Hydrocortisone Affects Fatigue and Physical Functioning Through Metabolism of Tryptophan: A Randomized Controlled Trial.

Context: Hydrocortisone (HC) treatment influences health-related quality of life (HRQOL) in secondary adrenal insufficiency (AI). Glucocorticoids regulate tryptophan metabolism through the kynurenine pathway, which modulates mood and energy homeostasis.

Objective: This study investigated whether tryptophan metabolism mediated the effect of HC dose on HRQOL in patients with secondary AI.

Design, Setting, and Patients: Forty-seven patients with secondary AI participated in this double-blind randomized controlled cross-over trial in the University Medical Center Groningen.

Intervention: Patients were treated for two 10-week periods with a daily HC dose of 0.2 to 0.3 mg/kg and 0.4 to 0.6 mg/kg body weight, respectively.

Main Outcome Measures: Diary data and questionnaires were used to assess HRQOL. Tryptophan, kynurenine and 3-hydroxykynurenine were measured in serum and dialyzed plasma and the kynurenine-to-tryptophan ratio (Kyn/Trp ratio) ratio was calculated.

Results: A higher dose HC was associated with increased levels of tryptophan (95% CI for mean difference 0.37 to 12.5, P = 0.038), reduced levels of kynurenine (95% CI, -0.49 to -0.10, P = 0.004) and 3-hydroxykynurenine (95% CI, -10.6 to -2.35, P = 0.003), and a reduced Kyn/Trp ratio (95% CI, -0.84 to -0.50, P < 0.001). The Kyn/Trp ratio mediated the effect of a higher dose HC on fatigue (P = 0.041) and physical functioning (P = 0.005).

Conclusion: Metabolism of tryptophan through the kynurenine pathway is reduced after a 10-week treatment with a higher dose HC and plays a role in the effect of HC on fatigue and physical functioning in patients with secondary AI.