Low-Dose Hydrocortisone for Treatment of Chronic Fatigue Syndrome - A Randomized Controlled Trial, 1998, McKenzie et al

[Andy]

Abstract

Context.— Chronic fatigue syndrome (CFS) is associated with a dysregulated hypothalamic–pituitary adrenal axis and hypocortisolemia.

Objective.— To evaluate the efficacy and safety of low-dose oral hydrocortisone as a treatment for CFS.

Design.— A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996.

Setting.— A single-center study in a tertiary care research institution.

Patients.— A total of 56 women and 14 men aged 18 to 55 years who met the 1988 Centers for Disease Control and Prevention case criteria for CFS and who withheld concomitant treatment with other medications.

Intervention.— Oral hydrocortisone, 13 mg/m2 of body surface area every morning and 3 mg/m2 every afternoon, or placebo, for approximately 12 weeks.

Main Outcome Measures.— A global Wellness scale and other self-rating instruments were completed repeatedly before and during treatment. Resting and cosyntropin-stimulated cortisol levels were obtained before and at the end of treatment. Patients recorded adverse effects on a checklist.

Results.— The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P=.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales. Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001).

Conclusions.— Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.

Open access, https://jamanetwork.com/journals/jama/fullarticle/188004

 

[Hutan]

There really wasn't much benefit:

In a randomized, double-blind, placebo-controlled trial in CFS, low-dose hydrocortisone treatment was associated with improvement in symptoms as measured by change in Wellness scores. This is the first such study, to our knowledge, to demonstrate improvement with a drug treatment of CFS.

Significant therapeutic benefit, however, was not evident by changes in other self-rating scales. More important, what little improvement might be attributable to hydrocortisone treatment was achieved at the expense of significant adrenal suppression.

We found that low-dose hydrocortisone treatment has mild side effects (Table 3) and affords minimal therapeutic benefit for CFS, but significantly suppresses adrenal responsiveness.

Given it was only the global wellbeing assessment that showed any difference, and then only a small benefit on average, it's likely that the benefit was mostly just the benefit that even healthy people can feel when given corticosteroids:

Many people enjoy the benefits of prednisone and other corticosteroids when they elevate mood, creating a sense of euphoria and excessive energy.

On the HPA axis hypothesis: (the cortisol levels in this sample were entirely normal - both morning cortisol and after ACTH. The values are given but no comment is made about their normality)

Fourth, the data bear importantly on the basic hypothesis under which this study was undertaken, namely that CFS symptoms are perpetuated through suboptimal activity of the HPA axis.15That the basal and stimulated-cortisol levels did not correlate with illness severity in this study (data not shown), nor were they predictive of clinical improvement or response to treatment, argue against the hypothesis. The fact that there was evidence of symptomatic benefit in hydrocortisone recipients, however, is concordant with this hypothesis, and yet the limited benefit indicates that mere supplementation of cortisol is not sufficient. It is possible that a more salutary effect would derive from a different low-dose regimen, or from specific supplementation of corticotropin-releasing hormone or pharmacologic augmentation of its release, were these latter options to become feasible.33,34

(it's odd that people are still bleating on about the HPA axis nearly 25 years after this study, and odder still that people keep trying to measure cortisol in people with ME/CFS when they keep finding nothing particularly remarkable.

 

[Wyva]

There really wasn't much benefit:





Given it was only the global wellbeing assessment that showed any difference, and then only a small benefit on average, it's likely that the benefit was mostly just that that even healthy people can feel when given corticosteroids:



On the HPA axis hypothesis: (the cortisol levels in this sample were entirely normal - both morning cortisol and after ACTH. The values are given but no comment is made about their normality)


(it's odd that people are still bleating on about the HPA axis nearly 25 years after this study, and odder still that people keep trying to measure cortisol in people with ME/CFS when they keep finding nothing particularly remarkable.

Thanks for this @Andy and @Hutan .

My cortisol level (and some other endocrine values) will be checked on Monday at Semmelweis University. It was my GP's idea but also the endocrinologist at the University offered me to do these tests, admittedly because that's the only thing he can do about me.

I have this bit of a fear in me that my cortisol level will be a bit low and then they'll recommend taking hydrocortisone to me based on that. (The same way everyone wanted to pin my disease on my very subclinical hypothyroidism, that is so subclinical that it is often even normal.)

