PATIENTS WITH CUSHINGS-DISEASE SECRETE ADRENOCORTICOTROPIN AND CORTISOL JOINTLY MORE ASYNCHRONOUSLY THAN HEALTHY-SUBJECTS

We examined serum concentration time-series for ACTH and cortisol in 2 0 patients with pituitary-dependent ACTH excess (Gushing's disease) an d in 29 age-and gender-matched controls. For each subject, blood sampl es were obtained at 10-min intervals for 24 h. Joint ACTH-cortisol syn chrony was quantified using the recently introduced cross-approximate entropy (cross-ApEn) statistic. In patients, cross-ApEn was greater th an in controls (1.686 +/- 0.051 us. 1.077 +/- 0.039, P = 3.45 x 10(-16 )), giving a sensitivity of 85%. In control subjects, but not in patie nts, cross-ApEn was correlated positively with age (r = 0.465, P = 0.0 11) There was no gender difference in cross-ApEn, nor a relationship b etween cross-ApEn and the 24-h ACTH and cortisol secretion, in patient s or controls. In contrast, the maximal cross-correlation coefficient for the ACTH and cortisol series after detrending the series was 0.394 +/- 0.033 in controls and 0.297 +/- 0.034 in patients with considerab le overlap of the subgroups, giving a sensitivity for this index of on ly 5%. In addition to previous findings of increased individual irregu larity of ACTH and cortisol release in Gushing's disease, we can now a lso demonstrate greater joint asynchrony of the circulating concentrat ions of these hormones. Thus, Gushing's disease disrupts ensemble netw ork secretory dynamics over individual hormone output. We conclude tha t, like GH-secreting pituitary and aldosterone-secreting adrenal tumor s, ACTH-secreting pituitary tumors exhibit significant loss of orderly hormone release patterns. Moreover, Gushing's disease is marked furth er by deterioriation of bihormonal synchrony between ACTH and cortisol release, thus suggesting further erosion of within-axis feedback cont rol.