These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in
chronic fatigue syndrome and 2) low-dose augmentation with
hydrocortisone therapy would improve the core symptoms. We measured
ACTH and
cortisol responses to human CRH, the
insulin stress test, and D-
fenfluramine in 37 medication-free patients with CDC-defined
chronic fatigue syndrome 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 test [either the
insulin stress test (n = 16) or D-
fenfluramine (n = 21)]. Baseline
cortisol concentrations were significantly raised in the
chronic fatigue syndrome group for the human CRH test only. Baseline
ACTH concentrations 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 control 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. These differences were significant when
ACTH responses were controlled. Urinary free
cortisol levels were lower in the
chronic fatigue syndrome group compared with the healthy group. These results indicate that
ACTH responses to pituitary and hypothalamic challenges are intact in
chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in
chronic fatigue syndrome. These data further suggest that the hypocortisolism found in
chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients were treated with a low-dose
hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free
cortisol collections, a human CRH test, and an
insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free
cortisol was higher after active compared with placebo treatments, but 0900-h
cortisol levels 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 patients who responded to active treatment (defined as a reduction in
fatigue score to the median population level or less). In this group, there was a significant increase in the
cortisol response to human CRH, which reversed the 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 the blunted
cortisol responses to human CRH.