素和SERM对女性尿失禁的影响。这将通过用雌激素、孕酮、雷洛昔芬、左旋美洛昔芬和生长激素治疗我们建立的大小便失禁大鼠模型，然后进行膀胱计量学分析来完成。具体目的2.阐明雌激素/孕激素引起尿失禁的分子机制。这将通过检查尿路、膀胱、阴道和盆底肌肉的肌球蛋白轻链磷酸化、Rho激酶表达和血管内皮生长因子启动子活性的可能变化来实现。具体目标3.确定更好的压力性尿失禁预防和治疗方案。这将首先通过建立原代培养的不同组大鼠的尿路平滑肌细胞和颈旁神经节神经元来完成，具体目标1。细胞和神经节细胞培养将用雌二醇、雷洛昔芬、睾酮和各种生长因子处理，并分析细胞增殖和轴突生长。明确雌激素调节A1a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结构来完成。

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.