Growth Hormone-releasing Peptide-2 Administration Research Articles

Evaluation of growth hormone-releasing peptide-2 for diagnosis of thyrotropin-producing pituitary adenomas.

Thyrotropin (TSH)-producing adenomas are a rare cause of hyperthyroidism and are a type of functional pituitary adenoma. The diagnosis of TSH-producing adenoma is a challenging problem in clinical endocrinology. Since growth hormone-releasing peptide-2 (GHRP-2) fails to induce TSH secretion in normal subjects, the effect of GHRP-2 on TSH levels was therefore examined in patients with TSH-producing adenomas. A total of 5 patients (4 women and 1 man) referred to our departments for further evaluation of pituitary hormones were followed-up using the GHRP-2, TSH-releasing hormone (TRH), octreotide, and bromocriptine tests to examine and evaluate TSH secretory dynamics in TSH-producing adenomas. Of 5 patients, 2 (40%) showed such a significant response, defined as a >50% increase in serum TSH level above baseline in the GHRP-2 test. Additionally, 1 patient showed a 48% increase in serum TSH level. In 1 patient whose adenoma was completely removed, basal serum concentrations of TSH were sufficiently suppressed after the operation, and serum TSH levels failed to increase in response to GHRP-2 administration. In 4 patients (80%), a poor response of serum TSH levels was observed in the TRH test. In 2 out of 5 patients (40%), serum TSH levels were significantly decreased following octreotide administration. No patient demonstrated a significant response to the bromocriptine test. In addition to TRH test, the GHRP-2 test as a potential diagnostic tool for TSH-producing pituitary adenomas.

Effects of GHRP-2 and Cysteamine Administration on Growth Performance, Somatotropic Axis Hormone and Muscle Protein Deposition in Yaks (Bos grunniens) with Growth Retardation.

The objective of this study was to investigate the effects of growth hormone-releasing peptide-2 (GHRP-2) and cysteamine (CS) administration on growth performance in yaks with growth retardation and try to elucidate its regulatory mechanisms. Trial 1, thirty-six 1-year-old Qinghai high plateau yaks (body weight 38–83.2 kg) were randomly chosen for body weight and jugular blood samples collection. The relationship between body weight and serum GHRH (P < 0.05, R = 0.45), GH (P < 0.05, R = 0.47), IGF-1 (P < 0.05, R = 0.62) was significantly correlated in yaks colonies with lighter body weights. Trial 2, fifteen 1-year-old Qinghai high plateau yaks with growth retardation (average body weight 54.8 ± 8.24 kg) were randomly selected and assigned to negative control group (NG), GHRP-2 injection group (GG) and cysteamine feeding group (CG), with 5 yaks per group. Another five 1-year-old Qinghai high plateau yaks with normal growth performance (average body weight 75.3 ± 2.43 kg) were selected as positive control group (PG). The average daily gain (ADG) of the GG and CG were significantly higher than those in the PG and NG (P < 0.05). Both GHRP-2 and CS administration significantly enhanced the myofiber diameter and area of skeletal muscle (P<0.05). GHRP-2 significantly enhanced the serum GH and IGF-1 levels (P < 0.05), and up-regulated GHR, IGF-1 and IGF-1R mRNA expression in the liver and skeletal muscle (P < 0.05), enhanced the mRNA expression of PI3K, AKt and mTOR in the skeletal muscle (P<0.05). CS significantly reduced the serum SS levels and the hypothalamus SS mRNA expression (P < 0.05), and enhanced GHR and IGF-1 mRNA expression in the liver (P < 0.05), decreased the mRNA expression of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) mRNA (P < 0.05). Conclusions: Growth retardation in yaks was primarily due to somatotropic axis hormones secretion deficiency. Both GHRP-2 and CS administration can accelerate growth performance and GH, IGF-1 secretion in yaks with growth retardation. GHRP-2 enhanced muscle protein deposition mainly by up-regulated the protein synthesis pathways, whereas CS worked mainly by down-regulated the ubiquitin-proteasome pathway.

One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patient.

