Doctors Debate Hydrocortisone for Chronic Fatigue Syndrome
By Anthony Cleare, et al. •
November 12, 2001
Editor’s Note: The following is a lively correspondence among several doctors regarding a report published by Anthony Cleare about hydrocortisone treatment for Chronic Fatigue Syndrome (CFS). Particularly controversial in this exchange, is the issue of cognitive behavioral therapy and psychiatry in relation to CFS. The correspondence concludes with Cleare’s response to the questions and objections raised by the other doctors. This correspondence was published in The Lancet medical journal, Volume 353, Number 9164, May 1999
Sir--Anthony Cleare and colleagues (Feb 6, p 455)1 report that low-dose hydrocortisone proved both effective and safe in reducing degree of disability due to Chronic Fatigue Syndrome (CFS). Nevertheless, rather surprisingly, they state that "we would not recommend the widespread use of hydrocortisone as a therapy strategy." Such a statement, along with their repeated advocacy of cognitive behavioral therapy, might betray their reluctance to admit that CFS, contrary to previous tenets,2 has more to do with endocrinology than with psychiatry.3 That reluctance is also revealed by their ill-concealed espousal of Leese and colleagues' idea4 that the hypocortisolism of CFS patients "may be merely the consequence of disrupted sleep and social routine". This view, however, is patently untenable.
Although night-shift working may well mimic the pituitary-adrenocortical dysfunction seen in CFS,4 it is far from causing all the physical symptoms and neuropsychological abnormalities that affect people with CFS. Conversely, CFS shares 36 features with Addison's disease,3 including all those symptoms and abnormalities.5 This fact clearly suggests that the hypocortisolism of CFS patients is not due to their disrupted sleep. This sleep pattern, on the contrary, is merely a well recognized consequence of adrenal insufficiency, as in the case of Addison's disease.5
In view of the astounding similarity between CFS and Addison's disease,3,5 Cleare and colleagues should assess whether low doses of both hydrocortisone and fludrocortisone, the two steroids that constitute the standard therapy for Addison's disease,3 could also benefit CFS patients. Encouragingly, fludrocortisone already lessens these patients' complaints.3
Via Savonarola 144, 35137 Padau, Italy
1 Cleare AJ, Heap E, Malhi GD, Wessely S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial. Lancet 1999; 353: 455-58. [Text]
2 Editorial. Frustrating survey of chronic fatigue. Lancet 1996; 348: 971.
3 Baschetti R. Investigations of hydrocortisone and fludrocortisone in the treatment of chronic fatigue syndrome. J Clin Endocrinol Metab (in press).
4 Leese G, Chattington P, Fraser W, Vora J, Edwards R, Williams G. Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome. J Clin Endocrinol Metab 1996; 81: 1867-70. [PubMed]
5 Baschetti R. Similarity of symptoms in chronic fatigue syndrome and Addison's disease. Eur J Clin Invest 1997; 27: 1061.
Sir--Anthony Cleare and co-workers1 report that the use of low-dose hydrocortisone (5 or 10 mg daily) is associated with substantial reductions in self-rated fatigue and disability in patients with CFS. Their regimen was not complicated by suppression of endogenous adrenal glucocorticoid secretion. McKenzie et al,2 however, obtained less impressive results with daily doses of 25-35 mg of hydrocortisone in CFS, and their doses led to endogenous adrenal glucocorticoid hyposecretion. These workers2 refer to Jefferies' report3 in which 371 patients were treated with 20 mg or less hydrocortisone daily in divided doses and at maximum intervals of 8 h. They summarized the findings of Jefferies as follows: "Low-dose glucocorticoid replacement, defined as 20 to 40 mg of hydrocortisone in divided daily doses, was felt to be safe, to cause no symptoms other than occasional gastric distress, and to benefit patients with chronic fatigue".
The dosages McKenzie, et al., used were larger than Jefferies recommended. Also, none of Jefferies patients were treated for CFS, hydrocortisone was used for up to 9 years, and patients withstood major surgical procedures and acute severe illnesses uneventfully without change in dosage.3 The findings suggest an adequate stress response.
The features of CFS and fibromyalgia overlap greatly,4 and these two conditions may well be different presentations of the same illness.4 Cortisol secretion is reduced in both CFS1,4 and fibromyalgia.4 Adrenal androgen secretion is as impaired in fibromyalgia as in CFS, as shown by reduced serum concentrations of dehydroepiandrosterone sulphate (DHEAS), and this decrease probably contributes to fatigue and pain in fibromyalgia.5 Serum DHEAS constitutes a more sensitive indicator of adrenocortical hypofunction than glucocorticoid secretion. Hydrocortisone at dosages of 20 mg daily (or even less) suppresses adrenal dehydroepiandrosterone secretion.3 These data implicate the beneficial effects of low doses of hydrocortisone in CFS as being attenuated by their suppressant effect on adrenal androgen secretion. The potential role of adrenocortical hypofunction in these often disabling conditions could be examined in a controlled trial of hydrocortisone in combination with DHEA supplementation in patients with CFS or fibromyalgia, or both.
