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Year : 2002  |  Volume : 48  |  Issue : 4  |  Page : 251-2

Reliability of the ACTH low dose test in the evaluation of adrenal insufficiency.

Correspondence Address:
S Laureti

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Source of Support: None, Conflict of Interest: None

PMID: 12571377

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Keywords: Adrenal Cortex Function Tests, Adrenal Gland Hypofunction, diagnosis,Corticotropin, diagnostic use,Human, Reproducibility of Results,

How to cite this article:
Laureti S, Falorni A. Reliability of the ACTH low dose test in the evaluation of adrenal insufficiency. J Postgrad Med 2002;48:251

How to cite this URL:
Laureti S, Falorni A. Reliability of the ACTH low dose test in the evaluation of adrenal insufficiency. J Postgrad Med [serial online] 2002 [cited 2023 Sep 23];48:251. Available from:

Adrenal insufficiency (AI) can be the consequence of a primary impaired function of the adrenal glands, of an inadequate secretion of ACTH due to hypothalamic-pituitary diseases or of an abrupt suspension of chronic steroid treatment.

In the presence of clinical signs and laboratory findings of AI, the diagnosis is usually straightforward. However, this is not a frequent occurrence. The recognition of the sub-clinical cases is more problematic. An early diagnosis of these forms is very important because AI is a potentially life-threatening condition which needs an adequate replacement therapy.

Sub-clinical cases of AI are usually characterised by normal basal cortisol and ACTH levels and require dynamic tests for the assessment of the function of the hypothalamic-pituitary-adrenal (HPA) axis.

The insulin tolerance test (ITT) has widely been considered the “gold standard” for detecting secondary adrenal failure, but it is not devoid of side effects and contraindications.[1],[2],[3],[4]

The standard high dose ACTH test (250 ?g) (HDT) has been used in the evaluation of both primary and secondary AI.[1],[5] The HDT is supra-physiological, because of the pharmacological ACTH concentration induced.[1],[2] With the aim of performing a physiological provocative test, very low doses of ACTH have been tested.[6] The lowest ACTH dose able to maximally stimulate the adrenal cortex in normal subjects is 1 ?g.[7] A large body of evidence, collected during the last 10 years, indicates that the low dose ACTH test (1?g) (LDT) shows a high sensitivity and specificity for the assessment of central AI in patients with hypothalamic-pituitary disorders. It demonstrates a strong correlation with the ITT.[3],[4],[8],[9]

The LDT offers a very high reliability in diagnosing mild forms of primary AI[10] or mild adrenal suppression by inhaled steroids in asthmatic children.[2],[9] In addition, the close correlation between cortisol, DHEA, 17OH-progesterone and aldosterone responses to the LDT in subjects with pre-clinical primary AI has also been shown.[11] An important point is that the LDT is free of side effects, is cost effective and can easily be used for exclusion of adrenal failure in outpatients.[1],[2]

The definition of a standardised cut-off point of peak cortisol response to the LDT is a critical issue. The value of 18 mg/dl seems to be adequate, even though some authors have proposed significantly lower values.[1],[2],[3],[4],[9] These differences in cut-off values may in part reflect changes in methods of preparation and storage of ACTH dilutions. The relatively small number of volunteer subjects enrolled in the different studies justifies some differences in the normal values observed. Differences in laboratory technologies add further variability in the results of different studies.

In addition, an important recommendation is that the LDT should never be used in cases of acute deprivation of ACTH (e.g. recent hypopituitarism), when the intact adrenal cortex can still respond normally to any change of plasmatic ACTH levels.[1],[2]

In conclusion, we think that the LDT can be considered reliable and should be used in the routine clinical practice. Its use as the first test in the evaluation of HPA axis function can be proposed. The establishment of a range of normal values for each centre is important for the interpretation of the results obtained in the patients studied. In the doubtful cases for a positive test (grey zone) a different provocative test should also be performed and interpreted taking into consideration the clinical picture. Finally, the standardisation of the preparation of ACTH dilution will reduce the variability of the LDT results. A very important help could be provided by the development of commercial preparations containing 1 ?g of ACTH.

 :: References Top

1.Ambrosi B, Barbetta L. The role of the low dose ACTH test in the evaluation of central hypoadrenalism. J Endocrinol Invest 1999;22:492-5.  Back to cited text no. 1    
2.Dickstein G. Hypothalamo-pituitary-adrenal axis testing: nothing is sacred and caution in interpretation is needed. Clin Endocrinol (Oxf) 2001;54:15-6.  Back to cited text no. 2    
3.Thaler LM, Blevins LS. The low dose (1 mg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998;83:2726-9.   Back to cited text no. 3    
4.Streeten DP. Editorial: shortcomings in the low-dose (1 mg) ACTH test for the diagnosis of ACTH deficiency states. J Clin Endocrinol Metab 1999;84:835-7.  Back to cited text no. 4    
5.Oelkers W. Dose response aspects in the clinical assessment of the hypothalamo-pituitary-adrenal axis, and the low-dose adrenocorticotropin test. Eur J Endocrinol 1996;137:27-33.  Back to cited text no. 5    
6.Dickstein G, Schechner C, Nicholson WE. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;80:1243-6.   Back to cited text no. 6    
7.Dickstein G, Spigel D, Arad E, Schechner C. One microgram is the lowest ACTH dose to cause maximal cortisol response. There is no diurnal variation of cortisol response to submaximal ACTH stimulation. Eur J Endocrinol 1997;137:172-5.  Back to cited text no. 7    
8.Dickstein, G. The low dose (1 mg) ACTH test: when and how to use it. Clin Endocrinol (Oxf) 1998;49:135.  Back to cited text no. 8    
9.Patel L, Clayton PE. Clinical usefulness of the low dose ACTH test. J Endocrinol Invest 1999;22:401-4.  Back to cited text no. 9    
10.Laureti S, Arvat E, Candeloro P, Di Vito L, Ghigo E, Santeusanio F, et al.Low dose (1 mg) ACTH test in the evaluation of adrenal dysfunction in pre-clinical Addison’s disease. Clin Endocrinol (Oxf) 2000;53:107-15.   Back to cited text no. 10    
11.Laureti S, Candeloro P, Aglietti MC, Giordano R, Arvat E, Ghigo E, Santeusanio F, Falorni A. DHEA, 17alpha-hydroxyprogesterone and aldosterone responses to the low dose (1 ug) ACTH test in subjects with pre-clinical adrenal autoimmunity. Clin Endocrinol (Oxf) 2002;57:677-83.  Back to cited text no. 11    

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