Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy

These neuroendocrine studies were part of a series of studies testing the h ypotheses that 1) there may be reduced activity of the hypothalamic-pituita ry-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation wi th hydrocortisone therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenflu ramine in 37 medication-free patients with CDC-defined chronic fatigue synd rome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge tes t [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)]. Bas eline cortisol concentrations were significantly raised in the chronic fati gue syndrome group for the human CRH test only. Baseline ACTH concentration s did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D-fenfluramine were similar for patient and co ntrol groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. T hese differences were significant when ACTH responses were controlled. Urin ary free cortisol levels were lower in the chronic fatigue syndrome group c ompared with the healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue synd rome and do not support previous findings of reduced central responses in h ypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal C RH secretion in chronic fatigue syndrome. These data further suggest that t he hypocortisolism found in chronic fatigue syndrome may be secondary to re duced adrenal gland output. Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled crossover design, with 28 days on each tr eatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo ar ms of treatment. Looking at all subjects, 24-h urinary free cortisol was hi gher after active compared with placebo treatments, but 0900-h cortisol lev els and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those pati ents who responded to active treatment (defined as a reduction in fatigue s core to the median population level or less). In this group, there was a si gnificant increase in the cortisol response to human CRH, which reversed th e previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of t he blunted cortisol responses to human CRH.