Newton et al A Review of Hypothalamic-Pituitary-Adrenal Axis Function in CFS

[Firestormm]

Review Article

A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome

Cara Tomas,1 Julia Newton,1 and Stuart Watson1,2

1Newcastle University, Newcastle upon Tyne NE1 7RU, UK
2Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK

Received 28 June 2013; Accepted 29 August 2013

Academic Editors: C. Bishop, P. de Gortari, G. Forster, and G. Hans

Copyright © 2013 Cara Tomas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge.

A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females.

Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder.

Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.

Comment from Team Newton Facebook here.

 

[Dolphin]

I'm not impressed with this:

Cognitive behavioural therapy (CBT) and graded exercise plans have demonstrated efficacy but with significant interindividual variation [4, 23, 78, 89]. These therapies modify illness perception and allow patients to make adjustment to optimise energy expenditure. CBT has been shown to increase cortisol levels by reversing some of the effects induced by low activity levels, depression and stress in early life [8,82, 90, 91].

Things are more complicated. Don't have time to write more at the moment.

 

[Snow Leopard]

I'd say they simply increase cortisol levels because those 'therapies' cause more stress for the patient.

This is the simplest answer right?

 

[Firestormm]

I'd say they simply increase cortisol levels because those 'therapies' cause more stress for the patient.

This is the simplest answer right?

I must read it, but I'd always assumed we were supposedly low in cortisol, and therefore an increase was considered a 'good' thing

 

[Snow Leopard]

To clarify my point further, I don't think that measuring cortisol (alone) is a good marker of anything in particular.

 

[aimossy]

I think they are suggesting a very complex muck up in these systems that need more analysis.

 

[peggy-sue]

My personal feelings about this are along the lines of that when we are in a position of having to carry on, despite feeling we need to stop, that it is an adrenalin rush/surge that gets us through it.

A social situation, just being with people, is more than enough to get my adrenalin going like mad. I go completely manic after a few days of it.

I strongly suspect we do (ab)use stress and adrenalin surges, just to get by.

 

[Esther12]

To clarify my point further, I don't think that measuring cortisol (alone) is a good marker of anything in particular.

I was just reading an article about this recently (not about CFS), arguing that there had been loads of bad research claiming to be important just on the basis of identifying changes in cortisol. It's not something I know much about tbh.

 

[peggy-sue]

Mine would be up and down all day long.

Put somebody beside me, adrenalin will kick in as I try to be sociable,
take them away and it will drop as I relax.
Get me anywhere near the gp's surgery, it will start rising.... and rising...

I honestly believe adrenalin "surges" are the only way I get anything done.

 

[Ema]

To clarify my point further, I don't think that measuring cortisol (alone) is a good marker of anything in particular.

It's a pretty great marker for adrenal insufficiency.

 

[Ema]

There is an argument for further trials of steroid treatment in patients selected on the basis of adrenal insufficiency, but the potential impact of long-term treatment including Cushing’s syndrome, osteoporosis, extreme mood changes, and seizures cautions against this approach [99].

Patients with adrenal insufficiency do not develop these type of side effects with physiological dosing of hydrocortisone. Why researchers insist on perpetuating these myths is beyond me. The literature is full of studies to the contrary.

Further, cortisol is REALLY difficult to measure. There are at least 4 different types of assays available and one will get significantly different results based on which assay is chosen. This seems like a huge problem to me especially considering how vital cortisol is to life.

Most assays also do not differentiate between cortisol and cortisone but of course that makes a tremendous difference in the body.

The ACTH stimulation test misses about half of those with secondary adrenal insufficiency which makes it a terrible screening test. Yet it's all we've got at the moment. These are the REAL problems here that need to be addressed - we need better testing to assess adrenal function and we need to accept that one can have partial adrenal insufficiency just the same way that one can have pre-diabetes.

I think it says something when we have terrible testing but abnormalities in cortisol metabolism are still always apparent when HPA axis function is studied in our population. Not one study has ever said that we have normal cortisol metabolism. They just can't figure out what to do about it outside of therapy apparently.

I don't think that HPA axis dysregulation and hypocortisolism are the cause of ME/CFS but they certainly are a symptom. And they are a symptom that can be successfully relieved in many cases by using physiological replacement doses of steroid hormones. I'm not sure why anyone would be against further studies yet somehow that is always the conclusion the researchers come to - hypocortisolism is present but the hormones shouldn't be replaced. That just seems nuts to me.

