Identification of novel phytoprogestins from hops and red clover

描述（由申请人提供）：激素替代疗法（HRT）是缓解更年期症状的最常用处方药。无争议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%。为了消除子宫妇女的这种风险，已经实施了以联合雌激素/孕酮替代的形式在HRT中加入孕酮。现在有相当多的证据表明，在HRT中加入合成孕激素会增加患乳腺癌的风险以及许多其他有害的副作用。为了应对与HRT相关的问题，数百万妇女正在探索使用植物药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，仅使用植物源性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。两种常见的补充剂，啤酒花和红三叶草，含有植物雌激素，结合和激活雌激素受体。有趣的是，当给卵巢切除的大鼠口服啤酒花和红三叶草时，用粗提取物处理的动物的子宫重量没有显著增加，但在给予等量纯植物雌激素的动物中显著增加。这项拨款提案的假设是，可以从植物提取物中鉴定出选择性天然孕酮化合物，以产生一种替代传统激素替代疗法的植物雌激素-植物孕酮组合物。在一种植物提取物中同时存在雌激素和孕激素受体激动剂可以提供雌激素用于缓解绝经期症状的益处和对抗子宫癌形成所必需的孕激素。选择性和更安全的孕激素也可以从植物来源中确定，改善HRT中使用的孕激素的整体行为。为了支持这一假设，提出了以下具体目标：目标1。植物提取物中是否含有植物孕激素？哪些纯化合物具有类似孕酮的活性？目标二。植物孕激素对子宫孕激素受体有特异性和选择性吗？目标3。植物孕激素对卵巢切除大鼠模型子宫增生有保护作用吗？这些研究将为使用具有雌激素和孕激素样活性的植物药提供明确的理由，但对于治疗更年期症状具有更高的选择性和更安全的特征。妇女已经在服用植物雌激素来治疗更年期症状，加入孕激素可以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，而加入孕激素可以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以满足缓解绝经期症状的需要，子宫增生的机会增加，使得新型植物孕激素的表征至关重要。

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.