Effects Of Exogenous Growth Hormone Research Articles

Exogenous growth hormone administration during total sleep deprivation changed the microRNA-9 and dopamine D2 receptor expressions followed by improvement in the hippocampal synaptic potential, spatial cognition, and inflammation in rats.

Disorders caused by total sleep deprivation can be modulated by the administration of growth hormone, which could affect the expression of microRNA-9 and dopamine D2 receptor expressions followed by improvement in the hippocampal synaptic potential, spatial cognition, and inflammation in rats. The present study aimed to elucidate the putative effects of exogenous growth hormone (GH) against total sleep deprivation (TSD)-induced learning and memory dysfunctions and possible involved mechanisms. To induce TSD, rats were housed in homemade special cages equipped with stainless steel wire conductors to induce general and inconsistent TSD. They received a mild repetitive electric shock to their paws every 10 min for 21 days. GH (1 mg/kg, sc) was administered to adult young male rats once daily for 21-day-duration induction of TSD. Spatial learning and memory performance, inflammatory status, microRNA-9 (miR-9) expression, dopamine D2 receptor (DRD2) protein level, and hippocampal histological changes were assayed at scheduled times after TSD. The results indicated that TSD impaired spatial cognition, increased TNF-α, decreased level of miR-9, and increased DRD2 levels. Treatment with exogenous GH improved spatial cognition, decreased TNF-α, increased level of miR-9, and decreased DRD2 levels after TSD. Our findings suggest that GH may play a key role in the modulation of learning and memory disorders as well as the ameliorating abnormal DRD2-related functional disorders associated with miR-9 in TSD.

Therapeutic effects of growth hormone in a rat model of total sleep deprivation: Evaluating behavioral, hormonal, biochemical and electrophysiological parameters

ObjectiveTotal sleep deprivation (TSD) causes several harmful changes in the brain, including memory impairment, increased stress and depression levels, as well as reduced antioxidant activity. Growth hormone (GH) has been shown to boost antioxidant levels while improving memory and depression. The present study was conducted to explain the possible effects of exogenous GH against behavioral and biochemical disorders caused by TSD and the possible mechanisms involved. Main methodsTo induce TSD, rats were housed in homemade special cages equipped with stainless steel wire conductors to induce general and inconsistent TSD. They received a mild repetitive electric shock to their paws every 10 min for 21 days. GH (1 ml/kg, sc) was administered to rats during induction of TSD for 21 days. Memory retrieval, anxiety, depression-like behaviors, pain behaviors, antioxidant activity, hippocampal level of BDNF, and simultaneously brain electrical activity were measured at scheduled times after TSD. Key findingsThe results showed that GH treatment improved memory (p < 0.001) in the PAT test of rats exposed to TSD. These beneficial effects were associated with lowering the level of anxiety and depression-like behavior (p < 0.001), rising the pain threshold (p < 0.01), increasing the activity of antioxidants (p < 0.01), hippocampal BDNF (p < 0.001), and regular brain electrical activity. SignificanceOur findings show that GH plays a key role in modulating memory, anxiety and depression behaviors, as well as reducing oxidative stress and improve hippocampal single-unit activity in the brain during TSD.

Exogenous growth hormone functionally alleviates glucocorticoid-induced longitudinal bone growth retardation in male rats by activating the Ihh/PTHrP signaling pathway

Glucocorticoid (GC)-induced longitudinal bone growth retardation is a common and severe adverse effect in pediatric patients receiving GC immunosuppressive therapy. Molecular mechanisms underlying GC-induced growth inhibition are unclear. GC withdrawal following short-term high-dose use is common, including in the immediate post-transplant period. However, whether skeleton growth recovery is sufficient or whether growth-promoting therapy is required following GC withdrawal is unknown. The aim of this study was to investigate the effect of exogenous growth hormone (GH) on growth plate impairment in GC-induced longitudinal bone growth retardation. Here, apoptotic chondrocytes in the hypertrophic layer of growth plates increased whereas Indian Hedgehog (Ihh) and Parathyroid Hormone Related Peptide (PTHrP) protein levels in the growth plate decreased following GC exposure. The hypertrophic zone of the growth plate expanded following GC withdrawal. Subcutaneously injected GH penetrated the growth plate and modified its organization in rats following GC withdrawal. Ihh and PTHrP expression in GC-induced apoptotic chondrocytes decreased in vitro. GH promoted chondrocyte proliferation by activating Ihh/PTHrP signaling. Downregulating Ihh using specific siRNAs increased chondrocyte apoptosis and inhibited PTHrP, Sox9, and type II collagen (Col2a1) protein expression. GH inhibited apoptosis of Ihh-deficient growth plate chondrocytes by upregulating PTHrP, Sox9, and Col2a1 expression. Thus, reversal of the effect of GC on growth plate impairment following its withdrawal is insufficient, and exogenous GH provides growth plate chondral protection and improved longitudinal growth following GC withdrawal by acting on the Ihh/PTHrP pathway.

