Endocrine Abstracts

Background

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. A P-value <0.05 was considered significant. Considering the exploratory study design, a P-value <0.1 was considered 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. On the lower HC dose the 24 hour urinary excretion of cortisol and cortisone were found to be lower in AC+ (P = 0.01 and P = 0.04, respectively). 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). In addition, perceived pain (P = 0.08), general fatigue (P = 0.04) and anxiety (P = 0.06) were higher in the AC+ group. On the higher HC dose, the 24 hour urinary excretion of cortisol and cortisone remained lower (both P≤0.01) in the AC+ group, whereas differences in the kynurenine pathway and quality of life were no longer present. A higher plasma aldosterone concentration was found in the AC+ group on the higher HC dose.

Conclusion

Patients susceptible to an adrenal crisis demonstrate lower urinary excretion of cortisol and cortisone as well as differences in the kynurenine pathway and QoL on a standardized lower hydrocortisone substitution dose when compared to patients who never experienced an adrenal crisis.