Novel Treatment of Menopausal Hot Flushes with an Extradiol Prodrug

描述(由申请者提供)：潮热在世界范围内构成了一个重大的公共卫生问题。这些围绝经期症状是女性在更年期过渡期间寻求医疗服务的主要原因。潮热经常对女性的生活质量产生负面影响，因为它们与焦虑/抑郁和导致疲劳、易怒和健忘的睡眠障碍有关，以及严重的身体不适和对工作的负面影响。虽然雌激素替代疗法(ERT)在预防潮热方面是有效的，但大量女性不能或不想服用雌激素，其外周副作用可能危及生命。其他疗法的疗效值得怀疑。因此，对于更好、更安全的ERT有着巨大的未得到满足的需求。在本应用中，我们建议17b-雌二醇(Q-E_2)的对苯二酚(Q-E_2)有可能被认为是最佳ERT。我们早些时候已经证明，Q-E_2是一种前体药物，在它被吸收后，它在选择性组织中通过酶催化的机制转化为E_2。这种转换在大脑中有效，但在子宫、乳房或脑下垂体中无效。因此，Q-E2的治疗不会像其他雌激素那样具有促子宫和促乳房的作用。由于E2是人类卵巢产生的主要和最有效的雌激素，我们建议将Q-E2视为一种前驱药物，用于治疗围绝经期症状，不仅包括我们在父母拨款中建议的潮热，还包括焦虑/抑郁和改变睡眠模式，利用这些更年期障碍的动物模型。我们的试验数据有力地表明，Q-E2可以阻止潮热大鼠模型中的潮热症状，减少行为绝望强迫游泳测试模型中的抑郁，但在阻止潮热症状的剂量下不会刺激MCF-7乳腺细胞或子宫的增殖。因此，Q-E2似乎是一种新颖、安全和理想的ERT，可用于缓解围绝经期症状，包括潮热、焦虑/抑郁和睡眠障碍。该附录描述了一系列实验，旨在评估口服Q-E2对(I)焦虑/抑郁大鼠和小鼠模型以及(Ii)大鼠和小鼠雌激素调节睡眠模式的效果。由于我们的实验室正在开发雌激素受体-α(ERa)或雌激素受体-β(Erb)选择性前体药物，实验还将涉及(ERa)基因敲除和(Erb)基因敲除小鼠，以确定对Q-E2的任何影响负责的ER。一种新颖而安全的ERT的发现将改善全世界数亿围绝经期妇女的生活质量，因此将对公共卫生产生巨大影响。尽管还没有进行实验测试，Q-E2也可能是男性男性更年期精神疗法的一种选择。 公共卫生相关性：更年期症状，如潮热、焦虑/抑郁和睡眠障碍，在世界范围内构成一个重大的公共卫生问题。虽然激素替代疗法可以缓解大多数女性的潮热，缓解焦虑/抑郁，改善睡眠，但大量围绝经期女性不能或不想服用激素，因为它们有副作用。因此，对更年期症状更好、更安全的治疗存在巨大的未得到满足的需求。该提案通过研究一种潜在的无责任雌激素替代疗法(ERT)来解决这一未得到满足的需求，该疗法利用潮热、焦虑/抑郁和睡眠模式的动物模型。雌激素的对苯二酚(前体药物)在脑内转化为雌激素，但在子宫和乳房中不转化为雌激素，从而为开发一种新型的、安全的、中枢神经系统选择性的ERT奠定了基础。

DESCRIPTION (provided by applicant): Hot flushes pose a significant public health concern world-wide. These perimenopausal symptoms are the primary reason that women seek medical care during the menopausal transition. Hot flushes often negatively impact the quality of life of women because they are associated with anxiety/depression and sleep disturbances resulting in fatigue, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work. Although estrogen replacement therapy (ERT) is efficacious in preventing hot flushes, a large number of women cannot or do not want to take estrogen, and the peripheral side-effects are potentially life threatening. The efficacy of the other therapies is questionable. Therefore, there is a huge unmet need for a better and safer ERT We propose in this application that para-quinol of 17b-estradiol (Q-E2) has the potential to be considered as the optimal ERT. We have shown earlier that Q-E2 functions as a pro-drug and following its absorption it is converted in selective tissues to E2 via an enzyme catalyzed mechanism. This conversion is effective in the brain but not in the uterus, breast, or the pituitary gland. Therefore, treatment with Q-E2 would not have uterotropic and mammotropic liabilities like any other estrogens. Since E2 is the primary and most potent estrogen produced by the human ovary, we propose to consider Q-E2 as a pro-drug for the treatment of perimenopausal symptoms including not only hot flushes as we proposed in the parent grant but anxiety/depression and altered sleep pattern by utilizing animal models of these menopausal disturbances. Our pilot data strongly indicate that Q-E2 blocks hot flush symptoms in a rat model of hot flush, reduces depression in the forced swim test model of behavioral despair, but does not stimulate proliferation in MCF-7 breast cells or the uterus at doses that block the hot flush symptoms. Therefore, Q-E2 seems to be a novel, safe, and optimal ERT for alleviating perimenopausal symptoms, including hot flushes, anxiety/depression and sleep disturbances. The supplement describes a series of experiments aimed at evaluating the effect of orally-administered Q-E2 in (i) rat and mouse models of anxiety/depression and (ii) rat and mouse models of estrogen-regulated sleep patterns. Since the development of estrogen receptor-alpha (ERa)- or estrogen receptor-beta (ERb)-selective pro-drugs are being developed in our laboratories, the experiments will also involve (ERa)-knockout and (ERb)- knockout mice to determine the ER responsible for any effects of Q-E2. The discovery of a novel and safe ERT would improve the quality of life of hundreds of millions of perimenopausal women world-wide and thus, would have a tremendous impact on public health. Although it has not been tested experimentally, Q-E2 might be a choice for psychiatric therapy of men in the andropause as well. PUBLIC HEALTH RELEVANCE: Peri-menopausal symptoms, such as hot flushes, anxiety/depression, and sleep disturbances pose a significant public health concern world-wide. Although hormone replacement therapy, alleviates hot flushes and ease anxiety/depression and improve sleep in the majority of women, a large number of peri-menopausal women cannot take or do not want to take hormones because of their side effects. Therefore, there is a huge unmet need for better and safer therapies for menopausal symptoms. The proposal addresses this unmet need by investigating a potentially liability-free estrogen replacement therapy (ERT) utilizing animal models of hot flush, anxiety/depression, and sleep pattern. Para-quinol of estrogen (pro-drug) is converted to estrogen in brain but not in uterus and breast, and therefore, provides the foundation to develop a novel and safe, central nervous system-selective ERT.