Studies on the regulation of growth hormone secretion in man

The availability of recombinant peptides, involved in linear growth, has invigorated the investigation of the neuroregulation of growth. The potentially unlimited quantities of GH available has led to an expansion in criteria for therapy to encompass children with growth failure from causes other than classical growth hormone deficiency, adults with growth hormone deficiency, and the elderly. Synthetic GHRH is a potent tool in the investigation of the growth axis and an alternative to GH therapy. Further understanding of the dynamics of growth should result from the recent availability of recombinant IGF-I for therapy of diseases associated with growth hormone resistance, and for the investigation of growth physiology. The studies described in this thesis take advantage of these advances to further understanding of the neuroregulation ofGH secretion in man. In a cohort of healthy male volunteers, a single subcutaneous injection of 40 pg/kg of IGF-I was not associated with side-effects, in particular hypoglycaemia was not a problem. Frequent venous sampling over 24 hours revealed a fall in plasma TSH, but secretion of the other pituitary hormones was unperturbed. IGF-I did not alter the pulsatile nature and quantity of GH secretion over 24 hours, but did result in potentiation of the GH response to GHRH. The regulation of linear growth is dependent on many factors. An experimental paradigm of pharmacological tests and overnight sampling compared GH dynamics in groups of tall and short young men. Insulin-induced hypoglycaemia and GHRH were unable to differentiate between the two groups. Overnight profiles of spontaneous GH secretion suggested mean pulse amplitude to be greater in taller individuals although the difference did not reach significance. Plasma growth hormone levels correlate with plasma oestrogen levels and are therefore greater in young women than men. In a group ofhealthy young men and women, no difference existed in either the GH responses to GHRH in a group of young men and women, or in the women at different stages of the menstrual cycle, indicative of a hypothalamic site of action for oestrogens. Many characteristics of the adult GH deficiency syndrome are associated with "normal" aging. Spontaneous GFI secretion decreases with age as did the response to GHRH in the subjects studied here. Modulation of cholinergic-regulated somatostatin secretion, with the anticholinesterase, pyridostigmine, augmented the GH response in all ages. However, the influence of pyridostigmine also diminished with age. Elevated circulating glucocorticoids are associated with impaired GH secretion and growth failure in children. Pretreatment with a potent synthetic glucocorticoid, dexamethasone, virtually obliterated the GH response to GHRH. However, pyridostigmine significantly increased the GH response, indicative that increased somatostatin secretion is responsible for the acute glucocorticoid-induced diminished GH secretion. GHRH therapy is of proven efficacy in the treatment of short stature and offers a theoretical advantage over GH of restoring pulsatile GH secretion. However, the short halflife of GHRH and the necessity of, at least, twice daily injection, limit its use. DC-21-346 was designed as a superpotent, degradation-resistant GHRH analogue, and in rats was fifty times as potent as conventional GHRH. Unfortunately, in normal volunteers DC-21-346 was only equipotent with conventional GHRH and therefore has no therapeutic future. It is anticipated that these findings will be the foundation of further studies of the neuroregulation ofGH secretion and ultimately improved management of disorders of the growth axis.