Brain-selective estrogen therapy for menopausal hot flushes in an advanced translational animal model

在先进的转化动物模型中脑选择性雌激素疗法治疗更年期潮热

• 批准号: 10534761
• 负责人: ISTVAN Jozsef MERCHENTHALER
• 金额: $ 61.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534761
• 关键词: Affect; Age Years; Aging; Alzheimer' s Disease; Andropause; Animal Model; Animals; Anterior Pituitary Gland; Anxiety; Behavior; Binding; Blood flow; Body Temperature; Brain; Breast; Cardiac Output; Cardiovascular Diseases; Chest; Chills; Clinical Trials; Compensation; Data; Development; Drops; Effectiveness; Elderly man; Elderly woman; Estrogen Therapy; Estrogen decline; Estrogens; Event; Exhibits; Face; Female; Flushing; Frequencies; Functional disorder; Genitourinary system; Gonadal Steroid Hormones; Heart; Hormonal; Hormones; Hot flushes; Human; Hyperplasia; Hypothalamic structure; Image; Incidence; Intervention; Life; Link; Longitudinal cohort study; Macaca mulatta; Medial; Medical; Menopausal Symptom; Menopause; Mental Depression; Modeling; Monitor; Monkeys; Moods; Neck; Neurokinin B; Nicotinic Acids; Oral; Organ; Osteoporosis; Ovarian aging; Ovariectomy; Palpitations; Participant; Patients; Pattern; Penetrance; Peripheral; Phenotype; Physiologic Thermoregulation; Postmenopause; Preoptic Areas; Primates; Process; Prodrugs; Production; Progestins; Property; Quality of life; Reporting; Research; Resources; Rhesus; Risk; Rodent; Shivering; Skin Temperature; Sleep; Sleep Disorders; Sweating; Symptoms; Tachykinin; Temperature; Testing; Training; Uterine Cancer; Uterus; Woman; Women' s Health; aged; associated symptom; cancer risk; cognitive function; cohort; drug discovery; early onset; effective therapy; experience; hormone therapy; improved; men; nonhuman primate; normal aging; novel; pharmacologic; prevent; receptor; response; restraint; side effect; success; translational model; translational therapeutics

ABSTRACT Menopause is an inevitable stage in normal human aging, affecting the quality of life of millions of women all over the world. Menopausal symptoms including hot flushes, sleep disorders, depression/anxiety, decline in cognitive function (Alzheimer’s disease is more prevalent in women and linked to estrogen), cardiovascular disease, genitourinary conditions, and osteoporosis. These symptoms have been shown to be causally linked to a sharp decline in circulating sex steroid concentrations after menopause. While men have similar decline in sex hormones, andropause symptoms are usually infrequent and mild. Consequently, menopausal symptoms are of considerably more pressing medical concern in elderly women than andropause in elderly men. Thus, this proposal focuses on women’s health and improved therapies for menopause. The most immediate and patient reported ‘unbearable’ symptom of the menopause are hot flushes, which cause not only physical discomfort but also negatively impact mood, behavior and general quality of life. Among current treatments of hot flushes, only estrogen therapy (ET) and hormone therapy (HT, estrogens and progestins) have satisfactory efficacy. Although ET/HT prevents hot flushes, they have unwanted side effects in the periphery, including the stimulation of the uterus and breast leading to a significantly increased cancer risk in these organs. Although there have been extensive efforts to develop safer estrogens, the lack of animal model(s) that naturally recapitulate the symptoms and pathophysiology of human menopause has had a tremendous negative impact on the success of this effort. Only humans and our close mammalian cousins exhibit menopausal hot flush symptoms in normal aging or with ovariectomy. However, the most commonly utilized model for thermoregulation is rodent, which is limited for translational drug discovery with human menopause as rodents do not normally flush and do not sweat. We developed an old-world advanced translational animal model which undergoes a menopausal process that is hormonally identical to that of human women. We show that ovariectomy induces hot flushes that are exacerbated by niacin and nearly eliminated by estrogen therapy. This also involved development of novel use of non-invasive thermal imaging to detect these events, alleviating the need for older train-and-restrain models used in this species for hot flush research in the past. Using this model, we propose to test a novel estrogen prodrug therapy using 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED). DHED has ideal properties for a translational therapy for hot flushes. In the prodrug form it is highly shelf-stable at room temperature, can be taken orally, has no peripheral bioactive properties in the prodrug form and it is selectively converted to estrogen only in the brain, resulting in no peripheral side effects on uterus/breast. We propose a comprehensive testing of the pharmacological effectiveness of DHED to treat hot flushes in our advanced translational model as a key step to human clinical trials.

抽象的 更年期是正常人类衰老的不可避免的阶段，影响了数百万妇女的生活质量 在世界上。更年期症状，包括潮红，睡眠障碍，抑郁/焦虑，下降 认知功能（阿尔茨海默氏病在女性中更普遍，与雌激素有关），心血管 疾病，生殖状况和骨质疏松症。这些症状已被证明与 更年期后循环性类固醇浓度的急剧下降。男人的性爱下降 荷尔蒙，andropause符号通常很少且温和。因此，更年期符号是 小学女性对基本女性的医学关注要多得多。那，这个 提案着重于妇女的健康和更改的改善疗法。 更年期的最直接和患者报告的“难以忍受”的症状是潮热，这是 不仅引起身体不适，还会导致情绪，行为和一般生活质量。之中 当前的潮红疗法，仅雌激素疗法（ET）和马酮治疗（HT，雌激素和 孕激素具有令人满意的有效性。尽管ET/HT可以防止潮热，但它们在 外围物，包括子宫和乳房的刺激，导致癌症风险显着增加 在这些器官中。尽管已经做出了广泛的努力来发展更安全的雌激素，但缺乏动物 自然概括人类更年期的症状和病理生理学的模型 对这项努力成功的巨大负面影响。只有人类和我们的亲密哺乳动物表亲展出 正常衰老或卵巢切除术中的更年期冲洗症状。但是，最常用的 温度调节模型是啮齿动物的 啮齿动物通常不会冲洗，也不出汗。 我们开发了一种旧世界的高级翻译动物模型，该模型经历了更年期的过程 与人类女性的荷尔蒙相同。我们表明卵巢切除术会影响热潮 烟酸加剧，几乎通过雌激素疗法消除。这也涉及开发新颖使用 非侵入性热成像以检测这些事件，减轻了对较旧的火车和弹跳模型的需求 过去，该物种用于冲洗研究。使用此模型，我们建议测试一种新的雌激素 使用10β，17β-二氢-1,4-Dien-3-One（DHED）的前药治疗。 DHED具有理想的特性 潮热的翻译疗法。在前药形式中，它在室温下高度稳定，可以是 口服，前药形式没有外周生物活性特性，它被选择性地转换为雌激素 仅在大脑中，导致对子宫/乳腺的外周副作用。我们提出了全面的测试 DHED在我们先进的翻译模型中处理潮红的药理有效性作为关键 步骤进行人类临床试验。