The hypothalamo–pituitary–adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

Figures & data

Figure 1 Tests of HPA axis function.

Table I.  Summary of the stimulation tests used in the investigation of HPA axis underactivity.

Stimulation test	Interpretation and abilities	Limitations
ITT	Peak cortisol value after ITT less than 500 or 550 nmol/l means underactivation of HPA axis. Test is only valid if symptomatic hypoglycemia (serum glucose < 2.2 nmol/l) is achieved. Accepted as gold standard in the evaluation of the integrity of the whole HPA axis.	Cannot localize the abnormality if the response is inadequate.
		Problems in reproducibility of the results.
		There are contraindications including epilepsy, ischaemic heart disease, previous cerebrovascular event, elderly.
Metyrapone test	Secondary adrenal failure is suggested if the 11-deoxycortisol response is less than 200 nmol/l and simultaneously measured serum cortisol is low (less than 200 nmol/l).	Limited availability of metyrapone itself and 11-deoxycortisol assay prevent the common use of the test.
	It is helpful in evaluating the pituitary ACTH reserve.	May precipitate symptomatic adrenal insufficiency
CRH stimulation	After 1 μg/kg ovine-CRH expected cortisol response is an increase of at least 275 nmol/l above baseline. But ACTH esponses are rmore variable (2–4-fold above baseline). It is useful in the differential diagnosis of-secondary adrenal failure, particularly to differentiate hypothalamic from pituitary disease.	Stimulated ACTH and/or cortisol levels are still not well standardized and lack of generally accepted cut-off levels make the CRH test less reliable.
		Because ACTH is extremely labile in vitro, careful specimen collection and handling is vital.
Vasopressin (AVP) infusion	Decreased ACTH response to AVP infusion (1 mIU/kg for 60 min) has been accepted as an indirect marker of low ambient CRH.	Less potent stimulus when compared to CRH. Not commonly used in clinical practice.
Standard ACTH stimulation test (250 μg)	Peak cortisol response of 550 nmol/l at any time during the test is generally accepted as normal response. Proposed as an alternative test to ITT.	ACTH stimulation test is not able to differentiate primary from secondary adrenal failure. 250 μg ACTH is a pharmacological dose and may result in underdiagnosis of HPA axis insufficiency.
Low dose ACTH stimulation test (1 μg)	Peak cortisol response of 500 nmol/l accepted as normal response.	Not commercially available: prepared by diluting 250 μg synacthen vials.
	It may be more useful than 250 μg ACTH test in the assessment of HPA axis insufficiency particularly in secondary adrenal failure and in detecting subtle HPA axis abnormalities.	Standardization of the test is not well established.
Glucagon stimulation test	GST is a simple and safe method in the assessment of ACTH secretion, it is a suitable alternative when the ITT is contra-indicated.	There is not enough clinical experience in HPA axis evaluation in CFS and FMS.
		Cannot localize the abnormality if the response is inadequate.

Table II.  Dynamic studies on the HPA axis in patients with CFS.

Study	Subjects	Challenge test	Method	Findings
Demitrack et al. (1991)	19 CFS/18 control	CRH	1 μg/kg ovine CRH at 2000 h	Blunted ACTH, normal cortisol response
	12 CFS/10 control	ACTH	0.003, 0.01, 0.1,1 μg/kg on separate days	Increased response of cortisol to lower and decreased response to higher doses of ACTH
Scott et al. (1998a)	14 CFS/14 control	CRH	100 μg ovine CRH at 1300 h	Similar basal ACTH and cortisol, blunted ACTH and cortisol response to CRH
Scott et al. (1998b)	20 CFS, 20 control	ACTH	1 μg	Similar basal cortisol, lower delta cortisol response to ACTH, 10% of control, 45% of CFS failed to respond above 250 nmol/l
Scott et al. (1999a,b)	CFS	CRH		Blunted ACTH and cortisol response to CRH
		DDAVP		Normalized ACTH and cortisol
		CRH-DDAVP		Response to CRH after DDAVP
Hudson and Cleare (1999)	20 CFS, 20 control	ACTH	1 μg	Similar baseline and delta cortisol
Kavelaars et al. (2000)	15 adolescent CFS/14 control	CRH	100 μg CRH at 1400 h	Similar basal ACTH and cortisol normal ACTH and cortisol response to CRH
Cleare et al. (2001b)	37 CFS, 28 control	CRH	100 μg ovine CRH 0900 h	Normal ACTH, blunted cortisol response to CRH,
	16 CFS	ITT		Normal cortisol response to ITT,
	21 CFS	d-Fenfluramine		Decreased cortisol response to d-fenfluramine
Altemus et al. (2001)	19 CFS, 19 control	AVP	1 U/kg/min for an hour	Decreased ACTH and rapid cortisol response to AVP
Gaab et al. (2002)	CFS	Psychosocial and physical stress test ITT		Significantly reduced ACTH similar plasma cortisol response in all tests, increased salivary cortisol in ITT
Gaab et al. (2004)	18 CFS, 17 control	ITT		Reduced ACTH area under curve response, similar salivary and plasma cortisol response
Izgi et al. (2005)	20 CFS, 15 control	ACTH metyrapone	1 μg 30 mg/kg	Lower peak cortisol response to ACTH, significantly lower 11 DOC response to metyrapone

Table III.  Dynamic studies on the HPA axis in patients with FMS.

Study	Subject	Challenge test	Method	Findings
Griep et al. (1993)	10 FMS, 10 control	CRH	After overnight dexamethasone	Increased ACTH
		ITT		Normal cortisol response to both CRH and ITT
Riedel et al. (1998)	16 FMS, 17 control	CRH		Increased basal ACTH and cortisol
				Increased ACTH response to CRH
Griep et al. (1998)	40 FMS, 14 control	CRH	100 μg	Increased ACTH, similar cortisol response to CRH
		ACTH	0.025 μg/kg after overnight dexamethasone	Similar cortisol responses to both doses of ACTH
		ACTH	0.1 μg/kg after overnight dexamethasone
Gursel et al. (2001)	20 FMS, 20 control	Exercise stress test		Slight decrease in ACTH in the control group, no change in ACTH in FMS group, decreased cortisol in both groups
Kirnap et al. (2001)	16 FMS, 16 control	ACTH	1 μg	Decreased peak cortisol in FMS group in all tests
		ACTH	250 μg	Similar peak cortisol responses to ITT and 250 μg ACTH
		ITT		Lower peak cortisol response to 1 μg ACTH
Riedel et al. (2002)	13 FMS, 13 control	CRH	100 μg	Normal ACTH and cortisol response to CRH
Calis et al. (2004)	22 FMS, 15 control	ACTH	1 μg	Decreased peak cortisol response to ACTH
		Metyrapone	30 μg/kg	Decreased 11 DOC response to metyrapone

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