Assessing the hypothalamo-pituitary-adrenocortical axis using physiological doses of adrenocorticotropic hormone

We compared cortisol responses to 1 microgram adrenocorticotropic hormone (ACTH), 250 micrograms ACTH and insulin-induced hypoglycaemia (IIH), in patients suspected to have secondary hypocortisolism. Twenty-four patients (16 with hypothalamopituitary disorders and 8 on long-term glucocorticoid therapy) and eight healthy controls, underwent all three test protocols, with intervals of one day between each test. Mean cortisol responses to all three tests were comparable in both groups, but were more closely correlated for IIH vs. the 1 microgram ACTH test (r = 0.96) than for IIH vs. the 250 micrograms ACTH test (r = 0.88). Seven patients had discrepant results; all had a normal peak cortisol response to 250 micrograms ACTH (> 550 nmol/l), but a subnormal response to 1 microgram ACTH. Six of these also had a subnormal response to IIH. Cortisol responses to IIH match more closely those for 1 microgram ACTH in individual instances than those for 250 micrograms ACTH. The standard 250 micrograms ACTH stimulation, being supraphysiological, leads to underdiagnosis of the hypocortisolaemic state. The 1 microgram ACTH stimulation test should replace the standard 250 micrograms ACTH stimulation test in assessing the hypothalamo-pituitary-adrenocortical axis in secondary hypocortisolism.