11-Oxyandrogens and Aging: Health Implications

摘要 肾上腺雄激素前体脱氢表雄酮(DHEA)及其硫酸盐(DHEAS)是已知的 有助于胎儿发育和肾上腺发育。肾上腺雄激素在青春期和青春期后的作用 在整个成年期，人们对此知之甚少。肾上腺也是独特的11- 雄烯二酮(A4)和睾酮(T)的氧化代谢产物，统称为11-氧雄激素。的 这些11-酮睾酮(11kT)及其5α还原产物11-酮二氢睾酮(11K-dht)是 生物活性雄激素，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的疾病的病理生理学中心，包括 先天性肾上腺增生症、肾上腺早熟或耐去势前列腺癌。11- 生理性衰老过程中的雄激素水平尚不清楚。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 在老年男性和女性中仍持续存在。此外，我们的初步数据表明，11kt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。 这项应用的总体目标是：1)确定11-氧雄激素在 男性和女性在整个成年期，特别关注衰老；2)确定11- 氧雄激素对衰老相关临床结局的影响，包括骨骼、代谢和心血管病理；3) 确定11-氧雄激素的生物活性潜力。设计了三个具体目标来解决关键问题 在成年期和衰老过程中，我们对肾上腺雄激素功能的了解存在差距。·在目标1中，我们将 首次描述女性循环中11-氧雄激素的纵向模式，从 生殖阶段，以及绝经后。我们将使用质谱仪来量化传统的性行为- 参与这项研究的569名妇女的3000多名血清中的类固醇和11-氧雄激素 全国妇女(天鹅)。·在目标2中，我们将检验11kt直接 对骨骼和心血管健康的影响。我们将量化一系列广泛的类固醇，包括11- 达拉斯心脏研究(DSH)的参与者，超过2400名男性和女性的氧雄激素。我们将利用富人 来自Swan和国土安全部的数据集，其中包括全面的健康历史和福祉调查 仪器(两项研究)，以及对骨骼、代谢和心血管的实验室和成像评估 健康(国土安全部)。·在目标3中，我们将测试11-氧雄激素的生物利用度及其芳香化潜力 对11-氧雌激素的影响。总之，这项工作将重新定义我们对生物活性雄激素在人类健康中的理解。 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.