Effect of growth hormone on semen parameters, partial hemogram, and testosterone level in Nili Ravi buffalo bulls

&lt;p&gt;El propósito de este ensayo fue examinar los posibles efectos de la hormona de crecimiento exógena (GH) sobre la calidad del semen, algunas variables del hemograma y la concentración de testosterona en suero de toros bubalinos Nili Ravi. Los búfalos del grupo tratado (n=3) fueron inyectados con 500 mg de somatotropina recombinante cada 15 días durante 10 semanas consecutivas, mientras que los del grupo control (n=3) recibieron igual volumen de solución fisiológica salina. Las muestras de semen fueron tomadas dos veces por semana y analizadas para evaluar los parámetros fisiológicos. Las muestras de sangre colectadas quincenalmente fueron analizadas para establecer el recuento de glóbulos rojos, la concentración de hemoglobina, el hematocrito, el volumen corpuscular medio (MCV), recuento de glóbulos blancos (WBC), tasa de neutrófilos y linfocitos, así como los niveles séricos de testosterona. Los datos obtenidos fueron analizados estadísticamente por medio del test-t de Student. Los resultados indicaron que el tratamiento con somatotropina aumentó significativamente (p&amp;lt;0,05) el volumen eyaculado (8,8±0,2 versus 7,7±0,2 ml), la motilidad del semen (72,6±0,4 versus 67,4±0,7%), la actividad de masa (3,35±0,07 versus 2,52±0,08), la concentración de espermatozoides (982,2±67,8 versus 731,9±50,5 millones/ml), los espermatozoides vivos (80,1±0,3 versus 75,8±0,5%) y el nivel de testosterona sérica (4,02±0,21 versus 2,37±0,07 ng/ml), comparados con los animales controles. En el hemograma aumentaron los linfocitos (p&amp;lt;0,05) y disminuyeron variables como volumen corpuscular medio, recuento de leucocitos y tasa de neutrófilos (p&amp;lt;0,05). Hemoglobina, concentración de eritrocitos y hematocrito permanecieron inalterados. Todos los parámetros investigados se situaron dentro de los rangos normales para toros bubalinos. En conclusión, el tratamiento de búfalos Nili-Ravi con somatotropina mejoró la calidad del semen y aumentó la testosterona sérica, sin provocar ostensibles efectos adversos en el estado general de los toros&lt;/p&gt;

Comparing the Behavioural Effects of Exogenous Growth Hormone and Melatonin in Young and Old Wistar Rats

Growth hormone (GH) and melatonin are two hormones with quite different physiological effects. Curiously, their secretion shows parallel and severe age-related reductions. This has promoted many reports for studying the therapeutic supplementation of both hormones in an attempt to avoid or delay the physical, physiological, and psychological decay observed in aged humans and in experimental animals. Interestingly, the effects of the external administration of low doses of GH and of melatonin were surprisingly similar, as both hormones caused significant improvements in the functional capabilities of aged subjects. The present report aims at discerning the eventual difference between cognitive and motor effects of the two hormones when administered to young and aged Wistar rats. The effects were tested in the radial maze, a test highly sensitive to the age-related impairments in working memory and also in the rotarod test, for evaluating the motor coordination. The results showed that both hormones caused clear improvements in both tasks. However, while GH improved the cognitive capacity and, most importantly, the physical stamina, the effects of melatonin should be attributed to its antioxidant, anxiolytic, and neuroprotective properties.

