Identification of novel phytoprogestins from hops and red clover

说明(申请人提供)：激素替代疗法(HRT)是最常用的缓解更年期症状的处方药。无人反对的雌激素替代疗法每使用5年，患子宫内膜癌的风险增加120%。为了消除有子宫的妇女的这种风险，已经实施了以雌激素/孕酮联合替代的形式在HRT中添加黄体酮。现在有相当多的证据表明，在激素替代疗法中添加合成孕激素会增加乳腺癌的风险以及许多其他有害的副作用。为了应对与激素替代疗法相关的问题，数百万妇女正在探索使用植物性药物和膳食补充剂来缓解更年期症状。然而，在没有孕激素的情况下只使用植物来源的雌激素的植物药可能会增加患子宫内膜癌的风险，类似于单独使用雌激素。啤酒花和红三叶草是两种常见的补充剂，它们含有能结合和激活雌激素受体的植物雌激素。有趣的是，当口服啤酒花和红三叶草给去卵巢的大鼠时，用粗提物处理的动物子宫重量并没有显著增加，但在给予同等剂量的纯植物雌激素的动物中，子宫重量显著增加。这项拨款建议的假设是，可以从植物提取物中鉴定出选择性的天然孕酮化合物，以产生一种植物雌激素-植物孕激素的组合，以替代传统的激素替代疗法。雌激素和孕激素受体激动剂同时存在于一种植物提取物中，既可提供雌激素缓解更年期症状的益处，也可提供抗击子宫癌形成所必需的孕酮。选择性和更安全的孕激素也可以从植物学来源确定，以改善HRT中使用的孕激素的整体行为。为了支持这一假说，我们提出了以下具体目标：目的1.植物提取物中是否含有植物孕激素？哪些纯化合物具有孕激素样的活性？目的2.植孕素对子宫孕酮受体是否具有特异性和选择性？目的3.在去卵巢的大鼠模型中，植孕素对子宫增生有保护作用吗？这些研究将为使用植物药提供明确的理由，这些植物药可能同时提供雌激素和孕激素样活性，但在治疗更年期症状方面具有更高的选择性和更安全的特征。女性已经在服用植物雌激素来治疗更年期症状，并入孕激素可能会预防子宫增生和子宫癌。 公共卫生相关性：妇女已经在服用植物提取物中的植物雌激素来治疗更年期症状，并入孕激素可能会预防子宫增生和子宫癌。随着女性寻找更有效的替代雌激素来满足缓解更年期症状的需要，子宫增生的机会增加，这使得新的植物孕激素的特征变得至关重要。

DESCRIPTION (provided by applicant): Hormone replacement therapy (HRT) is the most commonly prescribed medication for the alleviation of menopausal symptoms. Unopposed estrogen replacement therapy increases the risk of developing endometrial cancer by 120% for every 5 years of use. To eliminate this risk in women with a uterus, the addition of progesterone to HRT in the form of combined estrogen/progesterone replacement has been implemented. Considerable evidence now indicates that the addition of synthetic progestins to HRT increases the risk of breast cancer as well as many other deleterious side effects. In response to the problems associated with HRT, millions of women are exploring the use of botanicals and dietary supplements for the alleviation of climacteric symptoms. However, the use of botanicals with only plant-derived estrogens in the absence of progestins might increase the risk for developing endometrial cancer similar to estrogen alone. Two common supplements, hops and red clover, contain phytoestrogens that bind and activate estrogen receptors. Interestingly, when hops and red clover are given orally to ovariectomized rats, uterine weights are not significantly increased in animals treated with a crude extract but are significantly increased in animals given an equivalent dose of the pure phytoestrogen. The hypothesis of this grant proposal is that selective natural progesterone compounds can be identified from botanical extracts to generate a combined phytoestrogen-phytoprogestin alternative to traditional hormone replacement therapy. The presence of both estrogen and progesterone receptor agonists in one botanical extract may provide both the benefits of estrogens for alleviation of menopausal symptoms and the progesterone necessary to combat formation of uterine cancers. Selective and safer progestins might also be identified from botanical sources improving the overall behavior of the progestin used in HRT. In order to provide support for this hypothesis the following specific aims are proposed: Aim 1. Do botanical extracts contain phytoprogestins and what are the pure compounds responsible for the progesterone-like activity? Aim 2. Are phytoprogestins specific and selective for uterine progesterone receptors? Aim 3. Are phytoprogestins protective against uterine hyperplasia in an ovariectomized rat model? These studies will provide a clear justification for the use of botanicals that have the possibility of providing both estrogen and progestin-like activity but with more selective and safer profiles for the treatment of menopausal symptoms. Women are already taking phytoestrogens for menopausal symptoms, and incorporation of progestins may prevent hyperplasia and cancer of the uterus. PUBLIC HEALTH RELEVANCE: Women are already taking phytoestrogens in botanical extracts for menopausal symptoms, and the incorporation of progestins may prevent hyperplasia and cancer of the uterus. As women search for more potent alternative estrogens to satisfy the need for menopausal symptom alleviation, the chance for hyperplasia in the uterus increases and makes the characterization of novel phytoprogestins crucial.