Among patients with secondary adrenal insufficiency, a 10-week treatment with a higher dose of hydrocortisone lowered the metabolism of tryptophan, mediating the effects of the drug on fatigue and physical functioning, according to findings from a double-blind crossover study.
“Individuals who suffer from adrenal insufficiency report reduced quality of life due to a variety of mental and physical symptoms such as fatigue, depression and physical disabilities,” Freek J. H. Sorgdrager, of the department of laboratory medicine at the University of Groningen and University Medical Center Groningen, the Netherlands, and colleagues wrote. “Because of inadequate production of glucocorticoids, these persons require lifelong glucocorticoid replacement with hydrocortisone. Health-related quality of life ... was shown to be affected by changes in hydrocortisone dose, the dose scheme and the mode of hydrocortisone administration. The mechanisms behind this are poorly understood.”
Sorgdrager and colleagues analyzed data from 47 adults with secondary adrenal insufficiency receiving glucocorticoid substitution therapy for at least 6 months, recruited from the endocrine outpatient clinic of the University Medical Center Groningen, a tertiary referral center for pituitary surgery in the Netherlands. Researchers randomly assigned patients to one of two treatment groups. The first group received lower-dose hydrocortisone for 10 weeks before switching to a higher dose for a second 10-week treatment period, with both the investigator and patient masked to the study dose and group (n = 22; mean age, 53 years; 40.9% women). The second group received higher-dose hydrocortisone for 10 weeks before switching to the lower-dose formulation (n = 25; mean age, 51 years; 36% women). Dosing schemes were adjusted for weight. On the lower dose, patients received a cumulative daily dose of 15 mg to 20 mg hydrocortisone. On the higher dose, patients received a cumulative daily dose of 30 mg to 40 mg hydrocortisone. Total daily amount was divided over three oral dosages taken before breakfast, lunch and dinner. Researchers measured fasting levels of plasma tryptophan, kynurenine, 3-hydroxykynurenine, as well as domain-specific and generic health-related quality of life via the Patient Health Questionnaire-9, the Patient Health Questionnaire-15, the Hospital Anxiety Depression Scale and the Multidimensional Fatigue Inventory-20, with higher scores suggesting worse quality of life or symptom severity. Diary data for 45 patients were also assessed.
Researchers found that patients had increased levels of tryptophan when assigned the higher hydrocortisone dose (P = .038), as well as reduced levels of kynurenine (P = .004) and 3-hydroxykynurenine (P = .003) and a lower kynurenine to tryptophan ratio (P < .001). Additionally, researchers found that the kynurenine to tryptophan ratio mediated the effect of the higher hydrocortisone dose on patient-reported fatigue (P = .041) and physical functioning (P = .005).
“In short, on a higher [hydrocortisone] dose, with regard to the diary data, patients reported reduced symptoms of depression and reduced symptoms of pain,” the researchers wrote. “With regard to the questionnaire data, patients reported reduced symptoms of depression, general fatigue, mental fatigue, better motivation and improved physical functioning, vitality and general health perception.”
The researchers noted that the results prompt further investigation of the relevance of tryptophan metabolism along with kynurenine pathway as a mechanism of glucocorticoid-induced mental and physical health impairments. – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.