Effect of exogenous somatotropin and staged ovariectomy on mRNA expression of select ECM-related proteins in mammary tissue of prepubertal Holstein calves

Growth hormone (GH) and estrogen are essential stimulators of mammary cell proliferation and mammary development as mammals near puberty. Mammary ductal growth requires modifications of the extracellular matrix (ECM) for this tissue expansion to occur. Our purpose was to evaluate the effects of exogenous GH and ovariectomy (known to impact estrogen production) on gene expression of selected ECM proteins in the mammary parenchyma (PAR) and mammary fat pad (MFP) of prepubertal calves. Our hypothesis was that both GH and ovariectomy would alter the mRNA expression of multiple mammary ECM proteins. However, treatment with GH significantly reduced the expression of only fibronectin in PAR. However, the mRNA expression of all of the ECM proteins tested was numerically lower in PAR from GH treated calves. In contrast, staged ovariectomy decreased expression of fibronectin and heat shock protein 90 but increased expression of epimorphin in mammary PAR. In the MFP expression of Rac-1 and fascin were increased. These findings suggest that effects of exogenous GH on mammary gland composition are only marginally dependent on alterations in ECM proteins but the more pronounced effects of ovariectomy (reduced PAR mass and altered myoepithelial ontogeny) are more likely linked to changes in expression of ECM proteins.

The paracrine effect of exogenous growth hormone alleviates dysmorphogenesis caused by tbx5 deficiency in zebrafish (Danio rerio) embryos.

BackgroundDysmorphogenesis and multiple organ defects are well known in zebrafish (Danio rerio) embryos with T-box transcription factor 5 (tbx5) deficiencies, mimicking human Holt-Oram syndrome.MethodsUsing an oligonucleotide-based microarray analysis to study the expression of special genes in tbx5 morphants, we demonstrated that GH and some GH-related genes were markedly downregulated. Zebrafish embryos microinjected with tbx5-morpholino (MO) antisense RNA and mismatched antisense RNA in the 1-cell stage served as controls, while zebrafish embryos co-injected with exogenous growth hormone (GH) concomitant with tbx5-MO comprised the treatment group.ResultsThe attenuating effects of GH in tbx5-MO knockdown embryos were quantified and observed at 24, 30, 48, 72, and 96 h post-fertilization. Though the understanding of mechanisms involving GH in the tbx5 functioning complex is limited, exogenous GH supplied to tbx5 knockdown zebrafish embryos is able to enhance the expression of downstream mediators in the GH and insulin-like growth factor (IGF)-1 pathway, including igf1, ghra, and ghrb, and signal transductors (erk1, akt2), and eventually to correct dysmorphogenesis in various organs including the heart and pectoral fins. Supplementary GH also reduced apoptosis as determined by a TUNEL assay and decreased the expression of apoptosis-related genes and proteins (bcl2 and bad) according to semiquantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis, respectively, as well as improving cell cycle-related genes (p27 and cdk2) and cardiomyogenetic genes (amhc, vmhc, and cmlc2).ConclusionsBased on our results, tbx5 knockdown causes a pseudo GH deficiency in zebrafish during early embryonic stages, and supplementation of exogenous GH can partially restore dysmorphogenesis, apoptosis, cell growth inhibition, and abnormal cardiomyogenesis in tbx5 knockdown zebrafish in a paracrine manner.

Effect of exogenous somatotropin in Holstein calves on mammary gland composition and proliferation

