[Health Rising] ME/CFS Autopsy Study Finds a Wrecked HPA Axis: The 2025 IACFS/ME Conference Report #3

Verity said:
Do you mean the guidelines for diagnosing ME? The test is one of two tests given for diagnosing adrenal insufficiency, so it will probably not be listed separately from a general direction to rule out adrenal insufficiency. I think it is unlikely they’d list every necessary lab test for every potential ME mimic. I’ve never seen something like that. Correct me if I’m wrong!
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The Norwegian guidelines have a long list of tests that should be considered. I don’t know why they did it that way. It’s quite bad in general, the BPS lobby was heavily involved..
 
Utsikt said:
The Norwegian guidelines have a long list of tests that should be considered. I don’t know why they did it that way. It’s quite bad in general, the BPS lobby was heavily involved..
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Oh interesting. Then I have no idea why it wouldn’t be on there. Someone can correct me if I’m wrong, but I’m pretty sure it’s standard.
 
Jonathan Edwards said:
I think it is quite likely that we are looking at an artefact. I also think that although apparent loss of CRH cells seems unlikely s secondary to sleep changes or whatever, it might reflect the mode of death. I have not looked into this further but I ownder if we now anything about how these people died? Death from inanition might be associated with CRH cell exhaustion for instance
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Cause of death is listed in the narcolepsy autopsy study, it doesn’t appear to be explain CRH depletion. Similar proportions in cases and controls dying of cardiac events and other miscellaneous causes
 
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StellariaGraminea said:
Silly question probably, but could excess orexin (or it not being switched off (?) when it should) lead to burn out of CRH transcription?
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No idea, sorry. With these kinds of circuits you can pretty much only answer a question like that by directly looking—there are usually too many negative regulators, compensatory mechanisms, competitive binding possibilities etc. to be able to guess exactly what’ll happen in what direction at a transcriptional level as a consequence of XYZ in an aberrant state.
 
jnmaciuch said:
No idea, sorry. With these kinds of circuits you can pretty much only answer a question like that by directly looking—there are usually too many negative regulators, compensatory mechanisms, competitive binding possibilities etc. to be able to guess exactly what’ll happen in what direction at a transcriptional level as a consequence of XYZ in an aberrant state.
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Thank you for the answer & considering it. It seems these things are always hugely more complex when you go down to the nuts & bolts.
 
A very big part of the subjective experience of my illness is that ordinary activities become stressful and that I can't recover from this stress as easily as a normal person.

It feels like there are two different aspects of stress tolerance. The first is an acute response and the ability to endure stress for some time. The other aspect is how easily the body can get back to a normal healthy state and it is this aspect that seems to not work well.

I think this might be why I have the tendency to push myself (subject myself to stress and endure it for some time) but then up crashed and unable to recover from the effects of this stress in the same amount of time as a normal person. And sleep is definitely a big part of this inability to recover properly.

Maybe there is a component of the stress response system that hasn't been discovered which deals with recovery after stress, rather than resisting ongoing stress. Maybe that's where the origin of PEM is.
 
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Kitty said:
I don't think we should be concerned by unpublished results suggesting a condition that results in low levels of a hormone, when no one has found markedly dysregulated hormones in living people with ME/CFS.

Assuming it were real, people with the condition—who'd presumably show a much reduced responses to stress, as if they were on tranquillisers—would be treated by supplementing the missing hormone. But as the data's unpublished and has had no expert review, it's best filed in the Highy Dubious tray.
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I think there is annectdotal evidence of low cortisol and low thyroid due to low drive to thyroid and adrenals from hypothalamus - pituitary glands.

I have been interested in this rezewrch idea for 26 years....

Even spoke to Simon Wessley and Anthony Cleare at the Fatigue 2002 Conference in London following their research from 1999. I spoke to Professor Ted Dinan as well.

Epstein Barr virus can impact hypothalamus I remember reading.

All above lows consistent with my husband's readings from both thyroid 24 testing of urine and saliva testing for adrenal function.

NHS Synathen test just drive the glands, which work, albeit underpar.

The synthetic test essentially is looking for adrenal failure and Addisons. Plus they use a high dose to stimulate.
Never pick up suble deregulation.

Obviously, ME patients can have very different core problems, but this suggestion perfectly fits my husband's difficulties. He had EB in the 1970s.

Dr Durrant Peatfield was very helpful around that time too 2006.
 
jnmaciuch said:
Actually, transcription of CRH appears to require constitutive cAMP -> CREB signaling and can be suppressed by blocking that pathway. Insufficient stimulation of that signaling cascade means no activity at the promoter region to produce CRH for those cells to store.
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No doubt, but I am sceptical that the sort of studies that these things are based on translate much to clinical reality. I may be wrong. The remaining problem with this finding though, if we think these cells are unable to make CRH, seems to be that it suggests that there ought to be noticeable hypocortisolism and the evidence for that is unconvincing.
 
Jonathan Edwards said:
No doubt, but I am sceptical that the sort of studies that these things are based on translate much to clinical reality. I may be wrong.
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Sure, you could say that about any in vitro finding and both autopsy studies might be artifacts as well. Though if the in vitro findings provide a straightforward explanation logically consistent with both the narcolepsy and ME/CFS findings, that’s reason to at least not dismiss everything out of hand.