BackgroundIn Japan, growth hormone releasing peptide-2 (GHRP-2) is clinically used as a diagnostic agent for growth hormone secretion deficiency, but the therapeutic application of GHRP-2 has not been studied in anorexia nervosa. GHRP-2 reportedly exhibits agonistic action for ghrelin receptor and increases food intake.MethodsWe administered GHRP-2 to a patient with a 20-year history of anorexia nervosa to determine whether GHRP-2 treatment increases food intake and body weight. GHRP-2 was administered before every meal by an intranasal approach for 1 year.ResultsAlthough the patient reported a decreased fear of eating and decreased desire to be thin by our previous treatment, she was unable to increase food intake or body weight because of digestive tract dysfunction. Vomiting after meals caused by delayed gastric emptying and incurable constipation were prolonged, and sub-ileus and hypoglycemia were observed. GHRP-2 increased the feeling of hunger and food intake, decreased early satiety and improved hypoglycemia. The patient's body weight gradually increased by 6.7 kg (from 21.1 kg to 27.8 kg) in 14 months after starting GHRP-2 administration. The fatigability and muscle strength improved, and the physical and mental activities were also increased. No obvious side effects were observed after long-term intranasal administration of GHRP-2.ConclusionsPatients with a long-term history of eating disorder occasionally recover from the psychological problems such as fear for obesity but remain emaciated. We believe that ghrelin agonists such as GHRP-2 may be promising agents for the effective treatments of severe anorexia nervosa in a chronic condition.

거세면양에 있어서 에너지수준에 GHRP-2의 투여가 혈장 IGF-1, IGFBPs 및 hepatic GH 수용체에 미치는 반응

본연구는 정상으로 단백질을 급여한 거세면양에 있어서 에너지 첨가가 GHRP-2투여에 대한 IGF-1 및 IGFBPs에 대한 반응과, 고에너지 급여에 따른 GHRP-2투여가 hepatic GH 수용체에 미치는 영향을 검증하기 위하여 실시하였다. 시험 결과 HENP (CP 0.34 kg, TDN 1.83 kg/day DM intake)처리기간 동안 혈장 IGF-1 과 39-42kDa IGFBP-3수준은 LENP (CP 0.32 kg, TDN 0.87 kg/day DM intake)기간에 비하여 높게 나타났으나 (P<0.05), 혈장 34 kDa IGFBP-2와 24 kDa IGFBP-4는 영양처리에 의해 영향을 받지 않았다. 각 영양처리 기간동안 GHRP-2 (<TEX>$12.5\;{\mu}g/kg$</TEX> body weight/day)투여는 혈장 GH 반응이 촉진되었으며(P<0.05), 혈장 GH 평균 함량과 AUC증가에 있어서는 LENP처리 기간에 비하여 HENP처리기간에서 유의적으로 높게 나타났다(P<0.01). 특히 HENP에서 7일간 GHRP-2투여에 의한 일중 혈장 IGF-1 변화양상을 조사한 결과 투여 2, 6 및 7일에서 뚜렷한 증가양상이 보였다(P<0.05). 이에 반하여 LENP에서는 오직 투여 3일째에서 Saline구에 비하여 유의적인 증가를 확인하였다(P<0.05). IGFBPs의 ligand blotting 결과 HENP구에서 혈장 39-43 kDa IGFBP-3의 수준의 증가가 투여 6일과 7일에서 관찰되었으나 혈장 IGFBP-2수준은 두 영양처리시기에서 유의적인 차이를 관찰하지 못했다. 아울러 HENP구에 있어서 간세포막에 <TEX>$^{125}I-oGH$</TEX>의 결합력을 측정한 결과 GHRP-2투여에 의한 영향은 관찰되지 않았다. 이와 같은 결과는 거세면양에 있어서 단백질과 에너지 사이에 영양적 균형은 내인성 GH/IGF-1 axis는 물론 혈장 IGFBP-3수준의 변화에 영향을 미치고 있음을 시사한다. The purpose of this study was to determine the effect of energy supplement on responses of plasma insulin-like growth factor (IGF)-1 and IGF binding proteins (IGFBPs) to growth hormone-releasing peptide-2 (GHRP-2) administration in normal protein-fed wethers, and to observe the effect of GHRP-2 treatment on hepatic growth hormone (GH) receptor in well-fed wethers. Plasma IGF-1 and 39-42 kDa IGFBP-3 during the HENP (CP, crude protein 0.34 and TDN, total digestible nutrients 1.83 kg/day DM, dry matter intake) treatment period were higher than in the LENP (CP 0.32 kg and TDN 0.87 kg/day DM intake) period (P<0.05). The response of GH was stimulated by GHRP-2 (<TEX>$12.5\;{\mu}g/kg$</TEX> body weight/day) administration during both of the feed treatment periods (P<0.05). The area under curve (AUC) increment and average concentration of GH (0-180 min) with GHRP-2 administration was higher during HENP treatment than LENP treatment (P<0.01). During the HENP treatment period from day 1 to day 7 of twice daily GHRP-2 treatment, the plasma IGF-1 increment was increased on days 2, 6 and 7 of GHRP-2 administration (P<0.05). On the basis of ligand blotting, the proportions of plasma 39-43 kDa IGFBP-3 during the HENP treatment period only showed a significant difference on days 6 and 7 with GHRP-2 administration. No significant difference in the specific binding of <TEX>$^{125}I-labeled$</TEX> oGH to hepatic membranes was detected between the saline and GHRP-2 treatments of the HENP-fed wethers. These results suggest that the nutritional balance between energy and protein may affect the endogenous GH / IGF-1 axis as well as plasma IGFBP-3 levels.

GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia

It has been reported that growth hormone (GH)-releasing peptide-2 (GHRP-2), a ghrelin receptor agonist, has an anti-inflammatory effect. We investigated whether this GH secretagogue attenuates liver injury in LPS-treated rats. Wistar rats were simultaneously injected (ip) with LPS (1 mg/kg) and/or GHRP-2 (100 microg/kg). Serum levels of aspartate and alanine transaminases were measured as an index of liver damage. Circulating nitrites/nitrates and hepatic IGF-I and TNF-alpha were evaluated as possible mediators of GHRP-2 actions. LPS increased serum levels of transaminases and nitrites/nitrates. Moreover, LPS increased hepatic TNF-alpha and decreased hepatic IGF-I mRNAs. GHRP-2 administration attenuated the effects of LPS on transaminases, nitrites/nitrates, TNF-alpha, and IGF-I in vivo. This GHRP-2 effect does not seem to be due to modifications in food intake, since fasting did not modify serum levels of transaminases, serum nitrites/nitrates, and hepatic TNF-alpha mRNA both in vehicle rats and in LPS-injected rats. To elucidate whether GHRP-2 is acting directly on the liver, cocultures of hepatocytes and nonparenchymal cells and monocultures of isolated hepatocytes were incubated with LPS and GHRP-2. The ghrelin receptor agonist prevented an endotoxin-induced increase in transaminases and nitrite/nitrate release as well as in TNF-alpha mRNA and increased IGF-I mRNA from cocultures of hepatocytes and nonparenchymal cells, but not from monocultures. In summary, these data indicate that GHRP-2 has a protective effect on the liver in LPS-injected rats that seems to be mediated by IGF-I, TNF-alpha, and nitric oxide. Our data also suggest that the anti-inflammatory effect of GHRP-2 in the liver is exerted on nonparenchymal cells.

Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle

Chronic arthritis is a catabolic state associated with an inhibition of the IGF system and a decrease in body weight. Cachexia and muscular wasting is secondary to protein degradation by the ubiquitin-proteasome pathway. The aim of this work was to analyze the effect of adjuvant-induced arthritis on the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) as well as on IGF-I and IGF-binding protein-5 (IGFBP-5) gene expression in the skeletal muscle. We also studied whether the synthetic ghrelin receptor agonist, growth hormone releasing peptide-2 (GHRP-2), was able to prevent arthritis-induced changes in the skeletal muscle. Arthritis induced an increase in MuRF1, MAFbx (P < 0.01), and tumor necrosis factor (TNF)-alpha mRNA (P < 0.05) in the skeletal muscle. Arthritis decreased the serum IGF-I and its gene expression in the liver (P < 0.01), whereas it increased IGF-I and IGFBP-5 gene expression in the skeletal muscle (P < 0.01). Administration of GHRP-2 for 8 days prevented the arthritis-induced increase in muscular MuRF1, MAFbx, and TNF-alpha gene expression. GHRP-2 treatment increased the serum concentrations of IGF-I and the IGF-I mRNA in the liver and in the cardiac muscle and decreased muscular IGFBP-5 mRNA both in control and in arthritic rats (P < 0.05). GHRP-2 treatment increased muscular IGF-I mRNA in control rats (P < 0.01), but it did not modify the muscular IGF-I gene expression in arthritic rats. These data indicate that arthritis induces an increase in the activity of the ubiquitin-proteasome proteolytic pathway that is prevented by GHRP-2 administration. The parallel changes in muscular IGFBP-5 and TNF-alpha gene expression with the ubiquitin ligases suggest that they can participate in skeletal muscle alterations during chronic arthritis.

Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats

Chronic arthritis induces hypermetabolism and cachexia. Ghrelin is a gastrointestinal hormone that has been proposed as a treatment to prevent cachexia. The aim of this work was to examine the effect of administration of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) to arthritic rats. Male Wistar rats were injected with Freund's adjuvant, and 15 days later arthritic and control rats were daily injected with GHRP-2 (100 microg/kg) or with saline for 8 days. Arthritis induced an increase in serum ghrelin (P < 0.01) and a decrease in serum concentrations of leptin (P < 0.01), whereas GHRP-2 administration increased serum concentrations of leptin. GHRP-2 increased food intake in control rats but not in arthritic rats. However, in arthritic rats GHRP-2 administration ameliorated the external symptoms of arthritis, as it decreased the arthritis score (10.4 +/- 0.8 vs. 13.42 +/- 0.47, P < 0.01) and the paw volume. In addition, circulating IL-6 and nitrites/nitrates were increased by arthritis, and GHRP-2 treatment decreased the serum IL-6 levels (P < 0.01). To elucidate whether GHRP-2 is able to modulate IL-6 release directly on immune cells, peritoneal macrophage cultures were incubated with GHRP-2 or ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue receptor. Both GHRP-2 (10(-7) M) and ghrelin (10(-7) M) prevented endotoxin-induced IL-6 and decreased nitrite/nitrate release from peritoneal macrophages in vitro. These data suggest that GHRP-2 administration has an anti-inflammatory effect in arthritic rats that seems to be mediated by ghrelin receptors directly on immune cells.

Effects of the administration of growth hormone-releasing peptide-2 (GHRP-2) orally by gavage and in feed on growth hormone release in swine

The experiments were conducted to determine the effects of the administration of growth hormone-releasing peptide-2 (GHRP-2, also named KP102), both orally by gavage and in feed, on the release of growth hormone (GH) in swine and to investigate whether attenuation of the GH response occurs after short-term treatment with the peptide in feed. In the first experiment, saline or GHRP-2 at doses of 1, 4.5 and 9 mg/kg body weight (BW) was dissolved in 15 ml saline and administered orally as a bolus by gavage to cross-bred castrated male swine ( n = 6). Orally administered GHRP-2 stimulated dose-related increases in peak concentrations of GH, with a return to basal by 120 min. After administering GHRP-2 orally, peak concentrations of GH and areas under the GH response curves (GH AUCs) for 180 min were higher (P < 0.05) than those in saline controls. In Experiment 2, GHRP-2 at doses of 0 (served as control), 1, 4.5 and 9 mg/kg BW was mixed in 150 g of feed and offered to cross-bred castrated male swine ( n = 6) at 0900 hr and 1700 hr daily for a 3-d period. Administration of 1 mg/kg BW GHRP-2 to swine in feed failed to stimulate the release of GH, but GHRP-2 at doses of 4.5 and 9 mg/kg BW significantly (P < 0.05) increased plasma concentrations of GH after initial and final treatments at 0900 hr on Days 1 and 3 of treatment, respectively. Peak concentrations of GH and GH AUCs for 180 min after the initial and final treatments in the 4.5 and 9 mg/kg BW GHRP-2-treated swine were higher (P < 0.05) than those in controls. After 3 d of treatment with GHRP-2 in feed at doses of 4.5 and 9 mg/kg BW, GH responses to the peptide were maintained. The results of the present study indicate that the administration of GHRP-2 orally by gavage and in feed stimulates the release of GH in swine, and that the GH-releasing effect of the peptide does not become desensitized after short-term administration in feed.

