Cortisol levels in ME/CFS

[bobbler]

Throwing this link in here and hoping it is OK to the idea of the thread - although it seems to apply to measurement of hormones beyond just cortisol, I think it is interesting if the way things should be measured is indeed moving on:

Clinical Endocrinology—Time for a Reset?

research-information.bris.ac.uk

Clinical Endocrinology—Time for a Reset?​

Stafford L. Lightman* April 2024

Abstract​

Measurement of blood levels of circulating hormones has always been the cornerstone of the biochemical diagnosis of endocrine diseases, with the objective of detecting hormone excess or insufficiency. Unfortunately, the dynamic nature of hormone secretion means single-point measurements of many hormones often lack diagnostic validity. Endocrinologists have devised complex dynamic tests as indirect assessments of the functioning of the hormone system under investigation. Recent advances in the measurement of dynamic hormone changes across the day now offer an opportunity to reconsider whether there might be better ways both to diagnose and to monitor the therapy of endocrine conditions.

link to paper: https://academic.oup.com/jes/article/8/4/bvae024/7606556


Just scanned so far but there are interesting points that perhaps relate to other threads such as:

1. The first lesson is that if we have wearable sensor technology, we should be able to monitor a patient's hormone levels in their own home/work environment—which is, of course, what we actually want to know.

And the interesting part in the discussion before it (which included the issue of sleep affecting measures, but being something you'd want to measure as part of a cycle) reminded me of the dilemma we have with PEM vs exertion, influences impacting things and 'cycles' that we have with ME/CFS and experiments/tests that themselves involve eg travel or even just additional activity even if it was in the home (which then might necessarily cause compensation/change to other activities in a normal week in response)

 

[Sean]

And not just hormones either, I will bet. Homeostasis is certainly a thing, but it is a dynamic equilibrium on at least many measures (e.g. blood pressure).

When extended real-time collection of what are currently single point data can be done for days-months then a whole new set of patterns and understandings are likely to emerge, and help redefine health and sickness, and how to respond to it.

 

[Suffolkres]

Ah. I had not seen that. I think I now understand your previous comment about the low levels being related by some common artifactual influence. The apparent absence of cortisol in CSF makes no real sense as consequence of depleted CRH cells unless these cases are unusual instances of pre-terminal adrenal failure it seems. I think we need to see detailed published findings.

My husband demonstrated adrenal insufficiency, and did so in 2006 via saliva tests; hypothyroidism from plus 24 hour urinary collection testing. But NHS does not recognise these results done privately.

NHS Synthetic test did not show any abnormality.

Recent Cardioloy reviews also suggest secondary adrenal /thyroid problems as contributory to his symptoms pattern.

 

[forestglip]

This is on chronic fatigue, not ME/CFS, but it still may be interesting:

The association between hair cortisol levels, Epstein-Barr virus infections and chronic fatigue in adolescents, 2026, Kongsnes, Wyller et al

No association of pre-infection hair cortisol with 6 month chronic fatigue:

Preinfection hair cortisol concentration did not predict chronic fatigue six months after acute EBV infection.

Small correlation (R²=0.02) of higher chronic fatigue at 6 months with lower hair cortisol at 6 months:

A trend toward a positive association between preinfection hair cortisol and fatigue during acute infection, became significantly negative six months later.

 

[SNT Gatchaman]

Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS (2026)

Participants were slightly obese, predominantly women (76%), and with poor subjective health (e.g., mean quality of life 34 ± 14 on a 0-to-100 scale). Routine blood chemistry analyses did not reveal any general deviations from normal, as reflected by cortisol and C-reactive protein (CRP) levels in Table 1.

 

[forestglip]

A review of ME/CFS studies:

Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity, 2026, Woo et al (thread link)

We identified 46 case–control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls.

Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration.

 

[Jonathan Edwards]

A recent talk by Chris Pontng has been posted on the

Genetics: Chromosome 6 BTN2A2 and BTN3A3​

thread. He focuses in on HPA axis. We have already discussed a lot of the issues but I think this new talk provides a very nice focus for where things are at.