Pubertal mammary gland growth and development are hormonally regulated, but the details are poorly understood in calves. Our purpose was to evaluate the effects of exogenous growth hormone (GH) on the biochemical composition of the prepubertal mammary gland, mRNA expression of selected genes, and histological characteristics of the developing parenchyma (PAR). In this experiment, 19 calves (7±4 d of age) were randomly assigned to 1 of 2 treatments: bovine somatotropin (bST, 500mg; n=10) or placebo (Sal; 0.9% saline; n=9). Animals were treated every 3 wk beginning on d 23. Calves were assigned to an early (65 d; tissue harvested after 2 treatment injections) or late collection time (107 d; tissue harvested after 4 treatment injections). Calves were fed milk replacer and calf starter for 8 wk and starter and hay thereafter. Parenchyma and mammary fat pad (MFP) from one udder half were harvested for analysis of protein, lipid, and DNA. Additional tissues were preserved for histological analysis or snap-frozen for quantitative real-time PCR. Somatotropin treatment did not significantly alter the mass of PAR or MFP or the general pattern of development of epithelial structures. Significant increases were observed in protein/100kg of body weight (BW), total protein, DNA concentration, DNA/100kg of BW, and total DNA in 107-d calves, and a significant treatment by day interaction was observed for DNA and lipid concentrations in PAR. In MFP, a significant decrease was observed in protein/100kg of BW in bST-treated calves and in total MFP protein in 65-d calves. A treatment by day interaction was found for total protein, DNA, and protein/100kg of BW. In PAR, relative expression of ATPase-binding cassette 3 and growth hormone receptor were reduced by bST and both were lower in 107-d-harvest calves. Epithelial cell retention of bromodeoxyuridine (BrdU; possible indicator of stem-like cells) was greatest in 65-d bST-treated calves, and a significant time of sampling response and treatment × time interaction were observed. Expression of the proliferation marker protein Ki67 was numerically higher in bST-treated calves but the difference was nonsignificant. Retention of the BrdU label was reduced in 107-d calves. Exogenous growth hormone given to calves may affect mammary tissue composition and epithelial cell gene expression in subtle ways but exogenous supplementation with bST alone is not likely to alter overall development patterns or affect the mass of mammary parenchymal tissue. Whether such subtle changes have an effect on subsequent development or function is unknown.

Misleading Interpretations and Public Misinformation on Human Growth Hormone in Athletes

The article by Meinhardt and colleagues (1) isimportant and informative. This randomized, controlled trial evalu-ating the independent and synergistic effects of exogenous growthhormone and testosterone on selected physiologic and athletic per-formance measures is a valuable contribution to the scientific litera-ture. It also provides critical evidence to the ongoing social andscientific debate surrounding sports doping.The study shows significant increases in anaerobic work capac-ity, as measured by the Wingate cycle test, after 8 weeks of treatmentwith growth hormone, with and without concurrent testosteroneadministration. Although effect sizes were modest (0.22 to 0.38 forgrowth hormone alone and 0.61 for growth hormone and testoster-one), these findings suggest a previously unreported physiologic ef-fect that has potential implications for athletic performance. Theauthors correctly conclude, however, that the athletic significance ofthese findings is uncertain.Unfortunately, oversights in the presentation of this importantwork have led to erroneous interpretations in the mainstream mediathat compromise its effect and carry dangerous ramifications, espe-cially when viewed by an untrained audience.The characterization of anaerobic work capacity as “sprint ca-pacity” is inaccurate and misleading. Although equivocal supportexists for cycle ergometry as a significant predictor of sprinting per-formance (2, 3), it is widely recognized that additional factors, in-cluding strength and power, are important determinants (4, 5). Tosuggest even semantically that Wingate test performance and sprintcapacity are equivalent measures is wrong.More egregiously, even while acknowledging such limitations,the authors go on to speculate in specific terms how their findings inrecreational athletes translate to 100-meter running times and 50-meter swimming times in world-class competitors: “We do not knowhow an improvement in Wingate test performance translates to per-formance in the sporting field, but we speculate that the approxi-mately 4% increase in sprint capacity that we observed could trans-late to an improvement of 0.4 second in a 10-second sprint over 100meters or of 1.2 seconds in a 30-second swim over 50 meters.” Thisclaim is made without basis, evidence, or even a compelling expla-nation. Nonetheless, it forms the featured conclusion of numerousprominent media reports, including this from the

Hepatic adiponectin receptor R2 expression is up-regulated in normal adult male mice by chronic exogenous growth hormone levels

