Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth? (original) (raw)
Related papers
Pediatric Nephrology, 2000
Growth hormone (GH) and insulin-like growth factors (IGFs) are essential for normal growth and development during embryonic stages as well as postnatally. While GH has little effect on these processes prenatally, the IGFs are important during these stages. On the other hand the GH-IGF-I axis is important for pubertal growth. To determine whether postnatal growth and development are dependent on circulating or locally produced IGF-I, we deleted the IGF-I gene in the liver using the cre/LoxP system used for tissue-specific gene deletion. These animals demonstrated approximately 75%-80% reduction in circulating IGF-I and an approximate fourfold increase in circulating GH. Despite the marked reductions in circulating IGF-I, growth and development was apparently normal. Thus the original somatomedin hypothesis needs to be re-evaluated in the light of these new findings.
Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production
Journal of Bone and Mineral Research, 2011
Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two-to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions.
Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans
American journal of physiology. Endocrinology and metabolism, 2002
The importance of gender-specific growth hormone (GH) secretion pattern in the regulation of growth and metabolism has been demonstrated clearly in rodents. We recently showed that GH secretion in humans is also sexually dimorphic. Whether GH secretion pattern regulates the metabolic effects of GH in humans is largely unknown. To address this question, we administered the same daily intravenous dose of GH (0.5 mg. m(-2). day(-1)) for 8 days in different patterns to nine GH-deficient adults. Each subject was studied on four occasions: protocol 1 (no treatment), protocol 2 (80% daily dose at 0100 and 10% daily dose at 0900 and 1700), protocol 3 (8 equal boluses every 3 h), and protocol 4 (continuous GH infusion). The effects of GH pattern on serum IGF-I, IGF-binding protein (IGFBP)-3, osteocalcin, and urine deoxypyridinoline were measured. Hepatic CYP1A2 and CYP3A4 activities were assessed by the caffeine and erythromycin breath tests, respectively. Protocols 3 and 4 were the most eff...
2020
This chapter will describe the effects of long term exposure to growth hormone (GH) at the molecular level in the liver. Expression and activation of intermediates involved in GH-induced signaling were analyzed in transgenic mice overexpressing GH, as well as the influence of chronically elevated GH levels over Amend: epidermal growth factor receptor (EGFR) signaling. Several signaling mediators involved in cellular proliferation, survival and migration are altered in the liver of GH-transgenic mice. The molecular mechanisms underlying the prooncogenic pathology induced by prolonged exposure to elevated GH levels will be discussed. 1.1 Physiological actions of GH Growth hormone (GH), also known as somatotropin, is the main regulator of postnatal body growth, but its actions are not limited to corporal stature. GH has important metabolic functions on carbohydrate, lipid and protein metabolism, as well as on tissue maintenance and repair, cardiac and immune function, mental agility and ageing. It exerts its actions both directly, and by means of endocrine and paracrine insulin-like growth factor (IGF) 1. At the cellular level, GH modulates proliferation, differentiation, motility and apoptosis. GH secretion: Growth hormone, part of the somatotropic axis, is mainly synthesized in somatotroph cells from the anterior pituitary. Growth hormone secretion is regulated centrally, through the hypothalamic-portal circulation, by hypothalamic peptides: its synthesis and release are promoted by growth-hormone releasing hormone (GHRH) and inhibited by somatostatin, and it is also stimulated by stomach-derived ghrelin. Stress, exercise, malnutrition, and anorexia also promote its secretion. By means of negative feedback, GH inhibits its own secretion: in the short central loop, GH acts on somatotroph cells to generate IGF1 locally, that in turn inhibits the cell; and it acts at the hypothalamic level to inhibit GHRH synthesis and release and to stimulate both synthesis and release of somatostatin. In the long peripheral loop, GH acts on the liver to generate most of circulating IGF1, which inhibits GH secretion by a dual mechanism: direct inhibition of the somatotrophs and stimulation of somatostatin release. GH is also produced locally in many tissues, acting in an autocrine and www.intechopen.com Contemporary Aspects of Endocrinology 74 paracrine fashion. Central cholinergic stimulation increases the release of GH reducing the secretion of somatostatin. Glucocorticoids and metabolic substrates also affect GH secretion; treatment with glucocorticoids inhibits its release while fasting states with hypoglycemia, low circulating free fatty acids, and high circulating amino acid concentrations stimulate it. GH secretion presents sexual dimorphism: the frequency of pulses is higher in females. The difference is most striking in rats, where secretion profile in males is characterized by high amplitude pulses every 3-4 h, with almost non-detectable values between pulses. Female rats, on the contrary, have more frequent lower amplitude pulses, and thus present baseline GH levels (Waxman & Frank, 2000). Humans, on the other hand, present higher values at night, during the first hours of sleep, and lower values in the early morning. GH secretory pattern conditions the sexually dimorphic gene expression in the liver, particularly of proteins involved in steroid and drug metabolism. GH secretion presents age-dependency: circulating GH levels progressively rise during childhood, to achieve a maximum towards the end of adolescence in humans, and slowly diminish thereafter. By the sixth decade of life, they are only 20% of maximum (Turyn & Sotelo, 2004). GH function: Somatic growth: GH acts directly on bone and indirectly, through endocrine hepatic derived IGF1, as well as the locally produced factor. These growth promoting peptides act on the epiphyseal cartilage, inducing chondrocyte proliferation, which leads to longitudinal skeletal growth (Tritos & Biller, 2009). Longitudinal growth ceases when the epiphyses of the long bones fuse to the diaphyses. Oversecretion before this instance results in gigantism, whereas oversecretion afterwards results in acromegaly, characterized by abnormal growth of hands and feet, and roughening of the facial features: protrusion of brow and lower jaw, and nose enlargement. Lack of GH or GHR in humans results in severe short stature, reduced muscle mass, increased fat storage, decreased cortical bone mineral density and decreased fertility in females (Lichanska & Waters., 2008a). In animals, basically the same growth outcome can be observed, either in spontaneous mutants or in genetically engineered models. Notably, mice lacking GH or GHR live longer than their littermates (Bartke & Brown-Borg, 2004). Besides its effects on skeletal growth, GH regulates body composition, increasing muscle mass and decreasing adipose content. The relationship between GH status and body composition is evidenced in patients and animal models lacking GH, which become obese. In humans, symptoms of GH deficiency resemble those of ageing, when GH levels decline: loss of muscular mass and tone, loss of bone mineral density, loss of strength, abdominal obesity (Perrini et al., 2010). Metabolic actions: GH has important metabolic actions on lipid and carbohydrate metabolism. It presents both insulin-like and insulin-antagonistic actions, presumably the first are IGF1-mediated while the latter are directly exerted by the hormone, since the effects of IGF1 on lipolysis and gluconeogenesis are contrary to those of GH (Kaplan & Cohen, 2010). GH exerts lipolytic effects, principally at the visceral adipose tissue, resulting in an increase of circulating free fatty acids, by increasing adipose tissue hormone-sensitive lipase activity; at the same time, it inhibits glucose uptake in adipose tissue. On the other hand, in liver GH promotes triglyceride (TG) uptake and storage, and in skeletal muscle it induces TG uptake and utilization. GH also presents anabolic actions on protein metabolism, since it stimulates protein synthesis and inhibits its proteolysis (Vijayakumar et al., 2010). www.intechopen.com Effects of Growth Hormone (GH) Overexpression in Signaling Cascades Involved in Promotion of Cell Proliferation and Survival 75 The contrasting effects of GH and insulin on substrate metabolism depend on the nutritional status and food intake. Endogenous GH secretion is down-regulated by food intake, allowing insulin action on storage of nutrients. In a fasted state, GH secretion favors lipolysis. Between these two states, GH and insulin may act concomitantly to promote IGF1 production and therefore, protein synthesis. Usage of fatty acids as the energy source during fasting instead of glucose protects against excessive protein breakdown. Thus, GH is both anabolic and anti-catabolic in protein metabolism (Jorgensen et al., 2010). 