It's true that I'm happier off steroids for the moment. But I'm having another stim test next week and if it's low again, you can bet your bottom dollar I'll be back on the steroids that very same evening. Steroid treatment got me out of bed once and I'm sure as heck going to try it again if testing shows it is warranted.

Between this and the CBT reference, I think I've found this week's birdcage liner. Ugh.

Ema

 

[Legendrew]

From reading the paper I suspect that the proposed dysregulation of the Hypothalamic-Pituitary-Adrenal Axis is likely a consequence of the ongoing disease process and is not causative. The link with POTS appears to be a standout point made by the paper, from a personal view I suspect that the vascular issues in ME are likely much more central than this. Still, an interesting hypothesis and could be a potential target for some symptomatic relief.


As I say this is a personal view for the disease I myself experience and is unlikely to be universal given the numerous diseases likely under the heading of ME/CFS. For me too much exercise gives me awful dizziness and nausea along with the PEM for a few days later. I remember when I was withdrawing from university I had to walk half a mile from the finance office back to my halls of residence, it was a relatively warm day and by the time I got back I was dizzy, disorientated and felt nauseous. It took a good hour before the room stopped spinning and I could even sit up without vomiting. To me, this experience cemented in my mind that the problem for me lies with vascular problems and is supported by my low blood pressure at every reading (Strangely last time I had it taken it was 120:55 which the doctor thought nothing of.) Thankfully mu POTS type symptoms are barely noticeable so long as I pace myself although it means i'm housebound for 5-6 days a week.

With regard to the CBT/GET remark, I suspect this is likely a passing comment and from my personal reading it appears to be a brief mention to the area as opposed to broad point being made.

A vascular aetiology of CFS has also been proposed. This is a current research interest of our group and is exemplified by the relationship and overlap between CFS and postural orthostatic tachycardia syndrome (POTS) [79, 80] which typically presents with fatigue, dizziness, and an inability to exercise. HPA axis dysregulation, particularly hypocortisolaemia, can cause hypotension and may possibly mediate the fatigue experienced by CFS patients by inducing orthostatic hypotension and hence reducing cerebral perfusion [81].

 

[MeSci]

My personal feelings about this are along the lines of that when we are in a position of having to carry on, despite feeling we need to stop, that it is an adrenalin rush/surge that gets us through it.

A social situation, just being with people, is more than enough to get my adrenalin going like mad. I go completely manic after a few days of it.

I strongly suspect we do (ab)use stress and adrenalin surges, just to get by.

Me too. I suspect that that is why I appear to have less energy since starting my diet and supplements last year. I'm accepting it as a hopefully-temporary stage, as everything else is improved, including sleep, and I do feel considerably calmer, so a reduction in adrenaline production or receptor activity is a very plausible reason. I'm assuming that I can trust the energy I have more than before, as it is less likely to be 'false' energy. This means that I am less likely to over-exert myself, and pacing is generally easier.

 

[MeSci]

The ACTH stimulation test misses about half of those with secondary adrenal insufficiency which makes it a terrible screening test. Yet it's all we've got at the moment. These are the REAL problems here that need to be addressed - we need better testing to assess adrenal function and we need to accept that one can have partial adrenal insufficiency just the same way that one can have pre-diabetes.

I think it says something when we have terrible testing but abnormalities in cortisol metabolism are still always apparent when HPA axis function is studied in our population. Not one study has ever said that we have normal cortisol metabolism. They just can't figure out what to do about it outside of therapy apparently.

The rationale for the ACTH stimulation test appears stupidly simplistic to me. The doctors think that we may have a problem producing cortisol. But it doesn't appear to occur even to some top endocrinologists (such as the one I saw) that the problem producing cortisol may be due to a problem producing ACTH. So we may respond normally to exogenous ACTH, and produce cortisol. If we don't produce enough of our own ACTH, or produce it at the wrong times, our day-to-day cortisol will continue to be abnormal.

I don't think that HPA axis dysregulation and hypocortisolism are the cause of ME/CFS but they certainly are a symptom. And they are a symptom that can be successfully relieved in many cases by using physiological replacement doses of steroid hormones. I'm not sure why anyone would be against further studies yet somehow that is always the conclusion the researchers come to - hypocortisolism is present but the hormones shouldn't be replaced. That just seems nuts to me.

I think that HPA axis dysregulation and hypocortisolism could be part of a perpetuating loop.