Previous studies investigating the effects of exogenous growth hormone (GH) on the expression of adiponectin and the adiponectin receptors have generated seemingly conflicting results. Here, to determine the effects of chronic exogenous GH levels, we investigated the expression of adiponectin receptor R1 (adipoR1) in skeletal muscle and adiponectin receptor R2 (adipoR2) in the liver of normal C57BL/6 adult male mice 24 weeks after a single injection of rAAV2/1-CMV-GH1 viral particles. AdipoR1 and adipoR2 mRNA expression levels were determined by quantitative real-time reverse transcription-polymerase chain reaction. AdipoR1 and adipoR2 proteins were analyzed by Western blotting. Serum total and high molecular weight (HMW) adiponectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) kits for mice. The results demonstrated that the injection of rAAV2/1-CMV-GH1 within the concentration range of 1.0x1011 to 4.0x1011 viral particles significantly up-regulated hepatic adipoR2 gene expression. The serum HMW adiponectin level increased significantly with the concentration range of 2.0x1011 to 4.0x1011 rAAV2/1-CMV-GH1 viral particles. The injection of 4.0x1011 rAAV2/1-CMV-GH1 viral particles induced a significant increase in both serum glucose and insulin concentrations (p<0.05), and the homeostasis model assessment of insulin resistance (p<0.01). This may decrease body insulin sensitivity and therefore raise the potential risk of insulin resistance. However, exogenous GH levels did not significantly affect adipoR1 expression in skeletal muscle. In conclusion, chronic exogenous GH up-regulates hepatic adipoR2, rather than adipoR1, in vivo, and raises the serum HMW adiponectin level. However, the elevation of exogenous GH concentrations may increase the risk of insulin resistance.

Longitudinal growth in chronic hypokalemic disorders

Growth retardation remains a major complication in children with primary tubular disorders, despite adequate supplemental treatment with electrolytes, water and bicarbonate. Chronic hypokalemia, characteristic of some tubulopathies, impairs growth by mechanisms that are not well known. Association with growth hormone deficiency has been reported in patients with Bartter's or Gitelman's syndrome. Tissue-specific alterations of growth hormone and insulin-like growth factor I axis have been described in experimental models of potassium depletion. Hypokalemic rats gain less body length and weight than pair-fed normokalemic animals and, by contrast, develop renal hypertrophy. These rats have low circulating concentrations of insulin-like growth factor I, depressed messenger ribonucleic acid (mRNA) levels of this peptide in the tibial growth plate, and they are resistant to the longitudinal growth-promoting effects of exogenous growth hormone. The reason for this resistance remains to be defined. No alterations in the intracellular signaling for growth hormone have been found in the liver of hypokalemic rats. However, treatment with high doses of growth hormone is unable to normalize hypertrophy of the epiphyseal cartilage chondrocytes, which are severely disturbed in potassium depletion and likely play an important role in the pathogenia of growth impairment in this condition.

The Acid-Labile Subunit Is Required for Full Effects of Exogenous Growth Hormone on Growth and Carbohydrate Metabolism

Normal postnatal growth is dependent in part on overlapping actions of GH and IGF-I. These actions reflect GH stimulation of IGF-I production in liver and extrahepatic tissues, representing respectively the endocrine and autocrine/paracrine arms of the IGF system. Recent experiments in genetically modified mice show that each source of IGF-I can compensate for absence of the other but do not resolve their relative role in postnatal growth. In an effort to address this issue, we studied the GH responsiveness of mice harboring a null mutation of the acid-labile subunit (ALS). Null ALS mice have a substantial reduction in endocrine IGF-I but, unlike other models of plasma IGF-I deficiency, have no obvious additional endocrine defects. Wild type and null ALS mice of both sexes received daily sc injections of saline or recombinant bovine GH between d 35 and 63 of postnatal age. The GH-stimulated body weight gain of null ALS mice was reduced by more than 30% relative to wild type mice, irrespective of sex. Reductions in GH responsiveness were also seen for kidney and linear growth. Absence of ALS eliminated the ability of GH to increase plasma IGF-I despite intact GH-dependent stimulation of IGF-I expression in liver, adipose tissue, and skeletal muscle. GH treatment was also less efficient in antagonizing insulin action in null ALS mice. Overall, these results suggest that the GH effects mediated by endocrine IGF-I depends on ALS, and accordingly null ALS mice are less responsive to exogenous GH therapy.

