The one microgram adrenocorticotropin test in the assessment of hypothalamic-pituitary-adrenal function

Abstract

The possibility of assessing hypothalamic-pituitary-adrenal (HPA) function by the standard ACTH test (250mg) has been widely discussed in the past years and compared with the role of the insulin tolerance test (ITT). Recently, it was shown that low doses of ACTH, such as 1 mg i.v., induce a maximal adrenal response and, by reducing the discrepancies compared with the ITT also allow one to detect mild forms of secondary hypoadrenalism. In the present study the 1 mg ACTH test was performed in patients with hypothalamic-pituitary disease in order to assess adrenal function, and the results have been compared with those obtained after the insulin test. Fifty-seven patients (31 men and 26 women, aged 19-73 years) with hypothalamic-pituitary diseases were studied: 51 patients were affected with pituitary tumor and 6 patients had hypothalamic disorders. All these patients and 18 healthy volunteers (7 men and 11 women, aged 19-46 years) received 1 mg i.v. ACTH injection. In addition, the ITT (0.1-0.15 U/kg body weight) was performed in all patients. In normal subjects mean cortisol levels significantly (P < 0.001) increased from a baseline of 393 Ϯ 43 nmol/l to a peak of 770 Ϯ 41 nmol/l after 1 mg ACTH. In 44 patients with hypothalamic-pituitary disease 1 mg ACTH caused a cortisol rise similar to that of normal subjects (from 332 Ϯ 17 to 769 Ϯ 24 nmol/l; P < 0.001), while an impaired response (from 124 Ϯ 23 to 312 Ϯ 46 nmol/l) was observed in 13 cases (23%), 7 of them with low morning cortisol levels (10-127 nmol/l) and 6 with basal values at the lower limit of normality. The cortisol response to ITT was compared with that obtained after the 1 mg ACTH test: 10 patients failed both challenges, 4 patients who passed the ACTH test failed the ITT, while 3 patients who failed the ACTH test passed the ITT. The 23 out of 57 patients (40%) who showed a cortisol peak greater than 750 nmol/l after 1 mg ACTH had a normal response to ITT. A positive correlation between cortisol peaks after ACTH and after insulin was also found (r ¼ 0.68, P < 0.001). Assuming a 100% accuracy of ITT, the low dose ACTH test yielded a 71% sensitivity and a 93% specificity.In conclusion, the low-dose ACTH test is a useful, safe and inexpensive tool for the initial assessment of HPA function in patients with hypothalamic-pituitary disease. In fact, the ITT is unnecessary when cortisol peaks are greater than 750 nmol/l after 1 mg ACTH and also when very low cortisol basal levels indicate an overt hypoadrenalism. Within these limits the ITT is mandatory and its important role in the recognition of secondary adrenal failure is further confirmed.

Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?

“…The commonly used cortisone acetate dose was 25 mg/day (51 patients), while higher doses of 31.3 and 37.5 mg/day were used in seven and two patients respectively. After 2 months, cortisol secretion was assessed by low dose ACTH stimulation test (LDCT), after a 24-h steroid therapy withdrawal, as previously described (19,20). We decided to post-operatively re-evaluate the patients at 2 months in order to be sure that a post-operative stress condition was not still present.…”

“…In addition, most studies considered only post-surgical basal cortisol level or the presence of symptoms suggesting adrenal failure as a diagnostic tool for post-surgical hypocortisolism (12,15,17,18). However, a proper approach includes evaluation of cortisol level in basal conditions plus stimulation tests, such as low dose ACTH test or insulin tolerance test (ITT), the latter being the 'gold standard' for the diagnosis of adrenal insufficiency (19)(20)(21). As a consequence of this lack of knowledge, there is no consensus regarding the management of patients who are undergoing unilateral adrenalectomy for AI.…”

The role of high- and low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency

“…Exact timing of blood sampling is, therefore, very important with this test, and dilution errors of the 250 mg corticotropin 1-24 ampoule can also occur. I assume that in the three patients in the paper of Ambrosi et al (10) in whom the IHT was normal but the response to 1 mg corticotropin was subnormal, blood sampling time or dilution of the ampoule was not quite exact, because a test that stimulates the adrenal maximally (19) theoretically cannot result in a smaller cortisol response than the IHT that stimulates plasma ACTH to between 100 and 300 pg/ml in normal subjects.…”

“…The second paper in this issue dealing with corticotropin testing in patients with pituitary disease is by Ambrosi et al (10). These authors compared the results of the IHT (cortisol cutoff point 500 nmol/l) with a low-dose SCT (i.v.…”

“…Using the same plasma cortisol kit that was applied in the studies of Mayenknecht et al (20), we found the maximum cortisol values in the IHT to range between 600 and 1266 nmol/l, and the mean minus 2 standard deviations was 568 nmol/l. Thus, since the low-dose corticotropin test does not seem to fulfil the expectations put on it, in respect to its increased sensitivity for detecting mild SAI, it is understandable that Ambrosi et al in the paper published in this issue (10) had to take the same step as Bangar & Clayton (9), namely to pragmatically raise the cutoff point of the low-dose test in order to avoid underdiagnosis of SAI in patients with pituitary disease.…”