Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial, 1999, Cleare, Wessely et al

Hutan

Hutan

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https://pubmed.ncbi.nlm.nih.gov/9989716/
A J Cleare 1, E Heap, G S Malhi, S Wessely, V O'Keane, J Miell

Abstract
Background: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment.

Methods: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat.

Findings: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo.

Interpretation: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.
 
I think this old paper is interesting for a number of reasons. I posted it because of the current interest in hydrocortisone as a treatment for ME/CFS and Long Covid by Dr Nath and Dr Yamamura.

Wessely is an author. Is interesting to read the sorts of ideas he was willing to put his name to in 1999. The introduction starts:
Chronic fatigue syndrome affects up to 2·6% of people who attend primary care in the UK
1 and is also encountered in many medical specialties. Patients with chronic fatigue syndrome have a poor outcome: only 3% of patients spontaneously recover at 18 months of follow-up.2.


About 50% of patients with chronic fatigue syndrome have co-morbid major depression.3However, the results from placebo-controlled trials of antidepressants differ; some studies show moderate efficacy,4 whereas others do not.5 Controlled studies suggest that graded exercise therapy 6 and cognitive behavioural therapy 7, 8 are effective treatments, but are relatively expensive and not widely available because of a shortage of adequately trained therapists. In addition, many patients are wary of the rationale behind these treatments. Alternative effective treatments for chronic fatigue syndrome are needed.
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suggesting the criteria for a diagnosis of CFS is pretty wide, and it was known that natural recovery rates weren't great.


I haven't seen good evidence for the idea that people with ME/CFS have low cortisol levels, but that may not rule out a good response to the anti-inflammatory effect of hydrocortisone. These authors seem to predicate the whole HPA axis hypothesis on the idea of low cortisol:
Studies of the hypothalamo-pituitary adrenal (HPA) axis in chronic fatigue syndrome show a mild hypocortisolism of central origin, in contrast to the hypercortisolism of major depression.9, 10, 11, 12 Given the overlap between the symptoms of Addison's disease and chronic fatigue syndrome, Demitrack and colleagues 9 postulated that this hypocortisolism may be important in the mediation of central fatigue.9 There are suggestions that this underactivity of the HPA axis could result from factors that are secondary to the primary aetiology of chronic fatigue syndrome, such as sleep disturbance.13
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We included patients who fulfilled both international consensus criteria for chronic fatigue syndrome
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That's the Oxford and Fukuda criteria.


Finally, we looked at the effect of hydrocortisone on the HPA axis compared with placebo by paired t tests.
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. The participants' levels of cortisol were normal throughout, but did increase with the treatment.
Mean urinary free cortisol at baseline was 105 (84–127; reference range for laboratory 30–250 nmol per 24 h). The mean value after hydrocortisone was 141 (100–181) nmol per 24 h and was 97 (76–119) nmol per 24 h after placebo (95% CI for difference 14 to 74, p=0·006).
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They mention another study of hydrocortisone in CFS, with higher doses:
In their controlled study of hydrocortisone in chronic fatigue syndrome, McKenzie and colleagues
26 used 25–35 mg doses of hydrocortisone and found a slight therapeutic effect on some measures and evidence of substantial adrenal suppression. They concluded that the risks of hydrocortisone outweighed the benefits at this high dose, but did not rule out potential benefits from different low-dose regimens.
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Aside from the selection of patients (did they have ME/CFS?), the study looks to have been well done, with good blinding and no dropouts.

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We also do not know whether any treatment effects persist; indeed, we found a rapid attenuation of therapeutic effect when patients were switched to placebo.
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Effects were short-lived.

The clinical relevance of the effects of hydrocortisone are not known. Most of our patients did not enter the trial, because of psychiatric co-morbidity or concomitant medication. The effects of hydrocortisone on disability are less than those seen after cognitive behavioural therapy, although this greater improvement takes up to 12 months.
7 With cognitive behavioural therapy, fatigue is reduced less dramatically than disability,
7 which suggests that such therapy is effective at changing the behavioural and cognitive factors that contribute to the generation and perpetuation of avoidance, disability, and sleep disturbance, but that subjective fatigue may be related to factors modified more indirectly by therapy. This explanation would be consistent with our suggestion that fatigue is perpetuated, at least in some patients, by low concentrations of cortisol.
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The result did suggest that a significant minority of the patients did well with the hydrocortisone treatment, although the small study size and the poor criteria limit the conclusions that can be drawn. It will be quite ironic if the benefits did suggest something about the pathology of the illness, but that these authors failed to act on it because of their preoccupation with the benefits of CBT and GET.
 