Final Height in Children with Medulloblastoma Treated with Growth Hormone

Background: Medulloblastoma is the most frequent primary solid central nervous system tumour in children. The 5-year survival rate is at present at about 60%. Height in general is severely compromised in survivors. The present study is an extension of the investigation by the author’s group of the effect of exogenous growth hormone (GH) among medulloblastoma patients. Methods: A total of 113 patients with medulloblastoma (out of 682 cases documented in KIGS, Pfizer International Growth Database) were treated with GH till final height was achieved. At the start of GH therapy (median dose 0.18 mg/kg/week), patients were 8.9 years old and had a median height SDS of –1.6. Results: After 6.8 years of GH, final height SDS was –1.9, reflecting an overall loss in height of 0.3 SDS. This contrasted with an age-matched group of patients with idiopathic growth hormone deficiency (iGHD, n = 1,986), whose gain in height was 1.6 SDS on the same dose. The index of responsiveness averaged –0.9 during the first prepubertal year and –2.0 during total pubertal growth, thus indicating a major impairment in responsiveness to GH as compared to iGHD. Height at GH start, which correlated positively with the age at disease onset, was found to be the major determinant of final height. Conclusions: Our findings show that attempts to improve the height outcome in medulloblastoma must involve earlier recognition and treatment with higher-than-replacement doses of GH; additionally, modifications in cancer treatment programs need to be considered, such as lowering the dose of craniospinal irradiation or avoiding it as far as possible.

Lack of growth enhancement by exogenous growth hormone treatment in yellow perch ( Perca flavescens) in four separate experiments

The effect of exogenous growth hormone (GH) treatment on the growth of juvenile yellow perch ( Perca flavescens) was investigated in four experiments. In the first two experiments, juvenile yellow perch were reared at either 13 °C or 21 °C, and injected weekly with bovine GH (bGH) at 0.1, 1.0 or 10.0 μg/g body weight for 84 days. No significant growth enhancement in GH-treated fish was measured in fish in either of the experiments. In the third experiment, juvenile yellow perch were treated with estradiol-17β (E 2, 15 μg/g of diet), bGH (1.0 μg/g body weight) injected weekly or both hormones for 70 days at 21 °C. E 2 alone stimulated growth, but no further growth stimulation occurred in the E 2 + bGH-treated fish. In addition, no growth enhancement was found in fish treated with bGH alone. We measured no difference in serum insulin-like growth factor-I (IGF-I) levels between the treatment groups at 12 and 24 h after the final injection of GH; however, a drop in IGF-I levels after 24 h was observed. In a fourth study, the effect of recombinant yellow perch GH (rypGH, 0.2 or 1.0 μg/g body weight) injected weekly was evaluated in yellow perch juveniles. The fish were reared for 42 days at 18 °C. Neither GH dosages improved growth compared to control-injected and non-injected fish. Taken together, the lack of effect of mammalian GH or rypGH in our experiments suggests (1) low binding affinity between these hormones and the GH receptor in yellow perch, (2) that the endogenous GH levels were already at biologically maximal levels or (3) that other endocrine factors are needed in order for GH to promote yellow perch growth. The reduction in IGF-I levels 24 h after handling suggests a negative effect of handling stress on the GH-IGF-I axis in yellow perch.

Postreceptor Resistance to Exogenous Growth Hormone Exists in the Jejunal Mucosa of Parenterally Fed Rats

Our objective was to determine whether the intestinal mucosa is resistant to the mitogenic effects of exogenous growth hormone (GH) but sensitive to exogenous insulin-like growth factor-I (IGF-I) during total parenteral nutrition (TPN) because of decreased GH receptor (GHR) binding or postreceptor responsiveness to GH. First, only continuous i.v. administration of IGF-I, but neither pulsatile subcutaneous nor continuous i.v. GH, stimulated jejunal mucosal hyperplasia; however, both GH and IGF-I increased serum IGF-I and promoted similar whole-body growth after 8 d of exclusive TPN and 6 d of growth factor treatment in rats. This suggests a tissue-specific resistance to GH action in the intestinal mucosa during TPN. Second, exogenous GH during TPN did not reduce GH-specific binding in jejunum, suggesting that the inability of GH to stimulate mucosal hyperplasia is not due to low levels of the GHR. Third, IGF-I, but not GH, induced acute expression of c-fos (P < 0.009) and c-jun (P = 0.053) mRNAs in jejunum based on Northern analysis and in situ hybridization histochemistry 60 min after a single i.v. bolus of GH or IGF-I. This suggests that IGF-I, but not GH, activates early postreceptor growth-related signaling pathways in jejunum. In summary, the lack of early c-fos and c-jun induction in response to GH in TPN rats indicates that the jejunal mucosa is resistant to exogenous GH between GHR activation and induction of immediate early genes. This may contribute to the inability of mucosal cells to respond to the trophic effects of GH.

