Effects of a fragment of human growth hormone-releasing factor in normal and 'Little' mice

Clark, R. G.; Robinson, I. C. A. F.

doi:10.1677/joe.0.1060001

Cited by 45 publications

(15 citation statements)

References 17 publications

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“…Indeed, these authors advanced the hypothesis that the primary defect in the Little mouse lay in its inability to produce normal amounts of GH mRNA transcripts, the explanation we cur¬ rently favour for the dwarfism in our rats. On the other hand, the Little mouse is unable to respond to GRF in vivo (Clark & Robinson, 1985a) or in vitro (Jansson, Downs, Beamer & Frohman, 1986), whereas GRF does elicit GH release both in vivo (present paper) and in vitro (E. A. Campbell, R. G.…”

Section: Discussionmentioning

confidence: 57%

“…Our present knowledge indicates that the secretion and synthesis of GH is itself under the control of two hypothalamic peptides: somatostatin (Brazeau, Vale, Burgus et al 1973) which has an inhibitory influence and GHreleasing factor (GRF) which stimulates GH release (Guillemin, Brazeau, Bohlen et al 1982;Rivier, Spiess, Thorner & Vale, 1982). Mutations in mice which affect the pituitary GH system and produce dwarfism have proved useful in studying the role of GRF and GH in growth and development (Eicher & Beamer, 1976;Cheng, Beamer, Phillips et al 1983;Van Buul-Offers, 1983;Charlton, 1984;Clark & Robinson, 1985a). Currently there is no genetic mutation causing dwarfism through GH deficiency in rats.…”

Section: Introductionmentioning

confidence: 99%

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Growth hormone-deficient dwarfism in the rat: a new mutation

Charlton

Clark²,

Robinson³

et al. 1988

Journal of Endocrinology

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149

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Mutations in animals have provided insight into many aspects of normal and pathological human physiology. This paper reports the discovery and initial characterization of a new mutant dwarf rat. The mutation, inherited as an autosomal recessive, arose spontaneously in a breeding colony of Lewis rats at the Medical Research Council Cellular Immunology Unit, Sir William Dunn School of Pathology, Oxford, U.K., in 1985 and the strain has now been established both in Oxford and at Mill Hill. Body growth in the mutant is retarded such that at 3 months of age both males and females weigh approximately 40% less than their normal litter-mates, and continue to grow at a slower rate. The mutants show a selective reduction in pituitary GH synthesis and storage (pituitary GH concentrations were approximately 10% of normal in males and 6% in females). The concentration of their anterior pituitary trophic hormones (LH, TSH, prolactin and ACTH) were within the normal range in dwarf animals. Exogenous GH treatment for 5 days resulted in an increase in growth rate from 1.5 +/- 0.3 to 3.9 +/- 0.4 g/day in male mutants, and 0.8 +/- 0.2 to 3.1 +/- 0.1 g/day in females. Longitudinal bone growth rates were more than doubled by this treatment from 49 +/- 5 to 100 +/- 10 micron/day in females and from 52 +/- 11 to 131 +/- 16 micron/day in males. Dot blot and Northern blot analysis of pituitary mRNA extracts revealed that the GH message in mutants was between 20 and 25% of normal, and that the GH transcript was of normal size.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Growth hormone-deficient dwarfism in the rat: a new mutation

Charlton

Clark²,

Robinson³

et al. 1988

Journal of Endocrinology

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241

149

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“…Transfection of this receptor in cell lines confers GRF binding, and GRF-dependent stimulation of adenylate cyclase activity [5][6][7], The central importance of GRF-R signalling for both somatotrope proliferation and GH release is well demon strated by conditions of prolonged GRF excess or defi ciency. For example, overexposure to GRF in patients with ectopic GRF production [8] or in metallothionein-GRF transgenic mice [9] leads to pituitary somatotrope hyperplasia and gigantism [10], whereas reduced GRF activity leads to GH deficiency and dwarfism [11], This is well illustrated by the lit/lit mouse [12] whose marked somatotrope hypoplasia and severe dwarfism, associated with unresponsiveness to GRF in vivo [13] and in vitro [ 14], is now known to be caused by a single point mutation in the N-terminal extracellular domain of the lit/lit GRF-R which renders it non-functional [15], In these mice, somatotropes develop normally until birth, but post-natal expansion of this cell population fails to occur [16], Although some studies have focused on the regulation and expression of GRF in relation to GH synthesis [17] and somatotrope proliferation [10], very little is known about how this relates to GRF-R expression. We have pre viously characterized in some detail the in vivo responses to GRF in normal rats [18] and how they differ in the GH-deficient dwarf (dw) rat [19,20],…”

Section: Introductionmentioning

confidence: 99%

Pituitary Growth Hormone-Releasing Factor Receptor Expression in Normal and Dwarf Rats

