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Date: Sunday, Oct. 13, 1996 FOR IMMEDIATE RELEASE Contact: Laurie K. Doepel (301) 402-1663, doepel@nih.gov
Low doses of the steroid hydrocortisone have proved not to be an effective or appropriate treatment for people with chronic fatigue syndrome (CFS), according to preliminary results from a double-blind, placebo-controlled clinical trial conducted by researchers at the National Institute of Allergy and Infectious Diseases (NIAID). Stephen E. Straus, M.D., study director and chief of NIAID's Laboratory of Clinical Investigation, will discuss these findings during a talk on Sunday, Oct. 13, at the American Association for CFS research conference in San Francisco. Dr. Straus will deliver a plenary lecture reviewing the history of CFS clinical trials.
"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 produce cortisol.
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 treatment period.
"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 Services.
Reference: 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 1991;73(6):1224-34.
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