Cortisol levels in ME/CFS

Low cortisol or otherwise abnormal cortisol comes up frequently in the ME/CFS literature. Many researchers and clinician have been convinced that ME/CFS is the result of managing stress poorly and that it's all about a HPA axis (Hypothalamus, Pituitary and Adrenal Gland axis) problem. They have therefore repeatedly looked for abnormalities in cortisol levels.

However, if you look carefully at the studies that are supposed to support this contention, they tell a different story.

An early study claiming to show low cortisol in ME/CFS had an extremely biased selection. Mean levels found in studies have been variable - a tendency to lower but still normal levels in ME/CFS is easily explainable by the lower activity levels and relatively undemanding lives people with ME/CFS tend to lead. We know that people who routinely undertake physically demanding exercise have higher levels of cortisol - few people do that once they develop ME/CFS.

There's a similar story with peak morning cortisol. If people don't have to get up at 6.30 am, rush around getting the family organised, getting out the door and navigating rush hour traffic, then they don't have the same need for that peak morning cortisol as a person with ME/CFS who might be waking at 9 am and then doing a bit of online work from the couch.

We have also seen a post-Covid study where steroids taken for symptoms following severe Covid-19 infections probably suppressed cortisol levels.

So, I thought I'd do a bit of a casual review, a survey of some of the relevant studies, with links to the forum discussion about them. Edit - if you want to post about a study or make some comments about what I have posted , go right ahead.

 

Early studies
Melatonin Levels in Women with Fibromyalgia and Chronic Fatigue Syndrome, 1999, Korszun et al
This was a tiny study, but it found no evidence of abnormal levels of cortisol (or melatonin) in a small sample of women with CFS.


Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study, 1999, Scott et al
This one is really incredible. As I said on that thread:
"So, they screened people in a fatigue clinic for adrenal gland functioning (using the ACTH test). They don't say how many people they screened, but they do say that they only found 8 people with faulty adrenal gland functioning.

Comparing the size of the adrenal glands of these 8 subjects with 55 heathy controls, they found that the selected CFS subjects had smaller adrenal glands.

Of course, this tells us nothing about people with CFS with normal ACTH test results. Possibly these 8 people don't even have CFS - perhaps they have some other medical issue. Given there is no good evidence for people with ME/CFS having, on average, abnormal ACTH or cortisol levels, I don't think this study contributes to knowledge about ME/CFS.

And yet, it has recently been cited as evidence for an HPA axis-based theory of ME/CFS etiology."

 

Early studies
Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome, 2008, Roberts
That was a study I had not looked at until now. I'm constantly amazed at how bad these studies are. Wesseley and Chalder were co-authors.

The hypothesis was 'we know that people with CFS have low cortisol, we know that CBT fixes CFS, so we should see an increase in cortisol levels after CBT'.

Actually, the levels of cortisol in the participants were normal, before and after CBT - a fact that was not acknowledged in the paper.

Actually, even with the 'mark your own homework' approach of therapists assessing the improvement of people after the CBT intervention, a significant proportion of people were assessed as unchanged or worse after CBT.

And actually, the 'responders' to CBT had a smaller increase in cortisol levels than the non-responders.

This paper is therefore evidence of normal cortisol values in people with (ME)/CFS and evidence of changes in cortisol levels within the normal range being irrelevant to ME/CFS severity.

 

Review of early studies
The neuroendocrinology of chronic fatigue syndrome, 2003, Cleare
Cleare, who was a coauthor of the Roberts paper above, had earlier done this review of the evidence relating to HPA axis dysfunction in CFS.

Cleare notes:

He must have been disappointed with the outcome of the 2008 Roberts study (mentioned in the post above), which showed that changing the cortisol output did not change symptoms.

There's a paywall on the 2003 review, but I expect, based on what I have seen of later studies that most of the included studies did not find levels of cortisol outside the normal range for the majority of CFS participants.

We might have to come back to this review, after looking at each of the studies.

