Different Metabolic Pathways Associated With Total Cortisol Exposure and the Cortisol Time Profile: A Randomized Crossover Trial

Excess cortisol exposure and disruption of the circadian cortisol profile are both associated with adverse clinical outcomes. The aim of this study was to identify unique metabolites and metabolic pathways associated with total cortisol exposure and/or variation of the cortisol time profile. Eighteen adults with primary adrenal insufficiency (AI) received the same daily dose of hydrocortisone (HC) administered as a once-daily (OD) dual-release tablet and conventional HC tablets 3 times daily (TID) in a randomized, 12-week, cross-over trial. Serum and urine samples were collected during 24 h in-house standardized pharmacokinetic sampling days and metabolites were detected using liquid and gas chromatography-mass spectrometry (LC-MS and GC-MS). Total cortisol exposure was calculated by the area under the serum cortisol concentration-time curve and variability of the cortisol time profile was quantified by calculating the lag–1 autocorrelation from serum cortisol concentrations over 24 hours. During TID administration, total cortisol exposure was 20% higher and the cortisol time profile variability was larger, compared to OD administration. In total, 2406 metabolites were detected. Serum metabolites uniquely correlated with total cortisol exposure were involved in arginine biosynthesis, and alanine-aspartate-glutamate and tryptophan metabolism. Serum metabolites uniquely correlated with the cortisol time profile variability were involved in primary bile acid biosynthesis and cysteine-methionine metabolism. We identified different groups of metabolites and metabolic pathways that specifically correlate with total exposure and time profile variability of serum cortisol. These findings suggest that total cortisol exposure and the time profile of serum cortisol have independent metabolic and regulatory effects in the human body.