The neuroendocrinology of chronic fatigue syndrome, 2003, Cleare

[Hutan]

Abstract
Chronic fatigue syndrome (CFS) is a common and disabling problem; although most likely of biopsychosocial origin, the nature of the pathophysiological components remains unclear. There has been a wealth of interest in the endocrinology of this condition, which will be reviewed in this article. Most studied has been the hypothalamic-pituitary-adrenal (HPA) axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis.

Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication, and ongoing stress, it seems likely that HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS. Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear.

To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.


Link paywall

 

[Hutan]

Forestglip notes about this review:

For the cited review, I didn't look too closely, but Table 1 has 17 studies. Out of these, 9 found lower cortisol in CFS, 7 found no difference, and 1 found higher cortisol.

 

[forestglip]

These 17 reviewed studies are actually split across tables 1, 2, and 3. I thought it was one big table. The tables are looking at different cortisol measurements: blood, saliva, and urine. And there are a few repeat studies between tables, so it's fewer than 17 unique studies. But here are those tables:


And what it says about this:

Six studies were identified in which either serial samples were taken to evaluate morning (33) or evening (17) cortisol levels, or samples were taken over an extended period of the day (34 –37). Table 1 lists these studies. An additional six studies were identified that measured urinary free cortisol (UFC) in 24-h samples of urine (Refs. 17, 30, 35, and 38 – 40 and Table 2). Finally, five studies have used salivary cortisol measures (Refs. 40 – 43 and Table 3).

Summarizing these results, about half of the studies found some evidence for lowered cortisol levels at some point in the day. In terms of the methods of HPA axis assessment, the most striking results have been found with the studies of UFC. Indeed, the largest study of the HPA axis to date, which recruited 121 patients, found lowered levels of free cortisol (Ref. 39 and Fig. 1). On the plus side, these studies have (cumulatively) the largest number of participants. However, on the negative side, there are problems with using UFC measures. For example, it has been argued that 24-h UFC is an unreliable indicator of HPA activity (44). Assays for cortisol have a large variability at the lower end of the spectrum, making its use for detecting low levels less precise. Furthermore, free cortisol only represents 2–3% of the circulating cortisol metabolites (45); thus, any shift in cortisol metabolic pathways could potentially affect the measured UFC even if there were no change in cortisol production. Such a change has not been found in CFS to date when looked at (N. Taylor, personal communication) but can occur in major depression (46). It has also been proposed that commercially available kits for assessing UFC may systematically overestimate UFC in urine (47). One would like, therefore, to see corroboration from other methods. The results using salivary cortisol, which has several advantages [e.g., a noninvasive collection method, ability to be undertaken in naturalistic settings, measuring biologically active free cortisol (48)] are clearly less supportive, and those using blood intermediate.

 

[forestglip]

Preliminary reports from a recent meta-analysis of all studies of 24-h UFC and morning and afternoon plasma cortisol levels found a moderate overall effect size for reduced 24-h UFC (0.73) and morning cortisol (0.35) but with substantial heterogeneity between studies and larger effects sizes in samples recruited from tertiary compared with primary care (49). There were no differences in afternoon plasma cortisol levels. However, without additional details upon publication of this meta-analysis, it is difficult to assess what criteria were used in choosing studies. At present, there is insufficient evidence to make differential assessments of specific alterations in cortisol levels at specific times of the day.

49 is this conference paper, but I don't think there's an abstract:
Are Cortisol Levels Low in Chronic Fatigue Syndrome?: A Meta-analysis, 2002, Harvey et al

 

[Nightsong]

49 is this conference paper, but I don't think there's an abstract:

A. Harvey, G. Purdie, J. Bushnell, P. Ellis
Department of Psychological Medicine,
Wellington School of Medicine and Health Sciences,
University of Otago,
NZ

Are cortisol levels low in Chronic Fatigue Syndrome?: A meta-analysis

A number of studies suggest that cortisol may be lower in Chronic Fatigue Syndrome (CFS) than in healthy controls, whereas other studies have reported less convincing results.

Aim
To conduct a meta-analysis aimed at determining the status of hypocortisolism in CFS.

