Anabolic Actions Of Growth Hormone Research Articles

Effects of Growth Hormone and Nutritional Therapy in Boys with Constitutional Growth Delay: A Randomized Controlled Trial

To examine whether supplemental nutrition augments the anabolic actions of growth hormone (GH) in boys with constitutional delay of growth and maturation (CDGM). We conducted a randomized, controlled trial at an outpatient clinical research center. Subjects were 20 prepubertal boys (age, 9.3 ± 1.3 years) with CDGM (height standard deviation score, -2.0 ± 0.5; bone age delay, 1.8 ± 0.8 years; body mass index standard deviation score, -1.2 ± 1.0; peak stimulated GH, 15.7 ± 7.7 ng/mL), who were randomized (n = 10/group) to 6 months observation or daily nutritional supplementation, followed by additional daily GH therapy in all for another 12 months. t tests and repeated measures analyses of variance compared energy intake, total energy expenditure (TEE), growth, hormones, and nutrition markers. Energy intake was increased at 6 months within the nutrition group (P = .04), but not the observation group, and TEE was not statistically different within either group at 6 months. Addition of 6 months GH resulted in higher energy intake and TEE in the GH/nutrition group at 12 months (P < .01), but not in the GH group versus baseline. Height, weight, lean body mass, hormones, and nutrition markers increased comparably in both groups throughout 18 months. Boys with CDGM use energy at an accelerated rate, an imbalance not overcome with added nutrition. GH therapy increases growth comparably with or without added nutrition in these patients.

IGF-I abuse in sport: Current knowledge and future prospects for detection

As the tests for detecting growth hormone (GH) abuse develop further, it is likely that athletes will turn to doping with insulin-like growth factor-I (IGF-I). IGF-I mediates many of the anabolic actions of growth hormone. It stimulates muscle protein synthesis, promotes glycogen storage and enhances lipolysis, all of which make IGF-I attractive as a potential performance-enhancing agent. Pharmaceutical companies have developed commercial preparations of recombinant human IGF-I (rhIGF-I) for use in disorders of growth. The increased availability of rhIGF-I increases the opportunity for athletes to acquire supplies of the drug on the black market. The long-term effects of IGF-I administration are currently unknown but it is likely that these will be similar to the adverse effects of chronic GH abuse. The detection of IGF-I abuse is a challenge for anti-doping organisations. Research has commenced into the development of a test for IGF-I abuse based on the measurement of markers of GH action. Simultaneously, the effects of rhIGF-I on physical fitness, body composition and substrate utilisation in healthy volunteers are being investigated.

Effects of uremia and inflammation on growth hormone resistance in patients with chronic kidney diseases

Resistance to the anabolic action of growth hormone may contribute to the loss of strength and muscle mass in adult patients with chronic kidney disease. We tested this hypothesis by infusing growth hormone in patients to levels necessary to saturate hormone receptors. This led to a significant decrease of plasma potassium and amino acid levels in control and hyperkalemic patients with chronic kidney disease. These effects were completely or partially blunted in patients with elevated C-reactive protein levels. In forearm perfusion studies, growth hormone caused a further decrease in the negative potassium and protein balance of hemodialysis patients without inflammation but no effect was seen in patients with inflammation. Only IL-6 levels and age were found to be independent correlates in these growth hormone-induced variations in plasma potassium and blood amino acids. This shows that although a resistance to pharmacologic doses of growth hormone is not a general feature of patients with chronic kidney disease, there is a subgroup characterized by blunted growth hormone action. Our results support the hypothesis that uremia with inflammation, but not uremia per se, inhibits downstream growth hormone signaling contributing to muscle atrophy.

