Objective: To identify a biological predisposition for an adrenal crisis  in terms of  pharmacokinetics and pharmacodynamics of hydrocortisone as well as several glucocorticoid sensitive pathways in patients with or without an adrenal crisis.

Design: A retrospective analysis of a randomized controlled trial examining the effects of two different weight-adjusted hydrocortisone  dosages in patients with secondary adrenal insufficiency.

Methodes: Plasma cortisol and cortisone, 24-hour urinary steroid profile, the glucocorticoid sensitive tryptophan-kynurenine pathway and the renin-angiotensin-aldosterone system were determined by LC-MS/MS and GC-MS/MS. Quality of life  was examined using questionnaires. Statistical significance was set as a two-sided P< 0.05.

Results: 43 patients did not develop an adrenal crisis (AC – group), whereas 9 patients experienced at least one adrenal crisis (AC+ group) . 24 hour urinary excretion of cortisol and cortisone were found to be lower in the AC+ group (0.09 µmol/24h vs. 0.05 µmol/24h, P=0.01; 0.24 µmol/24h vs. 0.13 µmol/24h, P=0.04). No differences in PK and PD parameters of cortisol were observed. Kynurenine, 3-OH-kynurenine, and the kynurenine-tryptophan ratio was higher in the AC+ group (2.23 µmol/L vs. 2.64 µmol/L, P=0.03; 0.04 µmol/L vs. 0.05 µmol/L, P= 0.06; 0.03 vs. 0.04, P=0,06). In addition, perceived pain, general fatigue and anxiety were higher in the AC+ group (Z-scores -0.39 vs. -0.01, P=0.08; -0.16 vs. 1.02, P=0.04; -0.58 vs. 0.11, P=0.06).

Conclusion: Patients susceptible to an adrenal crisis demonstrate lower urinary excretion of cortisol and cortisone, differences in the kynurenine pathway and QoL when compared to patients who never experienced an adrenal crisis.