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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. FREE FULL TEXT
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.
ISI |
PUBMED
3.
Baschetti R. Chronic fatigue syndrome and neurally mediated
hypotension. JAMA. 1996;275:359.
4.
Baschetti R. Treatment for chronic fatigue syndrome. Arch Intern
Med. 1998;158:2266. FREE FULL
TEXT
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. FULL
TEXT | ISI |
PUBMED
6.
Baschetti R. Treating chronic fatigue with exercise: results are
contradictory for patients meeting different diagnostic criteria.
BMJ. 1998;317:600. FREE FULL
TEXT
| 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. FREE FULL TEXT
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. FULL
TEXT | ISI |
PUBMED
4.
Jefferies WM. Safe Uses of Cortisol. 2nd ed. Springfield,
Ill: Charles C Thomas Publisher; 1996.
| 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. FREE FULL TEXT
2.
Murphy BE. Steroids and depression. J Steroid Biochem Mol
Biol. 1991;38:537-559. FULL
TEXT | ISI |
PUBMED
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.
ABSTRACT
4.
Streeten DHP. The nature of chronic fatigue. JAMA.
1998;280:1094-1095. FREE FULL
TEXT
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. ABSTRACT
| 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. FREE FULL TEXT
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. ABSTRACT
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. FULL
TEXT | ISI |
PUBMED
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. FULL
TEXT | ISI |
PUBMED
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.
ABSTRACT
Edited by Margaret A. Winker, MD, Deputy Editor, and
Phil B. Fontanarosa, MD, Interim Coeditor.
JAMA. 1999;281:1887-1889.
THIS ARTICLE HAS BEEN CITED BY OTHER
ARTICLES
Fibromyalgia, Chronic Fatigue Syndrome, and Addison
Disease Baschetti Arch Intern Med
1999;159:2481-2481. FULL
TEXT
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