Characterization of Distinct Stat5b Binding Sites That Mediate Growth Hormone-stimulated IGF-I Gene Transcription

A key agent in the anabolic actions of growth hormone (GH) is insulin-like growth factor-I (IGF-I), a 70-amino acid secreted protein with direct effects on somatic growth and tissue maintenance and repair. GH rapidly and potently stimulates IGF-I gene transcription by mechanisms independent of new protein synthesis, and recent studies have linked the transcription factor Stat5b to a regulatory network connecting the activated GH receptor on the cell membrane to the IGF-I gene in the nucleus. Here we analyze two distinct conserved GH response elements in the rat IGF-I locus that contain paired Stat5b sites. Each response element binds Stat5b in vivo in a GH-dependent way, as assessed by chromatin immunoprecipitation assays, and consists of one high affinity and one lower affinity Stat5b site, as determined by both qualitative and quantitative protein-DNA binding studies. In biochemical reconstitution experiments, both response elements are able to mediate GH-stimulated and Stat5b-dependent transcription when fused to a reporter gene containing either the major IGF-I promoter or a minimal neutral promoter, although the paired Stat5b sites located in the second IGF-I intron were more than twice as effective as the response element that mapped approximately 73 kb 5' to the IGF-I exon 1. Taken together, our results define the initial molecular architecture of a complicated GH-regulated transcriptional pathway, and suggest that apparently redundant hormone response elements provide a mechanism for amplifying GH action at a physiologically important target gene.

Long-term maintenance of the anabolic effects of GH on the skeleton in successfully treated patients with acromegaly

Introduction: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established. Patients and methods: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57±1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2±7 years. Results: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck. Conclusion: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.

Soluble tumour necrosis factor α receptor 2, a serum marker of resistance to the anabolic actions of growth hormone in subjects with HIV disease

Soluble tumour necrosis factor α receptor 2, a serum marker of resistance to the anabolic actions of growth hormone in subjects with HIV disease

Soluble tumour necrosis factor α receptor 2, a serum marker of resistance to the anabolic actions of growth hormone in subjects with HIV disease

Therapies are still being sought for the prevention of loss of body weight and lean body mass in HIV disease. The purpose of the present study was to identify a serum marker that would help in selecting patients who may be appropriate candidates for the use of anabolic agents, such as growth hormone, to restore lean body mass. This study included 26 HIV-infected patients and nine healthy controls, assessed previously for the effectiveness of 2 weeks of growth hormone administration in the stimulation of protein synthesis in skeletal muscle. Serum levels of interleukins-1beta, -6 and -10 were not useful predictors of the anabolic response to growth hormone. Serum concentrations of tumour necrosis factor alpha (TNFalpha) were significantly elevated (P<0.05) in patients with AIDS and AIDS-related weight loss, and there was a significant correlation between the serum concentration of interleukin-1 receptor antagonist and stage of disease (P=0.03). However, the serum concentration of the soluble TNFalpha receptor type 2 was most predictive of an inability of muscle protein synthesis to respond anabolically to growth hormone (r=-0.42, P=0.01). These data suggest that inflammation impacts on the responsiveness of muscle tissue to an anabolic stimulus, and that the soluble TNFalpha receptor type 2 provides a useful serum marker for metabolic dysfunction in HIV disease, which can be used to identify individuals likely to respond to growth hormone-based anabolic therapy.

Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia

Chronic renal failure (CRF) is associated with resistance to the growth-promoting and anabolic actions of growth hormone (GH). In rats with CRF induced by partial renal ablation, 7 days of GH treatment had a diminished effect on weight gain and hepatic IGF-1 and IGFBP-1 mRNA levels, compared with sham-operated pair-fed controls. To assess whether GH resistance might be due to altered signal transduction, activation of the JAK-STAT pathway was studied 10 or 15 minutes after intravenous injection of 5 mg/kg GH or vehicle. Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered. JAK2, STAT1, STAT3, and STAT5 protein abundance was also unchanged. However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals. Phosphorylated STAT5 and STAT3 were also diminished in nuclear extracts. The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment. In conclusion, CRF causes a postreceptor defect in GH signal transduction characterized by impaired phosphorylation and nuclear translocation of GH-activated STAT proteins, which is possibly mediated, at least in part, by overexpression of SOCS proteins.

Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia

Chronic renal failure (CRF) is associated with resistance to the growth-promoting and anabolic actions of growth hormone (GH). In rats with CRF induced by partial renal ablation, 7 days of GH treatment had a diminished effect on weight gain and hepatic IGF-1 and IGFBP-1 mRNA levels, compared with sham-operated pair-fed controls. To assess whether GH resistance might be due to altered signal transduction, activation of the JAK-STAT pathway was studied 10 or 15 minutes after intravenous injection of 5 mg/kg GH or vehicle. Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered. JAK2, STAT1, STAT3, and STAT5 protein abundance was also unchanged. However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals. Phosphorylated STAT5 and STAT3 were also diminished in nuclear extracts. The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment. In conclusion, CRF causes a postreceptor defect in GH signal transduction characterized by impaired phosphorylation and nuclear translocation of GH-activated STAT proteins, which is possibly mediated, at least in part, by overexpression of SOCS proteins.

Effects of growth hormone and insulinlike growth factor-I on body growth and adult bone metabolism.

The anabolic action of growth hormone (GH) on bone is well demonstrated by the short stature and delayed bone maturation in children with GH deficiency and in acromegalic patients with increased cortical bone mass. The body growth is regulated by growth hormone and insulin-like growth factor-I (IGF-I). The classic somatomedin hypothesis of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have recently abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. The mice, in which IGF-I production had been inactivated in the liver, displayed a more than 80% reduction in serum IGF-I. In contrast, they demonstrated a normal postnatal growth, indicating that extrahepatic, autocrine/paracrine-acting IGF-I is the main determinant of postnatal growth. GH is also important for normal adult bone remodeling. Adults with GH deficiency have reduced bone mass, and GH treatment increases bone mass in GH-deficient adults. Future clinical studies will determine whether some patients with decreased bone mass for other reasons will benefit from treatment with GH alone or in combination with other treatments.

Growth factors in critical illness: regulation and therapeutic aspects.

The erosion of lean body mass observed during catabolic illness is still a major cause of morbidity and mortality. The known anabolic actions of growth hormone and insulin-like growth factor-I have stimulated interest in the use of these agents to mitigate the loss of muscle protein after injury. This review summarizes advances in our understanding of how nutrition, hormones and proinflammatory cytokines regulate the somatotropic axis in health and disease, and recent studies involving the use of growth hormone or insulin-like growth factor-I in the treatment of critically ill patients.

Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action.

The anabolic actions of GH are mediated by the production of insulin-like growth factor I (IGF-I) from the liver and by local production of IGF-I in extrahepatic tissues. Insulin facilitates the hepatic production of IGF-I by up-regulating GH receptors (GHRs) in the liver and augmenting the IGF-I response to GH. Although GHRs have also been identified in extrahepatic tissues that produce IGF-I, the possibility that IGF-I and insulin might partake in GHR regulation, thereby modulating the effects of GH locally has not received detailed study. The aim of this study was to investigate whether IGF-I and insulin are involved in the local regulation of GHRs, using osteoblasts as a model of GH-responsive extrahepatic tissues. We have used UMR106.06, a well differentiated rat osteoblast-like cell line that expresses GHRs and exhibits a mitogenic response to GH. IGF-I and insulin (0-10 nM) increased cell number and reduced [125I]GH binding in a concentration-dependent manner, with ED50 values of 0.8 and 0.3 nM, respectively. Although IGF-I increased cell number maximally by 36.9 +/- 1.2% (mean +/- SE) above the control value and insulin by 104.8 +/- 5.7% (P < 0.001), they decreased GH binding to 47.0 +/- 9.3% (P < 0.01) and 29.8 +/- 8.7% of the control value (P < 0.001), respectively. Scatchard analysis revealed that the down-regulation of GH binding was attributed to reduced receptor numbers and not binding affinity. The effects of IGF-I and insulin at submaximal concentrations were additive, although the combined effects did not exceed the maximal effect of either growth factor alone. Addition of an anti-IGF-I receptor antibody (alpha IR3) reversed the inhibition of GH binding induced by IGF-I, but not that caused by insulin; similarly, an antiinsulin receptor antibody (29B4) attenuated the inhibitory effect of insulin only. Addition of alpha IR3 alone or an ant-IGF-I antibody (Sm1.2) decreased cell number and increased GH binding in a concentration-dependent mode. GH at 1.5 nM significant increased cell number by 19.3 +/- 2.4% above the control level (P < 0.01), an increase that was reversed by alpha IR3. GH increased GH binding by 32.4 +/- 7.2% (P < 0.05) in cells treated with alpha IR3 to remove the secondary effect of IGF-I. In summary, IGF-I and insulin acted via specific receptors to stimulate cell proliferation and down-regulate GHRs in osteoblasts. GH stimulated cell proliferation, an action mediated by local production of IGF-I, and GH enhanced its own binding. The collective data suggest the presence of a peripheral negative feedback loop that allows IGF-I to limit locally the response of extrahepatic tissues to circulating GH.

Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p < 0.002) of GH on periosteal bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

Effects of growth hormone (GH) administration on functional hepatic nitrogen clearance: studies in normal subjects and GH-deficient patients.

A decline in serum urea levels and urinary urea excretion is usually seen after GH administration in humans, indicating overall protein anabolism. Whether this reflects the diminished supply of alpha-amino acids for urea synthesis or a substrate-independent hepatic mechanism is unknown. To pursue this we measured the urea nitrogen synthesis rate (UNSR) and blood alanine levels before, during, and after a 4-h constant iv infusion of alanine (2 mmol/kg BW.h). UNSR was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in total body water. The slope of the linear relationship between UNSR and circulating alanine levels represents the hepatic components of conversion of amino nitrogen and is denoted the functional hepatic nitrogen clearance (FHNC). Eight male volunteers were randomly investigated on three occasions: 1) after 12-h iv saline infusion, 2) after 12-h iv GH infusion (1 IU/h), and 3) after 2-day sc GH treatment (8 IU/day), followed by 12-h iv infusion of GH (1 IU/h). The UNSR (millimoles per h) during alanine infusion was significantly lower when the subjects were receiving GH therapy [maximum +/- SE, 133.0 +/- 6.9 (saline) vs. 96.7 +/- 11.1 (12-h GH; P < 0.01) vs. 106.5 +/- 7.5 (2-day GH; P < 0.05)]. FHNC (liters per h) was similar in all three studies [30.3 +/- 1.2 (saline) vs. 26.6 +/- 3.4 (12-h GH) vs. 27.0 +/- 2.6 (2-day GH)]. Six GH-deficient adult patients were randomly studied twice: 1) on regular daily (at 2000 h) sc GH therapy (3 IU/m2.day), and 2) after discontinuation of GH for 2 days. The UNSR during alanine infusion was likewise significantly lower when the patients were receiving GH therapy [147.7 +/- 11.7 mmol/h (no GH) vs. 123.9 +/- 9.1 mmol/h; P < 0.01]. FHNC (liters per h) values were similar in the two studies [29.2 +/- 3.8 (GH) vs. 27.5 +/- 4.5 (no GH)]. Our data confirm the anabolic action of GH and show that short term GH deprivation is associated with catabolism in terms of increased UNSR. The finding of unaltered FHNC suggests a GH-induced extrahepatic regulation of amino nitrogen conversion, rather than a substrate-independent hepatic mechanism.

Growth Hormone and Protein Metabolism

Adults with growth hormone (GH) deficiency have decreased lean body mass which can be normalized by GH treatment. The anabolic action of GH involves redistribution of nitrogen from ureogenesis to the extrahepatic anabolic process together with stimulation of amino acid uptake and protein synthesis.

The anabolic actions of growth hormone and thyroxine on protein metabolism in Snell dwarf and normal mice.

