Using Hydrocortisone to Treat Chronic Fatigue Syndrome

Abstract & Commentary

Source: McKenzie R, et al. Low-dose hydrocortisone for the treatment of chronic fatigue syndrome: A randomized controlled trial. JAMA 1998; 80:1061-1066.

Mckenzie and colleagues at the national institutes of Health studied the effect of hydrocortisone on the symptoms of chronic fatigue syndrome (CFS). Seventy patients (56 women and 14 men), aged 18-55 years, were selected from a potential group of 638 individuals with chronic fatigue. Reasons for exclusion included the subjects’ reluctance to withhold other medications (such as antidepressants and nonsteroidal analgesics), failure to meet the CDC’s CFS definition, complicating medical illnesses, and the like. By protocol design, all subjects’ fatigue began over a short time period (< 6 weeks). Symptoms in most subjects had been present for several years (mean 47-60 months in treated and placebo groups, respectively) before enrollment in the study. Many individuals had concomitant psychiatric diagnoses, such as somatoform pain disorder or somatization disorder, but such diagnoses were similar in both drug-treated and placebo groups. Patients received either placebo or hydrocortisone, 20-30 mg each morning and 5 mg each afternoon, for 12 weeks. Prior to treatment and frequently during treatment, patients’ subjective status was evaluated by a variety of self-administered rating systems, and subjects were additionally evaluated with a depression rating scale administered by a trained psychiatric specialist.

During the three-month treatment period, both placebo and treatment groups noticed improved "wellness" scores, a rating system that required subjects to gauge, on a scale from 0-100, how well they felt. On average, hydrocortisone-treated patients had greater improvement than the controls. The difference was modest, however, with an improvement on treatment of only 6 points in the treated group, compared to a 2-point improvement in placebo recipients (P = 0.06). When response was measured with other standardized rating systems, such as the Profile of Moods Questionnaire, Sickness Impact Profile, Beck Depression Inventory, and other instruments, slightly greater improvement occurred in hydrocortisone-treated patients, but the differences were still statistically insignificant.

Increased appetite, weight gain, and difficulty sleeping occurred in nearly half of the hydrocortisone-treated subjects. Significantly, adrenal suppression, as measured by morning serum cortisol levels or response to Cosyntropin, was seen in one-third of the corticosteroid recipients.

McKenzie et al conclude that the meager improvement in subjective wellness is outweighed by the adverse effects, primarily adrenal suppression, in patients with CFS treated with low-dose hydrocortisone.

COMMENT by Jerry D. Smilack, MD

Optimal therapy for CFS remains an enigma. Controlled clinical trials have failed to demonstrate any clear benefit from acyclovir,1 dialyzable leukocyte extract2 and fludrocortisone,3 and conflicting results from intravenous immunoglobulin.4-6 Reports of improvement using amantadine, antidepressants, vitamins, dietary manipulations, and cognitive behavioral therapy are anecdotal at best and need to be validated scientifically before credibility can be assessed.

Straus and associates at the NIH have hypothesized a role for an altered hypothalamic-pituitary-adrenal axis in the pathogenesis of CFS.1 To test this hypothesis, McKenzie et al have conducted a carefully designed, placebo-controlled study to determine whether hydrocortisone, given in doses that mimic normal daily cortisol physiology, might favorably affect symptoms in patients with CFS. The findings: a 12-week course of physiologic doses of hydrocortisone had minimal beneficial effect and came at the cost of measurable—if not clinically apparent—adrenal suppression. Basal serum cortisol levels and response to cosyntropin stimulation were blunted in hydrocortisone-treated subjects.

This study sheds incremental light on the chronic fatigue conundrum. Whether higher doses of corticosteroids might be more beneficial is an open question, but, given the adverse endocrinologic effects of even low-dose hydrocortisone in this study, will probably not be the subject of future inquiry.

Readers interested in updating their knowledge of CFS will find a recent supplement to the American Journal of Medicine (1998;105[3A]:Supplement) to be illuminating.


1. Straus SE, et al. Acyclovir treatment of chronic fatigue syndrome: Lack of efficacy in a placebo-controlled trial. N Engl J Med 1988;319:1692-1698.

2. Lloyd AR, et al. Immunologic and psychologic therapy for patients with chronic fatigue syndrome: A double-blind, placebo-controlled trial. Am J Med 1993;94: 197-203.

3. Peterson PK, et al. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med 1998;158:908-914.

4. Lloyd A, et al. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 1990;89: 561-568.

5. Peterson PK, et al. A controlled trial of intravenous IgG in chronic fatigue syndrome. Am J Med 1990;89: 554-560.

6. Vollmer-Conna U, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med 1997;103:38-43.

7. Demitrack MA, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991;3:1224-1234.