Adrenocorticotropic hormone (ACTH) response in ME/CFS

[forestglip]

There's been some discussion of ACTH response recently, so it seemed like a good idea to see all the findings together. Thanks to members who already posted and linked some of these papers. I found some more through PubMed and Google Scholar.

I'm not sure if I found all of the studies that tested ACTH response, so let me know if anyone finds any more, and I'll add them.

Year	Title	Authors	Cohort	Probe	ACTH response findings	Additional Notes	Links
1991	Evidence for Impaired Activation of the Hypothalamic Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome	Mark A. Demitrack, Janet K. Dale, Stephen E. Straus, Louisa Laue, Sam J. Listwak, Markus J. P. Kruesi, George P. Chrousos, Philip W. Gold	9M, 10F ME/CFS (Holmes 1988) (53% F) 13M, 5F healthy (28% F)	oCRH (1 mcg/kg, i.v., 8:00 PM)	⬇ Smaller ACTH response in ME/CFS	Females tested during follicular phase.	Article | S4ME
1995	Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome	Jenny Bearn, Theresa Allain, Patsy Coskeran, Neil Munro, Joan Butler, Alan McGregor, and Simon Wessely	4F, 5M CFS (Oxford and all but one fulfilled Holmes) 6F, 4M healthy	D-fenfluramine (30 mg, orally, 10:00 AM)	⬆ Larger ACTH response in ME/CFS	Premenopausal females tested during days 3-5 of menstrual cycle.	Article | S4ME
(This test is from the same study as above, Bearn 1995)			4F, 5M CFS (Oxford and all but one fulfilled Holmes) 6F, 2M healthy	Insulin (0.1 or 0.15 u/kg, i.v., 10:00 AM)	= Normal ACTH response in ME/CFS	Premenopausal females tested during days 3-5 of menstrual cycle.
1996	[Thesis] Neuroendocrine Alterations in Chronic Fatigue Syndrome	Tahir Majeed	(reports same data as following paper, Dinan 1997)				Article | S4ME
1997	Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome	Timothy G. Dinan, Tahir Majeed, Ena Lavelle, L.V. Scott, Carlo Berti, Peter Behan	6M, 8F CFS (Holmes 1988) 6M, 8F healthy	Ipsapirone (20 mg, orally, 9:00 AM)	⬇ Smaller ACTH response in ME/CFS	Females tested during early follicular phase.	Article | S4ME
1998	Blunted adrenocorticotropin and Cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome	L.V. Scott, S. Medbak, T.G. Dinan	6M, 8F CFS (Fukuda 1994) 6M, 8F healthy	oCRH (100 mcg, i.v., 1:00 PM)	⬇ Smaller ACTH response in ME/CFS	Females tested during follicular phase.	Article | S4ME
1998	Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome	L.V. Scott, F. Burnett, S. Medbak, T.G. Dinan	5M, 8F CFS (Fukuda 1994) 5M, 8F healthy	Naloxone (0.125 mg/kg, i.v. 1:00 PM)	⬇ Smaller ACTH response in ME/CFS	Females tested during early follicular phase.	Article | S4ME
1999	Desmopressin augments pituitary–adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers	L.V. Scott, S. Medbak, T.G. Dinan	6M, 6F CFS (Fukuda 1994) 9M, 2F healthy	oCRH (100 mcg, i.v., 1:00 PM)	⬇ Smaller ACTH response in ME/CFS	Females tested during early follicular phase.	Article | S4ME
(test from same study as above, Scott 1999)			6M, 5F CFS (Fukuda 1994) 7M, 4F healthy	DDAVP (10 mcg, i.v. 1:00 PM)	= Normal ACTH response in ME/CFS	Females tested during early follicular phase.
(test from same study as above, Scott 1999)			6M, 6F CFS (Fukuda 1994) 8M, 4F healthy	oCRH (100 mcg) + DDAVP (10 mcg) (i.v., 1:00 PM)	= Normal ACTH response in ME/CFS	Females tested during early follicular phase.
