"The analysis to date reveals that about half of the people on
placebo reported some improvement in well-being," comments Dr.
Straus, "and about two-thirds of those given hydrocortisone reported
a statistically greater degree of improvement. The greater benefit
seen in the hydrocortisone group, however, was modest, and there
was clear evidence of adrenal suppression by the drug." In fact, four
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 the
minimal improvement afforded by the drug can not, in our minds,
justify using this treatment for CFS."
"Any time long-term steroid therapy is considered, even a low
dose," he continues, "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. The adrenal gland then
can't respond well to sudden stressful events such as a heart attack
or an accident."
People with CFS often 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 remain
elusive, the search for them frustrated by the still unknown cause or
causes of the syndrome.
Five years ago, Dr. Straus, Mark Demitrack, M.D., now of Lilly
Research Laboratories in Indianapolis, and their colleagues, reported
that as a group, CFS patients had slightly lower levels of circulating
cortisol, the major glucose-regulating stress hormone, than did
healthy individuals. While a healthy person usually produces about
25 to 30 milligrams (mg) of cortisol per 24-hour period, on average,
the CFS patients produced about 5 to 8 mg less. Doctors have long
known that even subtle deficiencies in cortisol can be associated with
lethargy and fatigue.
Other studies by Dr. Straus and his colleagues 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. In response to a stressor, the
hypothalamus, a small area at the base of the brain, secretes CRH,
which activates the pituitary gland to secrete adrenocorticotropin
hormone (ACTH), which in turn stimulates the adrenal gland to
To determine if they could restore the hormonal balance and
thereby improve certain CFS symptoms, Dr. Straus and his NIAID
colleague, Robin McKenzie, M.D., designed a clinical trial to treat
CFS patients with hydrocortisone, a synthetic form of cortisol.
The NIAID trial opened in 1992. From some 600 carefully
screened individuals, the investigators enrolled 70 people with CFS.
"The strict entry criteria were an important part of the study design,"
says Dr. Straus. The investigators eliminated 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.
Half of the participants were randomly selected to receive low-
dose oral hydrocortisone and the other half a placebo. The
researchers tried to reproduce the natural diurnal fluctuations in
cortisol levels by administering two doses of treatment or placebo per
day (a larger dose early in the morning and a smaller dose in mid-
afternoon, equivalent to a total of about 25 to 30 mg of hydrocortisone
per day). The treatment period lasted 12 weeks, during which time all
participants were carefully monitored for adrenal suppression. To
assess benefit, participants completed multiple self-rating
questionnaires describing their energy levels, activities, moods and
symptoms for two weeks before, during and for six weeks after this
"Although the therapeutic outcome was disappointing,"
comments Dr. Straus, "we hope the results dissuade CFS patients
from using a drug that potentially could cause them harm."
What the trial results mean about their earlier laboratory
findings of reduced cortisol levels is uncertain, says Dr. Straus. "The
fact that the treatment worked to some degree 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."
Dr. Straus and his NIAID colleagues have been conducting
investigations of CFS since 1979. In 1984, after early research hinted
that CFS-like symptoms might be caused by a herpesvirus, the NIAID
group undertook a placebo-controlled trial to test the antiviral drug
acyclovir. The results, published four years later, found a large
placebo effect and showed the drug to be ineffective. Next, they
discovered the hormonal deficits and subsequently undertook the
hydrocortisone trial. Recently, NIAID began a third trial in
collaboration with investigators at Johns Hopkins University, who one
year ago reported preliminary information that CFS is associated with
neurally mediated hypotension, and that therapy directed at this
abnormal cardiovascular reflex may improve CFS symptoms in a
subset of people. The double-blind, placebo-controlled trial is testing
whether Fluorinef , a mineral-regulating steroid, can relieve CFS
symptoms of patients who also have neurally mediated hypotension.
"It's conceivable that just as there are deficits in the glucose-
regulating hormones, such as cortisol, in CFS patients, there may be
deficits in the mineral-regulating steroids also produced by the
adrenal gland," says Dr. Straus. "Supplementing the latter may yield
a more beneficial treatment effect because the regulation of the
hypothalamic-pituitary-adrenal axis is not as sensitive to changes in
circulating levels of these steroids."
NIAID, a component of the National Institutes of Health (NIH),
supports research on AIDS, tuberculosis and other infectious
diseases, as well as allergies and immunology. NIH is an agency of
the Public Health Service, U.S. Department of Health and Human
Demitrack MA, Dale J K, Straus S E, Laue L, Listwak S J, Kruesi M J
P, Chrousos G P, and Gold P W. Evidence for impaired activation of
the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue
syndrome. Journal of Clinical Endocrinology and Metabolism
NIAID press releases, fact sheets and other materials are
available on the Internet via the NIAID home page at