Growth Hormone Pretreatment in Man Blocks the Response to Growth Hormone‐releasing Hormone; Evidence for a Direct Effect of Growth Hormone

Ross, R. J. M.; Borges, Flávio Notarnicola da Silva; Grossman, Ashley; Smith, Roger; Ngahfoong, L; Rees, Lesley; Savage, Martin O.; Besser, G. M.

doi:10.1111/j.1365-2265.1987.tb03645.x

Cited by 76 publications

(34 citation statements)

References 22 publications

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“…but not ovine prolactin, resulted in significant suppres sion of hGHRH-analog-provoked GH rises. These findings suggest that enhanced SRIF release during a trough period of sponta neous GH secretory rhythm is induced by the preceding GH secretory burst, and also suggest a possible role for SRIF-mediated GH autoregulation in a physiological state.Previous studies support the concept that growth hormone (GH) itself can regulate its own secretion through an autofeed back mechanism in mammals including human [1][2][3][4][5][6][7][8][9][10][11]. Further more, accumulating evidence suggests an involvement of hypo thalamic somatostatin (SRIF) in autofeedback regulation mech anism for GH.…”

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confidence: 68%

Physiological Role of Somatostatin-Mediated Autofeedback Regulation for Growth Hormone: Importance of Growth Hormone in Triggering Somatostatin Release during a Trough Period of Pulsatile Growth Hormone Release in Conscious Male Rats

Sato

Chihara²,

Kita³

et al. 1989

Neuroendocrinology

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In mammals including human, it is generally accepted that growth hormone (GH) can regulate its own secretion through an autofeedback mechanism in which somatostatin (SRIF) may be involved. To explore a physiological role of SRIF-mediated GH autoregulation, the effect of exogenous human GH administration on plasma rat GH response to [D-Ala², Me²⁷]-human GH-releasing hormone-(l-28)-agmatine (hGHRH-analog), which does not crossreact with anti-rat GH-releasing hormone γ-globulin (GHRH-Ab), was examined in conscious male rats treated with GHRH-Ab in the absence and presence of anti-SRIF γ-globulin (SRIF-Ab). Enhanced SRIF release during a trough period of natural pulsatile GH secretion, suggested by the blunted GH response to exogenous hGHRH-analog, no longer occurred when major GH secretory bursts were abolished by GHRH-Ab treatment. On the other hand, when hGH was administered in GHRH-Ab-treated rats so as to simulate the quantity and dynamic change of GH in hypophysial portal circulation in rats exhibiting pulsatile GH secretion, hGHRH-analog-induced GH rises were significantly suppressed during the period corresponding to a GH trough. This suppression was completely prevented by simultaneous treatment with SRIF-Ab. Furthermore, administration of bovine GH, but not ovine prolactin, resulted in significant suppression of hGHRH-analog-provoked GH rises. These findings suggest that enhanced SRIF release during a trough period of spontaneous GH secretory rhythm is induced by the preceding GH secretory burst, and also suggest a possible role for SRIF-mediated GH autoregulation in a physiological state.

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confidence: 68%

Physiological Role of Somatostatin-Mediated Autofeedback Regulation for Growth Hormone: Importance of Growth Hormone in Triggering Somatostatin Release during a Trough Period of Pulsatile Growth Hormone Release in Conscious Male Rats

Sato

Chihara²,

Kita³

et al. 1989

Neuroendocrinology

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“…These findings have been cited as evidence that reduces the likelihood that IGF-1 is responsible for the feedback observed. 11 The role of central GHRH, SRIF, and GH is further complicated by the reciprocal interactions be- Figure 3. Ultrastructure of somatotrophs in pituitaries of GH agonist (E117L) mice, GH antagonist (G119K) mice, and GH receptor-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Growth Hormone (GH) Autoregulation in Pituitary Somatotrophs in GH Antagonist-Transgenic Mice and GH Receptor-Deficient Mice

