title: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.
abstract: Chronic fatigue syndrome is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would explain the clinical presentation. Because primary glucocorticoid deficiency states and affective disorders putatively associated with a deficiency of the arousal-producing neuropeptide CRH can be associated with similar symptoms, we report here a study of the functional integrity of the various components of the hypothalamic-pituitary-adrenal axis in patients meeting research case criteria for chronic fatigue syndrome. Thirty patients and 72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal axis was estimated by determinations of 24-h urinary free cortisol-excretion, evening basal plasma total and free cortisol concentrations, and the cortisol binding globulin-binding capacity. The adrenal cortex was evaluated indirectly by cortisol responses during ovine CRH (oCRH) stimulation testing and directly by cortisol responses to graded submaximal doses of ACTH. Plasma ACTH and cortisol responses to oCRH were employed as a direct measure of the functional integrity of the pituitary corticotroph cell. Central CRH secretion was assessed by measuring its level in cerebrospinal fluid. Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 +/- 8.7 vs. 148.4 +/- 20.3 nmol/L; P less than 0.01) and low 24-h urinary free cortisol excretion (122.7 +/- 8.9 vs. 203.1 +/- 10.7 nmol/24 h; P less than 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 +/- 26.4 vs. 225.4 +/- 34.5 pmol/L.min, P less than 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 +/- 0.6 vs. 7.7 +/- 0.5 pmol/L; P = NS). Although we cannot definitively account for the etiology of the mild glucocorticoid deficiency seen in chronic fatigue syndrome patients, the enhanced adrenocortical sensitivity to exogenous ACTH and blunted ACTH responses to oCRH are incompatible with a primary adrenal insufficiency. A pituitary source is also unlikely, since basal evening plasma ACTH concentrations were elevated. Hence, the data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency or a putative deficiency of an arousal-producing neuropeptide such as CRH is related to the clinical symptomatology of the chronic fatigue syndrome remains to be determined.
authors.affiliation: Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: M A
authors.initials: MA
authors.lastname: Demitrack
authors.forename: J K
authors.initials: JK
authors.lastname: Dale
authors.forename: S E
authors.initials: SE
authors.lastname: Straus
authors.forename: L
authors.initials: L
authors.lastname: Laue
authors.forename: S J
authors.initials: SJ
authors.lastname: Listwak
authors.forename: M J
authors.initials: MJ
authors.lastname: Kruesi
authors.forename: G P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: P W
authors.initials: PW
authors.lastname: Gold
mesh_terms: D000302:Adrenal Cortex / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000134:cerebrospinal fluid / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001519:Behavior; D003346:Corticotropin-Releasing Hormone / Q000134:cerebrospinal fluid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015673:Fatigue Syndrome, Chronic / Q000134:cerebrospinal fluid / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008297:Male; D008499:Medical Records; D008603:Mental Health; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D012756:Sheep
chemical_list: D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone