Corticosteroid inhibition of ACTH secretion.

Corticosteroid feedback inhibits the brain-hypothalamo-pituitary units of the adrenocortical system. Naturally occurring corticosteroids may have their primary actions in vivo at brain and hypothalamic sites of feedback, whereas synthetic glucocorticoids that do not bind to transcortin may act primarily on corticotropes and regions of brain outside the blood-brain barrier. There appear to be three major time frames of corticosteroid action: fast, intermediate and slow. These time frames probably are the consequence of three separate mechanisms of corticosteroid action at feedback-sensitive sites. The rapidity of occurrence of fast feedback is not compatible with a nuclear site of corticosteroid action, and protein synthesis is not required. The action of CRF on ACTH release may be inhibited by a rapid effect of corticosteroids at the cell membrane. Since stimulated, but not basal, ACTH and CRF release are inhibited in vitro, the corticosteroids may inhibit some event in stimulus-secretion coupling (e.g., cAMP production). Intermediate feedback also decreases ACTH release in response to stimulation of the corticotrope, but does not affect ACTH synthesis; CRF synthesis and release both appear to be affected by the intermediate corticosteroid action. The mechanism of intermediate feedback requires the presence of a protein whose synthesis is corticosteroid-dependent; however, the role of this protein is unknown. Intermediate feedback, like fast feedback, apparently does not involve inhibition of total ACTH stores or the releasable pool of ACTH since basal secretion of ACTH is also not inhibited in vitro within this time domain. On the other hand, slow feedback apparently involves the classical genomic steroid mechanism of action; slow feedback reduces pituitary ACTH content by decreasing levels of mRNA encoding for POMC, the ACTH precursor molecule. Slow feedback, therefore, inhibits basal as well as stimulus induced ACTH secretion. Corticosteroid-induced inhibition of basal ACTH secretion has been shown to occur within 2 h in vivo but not in vitro. The time course and sensitivity of this feedback effect is different than that demonstrated for stimulus induced secretion. This difference suggests that basal secretion is activated by different pathways to (CRF and) ACTH secretion. There is some evidence that suggests that whereas comparator elements are not reset during stress, a comparator element is reset during the course of the circadian rhythm so that different basal levels of steroid are achieved.(ABSTRACT TRUNCATED AT 400 WORDS)