Anabolic Effects Of Growth Hormone Research Articles

SUN-577 Effect of Growth Hormone Replacement on Metabolic Profile and Vascular System in Adult Patients with Congenital Hypopituitarism

Introduction: Growth Hormone (GH) stimulates two distinct processes: anabolic effect of GH on growth through IGF1, and catabolic effect of GH stimulating lipolysis. GH deficiency (GHD) in adulthood is characterized with abnormal body composition, impairment of physical capacity and lipid and glycemic metabolism, beyond increase cardiovascular risk (CVR) factors. While in acquired hypopituitarism, GHD is always associated with CVR in several studies and demonstrated human recombinant growth hormone replacement (hrGHr) improves CVR. In congenital hypopituitarism (CH), however, the consequences of GHD and hrGHr in adulthood are unclear. Objective: To evaluate daily hrGHr in metabolic profile and vascular system in adult patients with CH. Patients and Methods: Fifty-nine adults with CH were selected for the study. They were divided into 2 groups: 1- hrGHr: 15 male, 17 female with median age 35,8 yrs, hrGHr in adult life with 7.2 yrs median time in the dose of approximately 1U per day in order to keep IGF1 in the normal range for age and sex; 2- Without hrGHr: 12 male, 15 female with 38,4 yrs median age and without hrGHr in adult life of 10.6 yrs median time. Thirty-two healthy volunteers were selected as controls. Anthropometric parameters, dual-energy X-ray absorptiometry (DXA), lipid and glycemic profile, and structural and functional parameters of the arterial vessels (carotid intima media thickness, arterial stiffness and flow mediated dilation) were evaluated and compared between the groups. Results: In patients with rhGHr the abdominal waist/height (AW/H) ratio (0,49 ± 0,06), the fat percentage (30,7 ± 10,4) and fat index (7,6 ± 3,7) were lower than the group without replacement (p= <0,001, p= <0,001 and p= 0,028, respectively). The low values of the CA/H ratio, fat percentage and fat index were independent of the diagnosis ACTH deficiency with corticosteroid replacement. Higher triglycerides (111,7 ± 62,4) and lower HDLc (49,5 ± 19,1) levels in patients without hrGHr compared to controls (p= 0,020 and p= 0,005, respectively) were observed. There was no statistical difference between glycemic profile, metabolic comorbidities and structural and function parameters of the arterial vessels between groups and controls. Conclusions: GHD in CH does not lead to accelerated premature atherosclerosis and arteriosclerosis. The hrGHr in adults with CH have beneficial effects on lipid profile and body composition and hrGHr in adulthood should be individualized.

MON-LB069 When a Routine Postoperative Internal Medicine Consultation Unearths a Hidden Diagnosis

Although rare in incidence, acromegaly can present with secondary osteoarthritis due to anabolic effects of Growth Hormone (GH). The diagnosis can be potentially missed until later in its clinical course, leading to a lost opportunity to prevent further complications and irreversible changes attributed to acromegaly. A 32-year-old patient with history of mild Type 1 Von Willebrand (VW) disease and severe crippling bilateral osteoarthritis of the hips was admitted for elective right hip replacement. The etiology of the osteoarthritis was not clear, but was felt to be unlikely to be related to VW disease, in the absence of hemarthrosis. A routine Internal Medicine consult was requested by the Orthopedics service for co-management of the patient postoperatively as he was on placed on VW factor infusion. Intraoperative findings were notable for severe osteopenia and destructive deformity of the femoral head. On examination, the patient was moderately built with largely normal systems examination. Closer examination revealed prominent supraciliary arches and nose. Large hands were noted with sausage like appearing digits. On further questioning, patient mentioned that his shoe size has increased to size 13 from size 10 in the last 3-4 years. A comparison of a previous picture of his face (5 yrs. ago) to now confirmed the pronounced changes in facial features. He recalled his dentist mentioning about significant spacing between his teeth a year ago. An insulin like growth factor 1 (IGF1) level was ordered as a first part of the work up for Acromegaly. The level returned back at 1448 ng/ml (53-332 ng/ml). An MRI scan of the brain revealed a large macro-adenoma extending onto the right cavernous sinus and displacing the optic chiasma. He was referred to the pituitary clinic for further work up and ultimately underwent a partial 2 stage trans nasal endoscopic resection of the tumor followed by fractionated radiotherapy. He continues to be on octreotide and pegvisomant. With the increase in childhood obesity, there has been an increased incidence of osteoarthritis in young patients. The need for joint replacement in relatively young patients has also increased. While it is important to pursue joint replacement surgeries in these patients to prevent disability, careful evaluation of the cause of OA must be looked into, especially in young patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Effects of Adenotonsillectomy on Serum Levels of IGF-1 and IGFBP-3 and Growth Indices in Children with Adenotonsillar Hypertrophy or Recurrent Tonsillitis.

