Cortisol levels in ME/CFS

I did a salivary cortisol test (four samples throughout the day) quite a long time ago and my cortisol was well over the range in 3 out of the 4 samples, and 90% of the way through the range for the sample that wasn't over the range.

Much more recently I had my first ever blood cortisol test done at around 8.30am - 9am and that was over the range too.

I have read that very high stress can cause high cortisol and if the high cortisol lasts long enough then it becomes the patient's new "normal". If that is true then I wonder what causes cortisol to become low.
 
Post-COVID-19 condition in prospective inpatient and outpatient cohorts (2025, Scientific Reports)
PCC patients were manually distributed into three symptom clusters corresponding to their most dominant self-reported symptoms according to Global Burden of Disease Long COVID Collaborators guidelines (supplementary information).

Shortly, persistent fatigue with myalgia or mood swings (cluster 1) included bodily pain (myalgia), weakened muscular strength, numbness and tingling, fatigue, and mood disturbances.

Cognitive problems (cluster 2) included attention deficit and cognitive difficulties, and

ongoing respiratory problems (cluster 3) included exertional and resting dyspnea, persistent cough, and thoracic pain.
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During the 24-month follow-up, cluster 2 patients had lower cortisol levels than those belonging to clusters 1 and 3 (Supplementary Fig. 10 C). Twelve months post-infection, the difference was statistically significant (179 vs. 290 nmol/l, p = 0.031, and 179 vs. 351 nmol/l, p = 0.054). However, while the trend was similar throughout the follow-up, the differences did not reach statistical significance at any other time point, likely due to the small subgroup sizes.
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Between all long COVID (PCC) and healthy, it seems cortisol was only lower at the acute phase. Figure 4C:
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The overall cortisol levels were significantly lower in the acute phase – especially among inpatients with a severe disease. This can result from treatment with corticosteroids, suppressing endogenous cortisol production. However, we did not collect the samples uniformly at the same time of the day, resulting in increased variation in cortisol levels.
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Post-COVID-19 condition in prospective inpatient and outpatient cohorts (2025, Nature Scientific Reports)

In the whole group, spirometry results, orthostatic hypotension, or levels of soluble suppression of tumorigenicity 2, interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), or cortisol had no association with PCC. However, using symptom clusters, patients with cognitive problems had lower cortisol levels, while patients with ongoing respiratory or myalgic symptoms had higher levels of IL-6 and hs-CRP.
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Cortisol Patterns Are Associated with T Cell Activation in HIV, 2013, Patterson et al
Abstract

Objective
The level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.

Methods
We studied 128 HIV-infected adults who were not on treatment and had a CD4+ T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.

Results
Lower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4+ T cells (r = −0.26, p = 0.006). Participants with lower waking cortisol also showed a trend toward greater activation on CD8+ T cells (r = −0.17, p = 0.08). A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4+ (r = 0.24, p = 0.018) and CD8+ (r = 0.24, p = 0.017) activation.

Conclusions
These data suggest that the hypothalamic-pituitary-adrenal (HPA) axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV.
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This was interesting. They found the same pattern of lower waking cortisol levels that are reported in ME/CFS and found that it was associated with the level of T-cell activation.

I guess it is possible that lower waking cortisol levels are part of the sickness reponse. So, if your t-cells are activated, you are sick and it's probably not a good idea to be waking up, raring to get into your day. Instead, it's better to go 'ugh' and keep lying in bed. So there is some mechanism where activated t-cells (or some other response to the cause of the activated t-cells) dampens down the morning cortisol spike.

However, it's also possible that people with uncontrolled HIV feel pretty rubbish and aren't working and are spending more time in bed. And so perhaps it is their lifestyle (if I can call it that - the lifestyle of someone who is sick) that results in the lower waking cortisol. They routinely aren't leaping out of bed early in the morning, and so their cortisol production adjusts.

I don't think the authors have it right when they suggest psychological states influence progression of HIV. Rather, I suspect the causal mechanism goes in the other direction - the response to the virus makes you feel sick and possibly depressed, so you don't rush around in the morning, you sleep later - so you don't need that morning cortisol burst. And you probably don't load up on coffee first thing in the morning, which can also contribute to a morning cortisol spike.
 
Hutan said:
I don't think the authors have it right when they suggest psychological states influence progression of HIV. Rather, I suspect the causal mechanism goes in the other direction - the response to the virus makes you feel sick and possibly depressed, so you don't rush around in the morning, you sleep later - so you don't need that morning cortisol burst. And you probably don't load up on coffee first thing in the morning, which can also contribute to a morning cortisol spike.
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I agree that's such a weird framing. And I think it ignores the most obvious connection: that T cell activation modulates the HPA axis directly, independent of "psychological stressors." I continually see this weird insistent belief that HPA axis activity must somehow only be influenced by psychosocial stress and that changes in its activity must somehow be indicative of psychosocial stress. But it's a system that responds to a million and one things, psychosocial stress or lifestyle being only one
 
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