Carmignac¹,

Flavell²,

Robinson³

1996

Neuroendocrinology

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Growth hormone-releasing factor (GRF) regulates GH release and somatotrope proliferation via a specific G-protein-coupled receptor. Little is known about the endocrine factors that regulate the expression of the GRF receptor (GRF-R) in the pituitary gland. We have developed a sensitive solution hybridization/RNAse protection assay for GRF-R mRNA in rat pituitary extracts. GRF-R transcripts were readily detectable in similar amounts in normal male and female rats, but were markedly reduced in extracts from age-matched growth hormone (GH)-deficient dwarf (dw) rats of either sex. The reduced GRF-R expression would appear to reflect somatotrope hypoplasia rather than GH deficiency per se since a similar reduction in GRF-R expression was seen in a transgenic model of dominant dwarfism, whereas GRF-R expression was significantly elevated in rats with GH deficiency induced by hypothyroidism. We were unable to demonstrate significant effects on GRF-R expression with infusions of human GH (hGH) or insulin-like growth factor 1, which stimulate growth in dw rats, but dexamethasone treatment induced a significant, time-related increase in GRF-R mRNA levels. We conclude that this assay can usefully quantify pituitary GRF-R expression in normal rats, and its reduction in two different strains of mutant dwarf rats with somatotrope hypoplasia.

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“…Although this possibility may be contributory, it is unlikely to be the full explanation. The little mouse pituitary contains about 25% of the normal complement of somatotrophs and 4 -8% of the GH content of a normal pituitary (32,33). Translated to a GHRH-R-deficient human pituitary, this would represent between 0.5-1 mg stored GH.…”

Section: Discussionmentioning

confidence: 99%

Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹

Maheshwari¹,

Rahim²,

Shalet³

et al. 1999

The Journal of Clinical Endocrinology & Metabolism

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The mechanism of the synergistic relationship between GH-releasing peptide (GHRP) and GHRH with respect to GH secretion is poorly understood. We report the response to hexarelin, a potent GHRP, in patients affected with a homozygous mutation in the GHRH receptor gene, with consequent GHRH resistance and GH-deficient dwarfism. This newly described syndrome is the human homolog of the little (lit/lit) mouse. Intravenous administration of hexarelin (2 g/kg) to four male adult patients (dwarfs of Sindh) resulted in a complete lack of elevation in plasma GH levels (Ͻ1 ng/mL), an at least 50-to 100-fold deviation from the normal response. In contrast, plasma PRL, ACTH, and cortisol levels rose in a normal manner in response to hexarelin. We conclude that an intact GHRH signaling system is critical for GHRPs to exert their effect on GH release, but that the GHRH system is not necessary for the effect of GHRP on PRL and ACTH secretion. Hexarelin (and probably other GHRPs) are not effective agents for the treatment of patients with GHRH resistance due to GHRH receptor deficiency. (J Clin Endocrinol Metab 84: 956 -959, 1999) T HE GH-RELEASING peptides (GHRP) are a class of small peptides that stimulate GH and, to a lesser degree, PRL and ACTH secretion from the pituitary gland (1-3). They interact with a recently cloned specific receptor that is expressed in the hypothalamus and pituitary (4). Orally active nonpeptide GHRP mimetics that bind to the same receptor and act as GH/PRL/ACTH secretagogues have been developed (3). The GHRPs are believed to represent analogs of a still unknown endogenous ligand for the GHRP receptor. This putative ligand is thought to participate in the regulation of GH secretion, in conjunction with GHRH and somatostatin. GHRPs synergize with GHRH in releasing GH by an unknown, primarily hypothalamic mechanism; coadministration of GHRP with GHRH in vivo results in a large potentiation of the GHRH effect (5, 6). The effect of GHRP on GHRH action at the pituitary level is smaller and additive rather than synergistic (7,8). Despite efforts at elucidating the GHRH-GHRP relationship, the nature of their interaction remains poorly understood, partly because of the difficulty in isolating the effects of GHRH, somatostatin, and GHRP in vivo.To shed further light on the cross-talk between GHRH and GHRP, we studied individuals with a unique new syndrome of genetic GHRH receptor (GHRH-R) deficiency (dwarfism of Sindh) (9, 10) to determine the efficacy of GHRP in elaborating GH, PRL, and ACTH release in the absence of GHRH signaling. Patients affected by this mutation in the GHRH-R are profoundly GH deficient because of GHRH resistance at the pituitary level (9 -12). A practical aim of the study was to determine whether GHRP or its oral analogs may represent a therapeutic modality for the affected patients who live in a rural area of Pakistan where medical services are limited. Hexarelin, the GHRP used in this study, is a potent GHRP whose effects in normal human subjects are well characterized (1...

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Effects of a fragment of human growth hormone-releasing factor in normal and 'Little' mice

Cited by 45 publications

References 17 publications

Growth hormone-deficient dwarfism in the rat: a new mutation

Growth hormone-deficient dwarfism in the rat: a new mutation

Pituitary Growth Hormone-Releasing Factor Receptor Expression in Normal and Dwarf Rats

Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹

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Effects of a fragment of human growth hormone-releasing factor in normal and 'Little' mice

Cited by 45 publications

References 17 publications

Growth hormone-deficient dwarfism in the rat: a new mutation

Growth hormone-deficient dwarfism in the rat: a new mutation

Pituitary Growth Hormone-Releasing Factor Receptor Expression in Normal and Dwarf Rats

Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency1

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Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