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Previous Vol. 281 No. 20,
May 26, 1999

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Low-Dose Hydrocortisone for Chronic Fatigue Syndrome  
 

To the Editor: Dr McKenzie and colleagues1 suggest that hydrocortisone, despite its effectiveness against chronic fatigue syndrome (CFS), should not be used as a prolonged treatment for CFS because they found that "cautious hormonal supplementation" consisting of "low-dose" hydrocortisone caused a significant degree of adrenal suppression. Such suppression, however, may simply indicate that the dosage of hydrocortisone was neither cautiously low nor suitable for CFS patients. Hydrocortisone in dosages greater than 22 mg/d may harm even subjects with bilateral adrenalectomies,2 whose adrenal insufficiency is axiomatically absolute. Therefore, the 25- to 35-mg/d hydrocortisone dosage administered by McKenzie et al clearly represents an inappropriately high dosage for CFS patients, whose adrenal insufficiency is mild, since those authors report that "CFS patients excreted, on average, about 30% less cortisol in 24-hour urine collections than healthy, matched controls."1

During the twice-daily regimen of glucocorticoid replacement therapy, the second daily dose is usually administered in the evening.2 Therefore, it is unclear why McKenzie and colleagues administered the second daily dose of hydrocortisone at about 2 PM. This is even more surprising if we consider that they cite a study in which some authors of their group reported that basal cortisol levels of CFS patients were significantly reduced in the evening. In view of the many undesirable consequences of overtreatment with glucocorticoids,2 it is likely that 10 to 15 mg/d of hydrocortisone, split as 5 to 10 mg at 8 AM and 5 mg at 6 PM, would have provided greater benefit for McKenzie and coworkers' subjects, without producing adrenal suppression.

McKenzie and colleagues state that "mere supplementation of cortisol is not sufficient" in the treatment of CFS and propose future pharmacological options. Surprisingly, however, they fail to mention an available option I proposed 3 years ago3 and appears promising, namely, hydrocortisone plus fludrocortisone acetate. This mineralocorticoid, if administered properly,4 appears to improve CFS symptoms substantially.3 Scott and colleagues5 support the view that hydrocortisone plus fludrocortisone may benefit CFS patients, writing that "replacement therapy may more appropriately involve not only glucocorticoid, but mineralocorticoid supplements also."

The rationale for using both hydrocortisone and fludrocortisone in the treatment of CFS lies primarily in the similarity between CFS and Addison disease, which shares 26 features with CFS4 and is routinely treated with hydrocortisone plus fludrocortisone.2 Hormonal supplementation, however, could hardly benefit patients meeting the "Oxford" criteria for CFS because they have hypercortisolism.6


 
Riccardo Baschetti, MD
Padua, Italy

 
 

1. 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. MEDLINE

2. Peacey SR, Guo C-Y, Robinson AM, et al. Glucocorticoid replacement therapy: are patients overtreated and does it matter? Clin Endocrinol. 1997;46:255-261.

3. Baschetti R. Chronic fatigue syndrome and neurally mediated hypotension. JAMA. 1996;275:359. MEDLINE

4. Baschetti R. Treatment for chronic fatigue syndrome. Arch Intern Med. 1998;158:2266. MEDLINE

5. Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol. 1998;48:733-737.

6. Baschetti R. Treating chronic fatigue with exercise: results are contradictory for patients meeting different diagnostic criteria. BMJ. 1998;317:600. MEDLINE
 
JOC80004

To the Editor: We congratulate Dr McKenzie and colleagues1 on their excellent study but would like to correct an important error and add data that may increase the clinical utility of their study.

Our previously published pilot study2 and the work of Jefferies3, 4 suggests that using low-dose hydrocortisone (4 mg of hydrocortisone 1 mg of prednisone) in CFS at dosages of 7.5 to 20 mg/d is safe and effective. These low dosages have not caused the adrenal suppression3, 4 seen with the higher dosages (25-35 mg/d) used by McKenzie et al. They are also less likely to aggravate the already severe disruption of deep sleep present in CFS patients, as was seen in the study by McKenzie et al (P=.02 vs placebo).

McKenzie and colleagues' reference to Jefferies' work incorrectly notes that "low-dose glucocorticoid replacement, defined as 20 to 40 mg [daily] of hydrocortisone . . . was felt to be safe." Jefferies notes that 40 mg of hydrocortisone per day is an optimum full-replacement dosage; it is not the safe or optimum dosage for treating CFS. In the cited reference,3 Jefferies noted that "in our clinics the term 'low-dose' has referred to oral doses of cortisone or hydrocortisone totaling 20 mg or less daily." Thus, McKenzie and colleagues' underlying premise that the 25- to 35-mg/d dosage they used was what Jefferies (and others) considered to be low dose was incorrect.

