11-Oxyandrogens and Aging: Health Implications

摘要 已知肾上腺雄激素前体脱氢表雄酮（DHEA）及其硫酸盐（DHEAS） 有助于胎儿发育和肾上腺的形成。青春期后肾上腺雄激素的作用， 一直以来都不为人所知肾上腺也是独特的11- 雄烯二酮（A4）和睾酮（T）的氧化代谢物，统称为11-氧雄激素。的 11-酮睾酮（11 KT）及其5α-还原产物11-酮二氢睾酮（11 K-DHT）， 生物活性雄激素，其效力分别相当于睾酮（T）和双氢睾酮（DHT）。 这些11-氧雄激素是几种雄激素过多疾病的病理生理学的核心，包括 先天性肾上腺增生、肾上腺早期发育或去势抵抗性前列腺癌。11的作用- 氧雄激素在生理老化过程中是未知的。传统的雄激素雄烯二酮（A4）和 睾酮（T），也来自性腺，以及主要的肾上腺雄激素前体，DHEA 和DHEAS，随着年龄的增长而下降。有趣的是，我们最近发现11-氧雄激素的产生 仍然持续存在于两性的衰老个体中。此外，我们的初步数据表明，11 KT是 与骨降解生物标志物呈负相关，与血红蛋白和红细胞压积呈正相关。 本申请的总体目标是：1）确定在哺乳动物中循环的11-氧雄激素的趋势， 男性和女性在整个成年期，特别是对老龄化的关注; 2）确定11- 氧雄激素对衰老相关临床结局的影响，包括骨、代谢和心血管病理学; 3） 以确定11-氧雄激素的生物活性潜力。为解决关键问题， 我们对成年期和衰老期肾上腺雄激素功能的认识存在空白。·在目标1中，我们将 首次描述女性循环11-氧雄激素的纵向模式，从 生殖阶段和绝经后。我们会用质谱仪来量化传统性爱- 研究中纳入的569名妇女的3,000多份血清生物标本中的类固醇和11-氧雄激素， 全国妇女组织（SWAN）。·在目标2中，我们将检验11 KT具有直接的 影响骨骼和心血管健康。我们将对大量类固醇进行定量，包括11种- 氧雄激素，超过2400名男性和女性，参与达拉斯心脏研究（DSH）。我们会利用富人 来自SWAN和DHS的数据集，其中包括全面的健康史和幸福感调查 仪器（两项研究），以及骨、代谢和心血管的实验室和成像评价 卫生部。·在目标3中，我们将测试11-氧雄激素的生物利用度及其芳构化的潜力 到11-氧雌激素。总之，这项工作将重新构建我们对人类健康中生物活性雄激素的理解 和疾病

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.