Adenotonsillar hypertrophy (ATH) may present with growth retardation. Insulin-like growth factor 1 (IGF-1) mediates the anabolic effects of growth hormone (GH) on tissues. Most of the circulating IGF-1 molecules are bound to insulin-like growth factor-binding protein 3 (IGFBP-3). IGF-1 and IGFBP-3 serum levels reflect the levels of daily mean serum GH and are used as indices for evaluating the serum level of GH. This study aimed to determine the effect of adenotonsillectomy on IGF-1 and IGFBP-3 serum levels in patients with ATH or recurrent tonsillitis. Furthermore, we aimed to investigate the effect of adenotonsillectomy on growth indices such as weight and height. A total of 100 randomly selected children with a diagnosis of ATH or recurrent tonsillitis with a mean age of 10.2 ± 1.4 years (range, 3-17 years) were enrolled in the intervention group. Of those, 53 were boys and 47 were girls. The control group included 100 healthy children (62 boys and 38 girls) with a mean age of 8.5 ± 1.5 years (range, 4-15 years). Growth indices such as weight and height were measured and documented at the time of surgery and 6 months after the operation. Blood samples were taken preoperatively and repeated 6 months after adenotonsillectomy. The coated-tube immunoradiometric (IRMA) method was used to measure IGF-1 and IGFBP-3 levels. Postoperative IGF-1 and IGFBP-3 serum levels as well as weight and height showed were significantly greater in comparison with preoperative measurements in both the intervention and control groups (P<0.001). At the end of study, the intervention group showed significantly greater changes from baseline in IGF-1 and IGFBP-3 serum levels, weight, and height in comparison with the control group (P< 0.001). This study shows that adenotonsillectomy in children with ATH or recurrent tonsillitis increases IGF-1 and IGFBP-3 serum levels in comparison with preoperative levels by affecting the GH-IGF-1 axis, and subsequently leads to a faster increase in growth indices compared with healthy peers during the same period.

Effects of GH-IGF-I excess and gonadal status on bone mineral density and body composition in patients with acromegaly

Studies on body composition and bone mineral density in acromegaly have conflicting results. Our data point to an increase in lean mass, a decrease in adipose tissue, and that the anabolic effect of GH on bone is partially dependent on modifications in body composition. The effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) excess and gonadal status on bone mineral density (BMD) and body composition (BC) in acromegalic patients are uncertain. Bone mineral density and BC were evaluated by dual-energy X-ray absorptiometry (Prodigy-GE) in 75 patients (22 men and 53 women) with acromegaly, mean age 48.9 ± 14.5 years. Acromegaly was considered "controlled" when serum IGF-I was within the specific age-adjusted reference range, and serum GH was lower than 2.5 ng/mL. Comparisons between groups were performed using unpaired t test or Mann-Whitney U test. Categorical variables were analyzed by chi-square (x (2)) test. In order to compare data of different subgroups stratified by disease activity and gonadal status, one-way analysis of variance (ANOVA) and Bonferroni post hoc analysis were performed. To evaluate the correlation between GH and IGF-I and densitometric parameters, Pearson and Spearman rank order correlation were performed, as appropriate. There were no differences in BMD when considering disease activity and gonadal status. Active disease and eugonadism were positively correlated to an increase in lean mass and a decrease in fat mass. After multiple linear regression, there were positive correlations between GH and Z-score at lumbar spine and between lean mass and BMD at proximal femur. Our data support that GH-IGF-I excess and eugonadism have great influence on BC modifications and that the anabolic effects of GH-IGF-I on bone are, at least in part, dependent on these alterations in body composition.

