Metabolic Actions Of Growth Hormone Research Articles

Individual sensitivity to growth hormone replacement in adults.

The metabolic actions of growth hormone (GH) last a lifetime and involve several physiological functions associated with the control of body composition, energy metabolism, water regulation, immune response, cardiovascular performance, physical and mental work. Adult patients with GH deficiency (GHD) present a constellation of clinical findings, which include increased total and visceral body fat, low bone and muscle mass, reduced muscle strength, impaired anaerobic physical capacity, unfavorable cardiovascular profile, and poor quality of life. Recombinant human GH (rhGH) therapy has been proved to reverse or improve many abnormalities associated with GHD in adult life, but the therapeutic response is highly variable among patients and influenced by multiple factors, which are the main focus of this narrative review. Given the individual sensitivity of adult GHD patients to rhGH replacement, dose regimens evolved from weight-based to individualized dose-titration strategies, which improved efficacy and reduced the frequency of adverse events. Individual tailoring and maintenance doses of rhGH are mainly influenced by age, age at GHD onset, sex, body mass index, baseline GH status, quality of life and other pituitary hormone replacements. In addition, genetic background and poor adherence due to patient or product-related factors might play a role in the responsiveness to rhGH therapy. There have been attempts to develop predictive mathematical models to distinguish good and poor responders to rhGH therapy, but thus far none of them have been prospectively tested and validated in a large cohort of adult GHD individuals.

Emerging Mechanisms of GH-Induced Lipolysis and Insulin Resistance.

Growth hormone (GH) is a pleiotropic hormone that coordinates an array of physiological processes including growth and metabolism. GH promotes anabolic action in all tissues except adipose, where it catabolizes stored fat to release energy for the promotion of growth in other tissues. However, chronic stimulation of lipolysis by GH results in an increased flux of free fatty acids (FFAs) into systemic circulation. Hence, a sustained release of high levels of GH contributes significantly to the development of insulin resistance by antagonizing the anti-lipolytic action of insulin. The molecular pathways associated with the lipolytic effect of GH in adipose tissue however, remain elusive. Recent studies have provided molecular insights into GH-induced lipolysis and impairment of insulin signaling. This review discusses the physiological and metabolic actions of GH on adipose tissue as well as GH-mediated deregulation of the FSP27-PPARγ axis which alters adipose tissue homeostasis and contributes to the development of insulin resistance and Type 2 diabetes.

STAT5 Deficiency in Mature Adipocytes Results in Metabolically Healthy Adiposity, Reduced Growth Hormone Signaling in Adipose Tissue, and Decreased Energy Expenditure

STAT5 proteins promote adipocyte development and regulate adipose tissue function in vitro and in vivo. To further elucidate the role of STAT5 proteins in adipocytes, we used adiponectin-Cre and floxed STAT5 A/B mice to generate mice that lack both STAT5A and STAT5B in mature fat cells (STAT5AKO). Studies on several cohorts of both sexes of mice have revealed that STAT5AKO mice have increased adiposity. Notably, the adiposity phenotype disappears upon high fat feeding when growth hormone (GH) levels and GH signaling are diminished. Another striking observation is that obese STAT5AKO female mice are highly resistant to weight loss induced by low fat feeding when compared to floxed control mice that exhibit significantly enhanced weight loss and reduced adiposity. The adiposity of STAT5AKO mice is not a result of alterations in food intake or lean body mass. Furthermore, the increased adiposity in STAT5AKO mice is uncoupled from insulin resistance and metabolic dysfunction. It is well known that chronic elevation of GH is associated with insulin resistance. However, in most mammals a disruption of the IGF-1 axis accompanies altered GH signaling. Notably, STAT5AKO mice do not have alterations in circulating IGF-1 levels. In addition, the adiposity phenotype of STAT5AKO mice does not appear to be associated with alterations in basal or stimulated lipolysis. However, STAT5AKO female mice have a significant reduction in energy expenditure and fat oxidation. In summary, our extensive phenotypic characterization of STAT5AKO mice has shifted our understanding of the metabolic actions of growth hormone and functions of STAT5 proteins. Disclosure A.J. Richard: None. H. Hang: None. T.D. Allerton: None. C.M. Elks: None. J.M. Stephens: None.

