The role of the low dose (1 microgram) ACTH stimulation test in the evaluation of patients with pituitary diseases was systematically assessed by relating its results to those obtained on gold standard tests of hypothalamo-pituitary-adrenal (HPA) reserve, such as insulin-induced hypoglycemia or a metyrapone challenge. Ten patients with pituitary diseases (8 men and 2 women) and proven impairment of HPA function and 9 patients (5 men and 4 women) with similar pituitary pathologies but preserved HPA function were studied (pituitary controls). A group of 7 normal volunteers (3 men and 4 women) served as normal controls. None of the subjects was taking glucocorticoids on a chronic basis or had been taking any recently. All subjects underwent ACTH tests at 0800 h with 3 different levels of stimulation (1, 5, and 250 micrograms), and serum cortisol was assayed 0, 30, and 60 min after injection. A pass result was defined as a peak cortisol value of 497 nmol/L or more. Basal cortisol values were indistinguishable among the groups. Pituitary controls did not differ from normal controls for any of the challenges. In healthy controls, peak cortisol levels attained with the low dose stimulation were clearly lower than with the standard dose (670 +/- 39 vs. 919 +/- 50 nmol/L; P = 0.002). However, every normal control passed the low dose stimulation, whereas none of the patients with impaired HPA function did (P = 0.00005). Although the cortisol values achieved on the standard (250 micrograms) dose by the subjects with impaired HPA function were significantly lower than those in normal controls (P < 0.005), they were generally normal in absolute terms. Indeed, using the peak value criterion, 7 of these 10 patients would have qualified as pass on the 5-micrograms challenge, and 9 of 10 would have passed the 250-micrograms test. Thus, the low dose ACTH test appears to perform better than the standard pharmacological test. As we have shown that this test correlates well with reference tests of HPA function, it is suggested that it should replace the standard ACTH test in the diagnosis of secondary adrenal insufficiency.

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