Attenuated Morning Salivary Cortisol Concentrations in a Population-Based Study of CFS, 2008, Nater, Boneva, Reeves et al

[Hutan]

https://academic.oup.com/jcem/article/93/3/703/2598104?login=false
Attenuated Morning Salivary Cortisol Concentrations in a Population-Based Study of Persons with Chronic Fatigue Syndrome and Well Controls

Urs M. Nater, Elizabeth Maloney, Roumiana S. Boneva, Brian M. Gurbaxani, Jin-Mann Lin, James F. Jones, William C. Reeves, Christine Heim

Abstract
Context: A substantial body of research on the pathophysiology of chronic fatigue syndrome (CFS) has focused on hypothalamic-pituitary-adrenal axis dysregulation. The cortisol awakening response has received particular attention as a marker of hypothalamic-pituitary-adrenal axis dysregulation.

Objective: The objective of the current study was to evaluate morning salivary cortisol profiles in persons with CFS and well controls identified from the general population.

Design and Setting: We conducted a case-control study at an outpatient research clinic.

Cases and Other Participants: We screened a sample of 19,381 residents of Georgia and identified those with CFS and a matched sample of well controls. Seventy-five medication-free CFS cases and 110 medication-free well controls provided complete sets of saliva samples.

Main Outcome Measures: We assessed free cortisol concentrations in saliva collected on a regular workday immediately upon awakening and 30 and 60 min after awakening.

Results: There was a significant interaction effect, indicating different profiles of cortisol concentrations over time between groups, with the CFS group showing an attenuated morning cortisol profile. Notably, we observed a sex difference in this effect. Women with CFS exhibited significantly attenuated morning cortisol profiles compared with well women. In contrast, cortisol profiles were similar in men with CFS and male controls.

Conclusions: CFS was associated with an attenuated morning cortisol response, but the effect was limited to women. Our results suggest that a sex difference in hypocortisolism may contribute to increased risk of CFS in women.

 

[Hutan]

This is an old study, but it's part of a body of work that seems responsible for a lot of what I think are poorly evidenced assumptions about ME/CFS. It is also focused on a bugbear of mine - cortisol.

Criteria:

As in previous CDC population-based CFS studies (23, 32), CFS was defined by 1) a score of at least 13 on the general fatigue scale or at least 10 on the reduced activity scale of the MFI; 2) a score of no more than 70 in the physical function or no more than 50 role physical, or no more than 75 social function, or no more than 67 role emotional scales of the SF-36; and 3) at least four CFS defining symptoms and a score at least 25 on the SI (n = 113). Those who met none of the criteria were considered to be well (n = 124).

They note that previous studies have been contradictory:

In a previous study of a population-based sample of CFS subjects in Wichita, Kansas, we observed a flattened diurnal salivary cortisol curve; those with CFS had lower morning concentrations and higher evening concentrations than matched nonfatigued controls (19). Few other studies have evaluated morning salivary cortisol profiles, and the results have been contradictory (20, 21). Two studies have reported on 24-h serum cortisol in patients with CFS or fibromyalgia and healthy controls and found no substantial differences within the awakening time frame (22, 23).

Morning saliva collection:

Subjects were instructed to collect saliva on a regular workday within 3 d of their clinic visit by using Salivettes (Sarstedt, Newton, NC). They collected saliva immediately upon awakening (while still lying in bed) and 30 and 60 min later, recorded the collection times, and stored the salivettes in their refrigerators.

1) The cortisol awakening response was computed by subtracting the awakening time point from the peak after 30 min (8).

Study size:

Seventy-five people with CFS and 110 well controls (who were not taking medications known to influence endocrine or immune function) provided complete sets of morning saliva samples and fulfilled compliance criteria as defined above.

 

[Hutan]

Results

Salivary cortisol concentrations averaged across all three time points did not differ significantly between the two groups [F(1,177) = 0.19; P = 0.666].

The differences in the two cortisol profiles (CFS and healthy) are fairly minimal (that y axis is cut). The small difference in peak cortisol is easily explained by differences in typical morning activity demands. We have seen that bodies get used to activity levels, with cortisol levels being tailored to the demands. There is also evidence that early morning awakening produces a higher cortisol awakening response, which is more likely to be happening in the healthy (and working) group.

Normal awakening cortisol levels are 5 to 25 micrograms per deciliter (mcg/dL). The unit in the chart in this study is g/dL - I don't know if that chart is right, it doesn't seem right. But if you just look at the normal range - there's a really big range. And then if you look at figures in the chart, there's really very little separation between the means of the two groups.

 

[Hutan]

These results suggest that among the CFS group, lower cortisol awakening response was associated with worse physical fatigue.

This finding fits with the scenario of people who don't have to rush out to work (the more ill people with CFS) having a slightly lower morning cortisol response.

Normal values for a blood sample taken at 8 in the morning are 5 to 25 mcg/dL or 140 to 690 nmol/L. Normal values depend on the time of day and the clinical context. Normal ranges may vary slightly among different laboratories.

Awakening levels are about 5 g/dL in the chart. They said that they log transformed the data in order to analyse it, but reported actual values. But I can't see how they came up with 5g/dL - that's really different to the values reported by lots of references for morning cortisol. I'd appreciate it if someone could look at the paper and normal values, and see what they think.

 

[Dolphin]

Criteria:
As in previous CDC population-based CFS studies (23, 32), CFS was defined by 1) a score of at least 13 on the general fatigue scale or at least 10 on the reduced activity scale of the MFI; 2) a score of no more than 70 in the physical function or no more than 50 role physical, or no more than 75 social function, or no more than 67 role emotional scales of the SF-36; and 3) at least four CFS defining symptoms and a score at least 25 on the SI (n = 113). Those who met none of the criteria were considered to be well (n = 124).