And I'm really really not sure I would want to take hydrocortisone just like that, so I'm gathering this info you are sharing here. CDC is a also a bit of a help, on their page about ME/CFS they write:

Patients with ME/CFS commonly report physical or emotional stress before they become ill. Some patients with ME/CFS have lower levels of cortisol than healthy people, but their cortisol levels are still within the normal range. Therefore, doctors cannot use cortisol levels to diagnose or treat ME/CFS.​

 

[Suffolkres]

There really wasn't much benefit:





Given it was only the global wellbeing assessment that showed any difference, and then only a small benefit on average, it's likely that the benefit was mostly just the benefit that even healthy people can feel when given corticosteroids:



On the HPA axis hypothesis: (the cortisol levels in this sample were entirely normal - both morning cortisol and after ACTH. The values are given but no comment is made about their normality)


(it's odd that people are still bleating on about the HPA axis nearly 25 years after this study, and odder still that people keep trying to measure cortisol in people with ME/CFS when they keep finding nothing particularly remarkable.

Depends on what test you use and whether the correct test values are used to show the subclinical irregularities is my understanding....

Also whether the medication is the correct type ( not prednisolone) and correct low dosage...low being under 15- 20 mg of hydrocortisone.

MHRA recognise adrenal and thyroid 'insufficiency' most often not picked up by their 'gold standard' Synathen Test and high dose testing regime ......

 

[perchance dreamer]

I take 5 MG of prescribed hydrocortisone once a day when I wake up and do feel a little increased energy without noticeable side effects.

 

[Hutan]

Depends on what test you use and whether the correct test values are used to show the subclinical irregularities is my understanding....

MHRA recognise adrenal and thyroid 'insufficiency' most often not picked up by their 'gold standard' Synathen Test and high dose testing regime ......

Can you elaborate @Suffolkres?

 

[Amw66]

I take 5 MG of prescribed hydrocortisone once a day when I wake up and do feel a little increased energy without noticeable side effects.

My daughter worked up to 7.5mg and felt increasingly awful with side effects. If there's a sweet spot it eluded her.

Cortisol was marginally low , ( and probably explained by sleep shift) but I think the endocrinologist who took her on when she left paediatrics felt he should really be seen to be doing something , and at that point we didn't know too much about ME.

 

[Hutan]

I was given an ACTH test, also probably because the specialist felt he should do one test to show he had tried something. My morning cortisol level and ACTH response were normal.

 

[Milo]

Early on in my disease, I felt absolutely shitty, and I begged my doctor to do a Cortisol test. I did the AM and not sure if I did the PM that particular time, but the AM cortisol came back flagged at a critical low number, to the point where the lab phoned my doctor instead of just faxing the results. It was the Friday before Christmas holidays, and so I could not be seen by a specialist, but my dr consulted with one and it was decided to start me on Cortef until I could see an endo.

The Cortef did not touch me one bit. If I remember well I had 20mg in the morning and 10 at night but I could be wrong, it was a while ago. If did not do anything for me. A subsequent AM Cortisol while I was on Cortef rendered a still flagged very low result albeit marginally better. I submitted to the ACTH challenge test which ruled out Addison's (not remembering the sequence, whether I had stopped Cortef before the test or now) and did tapered Cortef, which was very difficult for a few months, as expected. That memory of the tapering is enough for me to avoid at all cost getting back on steroids, if at all possible.

Further testing months later show a low AM Cortisol, this time not extreme.

Edit to add: We have stopped testing AM Cortisol, just like we are not testing ANA despite a !:1280 titer and homogenous pattern. Problem solved .

 

[bobbler]

There really wasn't much benefit:





Given it was only the global wellbeing assessment that showed any difference, and then only a small benefit on average, it's likely that the benefit was mostly just the benefit that even healthy people can feel when given corticosteroids:



On the HPA axis hypothesis: (the cortisol levels in this sample were entirely normal - both morning cortisol and after ACTH. The values are given but no comment is made about their normality)


(it's odd that people are still bleating on about the HPA axis nearly 25 years after this study, and odder still that people keep trying to measure cortisol in people with ME/CFS when they keep finding nothing particularly remarkable.

So this seems to be from 1998, which to me underlines how if there were some sort of 'organised' function of going through the logical possibilities needing to be narrowed down and finessed over that period of time we all might be in a very different position. Part of it is obviously politics, and agree it gives me the heebeegeebees when I see the HPA axis getting used in a twisted way recently to sell what is really v old school stuff (back in the old days it was 'relaxation classes' being sold) about sympathetic system.

I don't know whether following this there were any studies that (and it is hindsight as we know more about PEM, the pushing over baseline a bit too much over months leading to crash etc) used different timeframes of measurement - whether the drug was taken for that time length or not, as the issue for ME/CFS is the short term fix making long-term worse. Or whether anyone built on it with better methodologies and working out quite what it is they are actually needing to measure (or even ask about) in people with ME/CFS to determine whether something is better or not.