 

Cortisol in hair
Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome, 2018, Roerink et al
This more recent one is from Knoop's team
People with CFS and the healthy controls didn't have statistically different cortisol levels in saliva throughout the day or in hair compared to controls. However, that did not stop the authors from noting in the Highlights 'Hypocortisolism has been described in CFS', which is sort of true, people have said it, but their study did not support that idea.

But, but, they know there must be something to find...

All they found was a difference in the cortisol awakening response

As I've noted, differences in awakening cortisol are to be expected, based on different lifestyle demands on the ME/CFS and control cohorts including normal wakening times. It has also been found that people in pain have a lower awakening cortisol.

I'm going to copy the chart and the conclusion the authors drew from it here, just because it illustrates how delusional people can be when their ideas about an illness become dogma:

I find myself amazed again on reading the things these authors wrote about their null result. The very slight difference in hair cortisol means between the CFS and healthy controls can be explained by different lifestyles. I would not be surprised if some of the healthy controls were hyper-healthy - we know that people who exercise a lot tend to have a higher level of cortisol. But, look at the
overlap in the chart! Hair cortisol level has no discriminative power.

 

Japanese study of yoga
The longitudinal effects of seated isometric yoga on blood biomarkers, autonomic functions, & psychological parameters of [PwCFS], 2019, Oka et al

This study measured cortisol levels in blood before and after 2 months of seated yoga (classes and practiced at home, for an average of 5.8 sessions per week). 15 participants, meeting multiple ME/CFS criteria.

Cortisol (μg/dL) reference range 3–20

Before 11.5 ± 8.3
After 10.4 ± 6.3
P value 0.552

So, the participants had very normal cortisol before and after the intervention. There was no significant change in cortisol after the yoga.

I don't think the Japanese researchers had got the BPS memo about needing to find low levels of cortisol in people with ME/CFS, and that increasing cortisol levels is the aim of exercise interventions. The Japanese researchers noted approvingly that cortisol dropped when measured at the beginning of a yoga session and then at the end of a yoga session.

 

Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach, 2020, Pednekar et al
This one is a thoroughly awful paper, it's hard to say what they found. There does not look to be any differences in cortisol between CFS and healthy control cohorts. That does not stop them suggesting that more studies on cortisol will produce the answers to CFS.

 

An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2011, Jason et al
This paper isn't a study, but I just wanted to flag it to show that even people that we might think understand ME/CFS quite well can have some whacky ideas built on this false idea that cortisol is central to the pathology of ME/CFS.

Also noting @Snow Leopard's point about day time napping possibly confounding morning cortisol levels

Edited to add:
Determinants of cortisol awakening responses to naps and nighttime sleep
which makes it clear that the morning peak is an expression of the Cortisol Awakening Response, which is a response to waking up, rather than the time of day. People who nap will have a different daily architecture of cortisol production. Loss of sleep during the night also affects cortisol patterns.

 

Hydrocortisone studies

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

32 participants. The participants' urinary free cortisol levels were normal throughout, although did increase with hydrocortisone.


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

Positive responses to hydrocortisone treatment were limited to one questionnaire among quite a number, were small and were in line with the positive response that healthy people also experience.

 

Long covid studies
Distinguishing features of Long COVID identified through immune profiling, 2022, Klein, Iwasaki et al
This Iwasaki paper has been very influential in promoting the idea of low cortisol in people with Long Covid.
A large study

Noting @cassava's excellent post on the Iwasaki thread - some references to papers to include.
Also my post in that thread about a paper that monitored the cortisol levels of Polish rowers undergoing training. Cortisol levels change, within weeks, with baseline activity levels.
And also my posting about the possibility that steroid medications during the acute illness and subsequently have supressed endogenous cortisol production

 

A German study of post-covid syndrome with a good sized sample of nearly 1000 people with PCS found no differences in (presumably serum) cortisol or ACTH levels. 11.6% of people were assessed as meeting ME/CFS criteria (I'm not sure which one)
Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year....[], 2025, Peter

 

The researchers screened 40 consecutive patients and only chose 10 for the study. It isn't all that clear why someone made the cut for the study. There's a lot of potential for bias there, and the researchers very easily could have included a requirement for the baseline to show low morning cortisol. The study is small and lacks credibility.