Low doses of the steroid hydrocortisone can cause slight improvement in
some chronic fatigue syndrome (CFS) symptoms but at the risk of inducing
adrenal suppression. This finding, researchers from the National
Institute of Allergy and Infectious Diseases (NIAID) claim, precludes
the use of hydrocortisone in people with the illness. Their report
appears in the September 23/30 issue of The Journal of the American
"The data show that about half the people on placebo and two-thirds of
those taking hydrocortisone reported some improvement in well-being,"
comments Stephen E. Straus, M.D., chief of the Laboratory of Clinical
Investigation at NIAID and senior author on the study. "The greater
benefit seen in the hydrocortisone group, however, was modest, and there
was clear evidence of adrenal suppression by the drug." Twelve of 33
patients on the therapy developed laboratory evidence of adrenal
insufficiency. "It was manageable and completely reversible," says Dr.
Straus, "but it's the kind of suppression that in the context of minimal
improvement afforded by the drug cannot, in our minds, justify using
this treatment for CFS.
"Any time that long-term steroid therapy is considered, even at a low
dose," adds Dr. Straus, "one needs to be concerned that the treatment
itself may suppress the adrenal gland's normal production of steroids,
which can lead to serious complications. When suppressed, the adrenal
gland can't respond well to sudden stressful events such as a heart
attack or an accident."
HYDROCORTISONE STUDY RATIONALE
People with CFS can suffer for years from an array of symptoms,
including prolonged, debilitating fatigue, unrefreshing sleep, muscle
pains, and memory and concentration problems. Although painkillers,
antidepressants and other symptom-based therapies can provide some
relief, specific treatments for CFS do not exist, the search for them
frustrated by the unknown etiology of the illness.
Several years ago, Dr. Straus and his colleagues found that CFS patients
had slightly lower levels of circulating cortisol, the major
glucose-regulating stress hormone, than did healthy individuals.
Doctors have long believed that even subtle deficiencies in cortisol can
result in lethargy and fatigue. A subsequent study indicated that the
low cortisol levels in the CFS patients might be due to deficiencies in
corticotropin-releasing hormone (CRH), a brain chemical that helps
regulate cortisol secretion.
To determine if they could restore the hormonal balance and thereby
improve certain CFS symptoms, Dr. Straus and his former NIAID colleague,
Robin McKenzie, M.D., designed a clinical trial to treat CFS patients
with hydrocortisone, a synthetic form of cortisol.
A SECOND STEROID STUDY UNDER WAY
Although the new JAMA report does not support the use of hydrocortisone,
a second trial led by Dr. Straus at NIAID together with scientists at
Johns Hopkins University is attempting to supplement a different class
of steroid hormones produced by the adrenal gland.
A JAMA editorial accompanying the hydrocortisone report notes that some
people with CFS manifest neurally mediated hypotension, an abnormality
of blood pressure control. Preliminary published data suggests that
treatment with fludrocortisone, a steroid drug that helps the body
retain salt and water, might be beneficial. The current study - which
is still open to recruitment - is testing fludrocortisone in 100
patients with CFS who also have neurally mediated hypotension.
(Interested volunteers can call 1-800-772-5464 ext. 659 at NIAID or
410-821-7253 at Hopkins to request more information.)
THE HYDROCORTISONE TRIAL AND ITS RESULTS
The trial opened six years ago at the National Institutes of Health
Clinical Center in Bethesda, Md. From 683 carefully screened
individuals, the investigators enrolled 70 people with CFS, although
only 66 were included in the final analysis. "The strict entry criteria
were an important part of the study design," says Dr. Straus. The
investigators rejected anyone for whom steroids would be contraindicated
- people with a history of ulcer disease, glaucoma, hypertension,
diabetes, untreatable tuberculosis or extreme obesity - as well as those
who required many other kinds of potent medications.
By random selection, half of the participants received low-dose oral
hydrocortisone and the other half a placebo. The researchers tried to
mimic the natural diurnal fluctuations in cortisol levels by giving two
doses of treatment or placebo daily (a larger dose early in the morning
and a smaller dose in mid-afternoon, equivalent to a total of about 25
to 35 milligrams of hydrocortisone per day). During the 12-week
treatment period, all participants were carefully monitored for adrenal
suppression. They completed multiple self-rating questionnaires
describing their energy levels, activities, moods and symptoms for two
weeks before, during and for six weeks after this treatment period.
Based on the primary self-rating instrument used, the Wellness scale,
54.3 percent of placebo recipients and 66.7 percent of those who
received treatment judged their symptoms as improved. The
hydrocortisone recipients experienced significantly greater average
improvement (6.3 vs. 1.7 points on a 100-point scale), and more of them
improved by at least 5, 10 or 15 points. Moreover, they improved more
rapidly and had consistently higher average increases in Wellness scores
than the placebo recipients.
Twelve of the patients, however - all from the 33 in the hydrocortisone
group -experienced significant adrenal suppression. None of an equal
number of placebo recipients did.
"Although the therapeutic outcome was disappointing," says Dr. Straus,
"we hope the results dissuade CFS patients from using a drug that
potentially could cause them harm.
"The fact that the treatment worked to some degree," he adds, "was
encouraging, but we would expect to see a greater benefit if low
cortisol levels were directly responsible for symptoms of CFS. The
amount of CRH may be more important than the amount of circulating
cortisol because CRH receptors are located in the brain, and it is an
important substance for stimulating mood, attention and activity.
Unfortunately, we don't have convenient ways of supplementing CRH."
However, supplementing other adrenal steroids, as they are doing in
their currently open trial, may yield a more beneficial treatment
effect, Dr. Straus says, because the regulation of the
hypothalamic-pituitary-adrenal axis is not as sensitive to changes in
the circulating levels of these steroids.
NIAID is a component of the National Institutes of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses
such as HIV disease and other sexually transmitted diseases,
tuberculosis, malaria, asthma and allergies. NIH is an agency of the
U.S. Department of Health and Human Services.
1. R McKenzie, A O'Fallon, J Dale, M Demitrack, G Sharma, M Deloria, D
Garcia-Borreguero, W Blackwelder and SE Straus. Low-dose hydrocortisone
treatment of chronic fatigue syndrome: a randomized controlled trial.
Journal of the American Medical Association 280, 1061-66 (1998).
2. DHP Streeten. The nature of chronic fatigue. Journal of the
American Medical Association 280, 1094-95 (1998).
Press releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.