1.2 GH-signaling 1.2.1 Growth hormone receptor Structure: GH exerts its functions by binding to its cognate receptor, the GHR. This receptor is a single-chain transmembrane glycoprotein which belongs to class I cytokine receptors. It is composed of three domains: the extracellular ligand-binding domain, arranged as two fibronectin type domains connected by a short flexible linker; the transmembrane domain; and the intracellular domain (ICD). The ICD has two motifs that bind tyrosine kinase JAK2, Box1 and Box2, and several tyrosine residues, which are substrates of JAK2 and become docking sites for phosphotyrosine binding molecules (Brooks et al., 2008). JAK2 is critical for GHR-signaling since GHR lacks intrinsic kinase activity. GHR is a member of the cytokine receptor superfamily, and is therefore structurally related to other members of this family, such as the receptors for prolactin, erythropoietin, thrombopoietin, leptin, interleukin 3, 5 and 6, granulocyte/macrophage colony-stimulating factor and interferon (Rosenfeld & Hwa, 2009; Lanning & Carter-Su, 2006). GHR loss of function mutations: The GHR mediates GH growth-related functions, as mutations in the receptor lead to severe stature deficit, similar to the lack of the hormone. Laron syndrome is a genetic disorder characterized by growth retardation and very short stature at adulthood (>5 SD), patients also present impaired muscle and bone development, as well as obesity and steatosis (Brooks et al., 2008). It is associated with deletions or mutations principally at the extracellular ligand-binding domain of the receptor; as a GH insensitivity syndrome, it is concurrent with high GH but low IGF1 circulating levels. GHR levels: Liver exhibits the highest GHR concentration, but it is also highly expressed in muscle, bone, kidney, mammary gland, adipose tissue, heart, intestine, lung, prostate, pancreas, cartilage, fibroblasts, and embryonic stem cells; in fact, GHR is expressed in almost every tissue of the body, indicating the relevance of GH action in every organ. Several factors regulate GHR concentration, including nutritional status and developmental stage. GHR levels are down-regulated by under-nutrition and fasting, while their levels gradually increase from birth to adulthood (Tiong & Herington, 1999). GH is a principal modulator of GHR, indeed it induces the synthesis of its own receptor (González et al., 2001; González et al., 2007). GHR turnover: at least two different mechanisms participate in the down-regulation of the mature form of the GHR at the plasma membrane: ligand-independent endocytosis and proteolytic cleavage (Flores-Morales et al., 2006). The protein breakdown consists of two steps: a metalloproteinase, the tumor necrosis factor-α converting enzyme (TACE), cleaves the extracellular portion of the receptor, close to the insertion point at the membrane. This generates the soluble form of the receptor, known as growth hormone binding protein (GHBP). After this process, the membrane-bound remnant is degraded by a γ-secretase...
Bioactive growth hormone in humans: Controversies, complexities and concepts
Growth hormone & IGF research, 2020
To revisit a finding, first described in 1978, which documented existence of a pituitary growth factor that escaped detection by immunoassay, but which was active in the established rat tibia GH bioassay. Methods: We present a narrative review of the evolution of growth hormone complexity, and its bio-detectability, from a historical perspective. Results: In humans under the age of 60, physical training (i.e. aerobic endurance and resistance training) are stressors which preferentially stimulate release of bioactive GH (bGH) into the blood. Neuroanatomical studies indicate a) that nerve fibers directly innervate the human anterior pituitary and b) that hind limb muscle afferents, in both humans and rats, also modulate plasma bGH. In the pituitary gland itself, molecular variants of GH, somatotroph heterogeneity and cell plasticity all appear to play a role in regulation of this growth factor. Conclusion: This review considers more recent findings on this often forgotten/neglected subject. Comparison testing of a) human plasma samples, b) sub-populations of separated rat pituitary somatotrophs or c) purified human pituitary peptides by GH bioassay vs immunoassay consistently yield conflicting results.
