Context: Adrenal crisis (AC) is a life threatening medical situation caused by an absolute or relative cortisol deficiency. A biological predisposition may be of importance, because some patients never experience an AC, whereas others are admitted repeatedly to the hospital for an AC. Differences in cortisol pharmacokinetics (PK) and/or pharmacodynamics (PD) may underlie this vulnerability.

Objective: To study PK and PD data of glucocorticoid sensitive pathways in patients with or without an AC.

Design: An exploratory analysis of well-characterized patients with secondary adrenal insufficiency who participated in a randomized controlled trial investigating the effects of two different hydrocortisone (HC) doses corrected for body weight .

Methods: Analysis of variables was performed on the lower HC dose (0.2-0.3 mg/kg body weight/day) as this was considered to better reflect the state of (relative) hypocortisolism. Variables of interest were also analyzed on the higher dose (0.4-0.6 mg/kg body weight/day). Plasma cortisol and cortisone, 24 hour urinary steroid profile, as well as the glucocorticoid sensitive tryptophan-kynurenine, and renin-aldosterone pathways were determined by LC-MS/MS. In addition, quality of life (QoL) was measured by means of questionnaires. Statistical significance was set a P< 0.05. Considering the exploratory study design, a P-value <0.1 was deemed to be of interest.

Results: Out of the 52 patients included in this study, 9 (17%) suffered from at least one AC. No differences in baseline characteristics were observed between patients with (AC+) and without (AC-) an adrenal crisis. The 24 hour urinary excretion of cortisol and cortisone were found to be lower in AC+ (P=0.01 and P=0.04, respectively) on the lower  dose of HC. No differences in plasma half-life and other PK parameters of (free) cortisol were observed. Kynurenine was higher in AC+ (P=0.03), as was 3-OH-kynurenine and the kynurenine-tryptophan ratio (both P=0.06)