*Patrick H Dessein, Edward A Shipton
*Rheumatology Unit, Milpark Hospital, Johannesburg 2109, Republic of South Africa; and Department of Anesthesiology, Baragwanath Hospital, Pain Relief and Research Unit, University of Witwatersrand, Johannesburg
1 Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial. Lancet 1999; 353: 455-58.
2 McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: results of a placebo controlled study of its efficacy and safety. JAMA 1998; 280: 1061-66. [PubMed]
3 Jefferies WM. Low-dose glucocorticoid therapy: an appraisal of its safety and mode of action in clinical disorders, including rheumatoid arthritis. Arch Intern Med 1967; 119: 265-78. [PubMed]
4 Buchwald D, Fibromyalgia and chronic fatigue syndrome: similarities and differences. Rheum Dis Clin North Am 1996; 22: 219-43. [PubMed]
5 Russell IJ. Neurochemical pathogenesis of fibromyalgia syndrome. J Musculoskeletal Pain 1996; 4: 61-92. [PubMed]
Sir--Although work such as that of Anthony Cleare and colleagues1 continues to improve our understanding about this disabling illness, I hope these workers can address several questions that remain after reading their report.
First, they reasonably postulate that the duration and dose of treatment could account for the disparities in therapeutic and adverse effects between their study and McKenzie and colleagues' trial.2 However, as demographic and illness factors affect prognosis, these variables also deserve comment. Compared with the McKenzie investigation, Cleare's study enrolled people with a shorter duration of illness, seemed to more stringently exclude those with psychiatric illness, and evaluated a smaller proportion of women. Such factors (protracted illness duration, concomitant psychiatric disease, and possibly female sex) may be related to a worse prognosis in CFS and could partly account for study differences.3 Indeed, the patients in the Cleare study with better pretreatment scores on the general health questionnaire (indicative of less psychiatric morbidity) were more likely to have responded. In this respect, were there other factors that predicted recovery?
Second, the accuracy of the assessment of adrenal axis suppression is an important methodological consideration. Cleare showed no evidence of adrenal axis suppression with the insulin suppression test, whereas McKenzie recorded quite a few patients with post-treatment adrenal suppression by use of the cortrosyn stimulation test. Though these two tests are equivalent in healthy populations, less is known about their comparability in those receiving steroid supplementation.4
Finally, I would welcome the investigators' response to William Jeffcoate's accompanying commentary5 that questions the validity of the use of the 24-h urinary free cortisol as a measure of cortisol. In the study, the post-treatment hydrocortisone group had a significantly higher 24-h urinary free cortisol than the placebo group; in part supporting a theory of relative adrenal insufficiency in CFS. However, Jeffcoate states 24-h urine cortisol is a poor measure of psychologic cortisol in those on supplementation. In view of Jeffcoate's concern, though the overall results of the study would still be valid, insight into the mechanism of response would become less apparent and necessitate a more complex model.
*Tom Rea, Dedra Buchwald
Box 359702, Department of General Medicine, University of Washington, Seattle, WA 98104, USA (e-mail:firstname.lastname@example.org)
1 Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized cross over trial. Lancet 1999; 353: 455-58.
2 McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA 1998; 280: 1061-66. [PubMed]
3 Joyce J, Hoptopf M, Wessley S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. QJM 1997; 90: 223-33. [PubMed]
4 Rasmuson S, Olsson T, Hagg E. A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 1996; 44: 151-56. [PubMed]
5 Jeffcoate WJ. Chronic fatigue syndrome and functional hypoadrenia--fighting vainly the old ennui. Lancet 1999; 353: 424-25.
Sir--In his commentary on the use of low doses of hydrocortisone as a possible treatment for CFS, William Jeffcoate1 states that the positive results obtained by Anthony Cleare and colleagues2 are more likely to exacerbate rather than settle differences among the medical profession about the cause and treatment of this controversial illness. Although most would accept that there will continue to be divergence of opinion about the role of physical and psychological factors in perpetuating CFS symptoms, there is, in fact, a growing consensus that neuroendocrine and neurotransmitter abnormalities could now form the basis for effective therapeutic intervention.
Trials such as that of Cleare and colleagues are undoubtedly helping to provide some answers, but I was surprised to find so few data for baseline endocrine assessments (i.e., insulin stress test, corticotrophin-releasing test, and measurement of urinary free cortisol). The fact that the mean urinary free cortisol at baseline was105 nmol per 24 h suggests that a large number of patients entering the trial had no laboratory evidence of hypocortisolaemia. Was this, in fact, the case? If so, and patients without hypocortisolaemia also showed a reduction in fatigue and disability, then we should seriously question whether hypocortisolaemia is an important factor in symptom production. An alternative explanation is that the mode of action of the hydrocortisone is independent of any hypocortisolaemia, and its main effect is on some other pathological abnormality--possibly even the way in which changes in immunological indices, including immunoreactivation, have been correlated with particular features of disease symptomatology.3
We now need to address whether the benefits of low-dose hydrocortisone can be sustained over a much longer time (with or without the continued use of the drug) and whether there is evidence of suppression of endogenous cortisol production when hydrocortisone treatment continues beyond 1 month. Further clarification is also required as to the extent hypocortisolaemia and adrenal atrophy4 could be contributing to symptoms and disability in CFS.