Advantages and disadvantages of GH/IGF-I combination treatment

Growth hormone (GH) is the primary regulator of insulin-like growth factor-I (IGF-I) production in a wide variety of tissues. There is much overlap in the endocrine, metabolic and anabolic effects of GH and IGF-I but both hormones have divergent effects on glucose metabolism, insulin sensitivity and differentiation of prechondrocytes. Theoretically combined administration of GH and IGF-I may be more effective than GH alone or IGF-I alone. Arguments in favor for this are: 1] Clearance of IGF-I may be markedly altered by the co-administration of GH and this will provide sustained actions of IGF-I. 2] Higher serum IGF-I levels are achieved with a combination treatment of GH and IGF-I than with GH treatment alone or IGF-I alone. In addition, combination therapy may have additive or synergistic effects. 3] The combination GH and IGF-I counteracts disadvantageous effects on glucose metabolism of either GH alone or IGF-I alone. 4] GH may exert direct actions on tissues independently from IGF-I. 5] Combination of GH and IGF-I may be more effective in improving tissue IGF-I levels. The combination therapy of GH and IGF-I might be beneficial in growth retardation, in certain specific subgroups of critically ill or catabolic patients and in the treatment of GH-deficient subjects with the metabolic syndrome and/or manifest diabetes. It is at present unknown whether an optimal balance between safety and efficacy can be achieved with the combination therapy of GH and IGF-I, since this combination has been evaluated in only a small number of patient populations and in studies of a relatively short duration. In addition, a disadvantage may be the financial costs of combination therapy of GH and IGF-I. In conclusion, there are many reasons for believing that administration of the combination therapy of GH and IGF-I could have advantages above GH alone or IGF-I alone. However, determination of whether co-administration of GH and IGF-I indeed is superior to either agent alone awaits further study.

Manipulation of the Growth Hormone Axis in Patients with HIV Infection

Patients with human immunodeficiency virus (HIV) infection often have a reduced mass of skeletal muscle and bone and a maldistribution of body fat. Loss of muscle mass, strength, and function are integral to the AIDS wasting syndrome and are associated with resistance to the anabolic effects of growth hormone. Administration of growth hormone in relatively high daily doses for 12 weeks improves muscle mass, strength, and function but leads to excess salt and water retention, the carpal tunnel syndrome, glucose intolerance, and insulin resistance, whereas the use of somewhat lower doses or an alternate-day regimen elicits similar beneficial effects with . . .

Therapeutic Potential of Ghrelin in the Treatment of Heart Failure

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for the GH secretagogues receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated, not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. Considering the haemodynamic and anabolic effects of GH, ghrelin may have beneficial effects on cardiac function and energy metabolism in heart failure through GH-dependent mechanisms. On the other hand, ghrelin has some GH-independent actions: ghrelin stimulates food intake and induces adiposity. Interestingly, ghrelin acts directly on the CNS to decrease sympathetic nerve activity. It also inhibits apoptosis of cardiomyocytes and endothelial cells. An experimental study has shown that repeated administration of ghrelin improves cardiac structure and function, and attenuates the development of cardiac cachexia in chronic heart failure (CHF). These results suggest that ghrelin has cardiovascular effects and regulates energy metabolism through GH-dependent and -independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of severe CHF.

Bone mineral density and turnover in patients with acromegaly in relation to sex, disease activity, and gonadal function

Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion. GH and insulin-like growth factor-I (IGF-I) exert anabolic activity in bones. Nevertheless, bone mineral density (BMD) loss is not uncommon in patients with acromegaly. It is assumed to be due to hypogonadism associated with the acromegaly. The aim of the study was to examine BMD at various skeletal sites and bone turnover and to assess the influence of impaired gonadal function and disease activity on BMD and turnover changes in acromegaly. A total of 62 patients were studied (40 women, 22 men). Among the women, 22 had active disease and 18 were cured; 16 women had normal gonadal function, and 24 were hypogonadal. Altogether, 12 men presented with active acromegaly, and 10 were cured; normal gonadal function was found in 10 men, and hypogonadism was diagnosed in 12 men. Controls were 30 healthy subjects. Densitometry using dual-energy X-ray absorptiometry of the lumbar spine, proximal femur, forearm, and total body was carried out. Bone turnover was studied based on serum osteocalcin, C-terminal collagen type 1 crosslinks, and bone alkaline phosphatase concentration. A disadvantageous effect of acromegaly on bone density was associated with hypogonadism in the distal radius (in women), the proximal femur (in men), and the total body (both sexes). An anabolic effect of GH during active acromegaly was present in the proximal femur only in men. We confirmed increased bone turnover in the presence of acromegaly, and these changes were similar regarding the activity of the disease and the gonadal status.

Tumor Necrosis Factor α Blockade Restores Growth Hormone Signaling in Murine Colitis

Cytokines including tumor necrosis factor alpha (TNFalpha) may create a state of growth hormone (GH) resistance in Crohn's disease. Anabolic effects of GH are mediated via phosphorylation of the signal transducer and activator of transcription (STAT)5b transcription factor. Although GH resistance in other settings has been linked to a defect in janus kinase-STAT signaling, the molecular basis for GH resistance in colitis was not known. We hypothesized that the GH-induced phosphorylation of STAT5b would be impaired in colitis, and that TNFalpha blockade would restore GH signaling. Growth, body composition, and molecular regulators of GH signaling were determined in interleukin-10 null mice with chronic colitis and wild-type controls, +/- treatment with an anti-TNFalpha antibody. Interleukin-10 null mice exhibited significant alterations in growth, body composition, and feed efficiency. Liver insulin-like growth factor 1 expression was reduced in colitic mice. This was associated with down-regulation of GH receptor (GHR) expression and impaired GH-dependent STAT5b activation. Down-regulation of GHR expression was associated with reduced nuclear abundance and DNA binding of the GHR gene-promoter transactivator, Sp3. TNFalpha down-regulated GHR abundance and prevented GH-induced tyrosine phosphorylation of STAT5 in rat hepatocytes in culture. TNFalpha neutralization up-regulated liver GHR abundance and restored GH activation of STAT5 and serum insulin-like growth factor 1 levels in colitic mice; this preceded improvements in weight gain and disease activity. GH resistance in experimental colitis is caused by down-regulation of GHR expression, thereby reducing GH-dependent STAT5 activation. TNFalpha blockade restores liver GH signaling and improves anabolic metabolism in this setting.

The Anabolic Effects of Growth Hormone (GH) and GH Secretagogues on Bone Mass and Density

Several antiresorptive agents have been developed for the treatment of osteoporosis and bone disorders. Few agents have been introduced that stimulate bone formation. Treatment with parathyroid hormone induces, however, a potent increase in hip and lumbar bone mineral density (BMD) and is now available in some countries. The present review focuses on growth hormone (GH) / GH secretagogues (GHSs). GH / GHSs stimulates bone turnover, thereby increasing bone mass and density. Keywords: growth hormone, growth hormone secretagogue, bone, bone mineral content, bone mineral density

