Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome, 2018, Roerink et al

Andy

Andy

Senior Member (Voting rights)
Abstract
Hypocortisolism has been found in CFS patients in blood, urine, and saliva. It is unclear if hypocortisolism can also be demonstrated using long-term cortisol measurements, such as cortisol in hair. In addition, the interaction between the HPA axis and the immune system, both expected to play an important role in CFS, is unclear.

The objective of the current study was to compare hair and salivary cortisol concentrations in a cohort of female CFS patients to those in healthy controls, and to test the effect of an interleukin-1 receptor antagonist (anakinra) on the HPA axis. Salivary cortisol concentrations of 107 CFS patients were compared to 59 healthy controls, with CFS patients showing a decreased cortisol awakening response (4.2 nmol/L ± 5.4 vs 6.1 nmol/L ± 6.3, p = 0.036). Total cortisol output during the day did not differ significantly in saliva, but there was a trend to lower hair cortisol in a subset of 46 patients compared to 46 controls (3.8 pg/mg ± 2.1 vs 4.3 pg/mg ± 1.8, p = 0.062). After four weeks of treatment with either daily anakinra (100 mg/day) or placebo, there was a slight decrease of hair cortisol concentrations in the anakinra group compared to an increase in the placebo group (p = 0.022).

This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long-term cortisol measures.
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Paywalled at https://www.sciencedirect.com/science/article/pii/S0018506X1730569X
 
I've only read the abstract, but there doesn't seem to be anything of any use here.

People with CFS and the healthy controls didn't have statistically different cortisol levels in saliva throughout the day or in hair.

People with CFS did have a statistically lower 'cortisol awakening response' (4.2 nmol/L vs 6.3 mol/L for the controls).

If you look at the standard deviations given with each average, you can see the very high variation.
(i.e. 4.2 + or - 5.4; 6.1 + or -6.3)
There is a huge overlap in values - some people with CFS had higher values, some healthy controls had lower values. So, even though statistically significant, it is not a very impressive difference.

Ok, so now they give a group of the people with CFS anakinra and a group a placebo for 4 weeks.

I found this study that shows that anakinra is supposed to lower cortisol because it is an IL-1 antagonist.
https://www.endocrine-abstracts.org/ea/0049/ea0049oc11.3

And that is exactly what they found - the people given anakinra did have lower cortisol. Entirely as could be expected. Even though they are measuring the cortisol in hair after 4 weeks - hopefully they got the right hair. (Why did they not report the change in salivary cortisol in the abstract?). And the decrease was a 'slight decrease', as was the decrease in various measures of cortisol observed in the study I linked above. So, it appears that there was nothing odd about the reaction of the people with CFS to the anakinra. Cortisol went down a bit.

And the people on the placebo had higher cortisol - demonstrating that variation in cortisol levels over time is normal.

This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long-term cortisol measures.
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Huh? There must be something extra in the main text that explains how they can conclude from this study that people with CFS have altered dynamics of the HPA axis. As far as I can see, there is nothing in the abstract that suggest this.

And I can't even work out what they are trying to say with the bolded bit. The authors reported that the cortisol levels in the hair of people with CFS and the healthy controls were not statistically different. So, how is that showing 'altered dynamics of the HPA axis'?

Maybe the full paper will make things clear, but I give them a 'fail' for supporting their conclusion with the data in the abstract.
 
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Thanks @Hutan. Were all tests of cortisol levels made in saliva?

As that is the only valid and reliable method ( to avoid bias from being affected by differences in cortisol binding proteins that may differ due to genetics) I think it´s important. Even endocrinologists here has denied that cortisol in blood should be unreliable, but after discussions they´ve admitted the risk of bias from that and even other factors.

Edit: corrections
 
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Reading the paper, the Cortisol Awakening Response is as follows:

Cortisol awakening response (CAR), which reflects the increase in cortisol concentrations in the first 30–45 min post-awakening (Clow et al., 2010). The CAR was calculated subtracting the awakening sample from the +30 min sample.
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So the figures I gave in my first post for normal values for morning cortisol don't apply. I'll adjust my post so I don't confuse people.
 
From Wikipedia on Cortisol awakening response:

Shortly after awakening, a sharp 38–75% (average 50%) increase occurs in the blood level of cortisol in about 77%[1] of healthy people of all ages. The average level of salivary cortisol upon waking is roughly 15 nmol/l; 30 minutes later it may be 23 nmol/l, though there are wide variations.​

So, even in healthy people, a significant percentage of people don't show a cortisol awakening response.

Waking up earlier increases the response (and it's likely the people with CFS were waking up later).
People in pain have a lower response. (And indeed this study found a statistically significant negative relationship between self-reported pain and the cortisol awakening response.)​

So, given that the cortisol awakening response wasn't very different, with a lot of variability in both the people with CFS and the controls, it seems likely that the average difference that was found can be explained by later wake up times and increased pain in the CFS group.
 
Here's the crucial figure showing how different the people with CFS are from healthy controls when it comes to cortisol in hair. The difference was not statistically significant.