Growth Hormone-Releasing Peptide-2 (GHRP-2) Acts Synergistically with Growth Hormone-Releasing Hormone (GHRH) to Release Growth Hormone (GH) in Swine

The aim of the present study was to examine the growth hormone (GH) response to the combined and repeated administrations of growth hormone-releasing peptide-2 (GHRP-2) plus growth hormone releasing hormone (GHRH) in swine. Six cross-bred castrated male swine, 130-135 days of age were used in this study. Animals were given a single intravenous (i.v.) injection of either GHRP-2 (30μg/kg BW), GHRH (1μg/kg BW) and GHRP-2 (30μg/kg BW) plus GHRH (1μg/kg BW) or 5ml saline (served as control) in random order with two days apart. GHRP-2 or GHRH alone and in combination with together stimulated the release of GH in swine. The peak concentrations of GH and areas under the GH response curve (GH AUC) for 120min after these treatments were significantly higher (P<0.01) than those in controls. The combined administration of these two peptides [GHRP-2 (30μg/kg BW) and GHRH (1μg/kg BW)] resulted in a GH AUC significantly greater than the arithmetic sum of those following their separate administrations (P<0.05), demonstrating the synergistic effect for GH release. GH responses to two successive i.v. injections of GHRP-2 (30μg/kg BW) plus GHRH (1μg/kg BW) at 2h interval in swine were increased after each injection; however, peak concentration of GH and GH AUC for 120min after the second injection were significantly lower (P<0.01) than those after the first injection. These results of the present study indicated that the combined administration of GHRP-2 and GHRH synergistically stimulates the release of GH in swine, and the GH responses to the co-administration of these two peptides decrease after the repeated injection. These findings suggest that GHRP-2 and GHRH act through different receptors and intracellular signal transduction and can be used together for stimulating further release of GH in swine.

The effects of growth hormone-releasing peptide-2 (GHRP-2) on the release of growth hormone and growth performance in swine

The effects of GHRP-2 (also named KP102), a new growth hormone-releasing peptide, on the release of growth hormone (GH) and growth performance were examined in swine. The single intravenous (i.v.) injection of GHRP-2 at doses of 2, 10, 30 and 100 μg/kg body weight (BW) to cross-bred castrated male swine stimulated GH release in a dose-dependent manner, with a return to the baseline by 120 min. The peak GH concentrations and GH areas under the response curves (GH AUCs) for 180 min after the injections of GHRP-2 were higher (P < 0.05) than those after the injection of saline. The GH responses to repeated i.v. injections of GHRP-2 (30 μg/kg BW) at 2-h intervals for 6 h were decreased after each injection. The chronic subcutaneous (s.c.) administration of GHRP-2 (30 μg/kg BW) once daily for 30 days consistently stimulated GH release. The GH AUCs for 300 min after the injections on d 1, 10 and 30 of treatment in GHRP-2-treated swine were higher than those in saline-treated swine. However, chronic administration of GHRP-2 caused a partial attenuation of GH response between d 1 and 10 of treatment. The chronic s.c. administration of GHRP-2 also increased average daily gain for the entire treatment period by 22.35% (P < 0.05) and feed efficiency (feed/gain) by 20.64% (P < 0.01) over the saline control values, but did not significantly affect daily feed intake. These results indicate that GHRP-2 stimulates GH release and enhancing growth performance in swine.

Effects of muscarinic and adrenergic blockade on growth hormone secretion induced by growth hormone-releasing peptide-2 (GHRP-2) in ovariectomized ewes.

This study was performed to investigate whether the blockade of cholinergic muscarinic and adrenergic pathways was involved in the GH-releasing effect of GH-releasing peptide-2 (GHRP-2) in ovariectomized ewes. Cholinergic muscarinic antagonist, atropine (0.2 mg/kg, i.v., 15 min before GHRP-2 administration) blunted the GH secretion caused by GHRP-2 (12.5 microg/kgBW). alpha-Adrenergic antagonist phentolamine (15 microg/kgBW x min, infusion from -15 to 30 min) did not affect the GH response to GHRP-2, and beta-adrenergic antagonist propranolol (0.25 mg/kgBW, i.v., 15 min before GHRP-2 administration) did not suppress the GHRP-2-induced GH release. These results showed that cholinergic muscarinic antagonist agent, atropine, exerts an inhibitory effect on GHRP-2-induced GH secretion in ovariectomized ewes.