Growth Hormone (GH)-Releasing Factor Stimulates Hypothalamic Somatostatin Release: An Inhibitory Feedback Effect on GH Secretion*

Abstract

GH-releasing factor (GRF) is a hypothalamic peptide that stimulates the secretion of pituitary GH. The possibility of feedback effects of GRF within the central nervous system was studied in conscious freely moving male rats with indwelling iv and intracerebroventricular (icv) cannulae. Animals were injected icv or iv with 10 ng-10 micrograms human (h) GRF(1-40)-OH (hGRF-40) or GRF(1-44)-NH2 (hGRF-44), and blood samples were obtained every 10-20 min from 1000-1400 h. GH secretion was pulsatile, with major secretory peaks at around 1200 h in most control animals. When 10 ng hGRF-40 were injected icv at 1100 h, immediately before the expected onset of the spontaneous GH secretory burst, GH secretion was suppressed during the following 2-h period. An iv injection of 10 ng hGRF-40 was without effect. In contrast, when 1 microgram hGRF-40 was injected icv or iv, plasma GH levels peaked at 20 and 10 min, respectively, and returned toward baseline shortly thereafter. The spontaneous GH secretory pulse after 1 microgram hGRF-40 (icv or iv) was suppressed in proportion to the magnitude of the GH secretory response to GRF (r = 0.78, p less than 0.01), and the prolongation of the interval between the injection of GRF and the subsequent spontaneous GH surge was directly related to the GH response to GRF (r = 0.85, p less than 0.001). The icv or iv injection of a larger dose of either hGRF-40 or hGRF-44 (10 micrograms) at 1100 h also resulted in marked and comparable increases in plasma GH levels, with peaks at 20 min (icv) and 10 min (iv) after injection. No changes in behavior or plasma glucose were observed up to 3 h after icv injection of any of the doses of hGRF-40 or of hGRF-44. The suppressive effect of centrally administered hGRF-40 (10 ng) on GH secretion was blocked by the iv administration of a specific antisomatostatin serum immediately before the injection of hGRF. These results demonstrate a dual action of GRF on spontaneous GH secretion and indicate the presence of an inhibitory feedback system within the central nervous system for the regulation of GH secretion which is mediated by hypothalamic somatostatin.

GHRH and TRH tests in patients with idiopathic and secondary GH deficiency. With special reference to GH response patterns to GHRH.

“…However, the following four explanations might be conceivable. Firstly, plasma GH response to GHRH and resultant increases in tissue (hypothalamic and pituitary) levels of Sm-C in these patients is insuficient to exert negative feedback effects on hypothalamo-pituitary axis (Copeland et Katakami et al 1986) due to the hypothalamic lesions. It is possible that these mechanisms are combined together to cause the smaller GH decline.…”

Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion

“…Thus we compare the impact of constant systemic GHRH stimulation under the assumption of either no or variable access of infused GHRH to SRIF neurons. A truncated transcript of the GHRH gene is expressed in the foregoing two hypothalamic nuclei, as quantitated by RT-PCR, sequencing of the cDNA product, and Northern blot hybridization (47); and, central delivery of synthetic GHRH stimulates SRIF release acutely in vivo in the adult male rat and in vitro from incubated fragments of the median eminence (1,2,11,24,27,29,(32)(33)(34)37).…”

“…However, the purely systemic-central nervous system (CNS) feedback structure fails to account for other fundamental experimental observations. The latter include 1) continued GH pulsatility under constant systemic GHRH stimulation, 2) a paradoxical suppressive effect of central GHRH action, and 3) peripheral SRIF withdrawal-induced rebound-like secretion of GH in the adult female rat (13,20,27,30,34,42).The present work formulates and implements an alternative model of GH autoregulation, which combines four distinct mechanisms: 1) long-loop, timedelayed stimulation of SRIF release by blood-borne GH (systemic-CNS control); 2) periventricular SRIF-dependent inhibition of pituitary GH release but not synthesis (CNS-pituitary regulation); 3) arcuate-nu- …”

“…However, the purely systemic-central nervous system (CNS) feedback structure fails to account for other fundamental experimental observations. The latter include 1) continued GH pulsatility under constant systemic GHRH stimulation, 2) a paradoxical suppressive effect of central GHRH action, and 3) peripheral SRIF withdrawal-induced rebound-like secretion of GH in the adult female rat (13,20,27,30,34,42).…”

Ghrelin, a Gastric Hormone with Diverse Functions

“…GH secretion is mainly regulated by GH-releasing hormone (GHRH) (Frohman & Jansson, 1986) and somatostatin (Katakami et al, 1986, which are stimulatory and inhibitory hormones respectively. Studies on GHS synthetic peptides and non-peptides which stimulate GH release indicated a distinct third pathway in addition to GHRH and somatostatin and the presence of a unique receptor (Bowers et al, 1984).…”