2000	Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome	Greta Moorkens, Joris Berwaerts, Herlindis Wynants, Roger Abs	18M, 55F CFS (Fukuda 1994) 9M, 12F healthy	Insulin (0.15 U/kg, i.v.,	= Normal ACTH response in ME/CFS	Females tested during early follicular phase.	Article | S4ME
2001	Hormonal Responses to Exercise in Chronic Fatigue Syndrome	John E. Ottenweller, Sua A. Sisto, Richard C. McCarty, Benjamin H. Natelson	17F CFS (Holmes and Fukuda) 14F healthy	Maximal exercise on treadmill	⬇ Smaller ACTH response in ME/CFS	Females tested during luteal phase.	Article | S4ME
2001	Abnormalities in response to vasopressin infusion in chronic fatigue syndrome	Margaret Altemus, Janet K. Dale, David Michelson, Mark A. Demitrack, Philip W. Gold, Stephen E. Straus	6M, 13F CFS (Holmes and Fukuda) 6M, 19F healthy	Vasopressin (1 mIU/kg/min from 9:30 to 10:30 AM, i.v.	⬇ Non-significantly smaller ACTH response in ME/CFS	Menstrual phase was not controlled for.	Article | S4ME
2001	Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy	A. J. Cleare, J. Miell, E. Heap, S. Sookdeo, L. Young, G. S. Malhi, V. O’Keane	12M, 25F CFS (Fukuda 1994) 14M, 14F healthy	hCRH (1 mcg/kg, i.v., morning)	= Normal ACTH response in ME/CFS	Females tested during days 1-7 of menstrual cycle. Paper also reports comparisons split by gender. ACTH responses to all probes were still not-significantly different. Paper also reports change in ACTH response to insulin and hCRH after trial of hydrocortisone. Response did not significantly change.	Article | S4ME
(test from same study as above, Cleare 2001)			12M, 25F CFS (Fukuda 1994) 14M, 14F healthy	D-fenfluramine (30 mg, orally, morning)	= Normal ACTH response in ME/CFS	Females tested during days 1-7 of menstrual cycle.
(test from same study as above, Cleare 2001)			12M, 25F CFS (Fukuda 1994) 14M, 14F healthy	Insulin (0.15 U/kg, i.v. morning)	= Normal ACTH response in ME/CFS	Females tested during days 1-7 of menstrual cycle.
2002	Hypothalamic-Pituitary-Adrenal Axis Reactivity in Chronic Fatigue Syndrome and Health Under Psychological, Physiological, and Pharmacological Stimulation	Jens Gaab, Dominik Hüster, Renate Peisen, Veronika Engert, Vera Heitz, Tanja Schad, Thomas H. Schürmeyer, Ulrike Ehlert		Psychosocial stress test	⬇ Smaller ACTH response in ME/CFS	Have only seen abstract.	Article | S4ME
(test from same study as above, Gaab 2001)				Exercise test	⬇ Smaller ACTH response in ME/CFS	Have only seen abstract.
(test from same study as above, Gaab 2001)				Insulin	⬇ Smaller ACTH response in ME/CFS	Have only seen abstract.
2004	Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome	Jens Gaab, Veronika Engert, Vera Heitz, Tanja Schad, Thomas H. Schurmeyer, Ulrike Ehlert	10M, 8F CFS (Fukuda 1994 and Sharpe 1991) 10M, 7F healthy	Insulin (0.15 U/kg, i.v., 9:00 AM)	⬇ Smaller ACTH response in ME/CFS		Article | S4ME
2005	Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome	Gaab, Jens; Rohleder, Nicolas; Heitz, Vera; Engert, Veronika; Schad, Tanja; Schürmeyer, Thomas H.; Ehlert, Ulrike		Psychosocial stress test		Have only seen abstract	Article | S4ME

ACTH: adrenocorticotropic hormone, CRH: corticotropin-releasing hormone, DDAVP: desmopressin, hCRH: human CRH, oCRH: ovine CRH

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Noting the following paper separately, since I don't have access to the abstract with the actual data, only this review mentioning it. It says that they tested ACTH response to buspirone. They don't say anything about the ACTH response difference, so I would assume it was normal.

