Estrogen Receptor-Selective Herbs for Menopause Symptoms

描述(申请人提供)：我们的长期目标是寻找安全有效的天然药物来预防更年期症状和骨质疏松症。目前，美国有3600万绝经后妇女，预计到2020年，这一数字将飙升至5000万。更年期的特点是严重的雌激素缺乏，这会导致潮热、阴道干燥、情绪波动和骨质疏松。尽管在过去的50年里，激素替代疗法(HILT)已经有效地治疗了这些疾病，但最近的临床试验发现，HRT与乳腺癌、心血管疾病和痴呆症的风险增加有关。激素替代疗法未能达到预期，使得迅速增长的更年期人口没有一个好的替代方案来预防潮热和骨质疏松症。因此，迫切需要发现更具选择性和更安全的雌激素。许多女性寻求HRT的替代品，特别是从植物中提取的雌激素，称为植物雌激素。观察性研究表明，在食用大豆和草药产品的亚洲女性中，更年期症状、骨质疏松症、心血管疾病和乳腺癌的发生率较低，这激发了人们对植物雌激素的兴趣。不幸的是，几乎没有科学数据表明它们在预防更年期症状和骨质疏松症方面有效。基于我们的研究表明，雌激素受体(ER)α介导乳腺癌细胞的增殖，ERβ抑制小鼠异种移植瘤的增殖和乳腺肿瘤的形成，我们正在使用分子生物学技术来鉴定对ERBβ具有选择性雌激素活性的草药。我们假设，ERβ选择性雌激素将比目前HRT方案中发现的与ERα和ERβ非选择性相互作用的雌激素更安全，并将有效地减少潮热和骨质疏松。为了发现ERbeta选择性的草药，我们在ERpha或ERbeta存在的情况下，用荧光素酶瞬时转染实验筛选了67种中药。其中7种草药用Erli选择性地调节转录，其中一些草药还招募了辅助调节因子GRIP1到ERbeta，并且对引起MCF-7乳腺癌细胞增殖的作用非常弱。这项建议的目标是：(1)利用分子生物学技术来确定草药如何具有ER选择性，以及这些草药是否在体内保持ER选择性。(2)鉴定中草药中与内质网选择性有关的活性成分。(3)确定哪类ER选择性草药在减少潮热的频率和严重程度方面最有效。识别雌激素受体选择性的草药可能会导致发现新的药物，这些药物保留了对骨骼和更年期症状的有益影响，但缺乏目前HRT中雌激素对乳腺和子宫内膜的促癌特性。

DESCRIPTION (provided by applicant): Our long-term objective is to identify safe and effective natural agents to prevent menopausal symptoms and osteoporosis. Currently, there are 36 million postmenopausal women in the USA, and this number is projected to soar to 50 million by the year 2020. Menopause is characterized by severe estrogen deficiency, which leads to hot flushes, vaginal dryness, mood swings and osteoporosis. Although these conditions have been effectively treated with hormone replacement therapy (HILT) for the past 50 years, recent clinical trials have found that HRT is associated with increased risk of breast cancer, cardiovascular disease and dementia. The failure of HRT to live up to expectations has left the rapidly expanding menopausal population without a good alternative that prevents both hot flushes and osteoporosis. Thus, there is a tremendous need to discover more selective and safer estrogens. Many women seek alternatives to HRT, particularly estrogens derived from plants, known as phytoestrogens. Interest in phytoestrogens has been fueled by observational studies showing a lower incidence of menopausal symptoms, osteoporosis, cardiovascular disease and breast cancer in Asian women who consume soy and herbal products. Unfortunately, little scientific data exists to show that they are effective at preventing menopausal symptoms and osteoporosis. Based on our studies showing that estrogen receptor (ER) alpha mediates breast cancer cell proliferation and ERBeta inhibits proliferation and breast tumor formation in mouse xenografts, we are using molecular biology techniques to identify herbs that exhibit selective estrogenic activity for ERBbeta. We hypothesize that ERBeta-selective estrogens will be safer than estrogens found in current HRT regimens that interact non-selectively with ERalpha and ERBeta, and will be effective at reducing hot flushes and osteoporosis. To discover ERbeta-selective herbs, we screened 67 Chinese herbs using transient transfection assays with luciferase reporters in the presence of ERalpha or ERBeta Seven herbs selectively regulated transcription with ERli Some of these herbs also recruited the coregulator, GRIP1 to ERBeta, and were very weak at causing the proliferation of MCF-7 breast cancer cells. The goals of this proposal are to: (1) employ molecular biology techniques to determine how herbs are ER-selective and if the herbs retain ER-selectivity in vivo. (2) identify active compounds in herbs responsible for ER-selectivity. (3) identify which class of ER-selective herbs are most effective at reducing the frequency and severity of hot flushes. Identifying ER-selective herbs could lead to the discovery of novel agents that retain the beneficial effects on bone and menopausal symptoms, but lack the cancer promoting properties of estrogens in current HRT on the breast and endometrium.