P0624 LIVER GROWTH HORMONE RESISTANCE PRECEDES GROWTH FAILURE IN EXPERIMENTAL COLITIS

Introduction: The combined effects of circulating cytokines and reduced caloric intake may cause growth hormone (GH) resistance in children with Crohn’s disease. Anabolic effects of GH are mediated via phosphorylation of the STAT5b transcription factor and subsequent up regulation of IGF-1 gene expression. The molecular basis for GH resistance in colitis was not known. We hypothesized that liver GH dependent phosphorylation of STAT5b would be impaired in colitis, and that this would precede growth failure. Methods: Interleukin 10 (IL-10) null mice on the C3H/HejBir background develop chronic colitis beginning at 4–6 weeks of age. Growth, body composition, and GH signaling in liver and skeletal muscle were characterized in IL-10 null mice and wild type (WT) littermates at 8 and 20 weeks of age. Results: Colitis was present in both sexes by 8 weeks of age. Maximal reductions in growth and body composition were observed in both sexes by 20 weeks of age; these were first apparent in male mice at 8 weeks. As expected, liver IGF-1 expression was reduced in colitic mice. This was associated with a significant reduction in nuclear phospho-STAT5 abundance at both 8 and 20 weeks, and down regulation of GH receptor (GHR) abundance. Down regulation of liver GHR expression was associated with reduced nuclear abundance and DNA binding of the GHR gene promoter transactivator, Sp3. By comparison, skeletal muscle STAT5 phosphorylation was relatively preserved in colitic mice, despite reductions in lean body mass in males. Tumor Necrosis Factor (TNF) pre-treatment of rat H4IIE hepatoma cells and C2C12 mouse myoblast cells reduced GHR abundance and impaired GH dependent STAT5 activation in the liver, but not muscle, cell line. Conclusion: Growth failure and reduced IGF-1 expression in experimental colitis were associated with down regulation of liver GHR abundance and impaired STAT5 phosphorylation. The defect in liver STAT5 phosphorylation occurred early in the course of colitis, coincident with the onset of reduced weight gain, and was reproduced by TNF treatment in a liver cell line. Therapies which block TNF may improve growth in children with Crohn’s disease in part by restoring hepatic GH signaling and IGF-1 expression.

Fracture risk is decreased in acromegaly--a potential beneficial effect of growth hormone.

Growth hormone (GH) is an anabolic hormone that may increase bone density and thus decrease fracture risk. Patients with acromegaly have an excess of GH, and we therefore investigated whether fracture risk was decreased in patients with acromegaly. We identified 206 patients newly diagnosed with acromegaly between 1983 and 1996 who underwent pituitary surgery. Each patient was compared with three age- and gender-matched controls randomly selected from the background population. Mean age at diagnosis was 46.0+/-12.6 years and 50% were women. Before diagnosis, six patients sustained six fractures during 2128 person years and after diagnosis six patients had ten fractures during 1282 years of follow-up. Among the controls, the corresponding figures were 23 subjects with 44 fractures during 6357 years of follow-up before diagnosis and 46 fractures in 28 subjects during 4051 person years. The fracture rate was significantly decreased before (incidence rate ratio: IRR=0.41, 95% CI: 0.18-0.93) but not after the diagnosis (IRR=0.69, 95% CI: 0.35-1.36) of acromegaly was made. Twenty-three patients had undergone measurements of bone mineral density by DXA after diagnosis, and their mean+/-SD Z-scores both in the lumbar spine (0.92+/-1.38) and femoral neck (0.54+/-1.02) were significantly higher than expected. A fracture before diagnosis was a significant risk factor for sustaining an incident fracture after diagnosis (RR=11.8, 95% CI: 4.7-29.3). In conclusion, fracture risk is significantly decreased in patients with acromegaly compared to controls probably due to an anabolic effect of growth hormone on bone.

Local anabolic effects of growth hormone on intact bone and healing fractures in rats.

The local effects of rat growth hormone (rGH) injected at the surfaces of intact tibial diaphyses and healing tibial diaphysial fractures were investigated in 10-month-old female rats. Intact diaphysial bones: rats were injected daily for 14 days with vehicle, 2 microg rGH, or 20 microg rGH at the surface of the right tibial diaphysis. After 10 days of injection the animals were labeled with calcein. At the rGH-injected location, increased external diaphysial bone dimensions and increased calcein-labeled area were seen, and the responses to rGH were dose dependent. The new bone formed at the periosteal surface was woven bone. At the opposite left tibia, no systemic effect of rGH was found. rGH did not influence body weight changes during the treatment, or muscle mass or serum IGF-I at the end of the treatment. Healing diaphysial fractures: a closed fracture was made in the right tibial diaphysis, and stabilized by medullary nailing. The fractures were tested after 21 days and 98 days of healing. During the first 21 days of healing, all rats were injected daily with either vehicle or 20 microg rGH at the surface of the fracture line. In the 21-day healing rGH group, ultimate load, ultimate stiffness, external callus dimensions, and external callus volume of the fractures were increased. rGH did not affect body weight changes during this healing period or serum IGF-I at the end of the healing period. In the 98-day healing rGH group, ultimate load was still increased compared with the vehicle group, although a ninefold increase took place in the vehicle group between days 21 and 98 of healing. External callus dimensions of the fractures were increased in the rGH group, whereas body weight changes during the healing period were not affected.