Jonathan Edwards said:
The remaining problem with this finding though, if we think these cells are unable to make CRH, seems to be that it suggests that there ought to be noticeable hypocortisolism and the evidence for that is unconvincing.
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If the narcolepsy autopsy study is even remotely representative of narcolepsy as a whole, it seems that critically low cortisol isnt a feature of CRH production loss there either. So either there’s a compensatory mechanism, or having even a few CRH-producing neurons is enough (or both)

pubmed.ncbi.nlm.nih.gov

Hypothalamo-pituitary-adrenal axis, glucose metabolism and TNF-α in narcolepsy - PubMed

Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case-control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
Suffolkres said:
low cortisol
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@Hutan has a great thread that goes through the evidence on cortisol in ME/CFS and it seems findings are inconsistent but not really suggestive of low cortisol.

Hutan

Thread '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...
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Also think this has the potential to be an important finding. Was anyone besides Cort able to watch the presentation?

Suppose there is this major depletion of CRH neurons: wouldn't this be visible on brain scans or is the region too small to be picked up by the tiny brain scan studies that we have in ME/CFS?

From a brief look at the literature, it seems that in narcolepsy, brain scans were able to pick up on things like reduced gray matter volume in the hypothalamus
Hypothalamic gray matter changes in narcoleptic patients | Nature Medicine
Neuroimaging in narcolepsy - ScienceDirect
 
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jnmaciuch said:
They might not die at all. The only thing being measured in these studies is antibody binding to CRH. It might only be the proteins involved in producing or secreting CRH that drop off because their production is dependent on other signals involved in circadian rhythm
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Good point. This recent PNAS paper argues that the cells likely still exist but have been reprogrammed epigenetically.
We demonstrate that a substantial number of HCRT neurons are present in the brain of patients, but HCRT gene is silenced by methylation. The epigenetic silencing is not restricted to HCRTbut also CRH and PDYN genes are methylated in the hypothalamus of patients. Our results strongly suggest that HCRT and CRH neurons are not destroyed but epigenetically deactivated, and possibilities exist to reactivate them to treat or even cure narcolepsy
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Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy | PNAS

So if that's the case, the question would be: what could be doing something similar in ME/CFS?
 
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ME/CFS Science Blog said:
Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy | PNAS

So if that's the case, the question would be: what could be doing something similar in ME/CFS?
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Good find! This paper you linked shows that the strongest methylation differences in the CRH promoter are in a CREB-binding region, which is consistent this review I also posted earlier in the thread: https://www.sciencedirect.com/science/article/pii/S0091302211000707) There are still a lot of unknowns about CRH regulation, but the review makes a pretty good case that the minimum necessary components for CRH production are cAMP/TORC activation and CREB phosphorylation.

So two possibilities for how epigenetic repression of CRH happens in narcolepsy:

1) the same (likely immune-related) signals in narcolepsy that block orexin production also lead to repression of CREB-binding regions in CRH neurons, or

2) CREB signaling in CRH neurons is dependent on regular stimulation by orexin from orexin-producing neurons. Since CREB phosphorylation is triggered by tons of other stimuli besides orexin, this option seems unlikely though technically possible.

Either way, there’s no evidence that narcolepsy-level orexin depletion is a feature of ME/CFS, so that does help narrow down potential options because we can assume that CREB should be getting phosphorylated at least daily by orexin signaling.

So in order to end up with the same CRH depletion as in narcolepsy but not orexin depletion, the mystery abnormality in ME/CFS would have to be something that either blocks phosphorylated CREB or blocks cAMP/TORC, without affecting ETS1 in orexin neurons.
 
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jnmaciuch said:
Good find! This paper you linked shows that the strongest methylation differences in the CRH promoter are in a CREB-binding region, which is consistent this review I also posted earlier in the thread: https://www.sciencedirect.com/science/article/pii/S0091302211000707) There are still a lot of unknowns about CRH regulation, but the review makes a pretty good case that the minimum necessary components for CRH production are cAMP/TORC activation and CREB phosphorylation.

So two possibilities for how epigenetic repression of CRH happens in narcolepsy:

1) the same (likely immune-related) signals in narcolepsy that block orexin production also lead to repression of CREB-binding regions in CRH neurons, or

2) CREB signaling in CRH neurons is dependent on regular stimulation by orexin from orexin-producing neurons. Since CREB phosphorylation is triggered by tons of other stimuli besides orexin, this option seems unlikely though technically possible.

Either way, there’s no evidence that narcolepsy-level orexin depletion is a feature of ME/CFS, so that does help narrow down potential options because we can assume that CREB should be getting phosphorylated at least daily by orexin signaling.

So in order to end up with the same CRH depletion as in narcolepsy but not orexin depletion, the mystery abnormality in ME/CFS would have to be something that either blocks phosphorylated CREB or blocks cAMP/TORC, without affecting ETS1 in orexin neurons.
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So, that points toward 'regulatory energetic failure' potentially?

'Regulatory energetic failure' of some sorts suppresses cAMP/TORC-CREB signaling because energy-sensing stress kinases actively shut down transcriptional coactivators to conserve energy, leading to functional depletion without structural loss?
 
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