Novel Treatment of Menopausal Hot Flushes with an Extradiol Prodrug

描述（由申请人提供）：潮热在全球范围内构成重大的公共卫生问题。这些围绝经期症状是妇女在绝经过渡期寻求医疗护理的主要原因。潮热通常会对女性的生活质量产生负面影响，因为它们与焦虑/抑郁和睡眠障碍有关，导致疲劳，易怒和健忘，以及急性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，但大量妇女不能或不想服用雌激素，并且外周副作用可能危及生命。其他疗法的疗效值得怀疑。因此，对于更好和更安全的ERT存在巨大的未满足的需求。我们在本申请中提出，17 b-雌二醇的对苯二酚（Q-E2）具有被认为是最佳ERT的潜力。我们之前已经表明，Q-E2作为前药发挥作用，并且在其吸收后，其在选择性组织中通过酶催化机制转化为E2。这种转换在大脑中有效，但在子宫、乳房或脑垂体中无效。因此，Q-E2治疗不会像任何其他雌激素那样具有促子宫和促乳房的倾向。由于E2是人类卵巢产生的主要和最有效的雌激素，我们建议考虑将Q-E2作为治疗围绝经期症状的前药，不仅包括我们在母基金中提出的潮热，还包括焦虑/抑郁和睡眠模式改变，方法是利用这些绝经期紊乱的动物模型。 我们的试验数据强烈表明，Q-E2阻断大鼠潮热模型中的潮热症状，减少强迫游泳测试行为绝望模型中的抑郁，但在阻断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似乎是一种新型、安全和最佳的ERT，可缓解围绝经期症状，包括潮热、焦虑/抑郁和睡眠障碍。 该补充描述了一系列旨在评价口服Q-E2在（i）焦虑/抑郁大鼠和小鼠模型和（ii）雌激素调节睡眠模式大鼠和小鼠模型中的作用的实验。由于我们的实验室正在开发雌激素受体-α（ER a）-或雌激素受体-β（ER b）-选择性前药，因此实验还将涉及（ER a）-敲除和（ER b）-敲除小鼠以确定负责Q-E2的任何作用的ER。 新型安全ERT的发现将改善全球数亿围绝经期妇女的生活质量，从而对公共卫生产生巨大影响。虽然Q-E2还没有经过实验测试，但它也可能是男性男性精神病治疗的一种选择。 公共卫生相关性：围绝经期症状，如潮热、焦虑/抑郁和睡眠障碍在世界范围内引起了严重的公共卫生问题。虽然激素替代疗法可以缓解潮热，缓解焦虑/抑郁，改善大多数女性的睡眠，但由于其副作用，大量围绝经期女性不能服用或不想服用激素。因此，对于更年期症状的更好和更安全的疗法存在巨大的未满足的需求。该提案通过利用潮热、焦虑/抑郁和睡眠模式的动物模型研究潜在的无责任雌激素替代疗法（ERT）来解决这一未满足的需求。雌激素的前体药物对苯二酚在脑中转化为雌激素，而在子宫和乳房中不转化，因此，为开发新型安全的中枢神经系统选择性ERT提供了基础。

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.