PTH ameliorates acidosis-induced adverse effects in skeletal growth centers: The PTH–IGF-I axis

Chronic metabolic acidosis (CMA) exerts profound adverse effects on bone metabolism thereby leading to impaired skeletal linear growth. We have recently shown that CMA in vitro causes distinct morphological changes in skeletal growth centers along with inhibition of endochondral differentiation. In addition, CMA causes an end organ resistance to the anabolic effects of growth hormone (GH) and locally produced insulin-like growth factor-I (IGF-I) in skeletal growth centers. Given the effects of parathyroid hormone (PTH) and PTH related protein (PTHrP) on the development of cartilaginous bone, we sought to determine whether PTH has any effects on the changes induced by CMA in skeletal growth centers. The interaction between PTH and IGF-I in growth centers during neutral or acidic conditions were studied specifically. An in vitro organ culture system using the murine mandibular condyle was employed as a model for endochondral active growth center. Condyles from six-day-old mice were cultured in BGJb medium of either neutral pH (pH approximately 7.4) or acidic pH (pH approximately 7.15) in the presence or absence of 10-10 mol/L [1-34] PTH. After 24, 48, 72 and 96 hours of culture, the condyles were washed, fixed in formaldehyde, and processed for paraffin embedding. Histologic markers of the growth center were assessed. In addition, the protein level and mRNA expression for various markers of cartilage differentiation were evaluated by immunohistochemistry and in situ hybridization, respectively. The abundance and expression levels of IGF-I and IGF-I receptor (IGF-I-R) were assessed also. Following incubation for 72 hours in acidic conditions, there was a marked attenuation of the chondroblastic zone, suggesting a defect in the process of cellular differentiation. Acidosis also down-regulated endochondral differentiation markers (cartilage specific proteoglycans, collagen type II). This was accompanied by a reduction in the expression of IGF-1, IGF-1 receptor and PTH receptors. PTH (10-10 mol/L) added to acidic cultures prevented the adverse effects of CMA on endochondral differentiation and increased the overall condylar growth, when compared to acidic conditions without PTH. PTH also up-regulated its own receptor in control as well as during acidic conditions, and increased the expression levels of IGF-1 and IGF-1 receptor in the acidotic condyle. Acidosis increased the expression of IGF-I binding protein-4 (IGFBP-4, an inhibitor of IGF-I activity), whereas coincubation with PTH during acidic conditions abrogated the up-regulation of IGFBP-4. Addition of a neutralizing antibody to IGF-I-R during PTH treatment under acidic conditions resulted in the abrogation of the ameliorative effect of PTH on endochondral differentiation. The protein kinase C (PKC) signaling pathway was modulated negatively by CMA. However, PTH activated PKC-alpha under both control and acidic conditions. The phorbol ester, PMA (phorbol 12-myristate 13-acetate), a PKC activator, mimicked the effect of PTH on chondrocyte differentiation. Parathyroid hormone at low concentration stimulates the differentiation and proliferation of cartilage cells and prevents the suppressive effect of acidosis on endochondral bone differentiation and on the IGF-I/IGF-I-R system in skeletal growth centers. Increased local production of IGF-I by PTH, which takes place even during acidotic conditions, mediates, at least in part, the ameliorative effect of PTH. Protein kinase C is probably one of the signaling pathways mediating the salutary effects of PTH on chondrocyte differentiation in growth centers. This study lends further credence to the notion that under certain conditions, PTH or PTHrP can exert anabolic effects in the skeleton. These findings may be of clinical-therapeutic significance in children and patients with CMA.

Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3.