Methods
Literature searches were carried out using Medline, PsycLIT, EMBASE, PsycINFO and relevant articles in peer reviewed journals. Inclusion criteria were; application of either the CDC (1988, 1994) or the Oxford (1991) diagnostic criteria, and comparable healthy controls. To investigate sources of heterogeneity, the test statistic Q was applied to the data. 24-hr UFC cortisol measures were compared with am and pm plasma cortisol samples and clinical variability was examined by performing a separate analysis on studies that had recruited patients through tertiary care providers as opposed to primary care.

Results
14 published studies (k) were found that met the inclusion criteria; n=344 CFS patients and n=272 healthy controls. A significant (p<0.0001) low to moderate effect size was found (-0.36) for reduced basal cortisol levels in CFS. However, there was significant heterogeneity amongst the studies (p<0.0001). Investigation of methodological differences revealed that 24-hr urinary cortisol were better at measuring basal cortisol levels, increasing the effect size (EF = -0.73, k=4), although there was still significant heterogeneity (p<0.01). Morning plasma cortisol levels also showed a significant effect size (EF = -0.35, k=4), substantially reducing the heterogeneity (p=0.50). Afternoon and evening plasma samples were unable to distinguish between groups (EF = 0.01, k=7), the heterogeneity was also reduced (p=0.045). Analysis of 7 studies that reported recruiting patients from tertiary care increased the effect size (EF = -0.63), although there was significant heterogeneity (p<0.01).

Conclusion
Reduced basal cortisol levels are relevant to the experience of Chronic Fatigue Syndrome. Patients seen in tertiary care perhaps show more endocrine abnormalities and clinical methodologies seem to be important in assessment procedures.

 

[Creekside]

Reduced basal cortisol levels are relevant to the experience of Chronic Fatigue Syndrome.

If cortisol levels are relevant, why doesn't supplemental cortisol reduce the symptoms?

 

[bobbler]

A. Harvey, G. Purdie, J. Bushnell, P. Ellis
Department of Psychological Medicine,
Wellington School of Medicine and Health Sciences,
University of Otago,
NZ

Are cortisol levels low in Chronic Fatigue Syndrome?: A meta-analysis

A number of studies suggest that cortisol may be lower in Chronic Fatigue Syndrome (CFS) than in healthy controls, whereas other studies have reported less convincing results.

Aim
To conduct a meta-analysis aimed at determining the status of hypocortisolism in CFS.

Methods
Literature searches were carried out using Medline, PsycLIT, EMBASE, PsycINFO and relevant articles in peer reviewed journals. Inclusion criteria were; application of either the CDC (1988, 1994) or the Oxford (1991) diagnostic criteria, and comparable healthy controls. To investigate sources of heterogeneity, the test statistic Q was applied to the data. 24-hr UFC cortisol measures were compared with am and pm plasma cortisol samples and clinical variability was examined by performing a separate analysis on studies that had recruited patients through tertiary care providers as opposed to primary care.

Results
14 published studies (k) were found that met the inclusion criteria; n=344 CFS patients and n=272 healthy controls. A significant (p<0.0001) low to moderate effect size was found (-0.36) for reduced basal cortisol levels in CFS. However, there was significant heterogeneity amongst the studies (p<0.0001). Investigation of methodological differences revealed that 24-hr urinary cortisol were better at measuring basal cortisol levels, increasing the effect size (EF = -0.73, k=4), although there was still significant heterogeneity (p<0.01). Morning plasma cortisol levels also showed a significant effect size (EF = -0.35, k=4), substantially reducing the heterogeneity (p=0.50). Afternoon and evening plasma samples were unable to distinguish between groups (EF = 0.01, k=7), the heterogeneity was also reduced (p=0.045). Analysis of 7 studies that reported recruiting patients from tertiary care increased the effect size (EF = -0.63), although there was significant heterogeneity (p<0.01).

Conclusion
Reduced basal cortisol levels are relevant to the experience of Chronic Fatigue Syndrome. Patients seen in tertiary care perhaps show more endocrine abnormalities and clinical methodologies seem to be important in assessment procedures.

