Growth hormone (GH), the pituitary hormone which stimulates statural growth and metabolism, is regulated by two hypothalamic peptides: GH-releasing hormone (GHRH) and somatostatin (SRIF). Most patients with GH deficiency (GHD) have a deficiency of GHRH secretion. This project aims to characterize the physiology of GHRH and SRIF regulation and to apply these findings in the diagnosis and therapy of GH deficiency and excess. Both dopaminergic (DA) and noradrenergic (NE) agents stimulate GH secretion, while beta-adrenergic agents (E) stimulate SRIF; but the detailed regulation of this system is not understood. Monkeys given diethyldithiocarbamate (DDTC), which inhibits conversion of DA to NE, show markedly reduced responses to GHRH and spontaneous GH secretion, which is not reversed with beta-adrenergic blockade. This indicates that DA requires local conversion to NE to stimulate GHRH secretion, and that NE may inhibit secretion of SRIF. Rats given chronic DDTC treatment show reduced growth. This provides a new model of reversible GHD. Since GHD largely results from deficiency of GHRH, GHRH therapy can treat GHD. We have conducted a cooperative trial of 1 year GHRH therapy in a large group of GHD children. GHRH is fully effective in restoring normal growth velocity in the majority of patients. GH responses to GHRH are highly variable, due to variable interference by SRIF. We have tested the utility of coadministration of SRIF blockade in combination with GHRH therapy of GHD. Preliminary results suggest that E blockade enhances the growth response to GHRH. GHRH is a large molecule, but we have found a high degree of GH-releasing activity in a synthetic hexapeptide (GHRP) which is effective orally. GHRP appears to stimulate release of GHRH. Pituitary tumors hypersecreting GH (acromegaly) retain responsivity to GHRH, although systemic counterregulatory responses (SRIF) are increased. We have developed a candidate ligand-directed cytotoxic agent for therapy of acromegaly by coupling GHRH to an organoboron compound which undergoes alpha decay when exposed to neutrons. Thus GHRH may form the basis of novel approaches to the therapy of GHD and GH excess.
