Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie ME/CFS: 2021, Stanculescu, Larsson and Bergquist

[borko2100]

HPA axis hypotheses have almost been done to death. The main problem is that basal serum cortisol (or the other markers discussed) is neither a sensitive, nor specific predictor of ME/CFS or symptoms.

Yes there is attenuated morning salivary Cortisol concentrations in some patients but this is not a consistent finding, just like serum cortisol. Note that cortisol is a feed-foward metabolic hormone, as it's main function is to stimulate gluconeogenesis. Salivary cortisol itself isn't terribly important and this can be explained by different sleep-wake activity patterns between patients and controls. There may also be a sort of sampling bias, namely participants who normally sleep in are getting up earlier than normal as they were told to collect samples from certain hours in the morning, for example. (and the participants don't want to admit they're actually sleeping at that time)

Yes, there is no way cortisol is at the root of ME/CFS. Certainly, reduced cortisol might be an effect of ME/CFS, but not the cause. Unless we get into more complicated things like cortisol receptors or something on the cellural level, then there might be something to it.

Also, being sedetary (as is the case in most CFS sufferers) surely affects a ton of hormones, so unless the control group is sedetary as well, finding differences in hormone levels between the two groups is not surprising at all. I am surprised more researchers don't control for this, by including sedetary controls for example. This is quite a great confounder that can't be ignored IMO. What is to say that most positive ME/CFS studies haven't found a result purely due to differences in activity levels? Exercising and being active affects a ton of bodily systems, so finding differences between sedetary and non sedetary individuals is quite likely.

 

[FMMM1]

HPA axis hypotheses have almost been done to death. The main problem is that basal serum cortisol (or the other markers discussed) is neither a sensitive, nor specific predictor of ME/CFS or symptoms.

Yes there is attenuated morning salivary Cortisol concentrations in some patients but this is not a consistent finding, just like serum cortisol. Note that cortisol is a feed-foward metabolic hormone, as it's main function is to stimulate gluconeogenesis. Salivary cortisol itself isn't terribly important and this can be explained by different sleep-wake activity patterns between patients and controls. There may also be a sort of sampling bias, namely participants who normally sleep in are getting up earlier than normal as they were told to collect samples from certain hours in the morning, for example. (and the participants don't want to admit they're actually sleeping at that time)

Or maybe patients simply have too much humor?
"Humor attenuates the cortisol awakening response in healthy older men"
https://www.sciencedirect.com/science/article/abs/pii/S0301051110000840

(this should be a clue that the finding is very non-specific)

Bergquist and colleagues discuss 'pulsatility' of ACTH release, but this has already been studied and the results are equivocal.

While the study of pulsatility of the various hormones in patients might be interesting, I think it is unlikely to lead to any breakthroughs given how much study there has already been of the HPA axis in ME/CFS patients.

Thank you very much @Snow Leopard

 

[unicorn7]

I am extremely happy with this paper.

I really like the comparison with the acute phase and chronic phase of ICU patients. I think in this group of patients there has been a lot of attention an research on the acute stadium, but not on the chronic phase. The post-sepsis groups do seem to experience a lot of the same problems as the ME/CFS group. The evolution from acute to chronic is more easily studied in this group. In ME/CFS, it is much harder, as we don't know at the beginning who are going to develop ME/CFS.

I think this paper gives a nice overview. Instead of going of and researching some very interesting but "out there" causes and solutions, I think a deep and thorough research to the function of these hormones, would be very valuable. We actually know that low cortisol, low thyroid, low GH and low testosterone cause extreme fatigue and problems with exertion. I don't know why this hasn't been studied in-depth yet.

There have been a lot of positive studies, but also a few negative ones. These theories really seem to resonate with a lot of the patients stories, I have read innumerable stories about patients who had one or more of the hormones very low.
Separately, I have heard a lot of positive stories from just taking one of these hormones: there are doctors working with fludrocortison, which seems to help with OI problems. Personally, I have been helped most with a physiological dose of cortisol. I also have had low T3 (combine with low TSH and low T4) for ages.

