Growth hormone-releasing hormone (GHRH) and somatostatin (SRIF) are the two hypothalamic peptides which together control growth hormone (GH) synthesis and release. This project aims: a) to study the neuroendocrine regulation of GH secretion; b) to define alterations in GHRH responses in different physiologic states, and to determine their cause; and c) to explore the efficacy of GHRH and analogues for treatment of GH deficiency and excess. 1) We have studied the mechanism underlying the indirect stimulation of GH by co-administering GHRH with insulin-induced hypoglycemia (ITT). ITT is capable of enhancing the response to even a maximally stimulating dose of GHRH, indicating that ITT must activate mechanisms other than release of endogenous GHRH. The likeliest possibility is that ITT suppresses somatostatin secretion. 2) GH secretion remains pulsatile during the continuous confusion of GHRH in both normal and acromegalic subjects, suggesting the somatostatin secretion is also intermittent, and variably blocks the response to GHRH. The frequency of GH pulses increases during GHRH infusions in normals, but is unchanged in acromegalics. This suggests that SRIF pulsatile secretion can change in response to elevations of GH or GHRH -- a finding we have confirmed in hypothalamic perifusions in vitro -- and that the frequency of episodic secretion in GHRH-infused normals resembles that seen in acromegaly. 3) An ongoing long-term dose-response study suggests that a dose of 10mcg/kg GHRH per day can restore normal growth velocity in many patients with GH deficiency. We do not see a significant different in response based on the pattern of administration, so long as the total daily is sufficient. The enhancement of GH responses to acute doses of GHRH by drugs which alter SRIF secretion has led us to study whether alteration of SRIF might also enhance the growth response to chronic GHRH therapy.