Hutan said:
That's the Oxford and Fukuda criteria.
The participants' levels of cortisol were normal throughout, but did increase with the treatment.
They mention another study of hydrocortisone in CFS, with higher doses:
Aside from the selection of patients (did they have ME/CFS?), the study looks to have been well done, with good blinding and no dropouts.
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Straus? one was NOT low dose but 25mgs I believe, leading to suppression.
I have tracked this since late 1990s.

In 1999 my son (aged 15) diagnosed with ME 1997, was given a low dose trial of this by private ex NHS consultatnt paediatrician. (1 month) as a 'test'.
An albeit short course but symptom alleviation and improvement after 4 days with positive outcome for the duration but crashed 4 days after stopped.

The course and trial was repeated in 2000, ( 3 months). again not a long period, and again a positive outcome; after 4 days improved and crashed 4 days after discontinuance.
Soon after he also suffered very severe hypoglycaemia low blood sugar whilst in hospital for tonsillectomy. and refused Low dose Hydrocortisone.

I asked for tests for adrenal function but they only did the 250 g synacthen test (which will not show insufficiency) especially with the high dose 250 g synacthen I understood. ( Not recommended one for suspected insufficiency)

'Low dose (1 microgram) Synacthen test for suspected adrenal insufficiencyhttp://www.pathology.leedsth.nhs.uk/dnn_bilm/Investigationprotocols/Synacthentestsshortlong/LowDose1μgShortSynacthenTest.aspxIndicationThis is performed for the investigation of adrenal insufficiency.
The standard Synacthen test utilising 250 g Synacthen has been used successfully for many years but it is now clear that 250 g represents approximately 500 fold greater dose than is required for maximal adrenal response.
The cortisol response to 250 g shows a steady increase for several hours, whereas the low dose which utilises 1microgram demonstrates a rise and fall within 60 min.

This request (and involvement with private consultant) caused the local doctor and team to view me as an FII mother....... as my friend's son was Panorama Child X on Panorama, I retreated.

The synacthen test itself had a marked positive effect for about 36 hours duration after it - though son had been too unwell to get to hospital for it at 9am and had to delay for 2 hours till 11 before it.

An adult female inpatient also had the synacthen test ( the SA wife of a friend of mine form Norfolk) and it also had a marked positive effect after on an her as an inpatient at The Romford Queens ME unit under Professor Findlay-
It was repeated and the same thing occurred.............

I went to the Fatigue 2001 Conference and spoke with both Wessley and Cleare. Both seemed unimpressed and disinterested about my observations and declined to discuss as did Leslie Findlay.
They said the synacthen test would not do this and relieve symptoms after.

I later spoke with Professor Ted Dinan who also was involved in this approach. By the he had moved to Ireland. He was extremely helpful.


Roll on to 2006, and my husband, also diagnosed with ME had private thyroid and adrenal salivary tests organsied by Dr Peatfield.

This indicated adrenal function (not Addisons but secondary failure and insufficiency) near collapse with subsequent thyroid poor drive from adrenals and hypo function.
He too was given synacthen test but 'high version' which they suggested showed a 'normal' response.
He started gently with nutri adrenal extract to prime him and after about six months low dose hydrocortisone which he is on still ( supported prescribed by GP).

Both had had allergy inflammatory symptoms which disappeared. Husband still on this regime 15 years later. No allergy no psoriasis etc,
 
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There are suggestions that this underactivity of the HPA axis could result from factors that are secondary to the primary aetiology of chronic fatigue syndrome, such as sleep disturbance.13
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So he was saying that there may be a physical problem but it is secondary to the deconditioning and exercise phobia that perpetuates CFS.

At the time, this sudden lurch of Wessely and White to doing physical research was because so many physical abnormalities were being found by the small trials ME researchers were doing. Years later they were still being held up as proof that they did not believe CFS was all in the mind.

