Growth hormone releasing factor infusion does not sustain elevated GH-levels in normal subjects

Abstract

To evaluate the dynamics of GH-secretion after infusion of growth hormone releasing factor, human pancreatic growth hormone releasing factor (hpGRF1-44) was infused over 2 and 5 h at a dosage of 100 \ g=m\ ghpGRF1-44/h into 11 healthy subjects. The infusion was started and terminated with a 50 \g=m\ghpGRF1-44 bolus injection. In 5 subjects 200 \ g=m\ g TRH was given 4 h after starting the infusion. In addition, 4 healthy subjects received 50 \g=m\ghpGRF1-44 bolus injection every 2 h. GRF, somatostatin, GH, Prl, and TSH were measured by radioimmunoassay. The initial 50 \ g=m\ g GRF bolus increased GH-levels in all 11 subjects with a maximum at 30 min (24.1 \ m=+-\5.1 ng/ml \ m=+-\ SE). However, though hpGRF1-44 was continuously infused and GFR-levels remained elevated, GH decreased to a minimum 270 min after start of infusion (2.6 \m=+-\0.6 ng/ml). The GH-response to the second bolus at the end of the infusion was lower compared to the first response (14.6 \ m=+-\ 3.4 ng/ml after 2 h and 7.6 \ m=+-\ 2.5 ng/ml after 5 h). TRH did not lead to a GH-increase during hpGRF1-44 infusion though Prl and TSH rose normally. The intermittent bolus injection of 50 \g=m\ghpGRF1-44 led to continuously decreasing GH-responses to the same GRF\x=req-\ dosage (I. bolus: 16.5 \ m=+-\1.6 ng/ml; II. bolus: 4.2 \ m=+-\ 0.8 ng/ml; III. bolus: 3.4 \m=+-\0.5 ng/ml). No change in somatostatin levels was observed.These findings show that GRF infusion or bolus injection in short intervals does not sustain elevated GH-levels.Pituitary GH is either not readily available for continuous GRF-stimulation or GH-secretion may be antagonized by increasing portal somatostatin levels which are not reflected in the peripheral circulation.

Effects of Growth Hormone-Releasing Hormone and Somatostatin on Sleep EEG and Nocturnal Hormone Secretion in Male Controls

“…The GH-stimulatory effect of repeated nocturnal GHRH injections is in accord with the effect of single and serial challenges during the daytime [23][24][25]. The only dif ference that emerged is that during the night the return of the plasma GH concentration to baseline is protracted, possibly because of enhanced responsivity of the somatotrophic system at this particular time.…”

Arginine Reinstates the Somatotrope Responsiveness to Intermittent Growth Hormone-Releasing Hormone Administration in Normal Adults

“…The lessening of GH response to repeated GHRH stimula tion was shown not to be due to an increased metabolic degra dation or clearance of the neurohormone [3]. The existence of a GHRH-induced reduction in the GH releasable pool and/or the occurrence of a receptor or post-receptor mechanism of downregulation of somatotropes [5,6] were also hypothesized.…”

“…In normal adults repeated GHRH administration leads to progressively decreasing somatotrope response [2][3][4], A GHRH-induced selective reduction of the GH releasable pool or, alternatively, the occurrence of a receptor or post-receptor mechanism of downregulation of the somatotropes were hy pothesized [5,6], Other evidence supported the hypothesis that somatotrope refractoriness to repeated GHRH stimulation is due to elicitation of a negative autofeedback likely mediated by enhanced SRIH release [2,4,[7][8][9]. Particularly, in agreement with this hypothesis, it was shown that the enhancement of the cholinergic activity by pyridostigmine, a cholinesterase inhibitor likely acting by inhibition of SRIH [9][10][11], reinstates and even potentiates the GH responsiveness to a GHRH bolus preceded by another GHRH stimulation [4] as well as by administration of methionyl-GH [8].…”

Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus.

“…Thus, alternative explanations, relating to changes in the intracellular response to GRH or to changes in somatostatin secretion, appear more plausible. Other published data relating to plasma GRH levels after injection of exogenous GRH (32)(33)(34) are also likely to be incorrect, since the contribution of GRH metabolites to total measured GRH immunoreactivity is unknown. Finally, our results should be helpful in designing modifications of the GRH sequence that are resistant to enzymatic degradation in order to develop superactive analogs.…”