Contemporary Aspects of Endocrinology, 2011
This chapter will describe the effects of long term exposure to growth hormone (GH) at the molecular level in the liver. Expression and activation of intermediates involved in GH-induced signaling were analyzed in transgenic mice overexpressing GH, as well as the influence of chronically elevated GH levels over Amend: epidermal growth factor receptor (EGFR) signaling. Several signaling mediators involved in cellular proliferation, survival and migration are altered in the liver of GH-transgenic mice. The molecular mechanisms underlying the prooncogenic pathology induced by prolonged exposure to elevated GH levels will be discussed. 1.1 Physiological actions of GH Growth hormone (GH), also known as somatotropin, is the main regulator of postnatal body growth, but its actions are not limited to corporal stature. GH has important metabolic functions on carbohydrate, lipid and protein metabolism, as well as on tissue maintenance and repair, cardiac and immune function, mental agility and ageing. It exerts its actions both directly, and by means of endocrine and paracrine insulin-like growth factor (IGF) 1. At the cellular level, GH modulates proliferation, differentiation, motility and apoptosis. GH secretion: Growth hormone, part of the somatotropic axis, is mainly synthesized in somatotroph cells from the anterior pituitary. Growth hormone secretion is regulated centrally, through the hypothalamic-portal circulation, by hypothalamic peptides: its synthesis and release are promoted by growth-hormone releasing hormone (GHRH) and inhibited by somatostatin, and it is also stimulated by stomach-derived ghrelin. Stress, exercise, malnutrition, and anorexia also promote its secretion. By means of negative feedback, GH inhibits its own secretion: in the short central loop, GH acts on somatotroph cells to generate IGF1 locally, that in turn inhibits the cell; and it acts at the hypothalamic level to inhibit GHRH synthesis and release and to stimulate both synthesis and release of somatostatin. In the long peripheral loop, GH acts on the liver to generate most of circulating IGF1, which inhibits GH secretion by a dual mechanism: direct inhibition of the somatotrophs and stimulation of somatostatin release. GH is also produced locally in many tissues, acting in an autocrine and www.intechopen.com Contemporary Aspects of Endocrinology 74 paracrine fashion. Central cholinergic stimulation increases the release of GH reducing the secretion of somatostatin. Glucocorticoids and metabolic substrates also affect GH secretion; treatment with glucocorticoids inhibits its release while fasting states with hypoglycemia, low circulating free fatty acids, and high circulating amino acid concentrations stimulate it. GH secretion presents sexual dimorphism: the frequency of pulses is higher in females. The difference is most striking in rats, where secretion profile in males is characterized by high amplitude pulses every 3-4 h, with almost non-detectable values between pulses. Female rats, on the contrary, have more frequent lower amplitude pulses, and thus present baseline GH levels (Waxman & Frank, 2000). Humans, on the other hand, present higher values at night, during the first hours of sleep, and lower values in the early morning. GH secretory pattern conditions the sexually dimorphic gene expression in the liver, particularly of proteins involved in steroid and drug metabolism. GH secretion presents age-dependency: circulating GH levels progressively rise during childhood, to achieve a maximum towards the end of adolescence in humans, and slowly diminish thereafter. By the sixth decade of life, they are only 20% of maximum (Turyn & Sotelo, 2004). GH function: Somatic growth: GH acts directly on bone and indirectly, through endocrine hepatic derived IGF1, as well as the locally produced factor. These growth promoting peptides act on the epiphyseal cartilage, inducing chondrocyte proliferation, which leads to longitudinal skeletal growth (Tritos & Biller, 2009). Longitudinal growth ceases when the epiphyses of the long bones fuse to the diaphyses. Oversecretion before this instance results in gigantism, whereas oversecretion afterwards results in acromegaly, characterized by abnormal growth of hands and feet, and roughening of the facial features: protrusion of brow and lower jaw, and nose enlargement. Lack of GH or GHR in humans results in severe short