Potent Growth Hormone Secretagogues Research Articles

In vivo studies with growth hormone (GH)-releasing factor and clonidine in rat pups: ontogenetic development of their effect on GH release and synthesis.

The demonstration that GH-releasing factor (GRF) stimulates GH synthesis and release in rat pups prompted studies to evaluate the effects on the same indices of clonidine (CLO), an alpha 2-adrenoceptor and potent GH secretagogue, purported to act in adult rats via GRF release. Our first aim was to ascertain whether CLO elicits GH release in rat pups via GRF, and if this is the case, to evaluate the ontogenetic development in 1- to 10-day-old pups of the GH response to acute CLO or GRF administration and, finally, the effects of short term CLO or GRF treatment on plasma and pituitary GH concentrations and on the GH response to an acute challenge with the homologous secretagogue. CLO (15 micrograms/100 g BW, sc) induced a clearcut GH rise in 10-day-old rats but not in pups pretreated with a specific anti-GRF serum. Moreover, unlike GRF (10(-8) M), CLO (10(-6) to 10(-5) M) did not stimulate GH release in vitro from anterior pituitaries of 10-day-old rats. In 1-day-old rats, neither CLO (15 micrograms/100 g BW, sc) nor GRF (20 ng/100 g BW, sc) stimulated GH release, whereas significant GH stimulation was elicited by GRF, but not CLO, in 5-day-old rats and by both secretagogues in 10-day-old rats. Short term treatment with CLO (15 micrograms/100 g BW, sc, twice daily) or GRF (20 ng/100 g BW, sc, twice daily) on postnatal days 1 through 5 did not modify either plasma or pituitary GH concentrations 14 h after the last drug administration, but did so when either secretagogue was administered on postnatal days 5 through 9. Finally, an acute challenge with GRF, but not with CLO, induced a further rise in the already elevated plasma GH levels of pups pretreated from postnatal day 5 through 9, but neither secretagogue did so in pups pretreated from postnatal days 1 to 5. Viewed together, these data indicate that in infant rats CLO releases GH via GRF release and that the somatotropes respond earlier to GRF (5 days) than the GRF-secreting structures do to alpha 2-adrenergic stimulation (10 days). Both GRF and CLO stimulate GH synthesis when administered repeatedly. However, whereas repeated GRF treatment has a priming effect on the somatotropes, CLO does not, probably because of down-regulation of hypothalamic alpha 2-adrenoceptors.

Effect of growth hormone releasing factor (GRF) on serum growth hormone (GH) and prolactin (PRL) in hypopituitary children

GRF may be of value in investigating growth disorders. An IV bolus of 0.5 μg/kg of GRF-44-NH2 (Peninsula Labs, USA) was given to 12 short normal children (N) and 24 children with documented GH deficiency (GHD). Serum GH and PRL were measured by RIA. In the N group. GRF induced a rapid and ample GH response :In the GHD group, mean peak GH after GRF was lower than in the N group (8.0±2.5 vs 39.2±5.1 ng/ml, p<0.001) but peaks within the normal range were seen in the youngest GHD patients. In the N group, PRL decreased continuously over the 3 hours of the test, a reflection of its normal circadian rythm (222±54 at 9 AM vs 108±27 μU/ml at 12 AM, p<0.05). In 7 GHD patients, PRL peaked 15 minutes after GRF (366±73 at 0 min vs 494±85 μU/ml at 15 min, p<0.05); in 2 patients with genetic GHD, PRL decreased to a nadir at 60 min, followed by a rebound; in the remainder of the GHD group there was no change in PRL. Conclusion : 1) GRF at a dose of 0.5 μg/kg is a potent GH secretagogue in children; 2) Some GHD children have GH responses to GRF within the normal range; 3) The PRL response to GRF in GHD is heterogeneous.

The Interrelationship of Growth Hormone (GH)-Releasing Factor and Somatostatin in Generation of the Ultradian Rhythm of GH Secretion*

To further delineate the relationship between GH-releasing factor (GRF) and somatostatin (SRIF) in generation of the ultradian rhythm of GH secretion, we used two GRF peptides, human pancreas (hp) GRF-44 and rat hypothalamic (rh) GRF, and studied their interaction with SRIF by passive immunization with a specific antiserum (AS) to SRIF. Freely moving, chronically cannulated male rats were given 10 micrograms of either hpGRF-44 or rhGRF, iv, during peak (1100 h) and trough (1300 h) periods of the GH rhythm. Six-hour plasma GH profiles were obtained after pretreatment with either SRIF AS or normal sheep serum (NSS) as a control. In NSS-treated rats, the plasma GH responses to both hpGRF-44 and rhGRF were significantly greater when the peptides were administered during peak than during trough periods. Immunoneutralization with SRIF AS eliminated these differences and permitted marked GH release in response to both peptides at 1300 h. In addition, SRIF AS augmented the GRF-induced GH response at 1100 h compared with that in NSS controls. The rhGRF peptide caused significantly more GH release than hpGRF under both conditions. These results demonstrate that 1) the GH-releasing abilities of the GRF peptides vary markedly according to the time of injection; 2) the weak GRF-induced GH response observed during trough periods of the GH rhythm is due to antagonization by endogenous circulating SRIF; and 3) the rat-derived GRF may be a more potent GH secretagogue than the human-derived peptide in the rat. The findings reported here together with the available evidence provide support for the hypothesis that GRF and SRIF are secreted tonically from the hypothalamus into the hypophyseal portal blood, and that superimposed upon this steady state release is an additional 3- to 4-h rhythmic surge of each peptide, providing for integration of the ultradian rhythm of GH secretion, as observed in peripheral blood.

Growth hormone-releasing factor stimulates pancreatic enzyme secretion.

Growth hormone-releasing factors (GRF's) from two human pancreatic tumors (hpGRF's) that caused acromegaly and from the rat hypothalamus ( rhGRF ) were recently isolated and characterized. Although these peptides are potent growth hormone secretagogues, they have not until now been described to have actions outside the pituitary. These GRF's were shown to stimulate digestive enzyme secretion from an exocrine pancreatic preparation in vitro, rhGRF being more than 100 times as potent as hpGRF. Adenosine 3',5'-monophosphate mediates this action of the GRF's.

Effect of synthetic thyrotrophin-releasing hormone and its analogues on growth hormone secretion in the domestic fowl (Gallus domesticus).

Variations in plasma growth hormone (GH) concentrations following iv or sc administration of synthetic thyrotrophin-releasing hormone (TRH, Pyr-His-Pro-NH2) have been followed in immature and adult domestic fowl. TRH markedly stimulated GH secretion in newly hatched (1 and 2 day old) chicks and in 6-week-old cockerels but in adult male or female birds of two strains had very little effect, if any. Intravenous injection of 4 TRH analogues (Pyr-His-Mep-NH2, Pyr-Meh-Mep-NH2, Pyr-Meh-Mep-NH and Pyr-Meh-Pro-NH2) were also potent GH secretagogues in 6-week-old birds. The stimulatory effect of TRH or the TRH-analogues on GH secretion was not dose-related.