Cytokines may cause an acquired growth hormone (GH) resistance in patients with inflammatory diseases. Anabolic effects of GH are mediated through activation of STAT5 transcription factors. We have reported that TNF-alpha suppresses hepatic GH receptor (GHR) gene expression, whereas the cytokine-inducible SH2-containing protein 1 (Cis)/suppressors of cytokine signaling (Socs) genes are upregulated by TNF-alpha and IL-6 and inhibit GH activation of STAT5. However, the relative importance of these mechanisms in inflammatory GH resistance was not known. We hypothesized that IL-6 would prevent GH activation of STAT5 and that this would involve Cis/Socs protein upregulation. GH +/- LPS was administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type (WT) controls. STAT5, STAT3, GHR, Socs 1-3, and Cis phosphorylation and abundance were assessed by using immunoblots, EMSA, and/or real time RT-PCR. TNF-alpha and IL-6 abundance were assessed by using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3. Therapies that block IL-6 may enhance GH signaling in inflammatory diseases.

Testosterone enhances the anabolic effect of growth hormone

Testosterone enhances the anabolic effect of growth hormone

Growth hormone and amino acid supply interact synergistically to control insulin-like growth factor-I production and gene expression in cultured ovine hepatocytes.

Many of the anabolic effects of growth hormone (GH) are indirect, occurring through GH-stimulated production of insulin-like growth factor-I (IGF-I) by the liver. As well as being regulated by GH, plasma IGF-I concentrations have been demonstrated to depend upon the level of dietary protein intake, with low protein diets being associated with reduced circulatory IGF-I levels. This inhibitory effect cannot be reversed by GH injection, suggesting that liver sensitivity to GH becomes impaired.To investigate the mechanisms through which protein supply affects GH sensitivity, primary cultures of ovine hepatocytes were grown in defined media, containing various proportions (0.2, 1.0 and 5.0) of jugular amino acid concentrations in fed sheep. Production of IGF-I by these cells was measured after 24 and 48 h in culture by radioimmunoassay. In the first 24-h period basal IGF-I production was the same in all defined media, and GH caused an approximately 2-fold increase in IGF-I release in cells grown in 1.0xor 5.0xamino acid media (P<0.01). Although GH appeared to increase IGF-I release in this period for cells grown in 0.2xamino acid media, this effect was not statistically significant. In the period from 24-48 h in defined media, both basal and GH-stimulated IGF-I production was dependent on amino acid availability (P<0.05 and P<0.001 respectively). Factorial analysis of variance demonstrated a strong positive interaction (P<0.001) between the effects of amino acid availability and GH, such that GH increased IGF-I production by more than 2-fold in cells grown in 5.0xamino acid media (P<0.01) but had no effect on production by cells grown in 1.0xor 0.2xamino acid media. Measurement of steady state concentrations of exon 1-derived IGF-I mRNAs using an RNase protection assay demonstrated that the observed effects on IGF-I peptide secretion were strongly associated with parallel effects at the RNA level. Incorporation of (35)S-methionine into cellular proteins over a 4-h period starting 20 h after transfer to defined culture media was not significantly reduced in 1.0xcompared with 5.0x amino acid media, although rates under both of these conditions were significantly higher than those seen in 0.2xamino acid media (P<0.01). The lack of correspondence between the dose-dependent effects of amino acid supply on cellular protein synthesis and those on basal and GH-stimulated IGF-I production, suggests that amino acid supply modulates IGF-I production through selective mechanisms. Steady state levels of the CCAAT/enhancer-binding protein beta (C/EBPbeta) isoforms, liver-enriched activating protein (LAP) and liver-enriched inhibitory protein (LIP) were determined by Western blotting. When levels of LAP were expressed relative to LIP levels in the same extracts, a significant decrease in the LAP:LIP ratio was observed in response to amino acid limitation (P<0.05). These data strengthen earlier arguments that synergistic interaction between the effects of amino acids and GH on hepatic IGF-I gene expression underlie nutrition-dependent changes in circulating IGF-I titres. The association between these effects and altered levels of C/EBPbeta isoforms suggests that CCAAT/enhancer mediated control of IGF-I gene expression may be involved in this phenomenon.