Modulation of brain insulin-like growth factor I (IGF-I) binding sites and hypothalamic GHRH and somatostatin levels by exogenous growth hormone and IGF-I in juvenile rats.

The effect of exogenous growth hormone (GH) and insulin-like growth factor I (IGF-I) on brain IGF-I binding sites (IGF-IR), and on the levels of growth hormone-releasing hormone (GHRH) and somatostatin was studied in hypophysectomized and intact juvenile male rats. Animals were injected subcutaneously twice daily (n = 5 each) with recombinant GH (rGH) (2.5 U/kg per day) or rIGF-I (500 microg/kg per day). In the hypophysectomized rats, serum GH and IGF-I levels were markedly suppressed and IGF-I levels were partially restored by GH treatment. There was a significant increase in IGF-IR binding capacity in the IGF-I-treated hypophysectomized rats compared to the saline-treated hypophysectomized animals (150.61 +/- 45.66 vs 41.32 +/- 12.42 fmol/mg, p < 0.05) but no significant difference in IGF-IR mRNA levels. GHRH levels in the saline-treated hypophysectomized group were significantly lower than in the saline-treated intact rats (31.2 +/- 11.2 vs 140.6 +/- 48.1 pg/mg tissue, respectively, p < 0.01); no effect was induced by GH or IGF-I (37.5 +/- 26.8 and 53.8 +/- 22.5 pg/mg tissue, respectively). However, in the intact rats, GH and IGF-I injection led to a decrease in GHRH content, which was significant in the GH-treated compared to the saline-treated animals (33.1 +/- 16.2 vs 140.6 +/- 48.1 pg/mg tissue, p < 0.01). No difference was found in somatostatin levels between intact and hypophysectomized rats (631.2 +/- 81.2 and 625.0 +/- 62.5 pg/mg tissue, respectively). However, in the hypophysectomized animals, GH and IGF-I treatment induced a significant increase in somatostatin levels (1300 +/- 193.7 pg/mg tissue, p < 0.01, and 912.5 +/- 81.2 pg/mg tissue, p < 0.05, respectively). Our findings suggest that the bioavailability of exogenous IGF-I is greater than that of GH-stimulated endogenous IGF-I. Because IGF-I is a potent neurotrophic agent, this effect may have important implications for states of neurodegenerative diseases.

The effect of growth hormone on the development of diabetic kidney disease in rats

Nephropathy is the most severe complication of diabetes mellitus. We investigated the effect of exogenous growth hormone (GH) administration on renal function and matrix deposition in the streptozotocin (STZ) model of type I-diabetic rat. Adult female STZ-diabetic rats (D), non-diabetic control rats injected with saline (C) and control and diabetic rats injected with bovine GH for 3 months (CGH and DGH, respectively) were used. The usual renal hypertrophy seen in D animals was more pronounced in the DGH group. Creatinine clearance increased only in the D rats, but not in the other groups, including DGH. Albuminuria was observed in the D animals but was significantly elevated in the DGH group. Glomeruli from DGH animals showed more extensive matrix accumulation (manifested as an increase in mesangial/glomerular area ratio). Renal extractable insulin-like growth factor (IGF-I) mRNA was decreased in the D and DGH groups, but renal IGF-I protein was not significantly increased. Renal IGF binding protein-1 was increased in the D groups and further increased in the DGH group, at both the mRNA and protein levels. GH-treated diabetic rats had less hyperfiltration and more albuminuria, concomitant with more glomerular matrix deposition, when compared with regular diabetic animals. This was associated with a significant increase in renal IGFBP-1, and dissociated from IGF-I changes. Thus, in this model, GH exacerbates the course of diabetic kidney disease.

