Improved Urinary Cortisol Metabolome In Addison Disease: A Prospective Trial Of Dual-Release Hydrocortisone

Context: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.Objective: This work aimed to study cortisol metabolism during DR-HC and TID-HC.Design: A randomized, 12-week, crossover study was conducted.Intervention and Participants: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls.Main Outcome Measures: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections.Results: Total cortisol metabolites decreased during DR-HC compared toTID-HC (P <.001) and reached control values (P =.089). During DR-HC, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) activity measured by tetrahydrocortisol + 5 alpha-tetrahydrocortisol/ tetrahydrocortisone ratio was reduced compared to TID-HC (P <.05), but remained increased vs controls (P <.001). 11 beta-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P <.01) but normalized with DR-HC (P =.358). 5 alpha- and 5 beta-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5 alpha-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5 beta-reductase activity.Conclusions: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventionalTID-HC replacement therapy, with increased 11 beta-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.