Abstract
Abstract Disclosure: T. Upton: None. E. Zavala: None. P. Methlie: None. M. Oksnes: None. M.A. Grytaas: None. K. Simunkova: None. S. Bensing: None. I. Botusan: None. K. Berinder: None. D.A. Vassiliadi: None. O. Kampe: None. S. Tsagarakis: None. E.S. Husebye: None. G.M. Russell: None. S.L. Lightman: None. Background: Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of disease. Since adrenal hormones are secreted with both circadian and ultradian periods, conventional single time point measures 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 this necessitates admission to a clinical research unit, can be stressful and disturbs normal sleep. Aim: To obtain automated ambulatory 24-hour profiles of adrenal steroids in healthy human subcutaneous tissue to characterize healthy variability without blood sampling. Methods: We used microdialysis, an ambulatory fraction collector and liquid-chromatography mass-spectrometry to obtain 72-point profiles of tissue free adrenal steroids over 24 hours in n=214 healthy volunteers. For validation, we compared tissue against plasma measurements in n=7 inpatient healthy volunteers. We used stationery statistics, time series analyses, and mathematical methods to characterise interindividual and intraindividual variability of these hormones at different times of the day. Results: There were no serious adverse events, and the method was well tolerated, allowing almost all normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-OHF, aldosterone, THF, and aTHF. Rhythmic hormones were highly correlated when measured across the day, especially cortisol with 18OHF (rs = 0.99), cortisol with cortisone (rs = 0.96) and cortisol and 18-OHF with corticosterone (rs = 0.96-0.97). There was a very strong correlation between mean values of cortisol and 18OHF with aldosterone (rs = 0.91-0.93), but aldosterone profiles were characterized by high interindividual variability. Tissue 18-OHF was the most highly correlated with plasma cortisol (rs 0.89, range 0.74—0.97, p<0.001), and 18-OHF phase was advanced with respect to tissue cortisol. The ratio of tissue cortisol:cortisone exhibited a stronger daily rhythm than in plasma, with cortisol concentrations often falling below cortisone in the late afternoon and early part of sleep.Using the data, we computed mathematically defined metrics (“dynamic biomarkers”) stratified by sex, age, and BMI to quantify individual variability of hormone rhythms. Provisional analysis suggests no evidence for an effect of sex on cortisol or 18OHF, but evidence for a small effect of BMI on total 24-hour cortisol, 18OHF, corticosterone, and aldosterone. Conclusions: These data provide, for the first time, an insight into the dynamics of adrenal steroids in tissue in real world setting and will serve normative reference data for establishing novel and improved biomarkers of endocrine disease. Presentation: Sunday, June 18, 2023
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