And yet, the authors still manage to conclude that:

"This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long-term cortisol measures." (i.e. in hair)
Screen Shot 2018-06-02 at 11.30.00 PM.png

And here's the paragraph discussing the null result for hair cortisol in more detail:
Despite the absence of a difference in total cortisol output in saliva, there was a trend to lower <hair cortisol> in CFS patients. It has been described that salivary cortisol is a reliable method to measure free circulating cortisol, but it is subject to day-to-day variation and the patients' compliance to the collection instructions (Hellhammer et al., 2007). <Hair cortisol> might be a more robust method to assess long-term/accumulated cortisol concentrations, and has shown a considerable intra-individual stability/reproducibility (Stalder et al., 2012b). In CFS, <hair cortisol> has not been assessed previously but lower concentrations have been found in patients with chronic stress conditions such as generalized anxiety disorder (GAD) (Steudte et al., 2011a) and adults with a history of childhood trauma (Dettenborn et al., 2013).​
 
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Ok, last post from me. This study is annoying for so many reasons. It was such a waste of research funds and the effort of the participants, some of whom had daily injections for a month. And the authors seem unshakeable in their beliefs about CFS despite their experiment giving them basically nothing to support those beliefs.

Here the authors are summing up how that result in Figure 2 above is so important. HCC is the hair cortisol.

In addition, there was a trend to lower HCC in patients (1). Especially the latter has important implications for future studies. When lower HCC can be confirmed in other studies, it might be used as a more stable and reliable tool for the evaluation of the HPA axis in CFS (2). Earlier studies found that urinary cortisol is able to predict response to CBT , and that salivary cortisol normalizes with adequate treatment (3) . However, in the light of the previously mentioned limitations of salivary cortisol, HCC might be an interesting alternative to predict the effect of treatment.​

1. the hair cortisol of the people with CFS was not significantly different to that of healthy controls - see Figure 2. What's the point of reporting p values if you are going to ignore them?
2. the anakinra trial failed to show a faulty HPA axis
3. Salivary cortisol was normal without treatment in this study
 
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The interesting aspect of this study is the fact that the day-night rythm (nycthemeral biorythm) may be disturbed. This rythm largely depends on the sleep-wake pattern influencing the thalamo-hypothalamic-adrenal axis. If the sleep pattern is disrupted (as is commonly the case in ME/CFS patients), this may be the cause of the lower early-morning cortisol. Some patients also dispay a significant decrease of the concentration of dehydro-epi-androsterone (DHEA) in blood, indicating a defective steroid secretion by the adrenal cortex. I consider this to reflect an important severity of the disease.
 
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The results are very weak indeed. And again, they assume causation rather than correlation. It's far more likely that minute differences in cortisol (and they are minute, if they differ at all), would be a consequence of HPA disruption, rather than assuming (as the authors do) that this is due to chronic stress and trauma. There's literally no evidence for their assumption.
 
Hutan said:
Shortly after awakening, a sharp 38–75% (average 50%) increase occurs in the blood level of cortisol in about 77%[1] of healthy people of all ages. The average level of salivary cortisol upon waking is roughly 15 nmol/l; 30 minutes later it may be 23 nmol/l, though there are wide variations.
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Conclusion: waking up is stressful. For some pathological reason, PwMEs continue to engage in this activity on an almost daily basis, probably because they are overly perfectionistic. They need careful instruction on how to modify their behaviour through a gently graded not waking up programme.
 
Or,
Waking up is stressful. For some pathological reason, PwME tend to put it off until later in the day, probably because they are lazy and don't want to engage with the world. They need careful instruction on how to modify their behaviour through a gently graded early waking up programme.

One of those two, or both. Or some other theory that identifies the faulty behaviour of PwME and the moral superiority of the researchers and that involves cortisol somehow (too little, too much, too little at 8 am, too much in forearm hair at 11.50 pm when the moon is full...) - because, well you know, it's all about stress.

(Edited to add my theory about a connection with werewolves)
 
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Hutan said:
From Wikipedia on Cortisol awakening response:

Shortly after awakening, a sharp 38–75% (average 50%) increase occurs in the blood level of cortisol in about 77%[1] of healthy people of all ages. The average level of salivary cortisol upon waking is roughly 15 nmol/l; 30 minutes later it may be 23 nmol/l, though there are wide variations.​

So, even in healthy people, a significant percentage of people don't show a cortisol awakening response.

Waking up earlier increases the response (and it's likely the people with CFS were waking up later).
People in pain have a lower response. (And indeed this study found a statistically significant negative relationship between self-reported pain and the cortisol awakening response.)​

So, given that the cortisol awakening response wasn't very different, with a lot of variability in both the people with CFS and the controls, it seems likely that the average difference that was found can be explained by later wake up times and increased pain in the CFS group.
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I did not know of the pain / cortisol relationship. Neither did our endocrinologist it seems as he was stumped by low base cortisol reading but ok response on ACTH test. ..
 
I remember Knoop and Nater are one of the German BPS proponents (they seem to be in Austria now). Seems they are desperately looking to confirm their stress-HPA axis hypothesis?
 
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