What if it is this simple as checking all these hormones? Shouldn't we find out? Even if it isn't the primary problems, if correcting secondary problems gives people their lives back, I'm fine with it. If this could help, the medicines are already there. We wouldn't have to develop new ones.

 

[FMMM1]

---

Also, being sedetary (as is the case in most CFS sufferers) surely affects a ton of hormones, so unless the control group is sedetary as well, finding differences in hormone levels between the two groups is not surprising at all. I am surprised more researchers don't control for this, by including sedetary controls for example. This is quite a great confounder that can't be ignored IMO. What is to say that most positive ME/CFS studies haven't found a result purely due to differences in activity levels? Exercising and being active affects a ton of bodily systems, so finding differences between sedetary and non sedetary individuals is quite likely.

I recall Jaime Seltzer [ME Action] saying this.

 

[leokitten]

I encourage people to read the entire paper.

Endocrine dysfunction hasn’t been studied to death in ME. Nothing has been studied to death in ME there’s never been any money to study anything to death we don’t know anything about this disease. Even the studies that have been done all have serious limitations or flaws (mostly due to lack of money or experience of ME researchers) that results are never satisfying.

The paper highlights how the pathophysiology of chronic critical illness was pretty much a mystery until they performed the studies to measure the pulsatility of pituitary secretions and that was a breakthrough because it revealed a central part of what was going wrong.

Critical illness researchers most certainly measured hormones in more standard ways before that and didn’t discover what was wrong. That is what this paper is saying about ME endocrine research.

The paper is trying to say that we should study the pulsatility of pituitary gland secretions to test this hypothesis because this is an oversight in ME research and could very well be important. I wouldn’t overthink this paper more than that, and I do think this is a study worth doing to at least disprove this hypothesis.

 

[Milo]

HPA axis hypotheses have almost been done to death. The main problem is that basal serum cortisol (or the other markers discussed) is neither a sensitive, nor specific predictor of ME/CFS or symptoms

I had metabolomic hormonal testing done which showed out of range metabolites. Of course these were not clinical tests, but it showed abnormalities. What it means and how to fix it, that’s another story.

 

[Snow Leopard]

The paper is trying to say that we should study the pulsatility of pituitary gland secretions to test this hypothesis because this is an oversight in ME research and could very well be important. I wouldn’t overthink this paper more than that, and I do think this is a study worth doing to at least disprove this hypothesis.

The HPA axis stuff was the hottest/most studied hypothesis back in the 90s and early 2000s and pulsatility of pituritary gland secretions has already been studied.

24 hour profile of cortisol, corticotropin (ACTH), growth hormone and prolactin.
https://journals.lww.com/psychosoma...itary_and_Adrenal_Hormone_Profiles_in.14.aspx
The only phasic finding was a reduction in ACTH secretion from 8-10 am compared to controls. But the authors concluded (and I agree):

However, given the presence of altered patterns of sleep and activity in CFS, it is perhaps more likely that such desynchronization is at least partly secondary to these changes rather than a primary pathophysiological cause.

But that was not the only study to investigate ACTH pulsatility
The following study found no difference in ACTH pulsatility for CFS patients:
https://www.sciencedirect.com/science/article/abs/pii/S0889159104000212

Which lends greater credence to the hypothesis that these altered patterns in some patients are secondary to altered sleep-wake-activity patterns.

 

[Snowdrop]

I have no clue or knowledge about why a study will or won't be funded but wonder whether finding ways to study ME without being specific might prove promising.

That is to say studying the endocrine system in a more general way for discoveries that can then be applied more specifically in further research. Ditto the immune system. There are many things that are unknown here. Surely shinning a light on discovering how our body systems work in more detail through research could yield benefits in a number of ways.

ETA: Or is this naive?

 

[Perrier]

The HPA axis stuff was the hottest/most studied hypothesis back in the 90s and early 2000s and pulsatility of pituritary gland secretions has already been studied.