These are the empiric criteria which are rubbish. For example, one could score 100 out of 100 on SF-36 physical functioning and still qualify if one had a lowish score on SF-36 emotional functioning as people with depression might. Other criteria are also loose.

 

[ukxmrv]

This finding fits with the scenario of people who don't have to rush out to work (the more ill people with CFS) having a slightly lower morning cortisol response.

The problem with assuming this is we don't actually know how this would change. My experience is that my morning cortisol has been low over decades and was also low at the time I was having to get up and go to work. For me it isn't any different at the times I was at home and unable to work.

 

[bobbler]

This is an old study, but it's part of a body of work that seems responsible for a lot of what I think are poorly evidenced assumptions about ME/CFS. It is also focused on a bugbear of mine - cortisol.

Criteria:


They note that previous studies have been contradictory:


Morning saliva collection:


Study size:

Subjects were instructed to collect saliva on a regular workday within 3 d of their clinic visit by using Salivettes (Sarstedt, Newton, NC).

So they all had to do a trip to the clinics then at some point in the next 3 days get up in the morning - so they will likely have over-exerted themselves with the visit itself and depending on individual situation will be in 'some form of' PEM - whether it is pre- (before the symptoms of crash really kick in but might be in the over-exerted, can't rest well phrase) or in the throngs of it is said person gets PEM that lasts or whatever. We know so little about PEM.

TO then talk about comparisons with other studies, without detailing the timings of those (which I guess they'd have been distracted by/functionedly-fixed on the cortisol-related timings instead of the PEM ones) just shows the naivity back then.

This is one where (whatever your opinion might be of the topic/area specifically) I think it flags the issue with 'knowing who and what they are studying in the patient and illness' with regards ME/CFS and PEM/stage of exertion.

That's why the reviews of literature become nonsense for this area - with what we know is likely to be really bad samples in general particularly where larger numbers have been recruited, and the definition is used flimisily.

 

[bobbler]

The problem with assuming this is we don't actually know how this would change. My experience is that my morning cortisol has been low over decades and was also low at the time I was having to get up and go to work. For me it isn't any different at the times I was at home and unable to work.

Agreed. My synacthen measures were almost identical 12years apart. Different working position (very full time -> nothing), exertion levels (if you only count 'what I do' and not the noise/vibration pollution + just basic tasks to survive vs severe ME I guess, I'd call that 'relative exertion (to threshold/limit)' and not what that bunch would try and infer was 'perceived' which is of course nonsense because I can 'see' how much a task is, then I 'know/observe' how my body is after that - the rude gits) and health/disability at those points (though had ME for both)

 

[Medfeb]

These are the empiric criteria which are rubbish. For example, one could score 100 out of 100 on SF-36 physical functioning and still qualify if one had a lowish score on SF-36 emotional functioning as people with depression might. Other criteria are also loose.

This! The relation of these findings to ME is impossible to discern

 

[Hutan]

The problem with assuming this is we don't actually know how this would change. My experience is that my morning cortisol has been low over decades and was also low at the time I was having to get up and go to work. For me it isn't any different at the times I was at home and unable to work.

Well, we know that, on average, habitual activity demands do affect cortisol levels, and quite quickly. That's not to say that every person diagnosed with ME/CFS has entirely normal cortisol levels. It's just that, when we look at the published data, there really isn't anything solid to suggest that people with ME/CFS are characterised by abnormal cortisol levels.

 

[Hutan]

So they all had to do a trip to the clinics then at some point in the next 3 days get up in the morning - so they will likely have over-exerted themselves with the visit itself and depending on individual situation will be in 'some form of' PEM - whether it is pre- (before the symptoms of crash really kick in but might be in the over-exerted, can't rest well phrase) or in the throngs of it is said person gets PEM that lasts or whatever. We know so little about PEM.

They did the saliva samples at home.

 

[bobbler]

They did the saliva samples at home.

Yes but at a point where they are in PEM from the visit. And with other studies that context of exertion in the run up (from a PEM perspective not just ‘cortisol’ that they might be focusing on - and from cortisol ie from a non-ME ‘exertion’ level /assumption re eg getting somewhere or sitting waiting in a chair for half an hour can be a lot) is relevant to know whether or not that is ‘interacting’.

 

[bobbler]

Well, we know that, on average, habitual activity demands do affect cortisol levels, and quite quickly. That's not to say that every person diagnosed with ME/CFS has entirely normal cortisol levels. It's just that, when we look at the published data, there really isn't anything solid to suggest that people with ME/CFS are characterised by abnormal cortisol levels.

I agree that looking at single cortisol levels seems really old hat as a measure given what we know about what cortisol is (reactive, apparently cyclical, affected by illness or injury states, pulsatory). Then adding in a ‘blob’ for the me/cfs bit re:the exertion vs threshold and PEM and times of day (many in PEM will find mornings harder than if not in PEM) it’s difficult to say there could be anything taken from averages without controlling for or at least noting a few of those elements. It was worth doing back then maybe on the off chance a quick crude check didn’t show massive significant differences but it’s not the same as if this has been part of the design for example if it were after pwme who weren’t so severe they have recovered from PEM if they had two weeks of rest post-visit and it was done then etc.

 

[Mithriel]

When Reeves was in charge of CFS studies at the CDC it was a low point for us. I remember someone looked at his patient cohort and showed how it was possible there was not a single person who had what we would now call ME/CFS.

The research from that time does not contain any information that would be useful for us. Sometimes you come across some of his findings being quoted and it infuriates me; he poisoned the well.