It was a pre-emptive strike to make sure they stayed the experts and could deflect all findings as a result of their theories, not instead.

It is the same now when our claims of harm are being rewritten as the normal effect of the process of increasing fitness.
 
Mithriel said:
So he was saying that there may be a physical problem but it is secondary to the deconditioning and exercise phobia that perpetuates CFS.

At the time, this sudden lurch of Wessely and White to doing physical research was because so many physical abnormalities were being found by the small trials ME researchers were doing. Years later they were still being held up as proof that they did not believe CFS was all in the mind.

It was a pre-emptive strike to make sure they stayed the experts and could deflect all findings as a result of their theories, not instead.

It is the same now when our claims of harm are being rewritten as the normal effect of the process of increasing fitness.
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The HPA axis is key as the hypothalamus can be damaged by virus like ENV I was told.
This can lead to lack of drive of the axis.
It was explained to us that the glands (thyroid and adrenal) can function poorly- low dose (subclinical ) low dose hydrocortisone supports the adrenal function allowing better thyroid function.
https://me-ireland.org/scientific/5.htm
Abnormal glandular functions & Abnormal HPA axis (Hypothalmus Pituary Adrenal axis)


(a) Shrunken adrenal glands and low hormone output

(b) Abnormal HPA axis (Hypothalmus Pituary Adrenal axis)

(a) Shrunken adrenal glands and low hormone output.

The result of excessive pressure or strain on the adrenal glands over time.
  • Scott LV, The J, Reznek R, Martin A, Sohaib A, Dinan TG. 1999 Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Endocrinology 24:759-768.
  • "There are striking similarities between chronic fatigue syndrome and Addison's disease, which share 26 features, including all of the neuropsychological symptoms"
    Canadian Medical Association Journal     http://www.cma.ca/cmaj/vol-160/issue-5/0636a.htm
  • Professor Ted Dinan and Dr. Lucinda Scott, St. Batholomew's Hospital, London. Radiology, 1998, 209 (supl) 411-412.

  • De Becker P, Roeykens J, Reynders M, Mc Gregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 2000;160:3270-3277

  • Bell, David S., M.D. The Doctor’s Guide to Chronic Fatigue Syndrome. 1993 Addison Wesley, pp. 115.

  • Shrunken adrenal glands confirmed by Research at St. James Hospital, Dublin, Ireland, in 2001.

  • Demitrack M, et al. Evidence for impaired activation of the hypothalamic-adrenal-pituitary axis in patients with CFS. J Clin Endocrin Metab 1991;73:1224-34.

  • McKenzie R, et al. Low-dose hydrocortisone for treatment of CFS. JAMA1998;280:1061-66.

  • Scott LV, Dinan TG: Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affect Disord 1998, 47:49-54.

  • Scott LV, et al. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology 1999;24:759-68.

  • Teitelbaum, Jacob, M.D., From Fatigued to Fantastic: A Manual for Moving Beyond Chronic Fatigue and Fibromyalgia. 1995 Deva Press, pp.36.


    The theories of Alfred J Plechner D.V.M. state that low amounts of free adrenal cortisone combined with too much adrenal estrogen and the subsequent binding of thyroid hormones by estrogen from the adrenals can contribute to a wide range of health related problems has support from other experts. The Great Smokies Diagnostic Laboratory (www.gsdl.com) states in their Adrenal Cortex Stress Profile that "Researchers have proposed that CFS is actually a disease of the hypothalamic-pituitary-adrenal axis. Unlike ordinary fatigue, however, CFS is typically characterized by low free cortisol levels and adrenal insufficiency. Raising cortisol levels by even small amounts has been found to improve unexplained fatigue symptoms in many CFS patients."
  • Demitrack MA et al. J Clin Endocrinol Metab 1991; 73: 1224

  • Demitrack, Mark A., Janet K. Dale, Stephen E. Straus et al.; "Evidence for the Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients With Chronic Fatigue Syndrome"; Journal of Clinical Endocrinology and Metabolism, December 1991.

  • NEUROENDOCRINE STUDIES IN CHRONIC FATIGUE SYMPTOMS
    Dr Anthony J Cleare, Senior Lecturer in Psychological Medicine, Guy's King's and St Thomas' school of Medicine, London.