We recently completed a randomized, double-blind study that tested the effectiveness of treating patients with fibromyalgia and CFS for hypothalamic dysfunction in an integrated manner (unpublished data, 1998). This included treating suspected hormonal deficiencies (including low hydrocortisone) and the sleep disorder simultaneously. Using this protocol (described previously2) in 72 patients (of whom 64 completed the study) resulted in a significant improvement in active vs placebo group (P<.0001 for the fibromyalgia impact questionnaire, analog scores, and tender point index). Seven patients in our study who were treated with low-dose hydrocortisone (eg, 2.5-20 mg/d) were given prestudy and poststudy hydrocortisone stimulation tests. Adrenal suppression was not seen. Average hydrocortisone levels were 386, 635, and 717 nmol/L before and 469, 635, and 717 nmol/L after hydrocortisone treatment.

These and previous data2-4 suggest that hydrocortisone dosages of 2.5 to 20 mg/d (combined with medications that improve deep sleep) are safe. In CFS and fibromyalgia patients who feel better when taking hydrocortisone these dosages may result in clinically important symptomatic improvement without causing adrenal suppression.


 
Jacob E. Teitelbaum, MD
Barbara Bird, MT, CLS
Alan Weiss, MD
Laurie Gould
Annapolis Research Center for Effective FMS/CFIDS Therapies
Annapolis, Md

 
 

1. 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. MEDLINE

2. Teitelbaum J, Bird B. Effective treatment of severe chronic fatigue: a report of a series of 64 patients. J Musculoskeletal Pain. 1995;3:91-110.

3. Jefferies WM. Low-dosage glucocorticoid therapy: an appraisal of its safety and mode of action in clinical disorders, including rheumatoid arthritis. Arch Intern Med. 1967;119:265-278. MEDLINE

4. Jefferies WM. Safe Uses of Cortisol. 2nd ed. Springfield, Ill: Charles C Thomas Publisher; 1996.
 
JOC80004

To the Editor: Dr McKenzie and colleagues1 continued their thorough studies of hypothalamic-pituitary-adrenal axis dysregulation in patients with CFS and found that treatment with hydrocortisone mildly increased their global wellness scale. However, several comments are in order. First, glucocorticoids often induce a feeling of euphoria.2 Because a control population was not studied, the effect may not be specific to patients with CFS since healthy volunteers may also feel "better" when treated with hydrocortisone.

Second, at the dosage of hydrocortisone used, significant mineralocorticoid activity may have contributed to the beneficial effect of hydrocortisone. We estimate that this dosage of hydrocortisone supplies approximately 50% of the mineralocorticoid replacement. The authors did not provide information on weight or orthostatic blood pressure changes, which may support the role of the mineralocorticoid properties of hydrocortisone on the improvement of CFS patients. In an open-label trial, fludrocortisone, a synthetic mineralocorticoid, improved orthostasis and symptoms of fatigue.3 These findings, coupled with the high incidence of orthostasis in patients with CFS3 and the fact that delayed orthostasis often results in the symptom of fatigue,4 further support the notion that these patients have impaired mineralocorticoid activity.

Third, because of the heterogeneous nature of CFS, it may be important to select patients with mild adrenal insufficiency for hydrocortisone to be effective. McKenzie et al excluded patients who had an onset of illness over a period of 6 weeks. We suspect that patients with adrenal insufficiency (mineralocorticoid or glucocorticoid) would have an insidious onset of illness, while patients with an infectious cause would present with a more acute onset. Thus, the authors may have excluded the very patients who would likely benefit from treatment.

Finally, it is noteworthy that in this and other studies, most patients with CFS are white. One possibility for this low representation of ethnic patients is that white patients consume less salt than those of other ethnicities, such as African American, Asian, and Hispanic. Bou-Holaigah et al3 noted that 61% of patients with CFS in their study were following a self-imposed sodium-restricted diet. We hypothesize that adequate salt intake may compensate for mild mineralocorticoid insufficiency and reduce orthostasis. Just as the corticotropin-releasing hormone-corticotropin-cortisol axis of patients with CFS has been well studied,5 studying the renin-aldosterone axis in depth in CFS patients may uncover a subset of patients with mineralocorticoid insufficiency who would benefit from fludrocortisone or salt treatment.


