The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism

Abstract

Objective: The 1 microgram ACTH stimulation test has been advocated as a sensitive indicator of the integrity of the hypothalamic-pituitary-adrenal axis in patients with suspected hypopituitarism. The aim of our study was to define the normal response to 1 microgram ACTH stimulation in a control population and to study the sensitivity and specificity of the test in a group of patients with suspected pituitary disease.

Design: A prospective analysis of the performance of the 1 microgram ACTH stimulation test in a group of patients with pituitary disease.

Patients: The cortisol response to 1 microgram ACTH was evaluated in 21 normal subjects and 65 patients with pituitary disease. The patients with pituitary disease were divided into two groups according to the 11-deoxycortisol response to overnight metyrapone: normal (11-deoxycortisol > 200 nmol/l) and subnormal ACTH secretory status (11-deoxycortisol < 200 nmol/l).

Measurements: In both controls and patients, blood was sampled for cortisol at - 15, 0, + 20, + 30, + 40 and + 60 minutes after intravenous administration of 1 microgram synthetic ACTH (Synacthen(R)). The overnight metyrapone test was performed only in the subjects with pituitary disease. Metyrapone (30 mg/kg) was administered orally at 2300 h and blood was sampled at 0830 h the following morning for 11-deoxycortisol.

Results: The 65 patients with pituitary disease were categorized according to the 11-deoxycortisol response to metyrapone as follows: 53 normal (11-deoxycortisol > 200 nmol/l) and 12 subnormal (< 200 nmol/l). The 12 patients who failed the metyrapone test had a significantly impaired cortisol response to low dose ACTH stimulation at all time points when compared with both the control group and the pituitary patients with a normal response to metyrapone (P < 0.001). Comparing the pituitary patients who had a normal response to metyrapone and the control subjects, there was no significant difference in the cortisol response to ACTH (P > 0.05). The minimum cortisol response at 30 minutes in the 21 control subjects was 414 nmol/l and this was defined as the minimum normal cortisol response to 1 microg ACTH. Using this criterion, six of the 12 patients with a subnormal response to metyrapone had a normal cortisol response to low dose ACTH stimulation. Empirically increasing the cortisol cut-off to 600 nmol/l increased the sensitivity of the low dose ACTH test to 83%, although the specificity was reduced from 100% to only 58%.

Conclusions: The normal cortisol response to low dose ACTH stimulation in 50% of the patients with ACTH deficiency proven on metyrapone testing suggests that the 1 microgram ACTH stimulation test, like the 250 microgram-test, lacks sensitivity for the diagnosis of ACTH deficiency.