Some CFS Patients Benefit From Low-Dose Steroid, But Side Effects Too Risky

"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 stero