Sylvia

Coschigano

Bellush

et al. 2000

The American Journal of Pathology

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Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone; however, there has been no evidence of GH autoregulation on the pituitary somatotroph. To determine the effects of GH on its own regulation, we examined the pituitaries of giant transgenic mice expressing a GH agonist (E117L), dwarf transgenic mice expressing a GH antagonist (G119K), and dwarf mice devoid of the GH receptor/binding protein (GHR/BP). In the E117L transgenic mice, the number and distribution of pituitary GH-immunoreactive cells were unchanged from nontransgenic littermate controls; an ultrastructural examination revealed typical, densely granulated somatotrophs. In contrast, the pituitaries of the G119K mice contained both moderately granulated somatotrophs and a sparsely granulated (SG) population with well-developed synthetic organelles and a distinct juxtanuclear globular GH-staining pattern. GHR/BP-deficient mice exhibited a marked reduction in the intensity of cytoplasmic GH immunoreactivity; however, prominent GH staining in the juxtanuclear Golgi was seen. GH-immunoreactive cells were increased in number, and the reticulin network pattern was distorted; stains for proliferating cell nuclear antigen confirmed mild hyperplasia. Electron microscopy showed that the somatotrophs were hyperactive SG cells with prominent endoplasmic reticulum membranes, large Golgi complexes, and numerous mitochondria. These findings are consistent with synthetic and secretory hyperactivity in pituitary somatotrophs due to the reduced GH feedback regulation. The changes are most striking in animals that are devoid of GHR/BP and less marked in animals expressing a GH antagonist; both models had reduced insulin-like growth factor-I levels, but the more dramatic change in the GHR/BP animals can be explained by abrogated GH signaling. This represents Growth hormone (GH) secretion is under the complex control of the hypothalamus with predominant stimulation by GH-releasing hormone (GHRH) and GH-related peptide (GHRP) and inhibition by somatostatin (SRIH). 1These effects are modulated by peripheral negative feedback signals, including the target growth factor of GH insulin-like growth factor-I (IGF-I), certain amino acids and nutrient metabolites, and other hormones, including glucocorticoids, that act at the level of the adenohypophysis and the hypothalamus.1 GH itself can alter its own regulation at the level of the hypothalamus, where it modulates the release of GHRH and SRIH.1 Thus far, however, there has been little evidence for a more direct role for GH in the autoregulation of the pituitary somatotroph. 2To determine whether GH participates in an autofeedback mechanism at the level of the pituitary somatotroph, we studied the pituitaries of giant transgenic mice expressing a GH agonist (E117L), dwarf transgenic mice expressing a GH antagonist (G119K), and dwarf mice that were devoid of the GH receptor/binding protein (GHR/BP). Materials and Methods Transgenic and GH Receptor-Deficient MiceProduction and characterizati...

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“…In addition, G i /G ocoupled dopamine-D2 and somatostatin receptors also inhibit GH secretion and somatomammotroph growth (3). It is tempting to speculate that GH may negatively regulate its own secretion; however, evidence for a non-IGF-mediated autocrine pituitary feedback by GH is indirect (4,61,62). The GH receptor is expressed in rat and human anterior pituitary and binds and internalizes radiolabeled GH, suggesting a role for GH to regulate its secretion from the pituitary (63)(64)(65)(66).…”

Section: Gh-induced Coupling To G Proteins and Lipid Signaling-mentioning

confidence: 99%

Growth Hormone-induced Diacylglycerol and Ceramide Formation via Gαi3 and Gβγ in GH4 Pituitary Cells

