The pituitary ACTH and hypothalamic CRH alterations at different periods after adrenalectomy (ADX) or Sham ADX were studied by measurement of ACTH and CRH contents by radioimmunoassay (RIA) in rats. We also studied the corticotroph alterations by immunohistochemistry and the in vitro pituitary responsiveness to CRH. Plasma ACTH presented a triphasic response after ADX. Anterior pituitary (AP) ACTH content decreased 3 h and 1 day after surgery, then rose over this period. Immunohistochemistry demonstrated an initial degranulation of the corticotrophs with a progressive increase in cells immunostained for ACTH and a positive correlation (r = 0.88) with AP ACTH content measured by RIA. Hypothalamic CRH content decreased after ADX, but returned to sham value 3 weeks later. Basal ACTH secretion in incubation medium was correlated with the AP ACTH content observed in vivo. The pituitary responsiveness to CRH was not the same at all times after ADX. It was absent 1 day after, presented an increase of 51%, 117% and 26% when compared with the basal ACTH output 3 h, 3 and 14 days after ADX, respectively. Our data suggest that after ADX the corticotroph undergoes a transitory decrease in ability to secrete ACTH after store depletion. During a later phase, however, there is a relative hyporesponsiveness of the corticotroph to CRH stimulation. These data indicate that CRH may be acting on a down-regulated pituitary or more additional factors play a role in the sensitization of the pituitary after ADX.