The individual effects of GH and thyroxine (T4) on protein metabolism were determined in dwarf and normal mice in vivo. The hormone deficiencies of dwarf mice (low serum concentrations of GH and T4) resulted in decreased protein synthesis rates in skeletal muscle and liver, but no difference in synthesis rates in heart. The efficiency of synthesis (g protein/g RNA per day; KRNA) was lower in all three tissues in dwarf compared with normal mice, but effects on RNA concentration were not consistent; there was no change in muscle, a decrease in liver and an increase in heart. Treatment of dwarf mice for 9 days with either human GH or T4 caused increases in body weight and length. Protein synthesis rates were increased in muscle, liver and heart by either hormone, though much more so with T4 than GH. In muscle and liver both GH and T4 treatment resulted in an increased RNA concentration, but T4 treatment also increased KRNA. In heart, both GH and T4 increased KRNA with no change in RNA concentration. GH caused no significant changes in protein degradation rates so that growth rates were increased. T4 increased degradation rates so that there was no increased net growth in muscle or liver; in heart, T4 did induce increased growth despite the large increase in degradation rate. Tibial length was increased by both hormones; GH treatment of dwarf mice also increased cartilage sulphate incorporation on day 9, but T4 treatment did not, suggesting that bone growth is transient with T4 treatment. Normal mice showed no changes in growth or tissue protein metabolism in response to GH, but following T4 treatment there was increased protein turnover due to higher tissue RNA concentrations, although only heart growth was increased. Thus normal mice showed almost no net response to GH or T4, but dwarf mice showed a large response to both hormones. The response was different, however, in that GH caused concomitant increases in growth rates whereas T4 altered body tissue proportions.

Effect of rat age on serum levels of growth hormone and somatomedins

The somatomedins are a family of hormones which appear to mediate many of the anabolic actions of growth hormone: these processes often exhibit an age-associated deterioration in intact animals. We have demonstrated the validity of a radioreceptor assay for the determination of somatomedin levels in rat serum. In this assay, we measure displacement of 125I-labeled Multiplication Stimulating Activity (MSA) from receptors prepared from human placental membranes. Results with this procedure confirm and extend a previous report from this laboratory indicating a significant decrease in somatomedin levels during the latter part of the lifespan. Data are presented to eliminate possible artifactual explanations for the observed age-related changes. Furthermore, we find that the decrease in somatomedin levels can not be a simple result of an age-related decrease in basal levels of growth hormone in serum. We conclude that the decrease with age in circulating levels of the somatomedins is most probably attributable to a decrease in the activity or responsiveness of the tissues (most probably liver) which secrete somatomedins in response to stimulation by growth hormone.

Suppression of growth hormone-dependent human serum sulfation factor by estrogen.

In view of the demonstrated metabolic antagonism of estrogen and growth hormone, the effect of estrogen administration upon serum sulfation factor was studied in four acromegalic patients, and in three growth hormone-treated hypopituitary patients. Sulfation factor was measured by a modification of Daughaday's rat rib cartilage method permitting statistical evaluation of validity, precision and fiducial limits for each individual assay. Estrogen in vitro had no effect upon the sulfation factor bioassay system. Shortterm estrogen therapy (7–18 days) promptly reduced elevated sulfation factor levels, hypercalciuria and hydroxyprolinuria in the acromegalic patients, without significantly affecting basal plasma growth hormone levels. Estrogenic antianabolic effect was frequently observed, as shown by elevations of BUN and of urinary nitrogen. In each of the growth hormone-deficient patients, subnormal sulfation factor levels rose to normal or high levels during HGH administration for four or six days, returning to initial levels within two days after cessation of HGH therapy. Estrogen given concurrently with an identical second course of HGH treatment completely prevented the rise of serum sulfation factor, of urinary calcium, and probably of hydroxyproline excretion, but did not affect the anabolic response to growth hormone. The parallel variations of urinary calcium and hydroxyproline with those of serum sulfation factor, suggest that the latter may participate in the mediation of the bone-resorptive action of growth hormone. However, responses to growth hormone in the estrogen-treated hypopituitary patients seemed to indicate that the stimulation of serum sulfation factor was not a necessary condition for the overall anabolic action of growth hormone.

The influence of the pineal gland on nitrogen metabolism.

SUMMARY The influence of the pineal gland on protein metabolism was investigated by using a test previously devised for studying the anabolic action of growth hormone. This test consists in measuring the accumulation of urea in blood after the intravenous administration of an amino acid mixture to nephrectomized rats injected with the test substance. Like growth hormone, pineal extract significantly reduced the quantity of urea formed, suggesting an anabolic action. In contrast, in pinealectomized animals, the quantity of urea formed significantly increased when compared with controls.

Anabolic action of growth hormone.

Anabolic action of growth hormone.