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This study aimed to identify metabolites and metabolic pathways uniquely associated with total cortisol exposure and\/or variation of the cortisol time profile. In a randomized, 12-week, cross-over trial 18 adults with primary adrenal insufficiency (AI) received the same total daily dose of hydrocortisone (HC) administered as a once-daily (OD) dual-release tablet and conventional HC tablets 3 times daily (TID). Serum and urine samples were collected during 24h 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 quantified as the area under the serum cortisol concentration-time curve and variability in the cortisol time profile was assessed by calculating the lag\u20131 autocorrelation from serum cortisol concentrations over 24 hours. Compared with OD dosing, TID administration resulted in a 20% higher total cortisol exposure and a greater variability in the cortisol time profile. In total, 2406 metabolites were detected. Pathway analysis of serum metabolites uniquely correlated with total cortisol exposure were involved in amino acid metabolism - including arginine, tryptophan and glutamate pathways - as well as glycerolipid metabolism. In contrast, metabolites uniquely associated with variability of the cortisol time profile were mapped to primary bile acid biosynthesis and cysteine-methionine metabolism. We identified distinct groups of metabolites and metabolic pathways that specifically correlate with either overall serum cortisol exposure or variability in its time profile, indicating that cortisol dose exposure and the circadian dynamics may exert independent metabolic and regulatory effects in humans, with potential implications for personalized hydrocortisone therapy.<\/jats:p>","DOI":"10.1038\/s41598-026-37816-0","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T18:34:36Z","timestamp":1770921276000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Different metabolic pathways associated with total cortisol exposure and the cortisol time profile: a randomized crossover trial"],"prefix":"10.1038","volume":"16","author":[{"given":"Johanna","family":"McQueen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence","family":"Garner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Chantzichristos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Lennern\u00e4s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Espiard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Ragnarsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhildur","family":"Bergthorsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanko","family":"Skrtic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudmundur","family":"Johannsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"issue":"2","key":"37816_CR1","doi-asserted-by":"publisher","first-page":"293313","DOI":"10.1016\/j.ecl.2005.01.002","volume":"34","author":"W. 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