Evidence for Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome
MARK A. DEMITRACK,
JANET K. DALE,
STEPHEN E. STRAUS,
LOUISA LAUE,
SAM J. LISTWAK,
MARKUS J. P. KRUESI,
GEORGE P. CHROUSOS and
PHILIP W. GOLD
Clinical Neuroendocrinology Branch National Institute of Mental Health; the Medical Virology Section, Laboratory of Clinical Investigation Bethesda, Maryland 20892
Child Psychiatry Branch Bethesda, Maryland 20892
National Institute of Mental Health; the Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases Bethesda, Maryland 20892
Developmental Endocrinology Branch, National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892
Address requests for reprints to: Mark A. Demitrack, M.D., University of Michigan Medical Center, 1500 East Medical Center Drive, 8D 8806, UH Box 0116, Ann Arbor, Michigan 48109-0116.
Chronic fatigue syndrome is characterized by persistent or relapsingdebilitating fatigue for at least 6 months in the absence ofa medical diagnosis that would explain the clinical presentation.Because primary glucocorticoid deficiency states and affectivedisorders putatively associated with a deficiency of the arousal-producingneuropeptide CRH can be associated with similar symptoms, wereport here a study of the functional integrity of the variouscomponents of the hypothalamic-pituitary-adrenal axis in patientsmeeting research case criteria for chronic fatigue syndrome.
Thirty patients and 72 normal volunteers were studied. Basalactivity of the hypothalamic-pituitary-adrenal axis was estimatedby determinations of 24-h urinary free cortisol-excretion, eveningbasal plasma total and free cortisol concentrations, and thecortisol binding globulin-binding capacity. The adrenal cortexwas evaluated indirectly by cortisol responses during ovineCRH (oCRH) stimulation testing and directly by cortisol responsesto graded submaximal doses of ACTH. Plasma ACTH and cortisolresponses to oCRH were employed as a direct measure of the functionalintegrity of the pituitary corticotroph cell. Central CRH secretionwas assessed by measuring its level in cerebrospinal fluid.
Compared to normal subjects, patients demonstrated significantlyreduced basal evening glucocorticoid levels (89.0 ± 8.7us. 148.4 ± 20.3 nmol/L; P < 0.01) and low 24-h urinaryfree cortisol excretion (122.7 ± 8.9 us. 203.1 ±10.7 nmol/24 h; P < 0.0002), but elevated basal evening ACTHconcentrations. There was increased adrenocortical sensitivityto ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50;P = 0.0015). Patients showed attenuated net integrated ACTHresponses to oCRH (128.0 ± 26.4 us. 225.4 ± 34.5pmol/Lmin, P < 0.04). Cerebrospinal fluid CRH levels in patientswere no different from control values (8.4 ± 0.6 us.7.7 ± 0.5 pmol/L; P = NS).
Although we cannot definitively account for the etiology ofthe mild glucocorticoid deficiency seen in chronic fatigue syndromepatients, the enhanced adrenocortical sensitivity to exogenousACTH and blunted ACTH responses to oCRH are incompatible witha primary adrenal insufficiency. A pituitary source is alsounlikely, since basal evening plasma ACTH concentrations wereelevated. Hence, the data are most compatible with a mild centraladrenal insufficiency secondary to either a deficiency of CRHor some other central stimulus to the pituitary-adrenal axis.Whether a mild glucocorticoid deficiency or a putative deficiencyof an arousal-producing neuropeptide such as CRH is relatedto the clinical symptomatology of the chronic fatigue syndromeremains to be determined.
Received February 20, 1991.
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