24 hour profile of cortisol, corticotropin (ACTH), growth hormone and prolactin.
https://journals.lww.com/psychosoma...itary_and_Adrenal_Hormone_Profiles_in.14.aspx
The only phasic finding was a reduction in ACTH secretion from 8-10 am compared to controls. But the authors concluded (and I agree):



But that was not the only study to investigate ACTH pulsatility
The following study found no difference in ACTH pulsatility for CFS patients:
https://www.sciencedirect.com/science/article/abs/pii/S0889159104000212

Which lends greater credence to the hypothesis that these altered patterns in some patients are secondary to altered sleep-wake-activity patterns.

Thanks for all this information. My understanding is that a good number of people who have ME also have high prolactin. Our family member does, for instance. Yet, the study above does not seem to find this.

 

[leokitten]

The HPA axis stuff was the hottest/most studied hypothesis back in the 90s and early 2000s and pulsatility of pituritary gland secretions has already been studied.

24 hour profile of cortisol, corticotropin (ACTH), growth hormone and prolactin.
https://journals.lww.com/psychosoma...itary_and_Adrenal_Hormone_Profiles_in.14.aspx
The only phasic finding was a reduction in ACTH secretion from 8-10 am compared to controls. But the authors concluded (and I agree):



But that was not the only study to investigate ACTH pulsatility
The following study found no difference in ACTH pulsatility for CFS patients:
https://www.sciencedirect.com/science/article/abs/pii/S0889159104000212

Which lends greater credence to the hypothesis that these altered patterns in some patients are secondary to altered sleep-wake-activity patterns.

Both of these small studies were referred to in the hypothesis paper. There were some important flaws in these studies, like not looking at disease severity or length of illness.

Remember pathophysiology isn’t only what disordered processes are occurring in all or most cases of ME/CFS. Some questions that are important to ask are for example what processes underlie why many cases get worse over time? Or why cases become severe and other don’t?

This is what the paper is stating, that comprehensive studies of ACTH pulsatility in ME/CFS have not been done. It might not underlie less severe ME/CFS but could be a driving factor as to why cases get worse over time or cases become severe.

 

[Snow Leopard]

Both of these small studies were referred to in the hypothesis paper. There were some important flaws in these studies, like not looking at disease severity.

The problem is that severity may simply be a confounding factor - those with more severe illness have different sleep-wake patterns, namely they sleep more and are less active in the morning. Studies may indeed find a difference, but it might not be at all relevant. It is important not to confuse cause with effect.

 

[leokitten]

The problem is that severity may simply be a confounding factor - those with more severe illness have different sleep-wake patterns, namely they sleep more and are less active in the morning. Studies may indeed find a difference, but it might not be at all relevant. It is important not to confuse cause with effect.

I understand that and indeed it could be true, but the two studies you referenced didn’t account for disease severity as a confounding factor or otherwise. We just don’t know and more comprehensive studies accounting for important clinical and demographic data should be done.

As a person who’s gone from mild to now moderate-severe, I see that long before we become severe, pwME spend more and more time inside, in the dark, resting, in bed, severely altered sleep patterns, etc.

For months and years we do this. The could have a dramatic impact on things like the endocrine system which could be an emerging factor at some stage in the disease process driving what causes many to get worse.

 

[Milo]

I understand that and indeed it could be true, but the two studies you referenced didn’t account for disease severity as a confounding factor or otherwise. We just don’t know and more comprehensive studies accounting for important clinical and demographic data should be done.

As a person who’s gone from mild to now moderate-severe, I see that long before we become severe, pwME spend more and more time inside, in the dark, resting, in bed, severely altered sleep patterns, etc.

For months and years we do this. The could have a dramatic impact on things like the endocrine system which could be an emerging factor at some stage in the disease process driving what causes many to get worse.

That’s an interesting comment @leokitten and it is a possibility that is worthy to be tested however in my case, my disease severity hasn’t changed much throughout the years, i spend time outside. But while i can wake up at 9 AM if I had to (and pay for it afterwards) i seemingly do much better going to sleep by 2 or 3 AM (with sleeping pills) and waking up at 1 in the afternoon. The chicken and the egg rule applies, what came first and is the sun involved?

 

[Mij]

My issue is feeling worse in the morning and feeling much better as the day progresses. Is this a cortisol issue? I feel almost normal after 6 pm. This has always been the case for me for 30 years.