Clinical and Pathogenetical Characterization of 238 Patients of a Chronic Fatigue Syndrome Italian Center (Racciatti, 1999)

Since many clinical features of CFS patients are also characteristic of glucocorticoid insufficiency and/or hypothalamic dysfunction (7,8), we studied the circadian rhythm of prolactin (PRL), thyrotropic hormone (TSH), adrenocorticotropic hormone (ACTH) and cortisol, and their response to a challenge test with a 5HT partial agonist--buspirone--in CFS patients and controls. No significant differences in circadian rhythm of hormones were found between CFS group and controls. After buspirone, each group showed percentage increments in PRL, CS and ACTH values, while TSH showed a decrease of mean values. The PRL percentage difference between peak and baseline was significantly higher in CFS patients than in control groups (p < 0.007) (9).

9. Racciatti D, Barberio A, Pizzigallo E et al. Neuroendocrine perspective of chronic fatigue syndrome. Journal of Musculoske Pain 1998; 6 (S2): 152.

 

[ScoutB]

This is really fantastic to have, thank you for all the work.

So a few studies reported a lower ACTH response to oCRH, but then the hCRH study found no difference. Based on some quick googling it sounds like oCRH has a longer half life and as a result typically provokes larger responses. It's also interesting that the 2001 hCRH study used 1 mcg of hCRH (?), while some of the oCRH studies used 100 mcg of oCRH. Though those could be equivalent doses for all I know.

 

[forestglip]

It's also interesting that the 2001 hCRH study used 1 mcg of hCRH (?), while some of the oCRH studies used 100 mcg of oCRH. Though those could be equivalent doses for all I know.

Ah, my mistake! The hCRH study should say 1 mcg/kg. Fixed.

 

[ScoutB]

Makes sense haha

 

[forestglip]

This paper highlights some potential confounders: Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome, 2004, Gaab et al

This is a study that found lower ACTH response to insulin in ME/CFS, as well as a correlation with duration of illness (the longer the duration, the smaller the response).

They suggest that the association with duration might be pointing to an effect of sedentariness on ACTH response:

The duration of CFS is of relevance for the development of physical deconditioning, which in its own right leads to many physiological abnormalities seen in CFS patients [40]. Almost all CFS patients report a profound reduction in activity levels compared to premorbid activity levels [11,41] and low levels of activity has been shown to be related to severe fatigue in CFS patients [42].

In comparison to endurance trained subjects, sedentary men show attenuated absolute integrated ACTH responses to exercise [49]. Also, overtrained athletes, experiencing generalized apathy, lethargy and change of sleep pattern, had attenuated HPA axis responses to the ITT, which normalized with recovery [50].

Spoiler: References

[49] Duclos M, Corcuff JB, Rashedi M, Fougere V, Manier G. Trained versus untrained men: different immediate post-exercise responses of pituitary adrenal axis. A preliminary study. Eur J Appl Physiol Occup Physiol 1997;75:343 – 50.

[50] Barron JL, Noakes TD, Levy W, Smith C, Millar RP. Hypothalamic dysfunction in overtrained athletes. J Clin Endocrinol Metab 1985; 60:803 – 6.

They also point out that changes in sleep in healthy people can also cause smaller ACTH response, so there is a possibility of poor sleep leading to smaller ACTH response in ME/CFS:

With regard to the possible influence of sleep problems on HPA axis functioning, Leese et al. [36], comparing endocrine responses to a CRH challenge test after night shift and day shift work, reported an attenuated integrated area under the response curve for both ACTH and cortisol after the night shift work.

Spoiler: References

[36] Leese G, Chattington P, Fraser W, Vora J, Edwards R, Williams G. Short-term night-shift working mimics the pituitary – adrenocortical dysfunction in chronic fatigue syndrome. J Clin Endocrinol Metab 1996;81:1867 – 70.