  • Cleare AJ. The neuroendocrinology of chronic fatigue syndrome.Endocr Rev.2003; 24:236–52.25.
  • Jason LA, Sorenson M, Porter N, Belkairous N (2010), "An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome", Neuroscience & Medicine, 2011, 2, 14-27, PMID: 21892413
  • Cleare AJ, O'Keane V, Miell J. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf).2001; 55:113–9
  • McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome : a randomized controlled trial. JAMA.1998;280:1061–6
  • Cleare AJ, Heap E, Malhi G S, et al. Low-dose hydrocortisone in chronic fatigue syndrome : a randomised cross over trial.Lancet.1999;353:455–8
 
As a former clinician having had several clients with secondary psychiatric disorders arising from primary endocrine disorder. I know it is a very difficult balancing act when it comes to adding exogenous hormones if the underlying pathological process has not been identified (like in ME). There is a a lot of interconnection with feedback loops and receptors with other endocrine systems, eg adrenal, thyroid, sex hormones.

One big problem is the risk of prescribing glucocorticoids which humans need for their stress response to trauma and infection. It is hard to get the dose right and then if someone needs surgery in an emergency it can be catastrophic and lethal. I agree Addison’s has many symptoms shared with ME but playing with hydrocortisone would need to be supervised by an endocrinologist, rather than a psychiatrist….

Even high dose topical steroids can cause problems with adrenal function and the feedback loops to the hypothalamus and pituitary and clinicians are always conscious of this when using steroids.

I would hazard a guess that this is why NICE and CDC added the instruction not to use glucocorticoids for the treatment of ME/CFS.

However, it looks like the imaging studies for adrenal size stalled. Maybe that is a potential area of exploration.
 
The CDC paper I shared above was a good RCT. It was only for 3 months but adrenal suppression was activated Steroids are well know to improve one’s sense of well being but the conclusions were minimal therapeutic benefit over risk but did state if new advances occurred it might be feasible. There were side effects too like weight gain etc.

There is a useful review of various low dose cortisol studies and clinicians experience here. https://www.healthrising.org/blog/2...tisone-fibromyalgia-chronic-fatigue-syndrome/. Dr Myhill appears to only use it on patients with proven adrenal deficiency. It would depend on the clinician’s confidence to prescribe this with full explanation of the risks but also whether the client needs ongoing blood tests to test for adrenal suppression, which would need to be ongoing, then there is cost/benefit factor for either the client or the health service.

Correction: the JAMA paper
 
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hibiscuswahine said:
The CDC paper I shared above was a good RCT. It was only for 3 months but adrenal suppression was activated Steroids are well know to improve one’s sense of well being but the conclusions were minimal therapeutic benefit over risk but did state if new advances occurred it might be feasible. There were side effects too like weight gain etc.

There is a useful review of various low dose cortisol studies and clinicians experience here. https://www.healthrising.org/blog/2...tisone-fibromyalgia-chronic-fatigue-syndrome/. Dr Myhill appears to only use it on patients with proven adrenal deficiency. It would depend on the clinician’s confidence to prescribe this with full explanation of the risks but also whether the client needs ongoing blood tests to test for adrenal suppression, which would need to be ongoing, then there is cost/benefit factor for either the client or the health service.

Correction: the JAMA paper
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Saliva tests can be used, though I believe there is some issue with comparing reference ranges in the various labs who offer this and that is important when testing for subtle changes or low adrenal levels - insufficiency.
NHS use saliva tests for Cushings which looks for high levels.

Interestingly, husband had seasonal asthma which was treated with oral steroids inhalers.
He always noticed symptom exacerbation when he stopped using them, not asthma but severe fatigue and other problems.
After he received an NHS ME diagnosis from out local specialist service, 2006 he looked into private medical tests and support and started low dose hydrocortisone.
Asthma has never reoccurred nor has psoriasis not any other allergy symptoms.

The asthma inhalers in effect deliver low dose steroids and children particularly are known to suffer problems when they take inhalers regularly and stop suddenly sometimes.
The local Endocrinolgy clinic do not support his use of hydrocortisone but say they are not worried about it!
GP has a much more pragmatic approach and prescribes as the Medicines and Health Regulatory Authority actually recommend low dose hydrocortisone for adrenal insufficiency.
 
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