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SUMMARY. The short Synacthen (tetracosactrin) test (SST) is an established method of assessing adrenocortical reserve, and is increasingly replacing the insulin tolerance test (ITT) for the assessment of the hypothalamic-pituitary-adrenal (HPA) axis. However, there is no consensus on how the test is performed, and various time points and routes of administration are used. The present study was done, first, to determine whether there was any difference in cortisol responses when Synacthen was administered intramuscularly compared with intravenously and, secondly, to compare cortisol responses at 30 and 60 min. We found no significant difference between the two routes of administration. However, cortisol responses at 60 min were significantly higher than at 30 min (P < 0·05). Previous validations for the use of the SST in place of the ITT have used cortisol responses 30 min after Synacthen. We conclude that where the SST is used to assess the HPA axis, cortisol response at 30 min after intravenous Synacthen should be used. Additional key phrases: Synacthen; insulin tolerance test; hypothalamic-pituitaryadrenal axisThe short Synacthen (tetracosactrin) test (SST) is an established method of assessing adrenocortical reserve and was first described by Woods et al. in 1965. 1 This original description concluded that measuring cortisol levels 30 min after intramuscular Synacthen was a valuable test of adrenal function in patients with suspected hypoadrenalism.Endogenous ACTH deficiency results in involution of the adrenal cortex with a consequent reduced response to exogenous ACTH. On the basis of this, the SST has also been advocated to assess the integrity of the hypothalamic-pituitary-adrenocortical (HPA) axis as an alternative to the traditional insulin tolerance test. Peak cortisol responses to insulin induced hypoglycaemia in the insulin tolerance (ITT) have been shown to correlate closely with cortisol responses at 30 min after intravenous? or intramuscular! injection of 250 l!g Synacthen in two large studies, but the SST has not been validated against the ITT at time points other than 30 min. However, a recent study of UK Correspondence: Dr T W M Wang. 112endocrinologists showed that, although 50% now employed the SST to assess the HPA axis, methods of doing the SST vary in different centres,'the majority employing the peak or the 60 min cortisol response in lieu of, or in addition to the 30 min value, for interpretation.' We reasoned that, if responses to Synacthen at 30 and 60 min are significantly different, this may result in differences in interpretation of results when assessing the HPA axis in patients. This study was designed to determine: (1) whether the cortisol responses to intravenous and intramuscular Synacthen were different, and (2) if there was a significant difference between 30-and 60-min cortisol responses to Synacthen. The validation of the use of the SST in place of the ITT has only been made at 30 min, and so if the 30-and 60-min responses were different, this would mean that only the 3D...