Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

Sg, Cella; Colonna, De Gennaro; Locatelli,; Ge, Bao-Feng; Gl, Rossi; Torsello, Antonio; Wb, Wehrenberg; Ee, Müller

doi:10.1203/00006450-199409000-00008

Cited by 13 publications

(5 citation statements)

References 26 publications

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“…Total RNA samples (20 µg/sample) were electrophoresed on 1·2% formaldehyde-agarose gel and transferred to nylon membranes (Hybond N; Amersham, Little Chalfont, Bucks, UK). The membranes were hybridized with a rat GH cDNA sequence (Cella et al 1994 …”

Section: Pituitary Gh Mrnamentioning

confidence: 99%

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Gennaro-Colonna

Rossoni²,

Cocchi³

et al. 2000

Journal of Endocrinology

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Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 µg/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 µg, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexarelin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

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Section: Pituitary Gh Mrnamentioning

confidence: 99%

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Gennaro-Colonna

Rossoni²,

Cocchi³

et al. 2000

Journal of Endocrinology

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“…In newborn rats, deprivation of endogenous GHRH with anti-GHRH antibodies permanently impairs growth rate, GH synthesis and pituitary morphology, but not GH concentration (24). The concomitant GH treatment seems to counteract some of these effects, improving the ability of the gland to respond to an acute GHRH challenge by increasing the cellular activity (25).…”

Section: Discussionmentioning

confidence: 99%

Growth hormone response to growth hormone-releasing hormone varies with the hypothalamic-pituitary abnormalities

Maghnie

Moretta

Valtorta

et al. 1996

European Journal of Endocrinology

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We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 +/- 4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI, Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30-09.00 h, as well as after infusion of GHRH (1-29) at escalating doses for 3h: 0.2 micrograms/kg at 09.00-10.00 h, 0.4 micrograms/kg at 10.00-11.00 h, 0.6 micrograms/kg at 11.00-12.00 h and an intravenous bolus of 2 micrograms/ kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1-29) was delayed (135-180 min) and extremely low (median 2mU/l). In group II it was delayed (135-180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185-210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75-120 min) but it declined rapidly (median 14.4 mU/l at 185-210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I (0.23 +/- 0.05 U/ml) than in groups II (0.39 +/- 0.13U/ ml, p < 0.01) and III (1.54 +/- 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1-29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1-29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group Ia patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained.

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“…For GHRH, a dose of 2 µg/kg s.c. in infant rats had previously been shown [36]to be effective in stimulating GH release, whereas in preliminary experiments in young adult rats, a dose of 20 µg/kg s.c. was required to induce significant GH release.…”

Section: Methodsmentioning

confidence: 99%

Hexarelin Modulates the Expression of Growth Hormone Secretagogue Receptor Type 1a mRNA at Hypothalamic and Pituitary Sites

et al. 2004

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Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

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Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

Cited by 13 publications

References 26 publications

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Growth hormone response to growth hormone-releasing hormone varies with the hypothalamic-pituitary abnormalities

Hexarelin Modulates the Expression of Growth Hormone Secretagogue Receptor Type 1a mRNA at Hypothalamic and Pituitary Sites

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