REGULATION OF HYPOTHALAMIC SOMATOSTATIN BY GLUCOCORTICOIDS

Glucocorticoids (GCs) play a key role in the physiology of the hypotha lamic-somatotroph axis, since these steroids enhance growth hormone (G H) gene transcription and increase GHRH receptor synthesis. However, G C excess inhibits normal growth in all species studied. This is mainly due to the impaired GH secretion observed during hypercortisolism, a situation in which GH responses to a number of stimuli, including GHRH , are blunted. The inhibitory effect of GCs on GH secretion seems to b e dependent on enhanced hypothalamic SS secretion. Since SS release is stimulated by beta-adrenergic agonism we tested the possibility that GC inhibition of GH secretion would depend on increased beta-adrenocep tor activity in SS-producing neurons. The experimental design consiste d in evaluating the GH response to GHRH in normal subjects after havin g induced hypercortisolism, with DEX, and blocking beta-adrenoceptors with propranolol (PRO). Moreover, to investigate the specificity of th is mechanism, GHRH-induced GH release was tested after inducing hyperc ortisolism and enhancing alpha(2)-adrenergic or muscarinic cholinergic tone, by giving clonidine (CLO) or pyridostigmine (PD), respectively. As expected, nocturnal DEX administration inhibited the GH response t o GHRH. In this situation of hypercortisolism, both PRO and CLO, but n ot PD, were able to reverse the inhibitory effect of DEX on GHRH-elici ted release. However, the potentiating effect of these drugs on the GH RH-induced GH secretion was only observed for PRO. These data confirm that GC excess inhibits GH release by increasing hypothalamic SS secre tion, and that the mechanism is mediated by GC-induced enhanced beta-a drenergic responsiveness. Therefore, the defective GHRH secretion obse rved in chronic hypercortisolism must be a consequence of the continuo us blockade that SS excess exerts on GHRH-producing neurons. Our postu late agrees with other data in the literature showing that GCs modulat e the secretion of some hypothalamic peptides by changing the responsi veness of the producing neurons from alpha(2)-adrenoceptors to that of beta-adrenoceptors.