Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Bristol BS1 3NY, UK.
Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Edgbaston B15 2TT, UK.
Sci Transl Med. 2023 Jun 21;15(701):eadg8464. doi: 10.1126/scitranslmed.adg8464.
Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of the disease. Because adrenal hormones are secreted with both circadian and ultradian periods, conventional single-time point measurements provide limited information about rhythmicity and, crucially, do not provide information during sleep, when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight, then this necessitates admission to a clinical research unit, can be stressful, and disturbs sleep. To overcome this problem and to measure free hormones within their target tissues, we used microdialysis, an ambulatory fraction collector, and liquid chromatography-tandem mass spectrometry to obtain high-resolution profiles of tissue adrenal steroids over 24 hours in 214 healthy volunteers. For validation, we compared tissue against plasma measurements in a further seven healthy volunteers. Sample collection from subcutaneous tissue was safe, well tolerated, and allowed most normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-hydroxycortisol, aldosterone, tetrahydrocortisol and allo-tetrahydrocortisol, and the presence of dehydroepiandrosterone sulfate. We used mathematical and computational methods to quantify the interindividual variability of hormones at different times of the day and develop "dynamic markers" of normality in healthy individuals stratified by sex, age, and body mass index. Our results provide insight into the dynamics of adrenal steroids in tissue in real-world settings and may serve as a normative reference for biomarkers of endocrine disorders (ULTRADIAN, NCT02934399).
节律是内分泌系统固有的，这些激素波动的紊乱发生在疾病的早期阶段。由于肾上腺激素的分泌具有昼夜节律和超昼夜节律，传统的单次测量提供的关于节律性的信息有限，而且关键是，在睡眠期间没有提供信息，此时许多激素从最低点到峰值波动。如果试图在夜间进行血液采样，则需要住院到临床研究单位，这可能会带来压力，并扰乱睡眠。为了克服这个问题并在其靶组织内测量游离激素，我们使用微透析、便携式分收集器和液相色谱-串联质谱法，在 214 名健康志愿者中进行了 24 小时的高分辨率组织肾上腺类固醇谱测量。为了验证，我们在另外 7 名健康志愿者中比较了组织与血浆测量。从皮下组织采集样本是安全的，耐受性良好，并且允许大多数正常活动继续进行。除了皮质醇，我们还确定了游离可的松、皮质酮、18-羟皮质醇、醛固酮、四氢皮质醇和 allo-四氢皮质醇的日变化和超昼夜变化，以及脱氢表雄酮硫酸酯的存在。我们使用数学和计算方法来量化不同时间点激素的个体间变异性，并为健康个体开发“动态标志物”，按性别、年龄和体重指数分层。我们的研究结果提供了对现实环境中组织中肾上腺类固醇动力学的深入了解，并可能成为内分泌失调生物标志物的正常参考（超昼夜节律，NCT02934399）。