Traditional and novel aspects of the metabolic actions of growth hormone

Growth hormone has been known to be diabetogenic for almost a century and it's diabetogenic properties fostered consideration of excessive and abnormal GH secretion as a cause of diabetes, as well as a role in the microvascular complications, especially retinopathy. However, besides inducing insulin resistance, GH also is lipolytic and a major anabolic hormone for nitrogen retention and protein synthesis. These actions are best illustrated at the extremes of GH secretion: Gigantism/acromegaly is characterized by excessive growth, CHO intolerance, hyperplasia of bone, little body fat and prominent muscle development, whereas total deficiency of GH secretion or action is associated with adiposity, poor growth, and poor muscle development. These actions also become apparent during puberty and pregnancy, times when GH secretion is increased and account for the characteristic changes in body composition and tendency to diabetes. More recently, tissue specific deletions of the GH receptor (GHR), have uncovered newer metabolic effects including it's essential role in triglyceride export from the liver when GHR is deleted in the liver, leading to hepatic steatosis and ultimately to hepatic adenoma formation, effects which may explain these findings in obesity, a state of diminished GH secretion and action. In addition deletion of GH action in muscle and fat is associated with specific patterns of disturbed phenotype and metabolic effects in CHO, fat, and protein metabolism affecting the specific tissue and whole body function. This chapter provides an overview of these classic and newer metabolic functions of GH, placing this hormone and its actions in a central role of body fuel economy in health and disease.

Renaissance of acromegaly after bariatric surgery

Dear Sir,The discouraging results provided by dietary andbehavioural treatments, and the virtually non-existent drugtreatments, have led to an exponential increase in use ofsurgery to treat obesity [1]. An increased prevalence ofobesity has also been reported in patients with acromegaly,a rare and severe systemic disease caused by a growthhormone (GH)-secreting pituitary adenoma, compared tothe general population [2]. In obesity, GH responses to awide variety of GH secretion stimulators, as well as 24 hspontaneous GH release are decreased, making difficultacromegaly follow-up. Moreover, insulin-like growth fac-tor-1 (IGF-1), which mediates some of the metabolicactions of GH, is reported to be decreased in obesity andnegatively correlated to visceral fat [3]. To the best of ourknowledge, we report the first case of a patient withacromegaly who underwent bariatric surgery and wedescribe the biochemical effects associated with the reso-lution of obesity and its comorbidities.A 55-year-old Caucasian woman with acromegaly wasreferred to our Obesity Unit in January 2006. Her historyincluded a long condition of morbid obesity since child-hood, with gradual increase of weight from her secondpregnancy, holding a weight in recent years around 115 kg.She had undergone a selective trans-sphenoidal removal ofa pituitary adenoma of 2.3 cm with suprasellar extension,impingement of the optic chiasm, and invasion of the leftcavernous sinus at age 35. Postoperatively, she was undertreatment first with bromocriptine and after with somatos-tatine-analogues at stable doses (lanreotide 90 mg oncemonthly). However, her serum IGF-1 values remainedabove the adjusted normal range.Her medical history revealed type 2 diabetes (T2D)treated with metformin and insulin without achievingadequate metabolic control, hypertension started onangiotensin-converting enzyme inhibitors with normaliza-tion of blood pressure, and sleep apnoea syndrome (SAS)requiring nasal continuous positive airway pressure(nCPAP) mask. In addition, the patient had been treated fordegenerative arthritis of the knees, and bilateral carpaltunnel compression syndrome had been surgically resolvedfew years before. The familial medical history was other-wise unremarkable.Clinical examination showed a female patient withtypical clinical signs of acromegaly, including coarse facialfeatures and enlargement of her hands and feet. Her weight,height and body mass index (BMI) were 106.3 kg, 142.0 cmand 52.5 kg/m

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Garvan Institute of Medical Research and Department of Endocrinology (V.B., U.M., J.G., G.J., K.K.Y.H.), St. Vincent’s Hospital, Sydney, NSW 2010, Australia; The University of New South Wales (K.K.Y.H.), Sydney, NSW 2052, Australia; Kolling Institute of Medical Research (R.C.B.), The University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065 Australia; and ANZAC Research Institute (M.J.S.), The University of Sydney at Concord, NSW 2139, Australia

