Temporally Discrete Effects of Corticosteroids on Hypothalamic-Pituitary-Adrenal Axis Function

Feedback inhibition of (CRH, AVP, and) ACTH secretion can be shown to exist in fast, intermediate, and slow time domains when corticosteroids are administered exogenously. Normally these segue smoothly from one to the other, but they can be distinguished mechanistically, and the degree of inhibition increases as the duration and amount of the corticosteroid exposure increases. In all time domains, the magnitude of the effect is strictly proportional to the dose of steroid, between the limits of threshold and saturating quantities.

1. The fast effects occur within milliseconds on neurons and must be exerted by an effect at the cell membrane. A membrane receptor has not yet been characterized. The iontophoresis of corticosteroids onto neurons or bathing tissue slices with corticosteroids shows effects within milliseconds to seconds on membrane function. Similarly, in animals the stimulation of pathways to CRH neurons does not evoke the normal response within minutes of a systemic injection of corticosteroids.

At the pituitary cortico- troph, CRH-stimulated ACTH secretion is inhibited within a few minutes of the application of corticosteroids; this inhibition is not altered by the inhibition of RNA or protein synthesis, showing that it is not mediated by the usual genomic effects of corticosteroids, although it may be mediated by interference with the generation of adenyl cyclase, the intracellular messenger for CRH.

The magnitude of the fast inhibition of ACTH secretion by corticosteroids acting on the corticotroph is small (-25% of the maximal inhibition possible); thus, fast feedback leaves the organism responsive to further stressors and capable of secreting nearly normal amounts of ACTH.

2. Intermediate feedback has its onset at approximately 30 min after a pulse or continuous exposure to the steroid and lasts for a period of hours. The inhibition of protein synthesis with cyclohexamide blocks this feedback and, although it is powerful and can completely inhibit CRH-induced ACTH secretion in the whole animal, ACTH secretion can usually be stimulated by further treatment with CRH or AVP.

This temporal domain of corticosteroid feedback appears to dampen the excitability in the HPA axis without abolishing it (i.e., excitability is returned to prestress levels so that subsequent responsivity is not excessive). At the pituitary, AVP-stimulated ACTH secretion is less sensitive than CRH to corticosteroid inhibition.

3. Slow feedback is found in conditions in which the supraphysiological levels of exogenous corticosteroids have been provided for days or weeks. All components of the HPA axis are unresponsive to stimulation, both by intense stressors and, at the pituitary, by CRH and AVP.

The CRH and AVP mRNA expression in the hypothalamus and proopiomelanocorticoid expression in the pituitary is markedly decreased. This condition is most frequently observed in humans with active Cushing disease or after prolonged treatment of disease with high levels of synthetic glucocorticoids; it takes months to recover from this inhibition when the high levels of steroid are removed.