That last one is a crux really - because if rather than 'skipping to the end' and being able to use lots of words to justify why a non-finding is maybe a finding, if only we'd had 20yrs of discussion about how given we don't know whether/what it is systems, cells, balances, body parts involved and how there is obvious short term triggers and longer term snowball effects we need to start working out what some of these 'measures' might want to be. Which would include timings, e.g. not just snapshot blood tests for certain things every so often now we now about things being pulsatory and interactive reactions etc. Heck some of these things it could be that they are useful for crashes or certain situations but not others (but that would require different methodology again)

And goodness knows what we really should be looking for when it comes to the short-term non-biology-based 'how do we measure whether someone is feeling better or worse' other than taking a group of switched-on patients who have had it for a while and ergo have been observing their own bodies for many years in a way scientists couldn't hope to catch up with without being ears-open to the intricacies of that.

Anyway I'm almost less bothered about the what - it may be part of the solution for some or not - just finding it interesting historically that this might've been an obvious one to rule in or out in a quite specific way, and imagine there were lots of other things and if there was a failure for this to 'take flight' what is behind that and what messages it gives for how the research planning/strategy process works when you have important conditions cropping up like this. I hope that the PSP/Lind thing with the short term 'helpful possible interim treatments' mission has a really careful planning approach to ensure this is gone about well this time.

 

[Suffolkres]

Can you elaborate @Suffolkres?

I will try and find their paper for you.

 

[ukxmrv]

My cortisol levels are consistently low in the mornings and rise in the evenings (but never high). This is been tested by bloods and saliva a few times over the decades. My low morning cortisol was low even when I was trying to work full time and getting up at 7.30am.
On the short synacten test the response has always been blunted. It's never been low enough for a dx of Addison's.

I feel better on Hydrocortisone supplements even at 5mg. The good effects include a visible change to the swelling in my face and body. As an example rather than getting the moon face side effect I get the opposite and my jaw line and cheek bones appear again and my ankles lose their puffiness.

 

[bobbler]

The following para is interesting:

"Efforts to identify causative factors in CFS are evolving as hypotheses are generated and tested. In the early 1980s it was speculated that persisting Epstein-Barr virus infection sustains the symptoms of CFS.9 That notion was rejected after careful epidemiologic and virologic studies and the negative outcome of a placebo-controlled trial of acyclovir.10,11 While a viral origin of CFS now seems remote, other hypotheses continue to be examined. A substantial body of work, for example, indicates subtle alterations in immune function affecting the numbers and activity of natural killer cells and various T-cell populations.12-14"

A close relative of mine had the same EBV at the same time as me, but happens to be on acyclovir back then I think for another condition. Hard to compare 'outcomes' between us though because of course they've got other comorbidities and things that affected health since and before that, but I always wondered if they have what I have (but that would be intrusive to ask Qs enough to be sure, you don't know how people suffer because aspects of this are so embarrasing frowned upon things like not being able to get up and not be late for something, sleep-related has so much judgement etc and to say 'but less bad' because of course for me if I'd been able to avoid certain situations I wouldn't have become severe etc)

And the last line relevant for me too as I had a condition to do with t-cells

To think they were already down these lines in 1980s I can't help but feel intrigued how much of a part funding, technology/techniques/knowledge differences from now to then, politics, etc played a part. But also where did these as an approx list of what angles did they try and what did they find were culdesacs/did research get curtailed or not be enough for these did they end up?

 

[LarsSG]

In the early 1980s it was speculated that persisting Epstein-Barr virus infection sustains the symptoms of CFS.9 That notion was rejected after careful epidemiologic and virologic studies and the negative outcome of a placebo-controlled trial of acyclovir.

Acyclovir doesn't even work for acute EBV! It's funny/depressing how we keep ruling things out based on flimsy evidence and then coming back around to them years later (e.g. it's not autoimmune because rituximab doesn't help, etc).

 

[Sbag]

There was a post by the ME Association about low cortisol and it was discussed at a conference last week.

https://meassociation.org.uk/2022/0...ormone-predicts-long-covid-in-study-cortisol/

Bloomberg article https://www.bloomberg.com/news/arti...n-stress-hormone-predicts-long-covid-in-study

 

[bobbler]

Acyclovir doesn't even work for acute EBV! It's funny/depressing how we keep ruling things out based on flimsy evidence and then coming back around to them years later (e.g. it's not autoimmune because rituximab doesn't help, etc).

Yes in a sense I can see why certain things can be circular because if there are different types (of either ME/CFS or indeed a medication or 'the regime' of it) you can see how things can cycle round where there is good reason due to a development.

But I like the fact that whilst this is historical for hydrocortisone we've also got discussion of these other things in its literature so you can sort of see the 'social history/history of science' or to be more precise 'history of the psychology or methodology of scientific discovery' (or something) aspect of it.

