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: 10327690
• 负责人: ISTVAN Jozsef MERCHENTHALER
• 金额: $ 59.17万
• 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/10327690
• 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; Data; Development; Drops; Effectiveness; Elderly man; Elderly woman; Estrogen Therapy; 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; Pharmacology; 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; Time; Training; Uterine Cancer; Uterus; Woman; Women' s Health; aged; associated symptom; base; cancer risk; cognitive function; cohort; drug discovery; early onset; effective therapy; experience; hormone therapy; improved; men; nonhuman primate; normal aging; novel; prevent; receptor; response; 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 更年期是人类正常衰老的必然阶段，影响着数百万女性的生活质量 世界各地。更年期症状包括潮热、睡眠障碍、抑郁/焦虑、智力下降 认知功能（阿尔茨海默病在女性中更为常见，与雌激素有关）、心血管 疾病、泌尿生殖系统疾病和骨质疏松症。这些症状已被证明与 绝经后循环性类固醇浓度急剧下降。而男性的性能力也有类似的下降 由于激素的影响，男性更年期症状通常很少见且轻微。因此，更年期症状是 老年女性的医疗问题比老年男性的男性更年期更为紧迫。因此，这个 该提案重点关注女性健康和改进更年期疗法。 患者报告的最直接、最难以忍受的更年期症状是潮热， 不仅会导致身体不适，还会对情绪、行为和总体生活质量产生负面影响。之中 目前治疗潮热的方法只有雌激素疗法（ET）和激素疗法（HT、雌激素和 孕激素）有满意的疗效。尽管 ET/HT 可以预防潮热，但它们也会产生不良副作用： 外周，包括刺激子宫和乳房，导致癌症风险显着增加 在这些器官中。尽管人们在开发更安全的雌激素方面做出了广泛的努力，但缺乏动物源性雌激素。 自然地再现人类更年期症状和病理生理学的模型已经有了 对这一努力的成功产生了巨大的负面影响。只有人类和我们的近亲哺乳动物才会表现出 正常衰老或卵巢切除术中出现的更年期潮热症状。然而，最常用的 体温调节模型是啮齿类动物，其在人类更年期的转化药物发现方面受到限制 啮齿类动物通常不会脸红，也不会出汗。 我们开发了一种旧世界先进的转化动物模型，该模型经历了更年期过程， 与人类女性的荷尔蒙相同。我们发现卵巢切除术会引起潮热 烟酸加剧，雌激素治疗几乎消除。这还涉及新用途的开发 使用非侵入式热成像来检测这些事件，从而减少对旧训练和约束模型的需求 过去用于该物种的潮热研究。使用这个模型，我们建议测试一种新型雌激素 使用 10β,17β-二羟基雌激素-1,4-二烯-3-酮 (DHED) 进行前药治疗。 DHED 具有理想的特性 潮热的转化疗法。在前药形式中，它在室温下具有高度的储存稳定性，可以 口服，前药形式没有外周生物活性，并且选择性地转化为雌激素 仅在大脑中，不会对子宫/乳房产生外周副作用。我们建议进行全面测试 在我们的高级转化模型中，DHED 治疗潮热的药理学有效性是关键 迈向人体临床试验。