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.

摘要 更年期是人类正常衰老的必然阶段，影响着千百万女性的生活质量 在世界各地。更年期症状包括潮热、睡眠障碍、抑郁/焦虑、 认知功能(阿尔茨海默病在女性中更常见，与雌激素有关)，心血管 疾病、泌尿生殖系统疾病和骨质疏松。这些症状已被证明与 绝经后循环性类固醇浓度急剧下降。而男性在性方面也有类似的下降 荷尔蒙、雄停滞症状通常少见且轻微。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紧迫。因此，这一点 该提案的重点是妇女健康和改善更年期治疗方法。 更年期最直接和最令人难以忍受的症状是潮热，这是 不仅会造成身体不适，还会对情绪、行为和总体生活质量产生负面影响。其中 目前潮热的治疗方法只有雌激素治疗(ET)和激素治疗(HT、雌激素和 孕激素)有令人满意的疗效。虽然ET/HT可以防止潮热，但它们在 外周，包括对子宫和乳房的刺激，导致癌症风险显著增加 在这些器官里。尽管已经做出了广泛的努力来开发更安全的雌激素，但缺乏动物 自然概括人类更年期症状和病理生理的模型(S)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展示 正常年龄或卵巢切除患者的绝经期潮热症状。然而，最常用的 体温调节的模型是啮齿类动物，这在人类更年期的翻译药物发现中是有限的 啮齿动物通常不会冲水，也不会流汗。 我们开发了一种旧世界先进的翻译动物模型，它经历了一个更年期过程， 在荷尔蒙上与人类女性完全相同。我们的研究表明，卵巢切除会导致潮热 烟酸加重，雌激素治疗几乎消除。这也涉及到小说用途的发展。 利用非侵入性热成像来检测这些事件，减轻了对较旧的训练和约束模型的需求 在过去用于本种的热冲洗研究。利用这个模型，我们建议测试一种新的雌激素 使用10β，17β-二羟基-1，4-二烯-3-酮(DHED)进行前药物治疗。DHED具有理想的性能，可用于 潮热的翻译性治疗。在前药形式中，它在室温下高度货架稳定，可以 口服，在前药形式中没有外周生物活性，它选择性地转化为雌激素 仅在大脑中使用，因此对子宫/乳房没有外周副作用。我们建议进行一次全面的测试 在我们的高级翻译模型中，DHED治疗潮热的药理有效性是一个关键 步入人体临床试验阶段。