Autocrine growth hormone production prevents apoptosis and inhibits differentiation in C2C12 myoblasts

Although C2C12 myoblasts express low levels of growth hormone receptor (GHR), we failed to see any effect of exogenous growth hormone (GH) on cell proliferation or differentiation. C2C12 cells stably overexpressing (sixfold) more in GHR (C2C12 GHR) grew faster than parental cells in media containing 2% serum, and proliferated while parental cells died, in the absence of serum. These effects were independent of exogenous GH but were inhibited by anti-GH and anti-insulin-like growth factor (anti-IGF-1) antibodies, consistent with a local production of GH, which we confirmed by RT-PCR and radioimmunoassay. In C2C12 GHR cells, we observed an increased activation of the Janus kinase 2 (Jak2), signal transducers and activator of transcription 5 (Stat5), mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) upon acute GH stimulation. GHR overexpression also inhibited the formation of myotubes and the expression of markers for myoblast differentiation. Taken together, our data suggest that GH acts as an autocrine factor in C2C12 cells, to enhance proliferation and to inhibit differentiation.

Effects of Exogenous Growth Hormone(GH)-Treatment on Carbon Tetrachloride(CCl4)-Induced Acute Liver Injury in GH-Deficient Mini Rats.

The effects of exogenous growth hormone (GH)-treatment on the development and regeneration of CCl4-induced acute hepatic injury were examined in GH-deficient Mini rats. Alanin aminotransferase (ALT) and asparate aminotransferase (AST) activities increased significantly at 24 and 48 hours (h) after CCl4-administration in both GH-treated and non treated groups, and they tended to be suppressed by GH-treatment. The expression level of insulin-like growth factor (IGF)-1 mRNA was higher in GH (+) CCl4 (+) group than in GH (-) CCl4 (+) group, especially at 72 h, and that of hepatocyte growth factor (HGF) mRNA was also higher in some points in the former group. Histologically, degenerative changes of hepatocytes observed at 24 and 48 h was less severe in GH (+) CCl4 (+) group than in GH (-) CCl4 (+) group. At 72 h, depositions of reticular fibers and extracellular matrix materials were less severe and the number of desmin- or α-SMA-positive cells was larger in GH (-) CCl4 (+) group than in GH (+) CCl4 (+) group. Proliferating cell nuclear antigen (PCNA)-labeling index of centrilobular hepatocytes increased at 48 h in both GH (+) CCl4 (+) and GH (-) CCl4 (+) groups, and it returned to the control level at 72 h in the former group while that in the latter group showed still higher level at 72 h. In this study, it was shown that CCl4-induced acute liver injury in Mini rats can be restored by exogenous GH-treatment, and upregulation of IGF-1 and HGF mRNAs may be involved in this phenomenon.

Effect of exogenous growth hormone on somatic growth, gonadal development, and hepatic CYP2C11 and CYP2C12 expression in prepubertal intact male rats

The influence of exogenous growth hormone (GH) on pubertal maturation, as assessed by growth, age of preputial separation, testicular development, and hepatic expression of sexually dimorphic cytochrome P450 (CYP) enzymes, was investigated. Treatment of 22-day old prepubertal intact male rats with twice daily subcutaneous (s.c.) injections of rat recombinant GH (0.12 microg/g body weight) for 12 or 21 days did not affect body weight, skeletal growth, or testicular weight. By comparison, GH suppressed hepatic CYP2C1 enzyme activity, protein, and mRNA levels but induced CYP2C12 expression. GH suppressed CYP2C11 expression by approximately 60% in prepubertal rats as compared with 30% in adult rats, whereas it increased CYP2C12 levels to 80% of the normal female levels but had no effect in adult male rats. Twice daily intravenous injections of GH suppressed CYP2C11 only. Increasing the s.c. dose of GH 30-fold produced little or no additional change in CYP2C11 or CYP2C12 expression, whereas it modestly in creased body weight and skeletal growth and reduced testicular weight. Overall, the present study provides the first demonstration that prepubertal administration (22-33 days of age) of GH at a pharmacologically relevant dose (0.12 microg/g twice daily) suppressed hepatic expression of CYP2C11 in 34-day-old intact male rats, suggesting that in this age group the liver is intrinsically responsive to transcription factors involved in the regulation of GH-dependent, sex-specific CYP gene expression. A higher dose (3.6 microg/g) of GH administered during the prepubertal period was required to elicit a modest effect on somatic growth and gonadal development.