 

[MeSci]

The rationale for the ACTH stimulation test appears stupidly simplistic to me. The doctors think that we may have a problem producing cortisol. But it doesn't appear to occur even to some top endocrinologists (such as the one I saw) that the problem producing cortisol may be due to a problem producing ACTH. So we may respond normally to exogenous ACTH, and produce cortisol. If we don't produce enough of our own ACTH, or produce it at the wrong times, our day-to-day cortisol will continue to be abnormal.

Replying to myself here - I did a lot of reading-up on the HPA axis a few years ago, and made a file of some of the relevant papers I found.

One is here, and says:

Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH). Because CRH and vasopressin secreted from the hypothalamus act synergistically at the pituitary to activate ACTH secretion, the ACTH response to peripheral infusion of vasopressin can provide an indirect measure of hypothalamic CRH secretion. We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome.

(For those not familiar with the sequence of cortisol production, it goes:

CRH leads to ACTH which leads to cortisol.)

Here is another, which concludes

DDAVP augments CRH-mediated pituitary-adrenal responsivity in healthy subjects and in patients with CFS. That DDAVP was capable of normalizing the pituitary-adrenal response to oCRH in the CFS group suggests there may be increased vasopressinergic responsivity of the anterior pituitary in CFS and/or that DDAVP may be exerting an effect at an adrenal level.

(DDAVP is aka desmopressin.)

Here is another, which says

The blunted response of ACTH to exogenous CRH stimulation may be due to an abnormality in CRH levels with a resultant alteration in pituitary CRH receptor sensitivity, or it may reflect a dysregulation of vasopressin or other factors involved in HPA regulation. A diminished output of neurotrophic ACTH, causing a reduced adrenocortical secretory reserve, inadequately compensated for by adrenoceptor upregulation, may explain the reduced cortisol production demonstrated in this study.

This paper says

At 24:00 and 04:00 hrs the CFS patients showed lower ACTH levels than healthy subjects

I think that's enough to be going along with. The ACTH-stimulation/'Synacthen' test is pointless in ME/CFS. I think I found one paper that suggested a modified version, but don't have the energy to seek that one out right now.

 

[peggy-sue]

Oh, for that to be described in a diagram using easy to understand boxes and arrows.....

Thanks, MeSci.

 

[MeSci]

Oh, for that to be described in a diagram using easy to understand boxes and arrows.....

Thanks, MeSci.

I expect there are some diagrams online. I can hopefully explain any bits people don't understand, although I think you have studied science too.

I was trying to find connections between adrenaline and cortisol in files I have saved, but ran out of energy before I finished looking at my search results. At least I found some answers to the question of why we pass the ACTH stim tests with flying colours, and hopefully people can print that stuff off and wave it at any doctors who want to do the test, or who quote their results as evidence that there's nothing wrong with our HPA axis. You tell 'em!

 

[peggy-sue]

I shall dig out my OU text books.
All this stuff is laid out nicely in flow diagrams - which I once used to know off by heart...
I might be a couple of days - I'm getting visitors tomorrow.

 

[MeSci]

I expect there are some diagrams online. I can hopefully explain any bits people don't understand, although I think you have studied science too.

I was trying to find connections between adrenaline and cortisol in files I have saved, but ran out of energy before I finished looking at my search results. At least I found some answers to the question of why we pass the ACTH stim tests with flying colours, and hopefully people can print that stuff off and wave it at any doctors who want to do the test, or who quote their results as evidence that there's nothing wrong with our HPA axis. You tell 'em!

This document has quite a good diagram of the HPA axis.

 

[Snow Leopard]

I think that's enough to be going along with. The ACTH-stimulation/'Synacthen' test is pointless in ME/CFS. I think I found one paper that suggested a modified version, but don't have the energy to seek that one out right now.

I did a great deal of research on this stuff a while back as the whole picture did not make sense to me.

Several interesting findings: ACTH itself is found to be overall low, even in the absence of specific suppression or stimulation tests.

In addition, GC receptor gene expression was found to be downregulated, rather than upregulated. Likewise GCR levels overall tend to be normal or very slightly low, rather than unregulated.

Likewise, CRHR1/CRHR2 have not be identified as being expressed abnormally in gene expression studies.

The abnormality does not seem to be the bodies ability to produce cortisol at these end points.

Either patients consistently have lower expected stress levels than controls (not as unexpected as it may sound), or something else is at play.

To me, all evidence points to downstream abnormalities, including interfering with vasopressin regulation or something else dysregulating the system and that the classical neuroendocrine model is too simplistic.