A lot points to methodology yet again, and the same measures that are useful and longitudinal follow-up etc. Even with EBV - which just as a layperson I believe might be seen as 'less variable/black box than ME' or at least on the 'there is a virus' front - how on earth they'd unpick what would be a result or non-result I don't quite know unless the impact was mind-blowing levels of efficacy, because what are you looking at as a measure, what else affects it comorbidity or situation-wise, not to mention that we now know it's only a small proportion who tend to be unlucky and have a really bad run of it so what sample could be big enough to be sure you're representative of that 'unknown'.

On the logic side I'm intrigued because whilst I relate acyclovir to other illnesses and diseases even know I couldn't be sure of a guess that said it definitely would or wouldn't help 'some' with ME/CFS either way which shows what a state information collection is in. And how undermining the lack of clinics with proper medics who followed-up over long term is for that. My relative can't have been the only one who was on acyclovir for something long-term, if it is common enough then since 1980 (havin said that I thought it came out in the 90s) then like rituximab we might have had a few anecdotals EDIT*: going through such ME clinics who might have seen whether those who took or started taking acyclovir suddenly seemed to change course on their ME. ie started noticing patterns in groups across these things working in certain 'types' more than others to inform better research.

Indeed, it's just a shame that small studies didn't channel into paths getting properly looked into - to an extent we could look back and see if something had significantly changed in knowledge or methods available to know whether an 'in or out' might have changed.

 

[bobbler]

OK had a proper-ish read through within my capabilities today. They did a synacthen test at the beginning and end which is in the adverse events section. They put bits in the literature review/intro about theories on blunted cortisol response in CFS. But they don't seem to have noted - unless I've missed it which I might have with my scanning - whether all participants showed the 'blunted response' in those synacthen tests at the beginning?

 

[Hutan]

They did a synacthen test at the beginning and end which is in the adverse events section. They put bits in the literature review/intro about theories on blunted cortisol response in CFS. But they don't seem to have noted - unless I've missed it which I might have with my scanning - whether all participants showed the 'blunted response' in those synacthen tests at the beginning?

On the HPA axis hypothesis: (the cortisol levels in this sample were entirely normal - both morning cortisol and after ACTH. The values are given but no comment is made about their normality)

Table 2 gives the baseline morning (resting) and ACTH response (stimulated) values (the first column is for the treated group and the second column is for the control group). It is these that I noted are entirely normal. To be clear, the cortisol levels and response to an ACTH test given in nmol/L were completely normal in the people with CFS in this study.




Morning cortisol (the study samples had means of 425 and 397 nmol/L)

Normal values for a blood sample taken at 8 in the morning are 5 to 25 mcg/dL or 140 to 690 nmol/L.

Normal values depend on the time of day and the clinical context. Normal ranges may vary slightly among different laboratories.

Cortisol in ACTH test (the study samples had means of 877 and 825 nmol/L)

The normal cortisol response 30 or 60 minutes after cosyntropin (ACTH[1–24]) is considered to be ≥18 μg/dL (500 nmol/L). This threshold is based on older serum cortisol assays. Specific monoclonal antibody immunoassays or LC-MS/MS may have lower thresholds for a normal response.

 

[bobbler]

Table 2 gives the initial morning (resting) and ACTH response (stimulated) values. It is these that I noted are entirely normal. To be clear, the cortisol levels and response to an ACTH test given in nmol/L were completely normal in the people with CFS in this study.

View attachment 17908


Morning cortisol (the study sample had values around 400 nmol/L)


Cortisol in ACTH test (the study sample had values around 850 nmol/L)

thanks for the heads up - made me realise it is in the figures section. Hm interesting, there is a reasonable enough std deviation and slightly frustrated the 'difference between resting vs stimulated' isn't reported, don't quite know how that would be useful but I guess std deviation again

really intrigued to note marital status has been included in the profile table ??

 

[Wyva]

Thanks for this @Andy and @Hutan .

My cortisol level (and some other endocrine values) will be checked on Monday at Semmelweis University. It was my GP's idea but also the endocrinologist at the University offered me to do these tests, admittedly because that's the only thing he can do about me.

I have this bit of a fear in me that my cortisol level will be a bit low and then they'll recommend taking hydrocortisone to me based on that. (The same way everyone wanted to pin my disease on my very subclinical hypothyroidism, that is so subclinical that it is often even normal.)

And I'm really really not sure I would want to take hydrocortisone just like that, so I'm gathering this info you are sharing here. CDC is a also a bit of a help, on their page about ME/CFS they write:

Patients with ME/CFS commonly report physical or emotional stress before they become ill. Some patients with ME/CFS have lower levels of cortisol than healthy people, but their cortisol levels are still within the normal range. Therefore, doctors cannot use cortisol levels to diagnose or treat ME/CFS.​

If anyone is interested, my cortisol turned out to be pretty low, but still within normal range. The CDC and Hutan were right.