 

[SNT Gatchaman]

Analysis Of Salivary Herpesviruses Reveals Associations Between HHV-6 And Long COVID Severity (2026, Preprint)

To capture diurnal dynamics of hormone production, salivary cortisol and testosterone were measured at 4 morning time points (in 15-minute increments from waking), an afternoon time point (8 hours after waking), and an evening time point (16 hours after waking) over two consecutive days using ELISA. […] Cortisol peaked 15-30 minutes after waking and was secreted at similar levels in participants with LC and controls. To quantify total Cortisol Awakening Response (CAR), AUC was measured from waking levels to 45 minutes, and it did not differ between LC and Control. Total cortisol production over the course of the day measured with AUC trended lower in LC than Control but did not reach significance (p= 0.076). Morning and whole day cortisol was not associated with LC status, herpes viral shedding, sex, BMI, hormonal medication use, or time from infection when assessed using a linear model.

there were no significant relationships between salivary cortisol, testosterone or estradiol and LC status or [LC Propensity Score]. Although we observed a trend towards lower whole-day salivary cortisol in those with LC, this was not statistically significant. These observations contrast with previous findings by Klein et al. of lower serum cortisol in people with LC. The discrepancy may be explained by diverences in measurement of free vs. bound hormone between serum and saliva, the viral variant that triggered LC, vaccination status, or by the fact that participants were enrolled ~2 years after their initial infection in this study, a much later time from infection than Klein et al.

 

[richie]

My husband demonstrated adrenal insufficiency, and did so in 2006 via saliva tests; hypothyroidism from plus 24 hour urinary collection testing. But NHS does not recognise these results done privately.

NHS Synthetic test did not show any abnormality.

Recent Cardioloy reviews also suggest secondary adrenal /thyroid problems as contributory to his symptoms pattern.

Teitelbaum addressed this .
The 250 unit test. commonly used. fires up the adrenals to max out potential. Another test uses 1 unit . It is much better for the detection of subtle adrenal insufficiency , rather than response to single crisis events. The NHS knows and uses this test but it is fiddly. It is nevertheless recognised.: https://mft.nhs.uk/app/uploads/2024/09/Low-Dose-Synacthen-Test-v8.pdf.
https://www.gloshospitals.nhs.uk/ou...-and-investigations/short-synacthen-test-sst/.
With a 24hr low cortisol you might have a case for getting him a short synacthen test.

 

[Suffolkres]

He had the standard short Synachen Test done 250iugs
and they refused the low dose one recommended. I did ask!
I briefed them but they regarded me wirh suspicion or worse........

 

[Suffolkres]

Short Synacthen Test (SST)

www.gloshospitals.nhs.uk

 

[SNT Gatchaman]

Historical/Wessely paper from 1995, mentioned most recently in the Buspirone challenge thread.

Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome (1995)

One convenient standardized model of stress is the insulin tolerance test (ITT), which stimulates growth hormone (GH), prolactin (PRL), adrenocorticotrophic hormone (ACTH) and cortisol secretion

Neuroendocrine strategies have also been applied to estimate central serotonin (5-HT) neurotransmission, as reflected by the size of the prolactin and cortisol responses to a range of serotoninergic agonists. […] Bakheit et al (1992) have demonstrated enhanced prolactin responses to buspirone, a 5-HT agonist selective for 5-HT1a receptors. In this study we have further explored serotonergic function using d-fenfluramine, which has a high degree of 5-HT specificity

All fulfilled recent consensus criteria for the diagnosis of chronic fatigue syndrome (Sharpe et al 1991). […] Ten normal controls were recruited from the staff and student body of King's College and Maudsley Hospitals.

There was no difference in the cortisol (F = 2.28; p = 0.14) or ACTH (F= 0.03;p = 0.86) responses to hypoglycemia between the two groups. There was also no significant difference in peak ACTH, cortisol, and prolactin concentrations between the patients and controls.

The d-fenfluramine test was conducted on nine patients (four women and five men) and 10 controls (six women and four men). […] Although there was no significant difference in the cortisol response (F = 1.14; p = 0.29), the ACTH response was significantly greater in the patient group (F = 4.08; p = 0.04). Peak cortisol concentrations achieved were not significantly different between the patients (372.2 ± 17.30 mmol/L-1) and controls (401.0 ± 15.82 mmol/L-1) (t = 1.23; df = 17; p > 0.2). Significantly higher peak ACTH concentrations were achieved in the patients (36.44 ± 4.45 pgml-1) than the controls (25.6 ± 2.78 pgml-1) (t = 2.11; df = 17; p = 0.05), however.