stature, reduced muscle mass, increased fat storage, decreased cortical bone mineral density and decreased fertility in females (Lichanska & Waters., 2008a). In animals, basically the same growth outcome can be observed, either in spontaneous mutants or in genetically engineered models. Notably, mice lacking GH or GHR live longer than their littermates (Bartke & Brown-Borg, 2004). Besides its effects on skeletal growth, GH regulates body composition, increasing muscle mass and decreasing adipose content. The relationship between GH status and body composition is evidenced in patients and animal models lacking GH, which become obese. In humans, symptoms of GH deficiency resemble those of ageing, when GH levels decline: loss of muscular mass and tone, loss of bone mineral density, loss of strength, abdominal obesity (Perrini et al., 2010). Metabolic actions: GH has important metabolic actions on lipid and carbohydrate metabolism. It presents both insulin-like and insulin-antagonistic actions, presumably the first are IGF1-mediated while the latter are directly exerted by the hormone, since the effects of IGF1 on lipolysis and gluconeogenesis are contrary to those of GH (Kaplan & Cohen, 2010). GH exerts lipolytic effects, principally at the visceral adipose tissue, resulting in an increase of circulating free fatty acids, by increasing adipose tissue hormone-sensitive lipase activity; at the same time, it inhibits glucose uptake in adipose tissue. On the other hand, in liver GH promotes triglyceride (TG) uptake and storage, and in skeletal muscle it induces TG uptake and utilization. GH also presents anabolic actions on protein metabolism, since it stimulates protein synthesis and inhibits its proteolysis (Vijayakumar et al., 2010).
Growth hormone as an early embryonic growth and differentiation factor
Anatomy and Embryology, 2004
In this review we consider the evidence that growth hormone (GH) acts in the embryo as a local growth, differentiation, and cell survival factor. Because both GH and its receptors are present in the early embryo before the functional differentiation of pituitary somatotrophs and before the establishment of a functioning circulatory system, the conditions are such that GH may be a member of the large battery of autocrine/paracrine growth factors that control embryonic development. It has been clearly established that GH is able to exert direct effects, independent of insulin-like growth factor-I (IGF-I), on the differentiation, proliferation, and survival of cells in a wide variety of tissues in the embryo, fetus, and adult. The signaling pathways behind these effects of GH are now beginning to be determined, establishing early extrapituitary GH as a bona fide developmental growth factor.
2020
This chapter will describe the effects of long term exposure to growth hormone (GH) at the molecular level in the liver. Expression and activation of intermediates involved in GH-induced signaling were analyzed in transgenic mice overexpressing GH, as well as the influence of chronically elevated GH levels over Amend: epidermal growth factor receptor (EGFR) signaling. Several signaling mediators involved in cellular proliferation, survival and migration are altered in the liver of GH-transgenic mice. The molecular mechanisms underlying the prooncogenic pathology induced by prolonged exposure to elevated GH levels will be discussed. 1.1 Physiological actions of GH Growth hormone (GH), also known as somatotropin, is the main regulator of postnatal body growth, but its actions are not limited to corporal stature. GH has important metabolic functions on carbohydrate, lipid and protein metabolism, as well as on tissue maintenance and repair, cardiac and immune function, mental agility and ageing. It exerts its actions both directly, and by means of endocrine and paracrine insulin-like growth factor (IGF) 1. At the cellular level, GH modulates proliferation, differentiation, motility and apoptosis. GH secretion: Growth hormone, part of the somatotropic axis, is mainly synthesized in somatotroph cells from the anterior pituitary. Growth hormone secretion is regulated centrally, through the hypothalamic-portal circulation, by hypothalamic peptides: its synthesis and release are promoted by growth-hormone releasing hormone (GHRH) and inhibited by somatostatin, and it is also stimulated by stomach-derived ghrelin. Stress, exercise, malnutrition, and anorexia also promote its secretion. By