Identification of novel phytoprogestins from hops and red clover

描述（由申请人提供）：激素替代疗法（HRT）是缓解更年期症状最常用的处方药。无对抗性雌激素替代疗法每使用5年，患子宫内膜癌的风险增加120%。为了在有子宫的女性中消除这种风险，已经实施了在HRT中以雌激素/孕酮联合替代的形式添加孕酮。现在有相当多的证据表明，在激素替代疗法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。针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，仅使用植物性雌激素的植物药物可能会增加患子宫内膜癌的风险，这与单独使用雌激素相似。两种常见的补充剂，啤酒花和红三叶草，含有结合并激活雌激素受体的植物雌激素。有趣的是，当给去卵巢的大鼠口服啤酒花和红三叶草时，用粗提取物治疗的动物子宫重量没有明显增加，但用等量的纯植物雌激素治疗的动物子宫重量明显增加。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的天然孕酮化合物，从而产生一种植物雌激素-植物孕激素联合疗法，以替代传统的激素替代疗法。在一种植物提取物中同时存在雌激素和孕酮受体激动剂，可能既提供了雌激素减轻更年期症状的好处，也提供了孕酮对抗子宫癌形成的必要条件。选择性和更安全的黄体酮也可能从植物来源中鉴定出来，以改善激素替代疗法中使用的黄体酮的整体行为。为了支持这一假设，提出以下具体目标：目标1。植物提取物是否含有植物黄体酮？产生黄体酮类活性的纯化合物是什么？目标2。植物黄体酮对子宫黄体酮受体有特异性和选择性吗？目标3。植物黄体酮对去卵巢大鼠模型的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，这些植物药有可能同时提供雌激素和类黄体酮活性，但在治疗更年期症状方面更具选择性和安全性。妇女已经在服用植物雌激素来治疗更年期症状，孕激素的结合可能会预防子宫增生和癌症。

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.