Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study



      Chronic fatigue syndrome has been associated with decreased function of the hypothalamic-pituitary-adrenal axis. Although neurally mediated hypotension occurs more frequently in patients with chronic fatigue syndrome than in controls, attempts to alleviate symptoms by administration of hydrocortisone or fludrocortisone have not been successful. The purpose of this study was to investigate the effect of combination therapy (5 mg/d of hydrocortisone and 50 μg/d of 9-alfa-fludrocortisone) on fatigue and well-being in chronic fatigue syndrome.


      We performed a 6-month, randomized, placebo-controlled, double-blind, crossover study in 100 patients who fulfilled the 1994 Centers for Disease Control and Prevention criteria for chronic fatigue syndrome. Between-group differences (placebo minus treatment) were calculated on a 10-point visual analog scale.


      Eighty patients completed the 3 months of placebo and 3 months of active treatment in a double-blind fashion. There were no differences between treatment and placebo in patient-reported fatigue (mean difference, 0.1; 95% confidence interval [CI]: −0.3 to 0.6) or well-being (mean difference, −0.4; 95% CI: −1.0 to 0.1). There were also no between-group differences in fatigue measured with the Abbreviated Fatigue Questionnaire, the Short Form-36 Mental or Physical Factor scores, or in the Hospital Anxiety and Depression Scale.


      Low-dose combination therapy of hydrocortisone and fludrocortisone was not effective in patients with chronic fatigue syndrome.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Fukuda K.
        • Straus S.E.
        • Hickie I.
        • Sharpe M.C.
        • Dobbins J.G.
        • Komaroff A.
        The chronic fatigue syndrome.
        Ann Intern Med. 1994; 121: 953-959
        • Barsky A.J.
        • Borus J.F.
        Functional somatic syndromes.
        Ann Intern Med. 1999; 130: 910-921
        • Demitrack M.
        • Dale J.
        • Straus S.
        • et al.
        Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.
        J Clin Endocrinol Metab. 1991; 73: 1224-1234
        • Gaab J.
        • Hüster D.
        • Peisen R.
        • et al.
        Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation.
        Psychosom Med. 2002; 64: 951-962
        • Rowe P.C.
        • Bou-Holaigah I.
        • Kan J.S.
        • Calkins H.
        Is neurally mediated hypotension an unrecognized cause of chronic fatigue?.
        Lancet. 1995; 345: 623-624
        • McKenzie R.
        • O’Fallon A.
        • Dale J.
        • et al.
        Low-dose hydrocortisone for treatment of chronic fatigue syndrome. A randomized controlled trial.
        JAMA. 1998; 280: 1061-1066
        • Cleare A.J.
        • Heap E.
        • Malhi G.S.
        • Wessely S.
        • O’Keane V.
        • Miell J.
        Low-dose hydrocortisone in chronic fatigue syndrome.
        Lancet. 1999; 353: 455-458
        • Peterson P.K.
        • Pheley A.
        • Schroeppel J.
        • et al.
        A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome.
        Arch Intern Med. 1998; 158: 908-914
        • Rowe P.C.
        • Calkins H.
        • DeBusk K.
        • et al.
        Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome.
        JAMA. 2001; 285: 52-59
        • World Health Organization
        SCAN. Psychiatric Publishers International/American Psychiatric Press, Geneva, Switzerland1994
        • Alberts M.
        • Smets E.M.
        • Vercoulen J.H.
        • Garssen B.
        • Bleijenberg G.
        Abbreviated Fatigue Questionnaire.
        Ned Tijdschr Geneeskd. 1997; 141: 1526-1530
        • Ware J.E.
        SF-36 health survey update.
        Spine. 2000; 25: 3130-3139
        • Zigmond A.S.
        • Snaith R.P.
        The Hospital Anxiety and Depression Scale.
        Acta Psychiatr Scand. 1983; 67: 361-370
        • Bland J.M.
        • Altman D.G.
        Multiple significance tests.
        BMJ. 1995; 310: 170
        • Parker A.J.R.
        • Wessely S.
        • Cleare A.J.
        The neuroendocrinology of chronic fatigue syndrome and fibromyalgia.
        Psychol Med. 2001; 31: 1331-1345
        • Leese G.
        • Chattington P.
        • Fraser W.
        • Vora J.
        • Edwards R.
        • Williams G.
        Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome.
        J Clin Endocrinol Metab. 1996; 81: 1867-1870
        • Baschetti R.
        Chronic fatigue syndrome, decreased exercise capacity, and adrenal insufficiency.
        Arch Intern Med. 2001; 161: 1558-1559
        • Gaab J.
        • Hüster D.
        • Peisen R.
        • et al.
        Low-dose dexamethasone suppression test in chronic fatigue syndrome and health.
        Psychosom Med. 2002; 64: 311-318
        • Natelson B.H.
        • Lange A.
        A status report on chronic fatigue syndrome.
        Environ Health Perspect. 2002; 110: S673-S677
        • Whiting P.
        • Bagnall A.M.
        • Sowden A.J.
        • Cornell J.E.
        • Mulrow C.D.
        • Ramirez G.
        Interventions for the treatment and management of chronic fatigue syndrome.
        JAMA. 2001; 286: 1360-1368
        • Wessely S.
        Chronic fatigue syndrome.
        JAMA. 2001; 286: 1378-1379