Adrenocorticotrophin (ACTH) deficiency undetected by standard dynamic tests of the hypothalamic-pituitary-adrenal axis.

Six patients (four females, two males; aged 18-65 years), previously treated by external pituitary irradiation (2000-4000 cGY in 8-15 fractions over 10-20 days) for pituitary tumours, presented with the symptoms of excessive and inappropriate tiredness suggestive of ACTH deficiency, despite a normal peak cortisol response to an insulin tolerance test (four cases) or to a glucagon stimulation test (two cases). These six patients were found to have significantly lower mean 24 h urinary free cortisol levels (100 +/- 40 nmol; mean +/- SD) compared with the mean value of 31 normal controls (210 +/- 70.8 nmol; P less than 0.01). In addition serum cortisol profiles based on a series of four timed samples between 0900-2300 h were subnormal (mean 130 nmol/l) in comparison with profiles obtained from 12 normal controls (mean 270 nmol/l) (P less than 0.001). Glucocorticoid replacement therapy promptly abolished their symptoms. These results suggest that a discordance between ACTH secretion under basal circumstances and ACTH response to pharmacological tests may exist in patients with ACTH deficiency. We speculate that defective endogenous corticotrophin-releasing hormone (CRF) secretion, due to radiation-induced damage at hypothalamic level, is one cause of this phenomenon.