 
Theodore C. Friedman, MD, PhD
Abby Adesanya
Cedars-Sinai Medical Center
Los Angeles, Calif

Russell E. Poland, PhD
Harbor-UCLA Medical Center
Torrance, Calif

 
 

1. 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. MEDLINE

2. Murphy BE. Steroids and depression. J Steroid Biochem Mol Biol. 1991;38:537-559. MEDLINE

3. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961-967. MEDLINE

4. Streeten DHP. The nature of chronic fatigue. JAMA. 1998;280:1094-1095. MEDLINE

5. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991;73:1224-1234. MEDLINE
 
JOC80004

In Reply: Our study of patients with CFS was designed to evaluate efficacy and safety of hydrocortisone.1 We reported that divided doses totaling 25 to 35 mg/d for 12 weeks provided significant but modest symptomatic relief and also significant adrenal suppression. Our conclusion, then and now, is that the risks associated with low-dose hydrocortisone treatment outweigh its potential advantages for patients with CFS.

Dr Baschetti and Dr Teitelbaum and colleagues suggest that the dosage we used was too high. We based our regimen on our prior observation that CFS patients secrete approximately 30% less cortisol per day than healthy subjects.2 Our hypothesis was that modest glucocorticoid supplementation might ameliorate CFS symptoms.

We were aware of the work by Jefferies,3 whose clinical experience led him to conclude that hydrocortisone dosages totaling 10 to 20 mg/d ameliorate fatigue. He reported, though, " . . . that low dosages of cortisone partly suppress endogenous adrenocortical production of . . . hydrocortisone to a degree proportional to the dosage." Thus, low-dose exogenous hydrocortisone treatment will not raise net glucocorticoid levels. Based on these considerations, we presumed that there would be no symptomatic improvement in CFS patients unless their glucocorticoid levels could be supplemented toward the normal range.

Perhaps, however, a lower dosage is effective. Teitelbaum et al summarize their own trial as suggesting benefit of low-dose hydrocortisone. We welcome a complete account of their methods and results. Since our report appeared, though, Cleare et al4 found that 5 to 10 mg of hydrocortisone per day provides symptomatic relief for patients with CFS. Moreover, they observed no evidence of adrenal suppression. Unfortunately, the extent of symptomatic benefit was modest, failing to achieve the study's primary therapeutic end point. In addition, treatment was provided for only 4 weeks, a duration that may be insufficient for such effects to be evident.

Thus, if defective glucocorticoid secretion is a primary problem in CFS, then low-dose replacement may, over time, worsen clinical outcome by inhibiting the remaining endogenous glucocorticoid production. In fact, we proposed that a more likely explanation for the findings in CFS is that peripheral glucocorticoid secretion is a downstream indicator of a more proximal disturbance in central nervous system function.2 Emerging lines of evidence regarding neuropsychological changes, psychiatric morbidity, and neurotransmitter levels in CFS are consistent with this view.

We agree with Dr Friedman and colleagues that the benefits observed in our report may reflect the expected effects on general well-being of short-term glucocorticoid administration to humans. Rather than being nonspecific effects, they likely reflect hydrocortisone's known ability to activate the central nervous system. We also agree with Friedman et al, and Baschetti that beneficial effects of hydrocortisone could have been mediated, in part, by its mineralocorticoid activity.5 In this regard, we and collaborators at Johns Hopkins University are conducting a placebo-controlled trial of fludrocortisone therapy in CFS. We await its completion for the insights that it will yield regarding the neuroendocrine disturbances in CFS and their potential amelioration.


 
Stephen E. Straus, MD
National Institute of Allergy and Infectious Diseases
Bethesda, Md

Robin McKenzie, MD
Johns Hopkins University School of Medicine
Baltimore, Md

Mark A. Demitrack, MD
Lilly Research Laboratories
Indianapolis, Ind

 
 

1. 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. MEDLINE

2. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991;73:1224-1234. MEDLINE

3. Jefferies WM. Low-dosage glucocorticoid therapy: an appraisal of its safety and mode of action in clinical disorders, including rheumatoid arthritis. Arch Intern Med. 1967;119:265-278. MEDLINE

4. Cleare AJ, Heap E, Malhi GS, Wessley S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999;353:455-458. MEDLINE

5. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961-967. MEDLINE
 
JOC80004
 
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Edited by Margaret A. Winker, MD, Deputy Editor, and Phil B. Fontanarosa, MD, Interim Coeditor.
 
 
 



 
 
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