Here is the sleep paper they cited: Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome, 1996, Leese et al

From the abstract:

After CRH injection, ACTH concentrations remained consistently higher during the night shift, but the integrated increase in ACTH concentration was lower (P < 0.05) than during the day shift. Conversely, the increase in cortisol concentration was greater during the night shift than the day shift (283 +/- 53 nmol.L-1 vs. 134 +/- 41 nmol.L-1, P < 0.05).

We conclude that the pituitary-adrenal responses to CRH are markedly disrupted after only 5 days of nighttime work. These abnormalities mimic those previously observed in patients with chronic fatigue syndrome. Neuroendocrine abnormalities reported to be characteristic of chronic fatigue syndrome may be merely the consequence of disrupted sleep and social routine.

 

[chillier]

A couple of blunted ACTH responses to exercise there too. Doing exercise tests, unlike the others is maybe something we would not need a clinician to do. Hanson group did post exercise proteomics using aptamers which you might think could be sensitive enough to detect ACTH if it's on the panel - which I don't know if it was. I don't think they reported anything. It looks like you get quite a short pulse of ACTH following these challenges so maybe the timing of sampling and handling of the samples really matters.

 

[chillier]

Also nice work @forestglip you put this together with amazing speed.

 

[Jonathan Edwards]

Jesus bejabers, I can't keep up with this.

 

[forestglip]

A couple of blunted ACTH responses to exercise there too. Doing exercise tests, unlike the others is maybe something we would not need a clinician to do.

Maybe prolactin and ACTH both measured after exercise, since prolactin also seemed blunted in Ottenweller 2001 (actually around 8 responses seemed blunted in that study). Though I think it'd be important to try to design the study to answer the question of if the results are due to deconditioning or not, which I think is especially important to consider with an exercise test. Maybe it could be statistically controlling for a physical activity parameter, like time upright or step count.

 

[forestglip]

Jesus bejabers, I can't keep up with this.

Me either. I've barely recovered from scouring through prolactin papers. I wasn't expecting there to be so many of these ACTH papers. I wonder what other promising things might be hiding in the thousands of old ME/CFS papers.

 

[Mij]

I did an ACTH stimulation test 25yrs ago. I was exercising (running) back then and experiencing delayed PEM. Came back normal. I don't think I would have been able to go through with this test during delayed PEM.

 

[SugarSquared]

What a treat to have another forestglip deep dive! So exciting.

I've barely recovered from scouring through prolactin papers.

Please take care of yourself though. Don’t let my excitement push you. If you need any help with accessing papers, let me know.

I’ve let contacting endocrinologists at UBC slide because of the possibility of other researchers looking into the prolactin responses, but this makes me think I should definitely be contacting people again. There are multiple endocrine findings that deserve replication.

 

[bobbler]

Me either. I've barely recovered from scouring through prolactin papers. I wasn't expecting there to be so many of these ACTH papers. I wonder what other promising things might be hiding in the thousands of old ME/CFS papers.

probably (ha! as if the to-do list wasn't long enough, so I know this is just what you want to see written but I forget if i dont write it at the time)

it is useful looking through these old things not just for what it might indicate but for lessons we might want to note down for when future research is coming through/advice - I mean if we look through all this thinking 'if only they'd just done x in the methodology' or of course we know about issues like PEM/controlling for certain obvious issues that could be significant and we don't know (like whether someone was lying down/how flat being expressed precisely, room hot, long journeys - delete as relevant to the test itself), things like dosage being constant for all or by bodyweight (and which one is relevant for what drug for what purpose) etc.

particularly when something might be being done at that point in time for a really functionedly-fixed interpretation/concept as we found with the old antidepressant stuff, but could have relevance and more of interest if those factors are at least noted to provide ability to slot them into bigger pictures later on as other findings from other areas come in (as +, -, ?, or 'depends on' type things - yep I'm imagining having some who are genius and can sit round bit whiteboards of different findings that happen at different points and try and slot it together like a giant puzzle ... it'd be interesting to know and picture the actual scenario over which such things take place lol!)