Growth Hormone (GH, Somatotropin) Growth hormone is a protein hormone of about 190 amino acids that is synthesized and secreted by cells called somatotrophs in the anterior pituitary. It is a major participant in control of several complex physiologic processes, including growth and metabolism. Growth hormone is also of considerable interest as a drug used in both humans and animals.

Biochemical Effects of Growth Hormone Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to take up and accumulate circulating lipids. Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.

Growth Hormone Effects on Growth Growth is a very complex process, and requires the coordinated action of several hormones. The major role of growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-I. IGF-I stimulates proliferation of chondrocytes (cartilage cells), resulting in bone growth. Growth hormone does seem to have a direct effect on bone growth in stimulating differentiation of chondrocytes. IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues. Metabolic Effects GH has important effects on protein, lipid and carbohydrate metabolism. In some cases, a direct effect of growth hormone has been clearly demonstrated, in others, IGF-I is thought to be the critical mediator, and some cases it appears that both direct and indirect effects are at play. Protein metabolism: In general, GH stimulates protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis and decreased oxidation of proteins. Fat metabolism: GH enhances the utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes. Carbohydrate metabolism: GH is one of a battery of hormones that serves to maintain blood glucose within a normal range. Growth hormone is often said to have anti-insulin activity, because it supresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver. Somewhat paradoxically, administration of growth hormone stimulates insulin secretion, leading to hyperinsulinemia.

Control of Growth Hormone Secretion Production of growth hormone is modulated by many factors, including stress, exercise, nutrition, sleep and growth hormone itself. However, its primary controllers are two hypothalamic hormones and one hormone from the stomach: Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone. Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. Somatostatin inhibits GH release in response to GHRH and to other stimulatory factors such as low blood glucose concentration. Ghrelin is a peptide hormone secreted from the stomach. Ghrelin binds to receptors on somatotrophs and potently stimulates secretion of GH. GH secretion is also part of a negative feedback loop involving IGF-I. High blood levels of IGF- I lead to decreased secretion of growth hormone not only by directly suppressing the somatotroph, but by stimulating release of somatostatin from the hypothalamus. GH also feeds back to inhibit GHRH secretion Integration of all the factors that affect growth hormone synthesis and secretion lead to a pulsatile pattern of release. Basal concentrations of growth hormone in blood are very low.

Disease States Giantism is the result of excessive growth hormone secretion that begins in young children or adolescents. Acromegaly results from excessive secretion of growth hormone in adults, usually the result of benign pituitary tumors.

The Endocrine Pancreas: Insulin and Glucagon The pancreas houses two distinctly different tissues. The bulk of its mass is exocrine tissue and associated ducts, which produce an alkaline fluid loaded with digestive enzymes which is delivered to the small intestine to facilitate digestion of foodstuffs. On the other hand, endocrine cells produce the hormones insulin and glucagon. Insulin and glucagon are critical participants in glucose homeostasis and serve as acute regulators of blood glucose concentration. From a medical perspective, insulin in particular is enormously important - a deficiency in insulin or deficits in insulin responsiveness lead to the disease diabetes mellitus.

Insulin and Carbohydrate Metabolism Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are: Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin. When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.

Insulin Insulin stimulates the liver to store glucose in the form of glycogen. Insulin has several effects in liver which stimulate glycogen synthesis. It activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. A well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves. When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon, which is secreted when blood glucose levels fall below the normal range.

Insulin and Lipid Metabolism Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed. When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids. Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells. From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.

Other Notable Effects of Insulin In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation. Insulin also increases the permiability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium- potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.

Glucagon Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. That is, glucagon has the effect of increasing blood glucose levels. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Glucagon stimulates breakdown of glycogen stored in the liver. When blood glucose levels are high, large amounts of glucose are taken up by the liver. Under the influence of insulin, much of this glucose is stored in the form of glycogen. Later, when blood glucose levels begin to fall, glucagon is secreted and acts on hepatocytes to activate the enzymes that depolymerize glycogen and release glucose. Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job. Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells.

Endocrine Control of Calcium and Phosphate Homeostasis Calcitonin, a protein hormone synthesized and secreted in humans primarily by parafollicular cells (C cells) in the thyroid gland. The overall effect of calcitonin is to lower the concentration of calcium in the blood when it rises above the normal value. It also lowers the concentration of phosphorus in the blood when levels exceed normal. Parathormone: The parathyroid glands secrete a hormone called parathormone (PTH), which is a polypeptide. PTH, regulates calcium metabolism in conjunction with calcitonin. In general, the action of parathormone is opposite in direction to that of calcitonin. Parathormone keeps the level of blood calcium up to its normal value; on the other hand, calcitonin ensures, through its hypocalcemic action, that the level does not rise far above this critical point. The combined actions of the two hormones serve to illustrate the importance of endocrine regulation in homeostasis.

Vitamin D Vitamin D acts to increase blood concentrations of calcium. It is generated through the activity of parathyroid hormone within the kidney. Far and away the most important effect of vitamin D is to facilitate absorption of calcium from the small intestine. In concert with parathyroid hormone, vitamin D also enhances fluxes of calcium out of bone.