means of negative feedback, GH inhibits its own secretion: in the short central loop, GH acts on somatotroph cells to generate IGF1 locally, that in turn inhibits the cell; and it acts at the hypothalamic level to inhibit GHRH synthesis and release and to stimulate both synthesis and release of somatostatin. In the long peripheral loop, GH acts on the liver to generate most of circulating IGF1, which inhibits GH secretion by a dual mechanism: direct inhibition of the somatotrophs and stimulation of somatostatin release. GH is also produced locally in many tissues, acting in an autocrine and www.intechopen.com Contemporary Aspects of Endocrinology 74 paracrine fashion. Central cholinergic stimulation increases the release of GH reducing the secretion of somatostatin. Glucocorticoids and metabolic substrates also affect GH secretion; treatment with glucocorticoids inhibits its release while fasting states with hypoglycemia, low circulating free fatty acids, and high circulating amino acid concentrations stimulate it. GH secretion presents sexual dimorphism: the frequency of pulses is higher in females. The difference is most striking in rats, where secretion profile in males is characterized by high amplitude pulses every 3-4 h, with almost non-detectable values between pulses. Female rats, on the contrary, have more frequent lower amplitude pulses, and thus present baseline GH levels (Waxman & Frank, 2000). Humans, on the other hand, present higher values at night, during the first hours of sleep, and lower values in the early morning. GH secretory pattern conditions the sexually dimorphic gene expression in the liver, particularly of proteins involved in steroid and drug metabolism. GH secretion presents age-dependency: circulating GH levels progressively rise during childhood, to achieve a maximum towards the end of adolescence in humans, and slowly diminish thereafter. By the sixth decade of life, they are only 20% of maximum (Turyn & Sotelo, 2004). GH function: Somatic growth: GH acts directly on bone and indirectly, through endocrine hepatic derived IGF1, as well as the locally produced factor. These growth promoting peptides act on the epiphyseal cartilage, inducing chondrocyte proliferation, which leads to longitudinal skeletal growth (Tritos & Biller, 2009). Longitudinal growth ceases when the epiphyses of the long bones fuse to the diaphyses. Oversecretion before this instance results in gigantism, whereas oversecretion afterwards results in acromegaly, characterized by abnormal growth of hands and feet, and roughening of the facial features: protrusion of brow and lower jaw, and nose enlargement. Lack of GH or GHR in humans results in severe short stature, reduced muscle mass, increased fat storage, decreased cortical bone mineral density and decreased fertility in females (Lichanska & Waters., 2008a). In animals, basically the same growth outcome can be observed, either in spontaneous mutants or in genetically engineered models. Notably, mice lacking GH or GHR live longer than their littermates (Bartke & Brown-Borg, 2004). Besides its effects on skeletal growth, GH regulates body composition, increasing muscle mass and decreasing adipose content. The relationship between GH status and body composition is evidenced in patients and animal models lacking GH, which become obese. In humans, symptoms of GH deficiency resemble those of ageing, when GH levels decline: loss of muscular mass and tone, loss of bone mineral density, loss of strength, abdominal obesity (Perrini et al., 2010). Metabolic actions: GH has important metabolic actions on lipid and carbohydrate metabolism. It presents both insulin-like and insulin-antagonistic actions, presumably the first are IGF1-mediated while the latter are directly exerted by the hormone, since the effects of IGF1 on lipolysis and gluconeogenesis are contrary to those of GH (Kaplan & Cohen, 2010). GH exerts lipolytic effects, principally at the visceral adipose tissue, resulting in an increase of circulating free fatty acids, by increasing adipose tissue hormone-sensitive lipase activity; at the same time, it inhibits glucose uptake in adipose tissue. On the other hand, in liver GH promotes triglyceride (TG) uptake and storage, and in skeletal muscle it induces TG uptake and utilization. GH also presents anabolic actions on protein metabolism, since it stimulates protein synthesis and inhibits its proteolysis (Vijayakumar et al., 2010).