The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity

Massoud, Ahmed F.; Hindmarsh, Peter C.; Brook, C. G. D.

doi:10.1046/j.1365-2265.1996.722543.x

Cited by 10 publications

(4 citation statements)

References 33 publications

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“…The desensitization phenomenon of GHRP has been reported previously. 22 23 24 25 26 In an animal study using transgenic growth-retarded rats, infusion of GHRP-6 for 7 days produced a dose-dependent increase in body weight gain and accelerated skeletal growth. 26 However, this growth promoting effect was observed only in the group infused with GHRP-6 at 3-h pulses.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

et al. 2018

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PurposeGrowth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats.Materials and MethodsThe serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects.ResultsOral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However, oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagogue receptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression.ConclusionOur results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatory effect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS.

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Section: Discussionmentioning

confidence: 99%

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

et al. 2018

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“…Even if the ACTH-and GH-releasing activities are intrinsic to the same receptor activation pathway, the relative magnitude of GH and ACTH release may vary markedly. For example, the combination of GHRPs with GHRH produce a synergistic effect on GH release but not on ACTH release, effectively enhancing the specificity of the response several fold (38), whereas the negative feedback effects of raised cortisol may be more pronounced on ACTH than on GH responses to GHRPs. Elevations in fasting blood glucose have been reported in elderly subjects dosed with an orally active GHRP for 4 weeks (39), so further work is clearly needed because even a small but consistent rise in cortisol accompanying GH stimulation could provide an undesirable extra diabetogenic drive in susceptible individuals.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone Secretagogues Stimulate the Hypothalamic-Pituitary-Adrenal Axis and Are Diabetogenic in the Zucker Diabetic Fatty Rat¹

Clark¹,

Thomas²,

Mortensen³

et al. 1997

Endocrinology

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Besides stimulating GH release, some GH secretagogues also release ACTH and adrenal steroids. Several novel classes of potent GH secretagogues have recently been described, and we have now tested their ability to release corticosterone in conscious normal rats. All analogs that released GH also stimulated corticosterone release to some degree, though the relative effects on GH and corticosterone varied somewhat. The corticosterone responses for some analogs were in the range of those obtained with CRF (2 microg, iv), whereas closely related analogs inactive for GH release failed to release corticosterone. Activation of the hypothalamic-pituitary-adrenal axis with GH release by GHRPs could be a highly diabetogenic combination in susceptible individuals. Therefore, a potent GHRP pentapeptide analog (G7039, 100 microg/day, sc, bid) was given to young obese male Zucker diabetic fatty rats (ZDF, n = 8/group) for 24 days. Other groups received hGH (500 microg/day, sc, bid), recombinant human insulin-like growth factor (rhIGF)-1 (750 microg/day, sc, infusion) or excipient, alone or in combination. Both G7039 and hGH increased weight gain, markedly raised serum glucose (G7039, 542 +/- 37; hGH, 725 +/- 30; excipient, 330 +/- 57 mg/dl) and doubled insulin levels but had opposite effects on serum triglycerides (G7039, 1412 +/- 44; hGH 501 +/- 46; excipient 1058 +/- 73 mg/dl) and fat depot weights. In contrast, treatment with IGF-1, alone or in combination with hGH or G7039, improved the diabetic state and stimulated growth. Thus, both G7039 and hGH treatment stimulated growth in ZDF rats, but greatly worsened diabetes, unless IGF-1 was coadministered. Some of the effects ofG7039 could be explained by GH release, but the effects on blood lipids and body fat were not seen with hGH and may reflect the additional activation of the hypothalamic-pituitary-adrenal axis by the secretagogue. The magnitude of these adverse effects in the ZDF animals suggest that chronic administration of GHRP analogs with cortisol-releasing activity to obese or diabetes-prone individuals warrants careful evaluation.

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“…It soon became clear that the GHS mechanism of action was quite different from that of GHRH, whose binding to its specific seven-transmembrane G protein-coupled receptor (GPCR) activates the cAMP protein kinase A signaling pathway [28]. Further data supporting that GHS and GHRH activate different receptors were provided by this simple demonstration: the first challenge with GHRH blunts the effects of a second stimulation with GHRH, whereas the first challenge with GHS does not affect GHRH effects, and when administered in combination, GHS synergizes with GHRH on GH release [29,30,31,32,33]. Moreover, GHS administration did not activate the physiological negative feedback mechanisms involving somatostatin and insulin-like growth factor-I (IGF-I) release [27].…”

Section: Growth Hormone Secretagogues (Ghs)mentioning

confidence: 99%

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

Bresciani

Rizzi

Coco

et al. 2019

IJMS

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Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

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The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity

Cited by 10 publications

References 33 publications

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

Growth Hormone Secretagogues Stimulate the Hypothalamic-Pituitary-Adrenal Axis and Are Diabetogenic in the Zucker Diabetic Fatty Rat¹

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

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The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity

Cited by 10 publications

References 33 publications

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

Growth Hormone Secretagogues Stimulate the Hypothalamic-Pituitary-Adrenal Axis and Are Diabetogenic in the Zucker Diabetic Fatty Rat1

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

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Growth Hormone Secretagogues Stimulate the Hypothalamic-Pituitary-Adrenal Axis and Are Diabetogenic in the Zucker Diabetic Fatty Rat¹