We investigated the episodicity of 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 25 healthy matched controls, with a recently introduced scale- and model-independent regularity statistic, approximate entropy (ApEn). The mean (+/-S.E.M.) ApEn value for plasma ACTH concentrations in Cushing's disease was 1.3817 +/- 0.033, and in controls 0.8394 +/- 0.049 (P < 10(-10)); for plasma cortisol concentrations the values were 1.4575 +/- 0.052 and 0.8637 +/- 0.020 respectively (P < 10(-10)), implying greater irregularity of release for both hormones in Cushing's subjects. The calculated sensitivity and specificity of ApEn for ACTH profiles were 94% and 100% respectively. For cortisol the sensitivity and specificity were both 100%. ApEn was not correlated with sex, age, or the total 24-h secretion rate of ACTH and cortisol in patients and controls. The increased ApEn in patients with Cushing's disease points to an increased disorderliness of ACTH and cortisol secretion compared with healthy controls. In conjunction with the available literature, we hypothesize more generally that autonomous endocrine tumors may be typified by reduced regularity, orderliness, or synchrony of the time structure of hormone release.