Liu

Robillard

Banihashemi

et al. 2002

Journal of Biological Chemistry

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Growth hormone (GH) secretion is regulated by indirect negative feedback mechanisms. To address whether GH has direct actions on pituitary cells, lipid signaling in GH 4 ZR 7 somatomammotroph cells was examined. GH (EC 50 ‫؍‬ 5 nM) stimulated diacylglycerol (DAG) and ceramide formation in parallel by over 10-fold within 15 min and persisting for >3 h. GH-induced DAG/ceramide formation was blocked by pertussis toxin (PTX) implicating G i /G o proteins and was potentiated 1.5-fold by activation of G i /G o -coupled dopamine-D2S receptors, which had no effect alone. Following PTX pretreatment, only PTX-resistant G␣ i 3, not G␣ o or G␣ i 2, rescued GHinduced DAG/ceramide signaling. GH-induced DAG/ceramide formation was also blocked in cells expressing G␤␥ blocker GRK-ct. In GH 4 ZR 7 cells, GH induced phosphorylation of JAK2 and STAT5, which was blocked by PTX and mimicked by ceramide analogue C2-ceramide or sphingomyelinase treatment to increase endogenous ceramide. We conclude that in GH 4 pituitary cells, GH induces formation of DAG/ceramide via a novel G␣ i 3/ G␤␥-dependent pathway. This novel pathway suggests a mechanism for autocrine feedback regulation by GH of pituitary function.Pituitary somatotrophs synthesize and secrete GH, 1 which acts at the liver and other tissues to stimulate IGF formation, promoting somatic growth throughout the body (1, 2). Secretion of GH is stimulated by hypothalamic GH-releasing hormone and inhibited by the hypothalamic tetradecapeptide somatostatin and by IGF. In addition, somatostatin agonists (e.g. octreotide) and dopamine-D2 agonists (e.g. bromocryptine) are used clinically to treat acromegaly (a syndrome produced by hypersecretion of GH) and to inhibit somatomammotroph growth and GH production (3). Negative feedback via autocrine actions of GH at the pituitary has been postulated (4) but is yet to be clearly demonstrated.The GH receptor is a member of the type I cytokine receptor superfamily, related to PRL and erythropoietin receptors that homodimerize to initiate signaling (5). The GH receptor signals through the JAK2 tyrosine kinase-signal transducer and activator of transcription 5 (STAT5) transcription factor pathway to induce gene expression (6 -9). Phosphorylation on residue Tyr-694 by JAK2 is obligatory for STAT5 activation (10). The two STAT5 variants, STAT5a and STAT5b, have 90% identical protein sequences and are independently regulated and activated in various cell types (11). Studies using STAT5a or STAT5b knockout mice have demonstrated that STAT5b, but not STAT5a, is required for GH-induced regulation of IGF1 and sex-specific steroidogenic enzymes in liver (11-13). While STAT5 activation is implicated in many GH actions, other signaling pathways not involving STAT5 appear to be recruited for GH-induced stimulation of other pathways including MAPK phosphorylation and phosphatidyl inositol 3Ј-kinase or protein kinase C activation (14, 15) in a cell type-dependent manner (16). Ceramide is a novel second messenger implicated in regulation of cell differentiation,...

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Growth Hormone Pretreatment in Man Blocks the Response to Growth Hormone‐releasing Hormone; Evidence for a Direct Effect of Growth Hormone

Cited by 76 publications

References 22 publications

Physiological Role of Somatostatin-Mediated Autofeedback Regulation for Growth Hormone: Importance of Growth Hormone in Triggering Somatostatin Release during a Trough Period of Pulsatile Growth Hormone Release in Conscious Male Rats

Physiological Role of Somatostatin-Mediated Autofeedback Regulation for Growth Hormone: Importance of Growth Hormone in Triggering Somatostatin Release during a Trough Period of Pulsatile Growth Hormone Release in Conscious Male Rats

Evidence for Growth Hormone (GH) Autoregulation in Pituitary Somatotrophs in GH Antagonist-Transgenic Mice and GH Receptor-Deficient Mice

Growth Hormone-induced Diacylglycerol and Ceramide Formation via Gαi3 and Gβγ in GH4 Pituitary Cells

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