HUMAN PANCREATIC GROWTH HORMONE-RELEASING FACTOR-40 (hpGRF-40) ALLOWS STIMULATION OF GH RELEASE BY TRH

Abstract

The effects of synthetic hpGRF-40 on GH release from continuously perifused male rat anterior pituitary cells were studied. Pulses (2.5 min) of hpGRF-40 stimulated GH release in a log-linear dose response relationship: concentrations of 0.03, 0.1, 0.3, 1, 3, 10, 30 and 100 nM given in a random order elicited a GH response above baseline of 1.2 +/- 0.3, 2.4 +/- 0.4, 2.8 +/- 0.2, 4.3 +/- 0.2, 6.2 +/- 0.7, 7.0 +/- 1.0, 8.7 +/- 1.7, and 10.8 +/- 0.8 micrograms/10(7) cells (mean +/- SEM; n = 3; r = 0.93), respectively. During a 5-h hpGRF-40 infusion, GH stimulation peaked within 5 min and waned to near baseline by the end of the fifth h. The integrated GH responses to 0.03, 0.1 and 0.3 nM hpGRF-40 were 37.6 +/- 7.4, 52.9 +/- 8.5, and 66.15 +/- 8.2 micrograms/10(7) (mean +/- SEM; n = 3; r = 0.72), respectively. The interaction of TRH and hpGRF-40 in the control of GH secretion was studied to investigate the mechanism of the "paradoxical" TRH stimulation of GH release associated with GH excess states in humans. Dispersed cells were perifused with either 100 nM TRH for 0.5 h, 5 nM hpGRF-40 for 4 h, or 5 nM hpGRF-40 for 4 h, to which a 0.5 h pulse of TRH was added at 2 h. GH levels did not change significantly in the presence of TRH alone. When TRH was added to the ongoing hpGRF-40 perifusion, GH release increased from 1.4 +/- 0.06 to 4.0 +/- 1.0 micrograms/min.10(7) cells (n = 4; P = 0.03). Thus, dispersed pituitary cells are highly sensitive to very low concentrations of hpGRF-40 administered as both an acute pulse and as a tonic infusion. When the cells are exposed to a maximal concentration of hpGRF-40 (i.e. 5 nM), TRH becomes a secretagogue at the pituitary level, thus suggesting the site and mechanism of the "paradoxical" GH response to TRH observed in some acromegalics.

Effect of Thyrotropin-Releasing Hormone on Growth Hormone Release in Normal Subjects Pretreated with Human Pancreatic Growth Hormone-Releasing Factor 1–44 Pulsatile Administration

“…Although the intracellular mechanisms involved are still unclear, GRF exposure seems to facilitate the expression of GH-releasing activity by TRH. This hypothesis is sup ported by the present data and the finding that GH respon siveness to TRH, already observed in some in vitro experi ments [6], was greatly amplified by GRF hyperstimulation of cultured rat somatotrophs [4], The lack of effect of TRH on GH release during GRF infusion reported by others [18] can be attributed to differences in GRF exposure both in term of time course and doses utilized.…”

“…Therefore, GH increase after TRH has been hypothesized to result from defective somatostatin secretion allowing so matotrophs to respond to TRH [31], or from TRH-induced somatostatin inhibition leading to GH release [14], or from anatomical or functional disconnection from CNS struc tures or, more generally, from derangements in the central control of GH secretion [23,29], In particular, the hypothe sis that TRH may directly stimulate GH release acting on de-repressed specific TRH receptors of adenomatous so matotrophs has been put forward to explain the occurrence of GH increase after TRH in about 40% of acromegalic pa tients [11,12], However, as it has been very recently re ported that this aberrant response also occurred in patients with acromegaly due to growth hormone-releasing factor (GRF) hypersecretion from pancreatic and extrapancreatic tumors [13,26,28], it has been suggested that prolonged ex posure to GRF excess may sensitize somatotrophs to re lease GH in response to TRH. This hypothesis was strenghtened by the observation that GRF hyperstimula tion of cultured rat somatotrophs induced GH responsive ness to TRH [4], but challenged by the finding that TRH administered intravenously during GRF infusion to normal subjects did not elicit any GH release [18].…”

Stimulation of Growth Hormone Release by Vasoactive Intestinal Peptide and Peptide PHI in Rat Anterior Pituitary Reaggregates

“…In the rat, GH release is inhibited by TRH through an action in the hypo thalamus [2] but is increased by a direct action in the pitui tary when the gland is disconnected, either anatomically or functionally, from the hypothalamus [5]. A stimulatory ac tion of TRH has also been described in superfused dis persed pituitary cells provided the cells were first exposed to GRF [1], In preliminary work we have confirmed the lat ter observations which are in clear-cut contrast with the in hibitory action of TRH observed when TRH and VIP are superfused simultaneously. Possibly, TRH may be either stimulatory or inhibitory depending on the sequence as which the various peptides are presented to the target cell.…”

Further Evidence That Thyrotropin-Releasing Hormone Participates in the Regulation of Growth Hormone Secretion in the Rat

“…In rats bearing hypothalamic lesions, more consistent GH stimulatory effects of TRH have been re ported [6,20], This stimulatory effect, however, was only confirmed in two in vitro studies using perifused rat ante rior pituitary fragments [4,23]. In perifused rat pituitary cells TRH stimulated GH release only after hp GRF-40 treatment [2]; in rat [23] or human [1] pituitary cell cultures TRH had no effect.…”