What’s tertiary care?

 

[SNT Gatchaman]

What’s tertiary care?

Primary care is seeing eg a GP or after hours clinic in the community. You refer yourself to primary care.
Secondary care is when your primary doctor would like help/advice and refers you to a specialist, so that could be a private specialist while still in the community or in a public outpatient clinic.
Tertiary care is hospital level inpatient capability, with eg advanced resuscitation, theatre, imaging and intensive care capabilities.
Quartenary care is typically a regional centre that does less common procedures not available in all hospitals.

An example of quartenary level would be cardiac or liver transplantation. You want to concentrate the experience of uncommon cases in a few people who then become skilled.* Quartenary can also be considered as a referral centre for other countries in relative proximity, even if those cases could in theory be handled at other tertiary hospitals in the assisting country.

There are similar levels for things like neonatal ICU (relevant in the recent Letby case, where the NICU was only level 2 capable but trying to handle level 3 babes) or trauma centres that can handle mass casualty events or complex multi-trauma in individuals.

---
* Mistakes -> experience, experience -> less mistakes.

In the ME/CFS world, very severe patients requiring nutritional support are not commonly seen in hospitals, so the teams largely seem to flounder, having never experienced a case. Typically great harm ensues and I am tracking a couple of such cases currently here.

I think there's a strong argument for a national centre in countries like the UK/NZ. I accept that that would mean travelling up front, but if the result was meaningful care in a specialised, low stimulus environment, staffed by a team that understood all the aspects highlighted by Jo in his Qeios papers and elsewhere, that would be very good for the patients.

You would then have the ability to enrol the patients into research studies, so that the #alltestsarenormal in those mild enough to get themselves to a community lab for blood tests or imaging studies, might just have a better chance of hitting on important and overlooked abnormalities.

 

[bobbler]

Primary care is seeing eg a GP or after hours clinic in the community. You refer yourself to primary care.
Secondary care is when your primary doctor would like help/advice andrefers you to a specialist, so that could be a private specialist while still in the community or in a public outpatient clinic.
Tertiary care is hospital level inpatient capability, with eg advanced resuscitation, theatre, imaging and intensive care capabilities.
Quartenary care is typically a regional centre that does less common procedures not available in all hospitals.

An example of quartenary level would be cardiac or liver transplantation. You want to concentrate the experience of uncommon cases in a few people who then become skilled.* Quartenary can also be considered as a referral centre for other countries in relative proximity, even if those cases could in theory be handled at other tertiary hospitals in the assisting country.

There are similar levels for things like neonatal ICU (relevant in the recent Letby case, where the NICU was only level 2 capable but trying to handle level 3 babes) or trauma centres that can handle mass casualty events or complex multi-trauma in individuals.

---
* Mistakes -> experience, experience -> less mistakes.

In the ME/CFS world, very severe patients requiring nutritional support are not commonly seen in hospitals, so the teams largely seem to flounder, having never experienced a case. Typically great harm ensues and I am tracking a couple of such cases currently here.

I think there's a strong argument for a national centre in countries like the UK/NZ. I accept that that would mean travelling up front, but if the result was meaningful care in a specialised, low stimulus environment, staffed by a team that understood all the aspects highlighted by Jo in his Qeios papers and elsewhere, that would be very good for the patients.

You would then have the ability to enrol the patients into research studies, so that the #alltestsarenormal in those mild enough to get themselves to a community lab for blood tests or imaging studies, might just have a better chance of hitting on important and overlooked abnormalities.

Thanks it’s because it’s in the method of then analysing these separately and I couldn’t work out if that was due to increased capability ie then being able to do 24hr cortisol or separated due to level of illness to end up there , or both?

 

[Snow Leopard]

People can hate me for saying this or whatever, but Cleare's 2003 review was actually quite decent for the time and there hasn't been much progress on this topic since.

 

[Kitty]

Is it likely there's a relationship between cortisol levels and the adrenaline response that leaves some pwME/CFS entirely unable to sleep (despite feeling exhausted) after over-exerting?