Insulin-like growth factor-I, but not growth hormone, is dependent on a high protein intake to increase nitrogen balance in the rat

The aim of the present study was to investigate the influence of dietary protein level on the protein anabolic effects of growth hormone (GH) and insulin-like growth factor-I (IGF-I). Female growing rats were fed on either a high- or a low-protein diet with crude protein contents of 222 and 83 g/kg respectively. The diets contained the same amount of metabolizable energy (15.1 MJ/kg) and were given during a 14 d period. During the same time, three groups of rats (n 8) on each diet received subcutaneous infusions of either saline, recombinant human GH (rhGH) or recombinant human IGF-I (rhIGF-I). rhGH and rhIGF-I were given in doses of 360 and 500 micrograms/d respectively. The low-protein diet alone reduced significantly (P < 0.05) IGF-I concentrations in serum and in tissue taken from the gastrocnemius muscle as well as IGF-I mRNA from the same muscle. The responses to rhGH and rhIGF-I in terms of muscle IGF-I and its mRNA were variable. However, when rhIGF-I was infused into rats on the high-protein diet, significantly elevated levels of IGF-I in muscle tissues could be observed. This was associated with a significantly (P < 0.05) increased N balance, whereas rhGH significantly (P < 0.05) enhanced the N balance in rats on the low-protein diet. Thus, it can be concluded that the level of dietary protein ingested regulates not only the effect of IGF-I on whole-body N economy but also the regulation of IGF-I gene expression in muscles. The exact mechanism by which GH exerts its protein anabolic effect, however, remains to be elucidated.

The effects of amino acid supply on the sensitivity of IGF-1 secretion to growth hormone stimulation in ovine hepatocytes

Many of the anabolic effects of growth hormone (GH), including promotion of lean tissue growth, are mediated by the actions of insulin-like growth factor-1 (IGF-1) (Gluckman et al, 1987). It is known that the response of hepatic IGF-1 synthesis to GH may be modulated by alterations in levels of feeding or changes in protein supply (Pell et al, 1993). The aim of the current study was to develop an in vitro model to characterise interactions between amino acid supply and GH on hepatic IGF-1 release in ruminants.Ovine hepatocyes were prepared by a modification of a published method (Luo et al, 1992) from the median lobe of livers removed immediately after slaughter from sheep killed at a local abattoir. Free amino acid concentrations in test media were 5x, 1x and 0.2x physiological concentrations based upon in vivo ovine portal venous blood data (Lobley et al, 1995).

Anabolic Effects of Growth Hormone Treatment in Young Children with Cystic Fibrosis

Background: Malnutrition is commonly found in children with Cystic Fibrosis (CF) and is characterized by poor weight gain and linear growth. Almost one-third of children with CF are below 5th percentile for weight and height. Intensive nutritional supplementation may not result in sustained improvement in weight gain and linear growth.Objective: To evaluate the anabolic effects of GH, Humatrope (Eli Lilly, 0.05 mg/kg/day) was administered to five children with CF (3 males/2 females) for an average period of 2 years.Methods: All patients were maintained on caloric intake of 1.3–2.0 times the recommended daily allowance. Patients underwent standard growth hormone (GH) stimulation studies and measurement of IGF-1 and IGFBP-3.Results: The mean ± SE for age and skeletal age were 3.2 ± 0.85 years and 2.0 ± 0.45 years, respectively. Growth was assessed by determining both weight and height, which were normalized for age and sex by calculating Z scores using HANES I reference data. Differences in Z scores between clinic visits (ΔZ) were calculated for both weight and height to determine changes in growth velocity. The mean Z scores for weight and height were markedly attenuated in CF children as compared with healthy children (−1.95 ± 0.23 and −2.8 ± 0.27, respectively). The mean ± SE for maximum stimulated GH value, IGF-1 and IGFBP-3 were 9.2 ± 1.2 ng/dl, 67 ± 6 ng/ml, and 1.7 ± 0.22 mg/L, respectively. GH treatment improved weight and height Z scores (−0.11 ± 0.05 and −0.94 ± 0.18, p<0.01) significantly. The ΔZ scores for weight and height were significantly increased during first and second year of GH treatment (p<0.02). Also, the average values of IGF-1 and IGFBP-3 were significantly increased as compared to pretreatment values (186 ± 37 ng/ml and 3.0 ± 0.22 mg/L, p<0.01).Conclusions: GH treatment significantly improves weight and linear growth in young patients with CF. These data suggest that anabolic effects of GH may be beneficial for treatment of malnutrition in children with CF.