Combined amplification of the pulsatile and basal modes of adrenocorticotropin and cortisol secretion in patients with Cushing's disease: evidence for decreased responsiveness of the adrenal glands

Abstract

We investigated 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 23 healthy controls. Blood samples were taken at 10-min intervals, and data were analyzed with a multiparameter deconvolution technique. The patients had the same number of ACTH pulses per 24 h as the controls (34 vs. 32/24 h) and similar plasma ACTH half-lives (17.4 +/- 0.7 vs. 19.3 +/- 0.5 min). The mass of ACTH secreted per pulse was increased, which was caused by an increased maximal secretion rate and prolonged secretion burst duration. The number of resolved cortisol pulses was less than that for ACTH, but higher in patients than in controls (24 vs. 17/24 h), with similar half-lives in both groups (57 +/- 2 vs. 59 +/- 4 min). The mass of cortisol secreted per pulse was higher in patients than in controls due to an increased maximal secretion rate attained within each burst. The mean total mass of 24-h cortisol production was 12.8 mg in controls (range, 6.7-20 mg) and 46 mg (range, 13.4-154) in patients. Basal secretion rates of ACTH and cortisol were increased 19-fold (ACTH) and 7-fold (cortisol) above control values in patients with Cushing's disease (P < 0.0002). The ratio of total 24-h cortisol and ACTH production (in mass units per L distribution volume) was 23 +/- 1.9 in controls and 11 +/- 2.3 in patients (P < 0.001). The secretory parameters for ACTH showed strong diurnal rhythms in control subjects, but were not significant in six patients. Diurnal rhythms for cortisol could be detected in only five patients. From these observations we conclude that cortisol and ACTH release in Cushing's disease is highly pulsatile, with the preservation of diurnal properties in only some patients. Markedly amplified total daily hormone secretion was attributed to a 19-fold (ACTH) and 7-fold (cortisol) higher basal secretion rate, increased secretory burst mass (ACTH and cortisol), and frequency (cortisol) in Cushing's disease. In addition, the apparent response of the adrenal gland to increased ACTH levels is diminished, suggesting decreased responsiveness of the adrenal glands.