It might be a daft question, I don't really understand this stuff. But it's a very distinctive symptom, and it's not the same as a healthy person going to a concert and being so wowed by the performances that it takes a while to wind down afterwards.


[Edited slightly to tidy up]

 

[Arnie Pye]

Is it likely there's a relationship between cortisol levels and the adrenaline response that leaves some pwME/CFS entirely unable to sleep (despite feeling exhausted) after over-exerting?

Ever since I started looking into and testing my own cortisol levels I have come to the conclusion that my almost life-long severe insomnia was caused by high cortisol. But I am aware that I've never had a test for my adrenaline levels, and have no idea if anyone ever tests adrenaline, or if such a test is even available.

I assumed that cortisol was something that stayed fairly static, although obviously it could have long-term changes up or down. But adrenaline was something that I thought went up and down quite rapidly when someone was stressed.

My cortisol has been over the range for a long time, although I think it has reduced a little bit over the years - and my insomnia is not quite such a severe problem as it used to be. But it does feel as if it is on a knife edge and it wouldn't take much to bring it back.

I have tested my cortisol in saliva, and that was way over the range. But when tested in blood my cortisol is only slightly over the range. I don't know what that means for my health.

 

[Hutan]

I assumed that cortisol was something that stayed fairly static, although obviously it could have long-term changes up or down. But adrenaline was something that I thought went up and down quite rapidly when someone was stressed.

Cortisol levels are radically different depending on what time of day you test (specifically, how long after your usual wake up time and your latest wake up time). And other things seem to affect it such as pain and other stressful events.

Cortisol levels also change to match the level of physical activity - that seems to happen over a few weeks.

 

[Snow Leopard]

Is it likely there's a relationship between cortisol levels and the adrenaline response that leaves some pwME/CFS entirely unable to sleep (despite feeling exhausted) after over-exerting?

It's hypothetically possible, they both have metabolic effects (in terms of regulating blood sugar etc).

But how do you know the insomnia is due to an adrenaline response?

 

[Kitty]

But how do you know the insomnia is due to an adrenaline response?

I don't, really. It's just that I feel the same as I do when nervous or if I've had a bit of fright. Thumping heart, brain on high alert, tense, butterflies, hands sometimes a bit trembly. People usually describe that as an adrenaline rush, though of course it's not usually a medical opinion!

 

[Arnie Pye]

Cortisol levels are radically different depending on what time of day you test (specifically, how long after your usual wake up time and your latest wake up time). And other things seem to affect it such as pain and other stressful events.

I'm familiar with the circadian rhythm of cortisol output. When I tested my cortisol with a saliva test it was one which required providing samples four times throughout the day. Every result except one was well over the range - and the one that wasn't over the range was very high in range. I've only had cortisol in blood tested once and that sample was taken at 8.30am which is roughly when doctors usually expect to see the maximum cortisol output of the day, and mine was over the range.

I've read that in Cushing's Disease cortisol testing doesn't produce the standard shape of graph throughout the day, instead it produces a much straighter, horizontal line at a high level. Since mine was never like that (the graph was the right shape it was just too high) I never bothered talking to a doctor about it because I was convinced they would have found a way to blame my mental health for it. But, personally, I blame an abusive childhood and doctors refusing to believe in or treat the excruciating pain I had as a result of botched surgery when I was a teenager. I was given the first pain relief that actually helped when I was 55. Doctors still automatically treat me as if I am a drug-seeking, attention-seeking, hypochondriacal liar every time they see me. So these days I only consider seeing them if I have a problem which is visible.

These attitudes are also why I would do everything humanly possible to reject a diagnosis of ME. It would never get me any more help with my health than I've had up to now.

Edit : That last paragraph is not intended to be disrespectful to people with ME. I think I have ME myself. I just don't want a formal diagnosis from a doctor because I have never been convinced that such a diagnosis is helpful to many people.

 

[Creekside]

And other things seem to affect it such as pain and other stressful events.

How much effect does environment and activity have on cortisol levels? I'm just wondering if measured levels could be misleading because the waiting room TV was showing aggressive sports vs something calming, or there was a pleasant person to chat with vs some really unpleasant person swearing abusively.