Friars Cottage Surgery, Chalford Hill, Gloucestershire GL6 8EH, UK
1 Jeffcoate WJ. Chronic fatigue syndrome and functional hypoadrenia--fighting vainly the old ennui. Lancet 1999; 353: 424-25.
2 Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial. Lancet 1999; 353: 455-58.
3 Hassan IS, Bannister BA, Akbar A, Weir W, Bofill M. A study of the immunology of the chronic fatigue syndrome: correlation of immunologic parameters to health dysfunction. Clin Immunol Immunopathol 1998; 87: 60-67. [PubMed]
4 Teh J, Scott L, Dinan E, Sohaib A, Reznek RH. Adrenal size in chronic fatigue syndrome. Radiology 1998; 209 (suppl): S411-12.
Sir--Contrary to Riccardo Baschetti's assertion, we did not advocate any particular therapy. Nevertheless, cognitive behavioral therapy is a proven, replicated, safe, and lasting treatment for CFS.1 Our reasons for remaining cautious about hydrocortisone relate to the short-term nature of our trial, the lack of adequate replication, the possibility of side-effects in longer term use,2 and the availability of proven alternatives. Patrick Dessein and Edward Shipton suggest that results from the Jefferies' 1967 study endorse the safety of a 20-40 mg daily dose of hydrocortisone. However, in view of McKenzie and co-workers' careful study,2 we would be reluctant to expose our patients to the real risk of adrenal insufficiency in exchange for the slight gains reported.
Why did our results differ from those of McKenzie and colleagues? In addition to the different dose and duration of treatment, Tom Rea and Dedra Buchwald are correct to point out the different sample characteristics in the studies. However, in our sample only lower pretreatment GHQ scores affected outcome. With respect to the other variables Rea and Buchwald mention, responders (mean age 36 years) were the same age as non-responders (35 years), and the proportion of female responders (seven of 20) was no less than for men (two of 12).
The insulin stress test is the gold standard for assessment of hypothalamic-pituitary-adrenal (HPA) axis integrity as a whole. Since hypothalamic or pituitary responses might be altered in CFS,3 we chose this test in preference to a direct adrenal stimulus such as cortrosyn. We acknowledge that urinary free cortisol is a crude measure of adrenal function, but our main aim was to check that active treatment did result in a return to normal of the previously reported lower urinary free cortisol in CFS.
Charles Shepherd is correct to point out that our patients did not have frank hydrocortisolism; this diagnosis would exclude the diagnosis of CFS according to the US Centers for Disease Control and Prevention. We postulate that it is a change relative to the pre-illness state that is relevant, and that reversing the lowered cortisol concentration reduces mean fatigue values. However, hydrocortisone might act via another mechanism--e.g., through effects on brain serotonin.4
The suggestion that DHEA/DHEAS may also be important requires further work, though not all studies report reductions in CFS and some show an increase. With respect to Baschetti's suggestion, a recently published randomized controlled trial has shown that fludrocortisone is ineffective.5
The cause of CFS is likely to be multifactorial, with impaired HPA axis function a factor in some cases. Furthermore, HPA axis changes themselves might have several components. Rather than ill-concealed espousal, exploring these factors could increase our understanding. Thus, perhaps we should evaluate the contributions of sleep disturbance, physical inactivity, disruption of circadian rhythm, psychiatric illness, pain, and the effects of past or present medication to the final HPA axis disturbance. Prospective cohort studies of patients at different stages of the illness (i.e., during acute, sub-acute, and chronic fatigue) could also help. Not all studies find hypocortisolism in CFS, and it is perhaps the heterogeneity of these features in CFS that underlie the divergent findings seen so far.
*Anthony J Cleare, Veronica O'Keane, John P Miell
Department of Psychological Medicine, Guy's, Kings and St Thomas' School of Medicine, London SE5 8AZ, UK (e-mail:email@example.com)
1 Wessely S, Hotopf M, Sharpe M. Chronic fatigue and chronic fatigue syndromes. Oxford: Oxford University Press, 1998.
2 McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone treatment of chronic fatigue syndrome: results of a placebo controlled study of its efficacy and safety. JAMA 1998; 280: 1061-66. [PubMed]
3 Demitrack M, Neuroendocrine correlates of chronic fatigue syndrome: a brief review. J Psychiatr Res 1997; 31: 69-82. [PubMed]
4 Cleare AJ, Bearn J, Allain T, et al. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord 1995; 35: 283-89. [PubMed]
5 Peterson PK, Pheley A, Schr oeppel J, et al. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med 1998; 158: 908-14. [PubMed]
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