11-Oxyandrogens and Aging: Health Implications

11-氧雄激素与衰老：健康影响

• 批准号: 10576446
• 负责人: Adina F Turcu
• 金额: $ 57.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576446
• 关键词: 11-ketotestosterone; Address; Adrenal Glands; Adult; Age; Aging; Androgens; Androstenedione; Aromatase; Binding; Biological; Biological Availability; Biological Markers; Cardiovascular Pathology; Cardiovascular system; Clinical; Cognitive; Congenital adrenal hyperplasia; Cross-Sectional Studies; Data; Data Set; Development; Disease; Elderly; Eligibility Determination; Estrogens; Fatty acid glycerol esters; Fetal Development; Fracture; Functional disorder; Goals; Gonadal Steroid Hormones; Gonadal structure; Health; Heart; Hematocrit procedure; Hemoglobin; Human; Image Analysis; Individual; Knowledge; Laboratories; Longitudinal cohort; Longitudinal trends; Mass Spectrum Analysis; Measurement; Measures; Menopause; Metabolic; Outcome; Participant; Pathology; Pattern; Perimenopause; Personal Satisfaction; Phenotype; Physiological; Physiology; Play; Postmenopause; Premenopause; Production; Puberty; Public Health; Recording of previous events; Research; Role; SHBG gene; Sampling; Serum; Sexual Health; Site; Source; Stanolone; Steroids; Sulfate; Surveys; Testing; Testosterone; Time; Time trend; Visit; Woman; Work; age related; androgen excess; androgenic; bone; bone health; bone loss; cardiometabolic risk; cardiovascular health; castration resistant prostate cancer; cohort; comorbidity; dehydroepiandrosterone; design; epidemiology study; fetal; gonad function; intraperitoneal; men; multi-ethnic; multi-racial; new therapeutic target; novel therapeutic intervention; premature adrenarche; reproductive; sex; trend

ABSTRACT The adrenal androgen precursors dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are known to contribute to fetal development and adrenarche. The role of adrenal androgens following puberty and throughout adulthood has been poorly understood. The adrenal glands are also the source of unique 11- oxygenated metabolites of androstenedione (A4) and testosterone (T), collectively termed 11-oxyandrogens. Of these, 11-ketotestosterone (11KT) and its 5α-reduced product, 11-ketodihydrotestosterone (11K-DHT), are bioactive androgens, with potency equivalent to testosterone (T) and dihydrotestosterone (DHT), respectively. These 11-oxyandrogens are central to the pathophysiology of several disorders of androgen excess, including congenital adrenal hyperplasia, premature adrenarche, or castration-resistant prostate cancer. The role of 11- oxyandrogens during physiological aging is unknown. The traditional androgens androstenedione (A4) and testosterone (T), which also derive from the gonads, as well as the major adrenal androgen precursors, DHEA and DHEAS, decline with aging. Intriguingly, we have recently found that the production of 11-oxyandrogens remains sustained in aging individuals of both sexes. Moreover, our preliminary data suggest that 11KT is associated inversely with bone degradation biomarkers, and directly with hemoglobin and hematocrit. The overall objectives of this application are: 1) to define the trends of circulating 11-oxyandrogens in men and women throughout adulthood, with particular focus on aging; 2) to determine the implications of 11- oxyandrogens on aging-related clinical outcomes, including bone, metabolic, and cardiovascular pathology; 3) to define the bioactivity potential of 11-oxyandrogens. Three specific aims have been designed to address critical gaps in our knowledge of adrenal androgen function throughout adulthood and aging. • In Aim 1, we will characterize for the first time the longitudinal patterns of circulating 11-oxyandrogens in women, beginning with reproductive stages, and following menopause. We will use mass spectrometry to quantify traditional sex- steroids and 11-oxyandrogens in over 3,000 serum biospecimens from 569 women included in the Study of Women Across the Nation (SWAN). • In Aim 2, we will test the working hypothesis that 11KT has direct implications on bone and cardiovascular health. We will quantify an extensive set of steroids, including 11- oxyandrogens, in over 2400 men and women, participants in the Dallas Heart Study (DSH). We will use the rich datasets from both the SWAN and DHS, which include comprehensive health history and wellbeing survey instruments (both studies), as well as laboratory and imaging evaluations of bone, metabolic, and cardiovascular health (DHS). • In Aim 3, we will test the bioavailability of 11-oxyandrogens and their potential to be aromatized to 11-oxyestrogens. Together, this work will reframe our understanding of bioactive androgens in human health and disease.

抽象的 肾上腺雄激素前体脱氢表雄酮（DHEA）及其硫酸盐（DHEAS）是已知的 为胎儿发育和肾上腺素造成贡献。肾上腺雄激素在青春期和 经过成年，人们对成年的了解很少。肾上腺也是独特的11-的来源 雄酮二酮（A4）和睾丸激素（T）的氧代谢产物，共同称为11-氧和糖基因。的 这些，11-酮睾丸酮（11KT）及其5α还原的产品，11-酮二氢睾丸激素（11K-DHT）是 生物活性雄激素，其效力分别与睾丸激素（T）和二氢睾丸激素（DHT）相等。 这些11-氧和糖基因是多种雄激素疾病的病理生理的核心，包括 先天性肾上腺增生，过早的肾上腺素或持续性前列腺癌。 11-的作用 物理衰老期间的催产剂尚不清楚。传统的雄激素雄激素（A4）和 睾丸激素（t）也源自性腺，以及主要的肾上腺雄激素前体DHEA 和dheas，随着衰老而下降。有趣的是，我们最近发现11-氧和生物的产生 在男女的老年人中保持持久。而且，我们的初步数据表明11KT是 与骨降解生物标志物相关，直接与血红蛋白和血细胞比容有关。 该应用程序的总体目标是：1）定义循环11-氧和的趋势 整个成年期男人和女人，特别关注衰老； 2）确定11-的含义 与衰老相关的临床结局的氧和树脂，包括骨，代谢和心血管病理； 3） 定义11-氧和生物体的生物活性潜力。已经设计了三个特定目标来解决关键 在整个成年和衰老中，我们对肾上腺雄激素功能的了解的差距。 •在AIM 1中，我们将 首次表征女性循环的11-氧和生物体的纵向模式，从 生殖阶段，以及更年期之后。我们将使用质谱法来量化传统性别 - 在研究中包括569名女性的3,000多名血清生物测量中的类固醇和11-氧和果糖。 全国妇女（天鹅）。 •在AIM 2中，我们将测试11KT有直接的工作假设 对骨骼和心血管健康的影响。我们将量化一组广泛的类固醇，包括11-- 达拉斯心脏研究（DSH）的2400多名男性和女性的Oxyandrogens。我们将使用富人 天鹅和DHS的数据集，其中包括全面的健康历史和福祉调查 仪器（既有研究），以及骨，代谢和心血管的实验室和成像评估 健康（DHS）。 •在AIM 3中，我们将测试11-氧和生物的生物利用度及其芳香的潜力 到11-氧雌激素。这项工作将共同反映我们对人类健康中生物活性雄激素的理解 和疾病。