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
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
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
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