We have shown that patients with CFS have a selective impairment of hypothalamopituitary responsiveness to the stress of hypoglycemia, confined to the prolactin response, whereas GH, ACTH, and cortisol responses are not affected.

 

[forestglip]

Contrasting neuroendocrine responses in depression and chronic fatigue syndrome, 1995, Cleare et al

Baseline-circulating cortisol levels were highest in the depressed, lowest in the CFS and intermediate between the two in the control group (P = 0.01).

This study reported low cortisol in ME/CFS. However, it should be noted that for "baseline", they used cortisol levels 1 hour after administration of the serotonin-releasing agent d-fenfluramine. Also, the p-value above is when comparing the ME/CFS, depression, and healthy groups all at once to detect if any of the groups are different from each other, which could be significant just from depression having high cortisol, for example.

When they compared ME/CFS to just their matched controls, it was not significant.

Mean diff[baseline CORT] was - 47 nmol/l (95% CI - 148-54; NS)

(This is saying that the average difference between an ME/CFS patient and their matched control was 47 nmol/l lower in ME/CFS, but it was not significant (NS).)

 

[SNT Gatchaman]

Cerebrospinal fluid opening pressure in relation to symptomatology and craniocervical anatomy in patients with myalgic encephalomyelitis/chronic fatigue syndrome (2026) —

A total of 34 patients were included in the present study, selected from a larger case–control study including 40 patients diagnosed with ME/CFS according to the Canadian Consensus Criteria (CCC)

Participants were, on average, 46 years old, female (77%), and slightly overweight (mean BMI 25.2), with a high occurrence of general joint hypermobility (41%). Levels of serum cortisol, TSH, and CRP were all within the normal range.

 

[forestglip]

Plasma cortisol was not significantly different from healthy controls in these studies:

Hormonal Responses to Exercise in Chronic Fatigue Syndrome (Ottenweller et al. 2001)




Desmopressin Augments Pituitary–Adrenal Responsivity to Corticotropin-Releasing Hormone in Subjects with Chronic Fatigue Syndrome and in Healthy Volunteers (Scott et al. 1999)

 

[forestglip]

Low urinary cortisol reported in:

Evidence for Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome (Demitrack et al. 1991)

Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 ± 8.7 us. 148.4 ± 20.3 nmol/L; P < 0.01) and low 24-h urinary free cortisol excretion (122.7 ± 8.9 us. 203.1 ± 10.7 nmol/24 h; P < 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 ± 26.4 us. 225.4 ± 34.5 pmol/Lmin, P < 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 ± 0.6 us. 7.7 ± 0.5 pmol/L; P = NS).

Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers (Scott & Dinan, 1998)

Urinary free cortisol excretion (UFC) was compared in 21 patients with chronic fatigue syndrome (CFS), in 10 melancholic depressives and in 15 healthy controls. Patients with depression had UFC values which were significantly higher than healthy comparison subjects, whereas UFC excretion of CFS patients was significantly lower than the comparison group.

---

Normal salivary and urinary cortisol reported in:

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia) (Young et al. 1998)

Methods:
Basal activity of the HPA was assessed using salivary and urinary cortisol collection over a 24-hour period in 22 (12 male; 10 female) patients meeting criteria for CFS and appropriate controls.

Results:
Salivary and urinary cortisol measurement did not differ between CFS patients and controls.

---

Normal serum cortisol reported in:

Core body temperature is normal in chronic fatigue syndrome (Hamilos et al. 1998)

In simultaneously collected blood samples, each group showed a similar circadian profile of serum cortisol with a peak occurring at 08:00.

 

[forestglip]

Decreased tryptophan availability but normal post-synaptic 5-HT2c receptor sensitivity in chronic fatigue syndrome (Vassallo et al., 2001)

We recruited 20 patients (16 women, four men) [...] Subjects all met criteria for ICD-10 neurasthenia. In addition, all but one met the Oxford criteria and Centre for Disease Control (CDC) criteria for CFS. [...] We also studied 21 healthy control subjects (16 women and five men).

Baseline plasma cortisol levels did not differ between patients with CFS and controls (21.8 ± 2.5 v. 23.1 ± 3.1 μg/100 ml, P = 0.75).