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

The metabolic action of GH is attenuated by estrogens administered via the oral route. Selective estrogen receptor modulators lower IGF-I to a lesser degree than 17beta-estradiol in GH-deficient women, and their effect on fat and protein metabolism is unknown. The aim of the study was to compare the modulatory effects of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, on the metabolic action of GH. We conducted an open-label, two-group, randomized, two-period crossover study. Ten hypopituitary women received GH therapy alone (0.5 mg/d) and GH plus 17beta-estradiol (E(2); 2 mg/d). Eleven hypopituitary women received GH therapy alone and GH plus raloxifene (R; 60 mg/d). The treatment duration was 1 month, with a 4-wk washout period. IGF-I, IGFBP-3, resting energy expenditure, and fat oxidation were quantified by indirect calorimetry. We measured whole body leucine turnover from which leucine rate of appearance and leucine incorporation into protein were estimated. GH significantly stimulated all outcome measures. During GH treatment, addition of R significantly reduced mean IGF-I but not IGFBP-3, whereas E(2) reduced both IGF-I and IGFBP-3 levels. Cotreatment with R but not E(2) significantly attenuated the stimulatory effects of GH on fat oxidation. There was a strong trend (P = 0.08) toward a greater reduction in leucine incorporation into protein after R compared to E(2) cotreatment. The modulatory effects of E(2) and R at therapeutic doses on GH action are different. R during GH therapy exerts a greater inhibitory effect on lipid oxidation and protein anabolism compared to E(2).

An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway

The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist. Mutations disabling this conformational change cause impairment of ERK but not JAK2 and STAT5 activation by the GHR in FDC-P1 cells. This results from the use of two associated tyrosine kinases by the GHR, with JAK2 activating STAT5, and Lyn activating ERK1/2. We provide evidence that Lyn signals through phospholipase C gamma, leading to activation of Ras. Accordingly, mice with mutations in the JAK2 association motif respond to GH with activation of hepatic Src and ERK1/2, but not JAK2/STAT5. We suggest that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment. Our findings could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.

Chronic resistance training in women potentiates growth hormone in vivo bioactivity: characterization of molecular mass variants

This investigation determined the influence of acute and chronic resistance exercise on responses of growth hormone (GH) molecular variants in women. Seventy-four healthy young women (23 +/- 3 yr, 167 +/- 7 cm, 63.8 +/- 9.3 kg, 26.3 +/- 4.0% body fat) performed an acute bout of resistance exercise (6 sets of 10 repetition maximum squat). Blood samples were obtained pre- and postexercise. Resulting plasma was fractionated by molecular mass (fraction A, >60 kDa; fraction B, 30-60 kDa; and fraction C, <30 kDa) using chromatography. Fractionated and unfractionated (UF) plasma was then assayed for GH using three different detection systems (monoclonal immunoassay, polyclonal immunoassay, and rat tibial line in vivo bioassay). Subjects were then matched and randomly placed into one of four resistance exercise training groups or a control group for 24 wk. All experimental procedures were repeated on completion of the 24-wk resistance training programs. After acute exercise, immunoassays showed consistent increases in UF GH samples and fractions B and C; increases in fraction A using immunoassay were seen only in the monoclonal assay. No consistent changes in bioactive GH were found following acute exercise. Conversely, chronic exercise induced no consistent changes in immunoassayable GH of various molecular masses, whereas, in general, bioassayable GH increased. In summary, although acute exercise increased only immunoactive GH, chronic physical training increased the biological activity of circulating GH molecular variants. Increased bioactive GH was observed across all fractions and training regimens, suggesting that chronic resistance exercise increased a spectrum of GH molecules that may be necessary for the multitude of somatogenic and metabolic actions of GH.

Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.

Metabolic actions of growth hormone: direct and indirect

GH may exert metabolic effects either directly or indirectly through increased production of IGF-I. GH administration increases circulating IGF-I levels via stimulation of hepatic synthesis and secretion of IGF-I; it may also enhance local IGF-I synthesis, which exerts paracrine or autocrine effects. Figure 2 summarizes the metabolic effects of GH and IGF-I. Administration of GH and IGF-I in adult humans has been demonstrated to enhance protein anabolism. Combined administration of GH and IGF-I was observed to be more anabolic than either IGF-I or GH alone. Evidence is presented that protein accretion results mainly from direct effects of GH on tissues; additional indirect effects via IGF-I production are also likely. Administration of GH has been reported to produce carbohydrate intolerance with elevated plasma insulin levels, resulting from insulin resistance. in contrast, insulin sensitivity increased during administration of IGF-I, which exerts hypoglycaemic effects even with concomitant suppression of insulin secretion. A major direct metabolic effect of GH is to increase fat mobilization and oxidation, and thereby to reduce total body fat; there is no evidence that IGF-I acts directly on adipose tissue in vivo. GH administration results in sodium retention via stimulation of Na-K-ATPase. It is suggested that part of the effects of GH on tubular function (e.g. phosphate reabsorption) are mediated via IGF-I. Energy expenditure may be increased by administration of either GH or relatively high doses of IGF-I. One of the reasons for this phenomenon is an increase in lean body mass; GH may increase energy expenditure additionally be enhancing the production of T3 and by increasing lipid oxidation.

Metabolic actions of growth hormone in man.

GH continues to be produced after the cessation of childhood growth and is the most abundant pituitary hormone in the adult pituitary. There is strong evidence that GH continues to exert significant biological effects on body metabolism in adult humans. The actions of GH may be direct or indirectly mediated by IGF-1. The direct actions of GH impart major effects on glucose, lipid and sodium homeostasis. GH administration causes hyperinsulinaemia and impairs the ability of insulin to suppress hepatic glucose production and to stimulate glucose uptake and oxidation. GH enhances fat utilisation by stimulating lipolysis and fat oxidation. The significance of these effects is reflected in the finding of increased adiposity in GH deficiency (GHD) and reduced fat mass in acromegaly. GH causes sodium retention which occurs in part through activation of the renin-angiotensin system. Extracellular water volume is diminished in GHD and increased in relation to the extent of GH excess in acromegaly. Lean body mass is reduced in GHD and restored by GH treatment. The anabolic actions of GH are mediated by IGF-1. Studies of whole body protein metabolism show that this occurs through the stimulation of protein synthesis, reduction in protein oxidation but not inhibition of protein breakdown. GH plays an important role in the regulation of substrate metabolism and body composition in man.

Magnetic resonance imaging evaluation of adipose tissue and muscle tissue mass in children with growth hormone (GH) deficiency, Turner's syndrome, and intrauterine growth retardation during the first year of treatment with GH.

Measurement of muscle and fat tissue mass by magnetic resonance imaging of the thighs was used to study the metabolic effect of human (h) GH in 23 GH deficiency, 8 Turner's syndrome, and 14 intrauterine growth retardation prepubertal patients. They were evaluated before and 1, 3, 6, and 12 months after the onset of hGH treatment. Seven normal children were followed longitudinally as controls. During hGH treatment, a significant increase in muscle tissue and decrease in adipose tissue cross-sectional areas was observed, leading to a dramatic increase in the muscle/adipose tissue cross-sectional area ratio in each period studied. These findings remained highly significant when corrected for the small variation observed in controls. The body mass index was correlated with muscle and adipose tissue cross-sectional area at each time point (P < 0.0001). The muscle cross-sectional area increment correlated with the first year height velocity (P < 0.01). This study indicates that in children with and without GH deficiency, hGH therapy induces rapid and intense variation of muscle and adipose tissue mass, and that magnetic resonance imaging can be used to study some aspects of the metabolic actions of GH.

Metabolic actions of growth hormone in pigs.

Metabolic actions of growth hormone in pigs.

Pseudohypopituitary dwarfism with normal plasma growth hormone and low serum sulfation factor

A 7 5/12-year-old Persian Jewish child exhibiting many typical clinical features of dwarfism associated with isolated deficiency of growth hormone was studied. Basal plasma growth hormone values were within normal limits and rose during insulin-induced hypoglycemia to high levels. The serum sulfation factor level was low and did not rise with administration of human growth hormone. Studies performed under metabolic balance conditions showed some evidence of resistance to the metabolic actions of growth hormone as well. This patient manifested clinical signs of growth hormone deficiency which were due to defective generation of sulfation factor rather than impaired growth hormone production.

Long Term Corticosteroid Treatment and Growth

Besides the well-known side effects, long term corticosteroid treatment in pharmacological doses causes inhibition of statural growth in children. This is of special importance in asthmatic children, since their growth may be impaired by the disease itself. The degree of inhibition of growth depends on the type of corticosteroids used (the inhibition by synthetic derivatives is stronger than that by hydrocortisone), on the dosage, and on the duration of treatment. The mechanisms leading to an inhibition of growth are not fully understood: possibly the corticosteroids inhibit the release of growth hormone from the pituitary, or they antagonize the metabolic action of growth hormone peripherally. In an effort to avoid the growth-inhibiting effect of corticosteroids, different approaches have been tried: Replacement of corticosteroids by ACTH seems to have normalized the growth rate in some cases, but failed to do so in others. A final evaluation of the value of ACTH with respect to growth can therefore not yet be made. At the present time, therapy with corticosteroids at an alternate day schedule seems to be promising: the daily dosage is doubled, but the corticosteroids are given only every other day. Treated in this way, the patients observed so far, have been able to maintain a normal growth rate.