GH Regulates Growth During Childhood and Remains Important Throughout Life

As its name implies, growth hormone (GH) promotes the growth of the human body. It does not appear to stimulate fetal growth, nor is it an important growth factor during the first few months after birth. Thereafter, it is essential for the normal rate of body growth during childhood and adolescence.

Growth hormone (also called somatotropin) is secreted by the anterior pituitary throughout life and remains physiologically important even after growth has stopped. In addition to its growth-promoting action, GH has effects on many aspects of carbohydrate, lipid, and protein metabolism. For example, GH is thought to be one of the physiological factors that counteract and, thus, modulate some of the actions of insulin on the liver and peripheral tissues.

The Structure and Synthesis of Human GH. Human GH is a globular 22 kDa protein consisting of a single chain of 191 amino acid residues with two intrachain disulfide bridges. Human GH has considerable structural similarity to human PRL and placental lactogen.

Growth hormone is produced in somatotrophs of the anterior pituitary. It is synthesized in the rough ER as a larger prohormone consisting of an N-terminal signal peptide and the 191-amino acid hormone. The signal peptide is then cleaved from the prohormone, and the hormone traverses the Golgi apparatus and is packaged in secretory granules.

Hypothalamic growth hormone-releasing hormone (GHRH) regulates the production of GH by stimulating the expression of the GH gene in somatotrophs. Expression of the GH gene is also stimulated by thyroid hormones. As a result, the normal rate of GH production depends on these hormones. For example, a thyroid hormone deficient individual is also GH-deficient. This important action of thyroid hormones is discussed further in Chapter 33.

Regulation of GH Secretion by GHRH and Somatostatin.

The secretion of GH is regulated by two opposing hypo-thalamic releasing hormones. GHRH stimulates GH secretion and somatostatin inhibits GH secretion by inhibiting the action of GHRH. The rate of GH secretion is determined by the net effect of these counteracting hormones on somatotrophs. When GHRH predominates, GH secretion is stimulated. When somatostatin predominates, GH secretion is inhibited.

Human GHRH is a peptide composed of a single chain of 44 amino acid residues. A slightly smaller version of GHRH consisting of 40 amino acid residues is also present in humans. GHRH is synthesized in the cell bodies of neurons in the arcuate nuclei and ventromedial nuclei of the hypothalamus. The axons of these cells project to the capillary networks giving rise to the portal vessels. When these neurons receive a stimulus for GHRH secretion, they discharge GHRH from their axon terminals into the hy-pophyseal portal circulation.

GHRH binds to receptors in the plasma membranes of somatotrophs (Fig. 32.10). These receptors are coupled to adenylyl cyclase by a stimulatory G protein, Gs. The interaction of GHRH with its receptors activates adenylyl cy-clase, increasing the concentration of cyclic AMP (cAMP) in the somatotroph. The rise in cAMP activates protein kinase A (PKA), which, in turn, phosphorylates proteins that stimulate GH secretion and GH gene expression. GHRH binding to its receptor also increases intracellular Ca2+, which stimulates GH secretion. In addition, some evidence suggests that GHRH may stimulate PLC, causing the hy-

Somatotroph

Somatotroph

Somatotroph Receptors

^NGUREIHn^ The actions of GHRH and somatostatin on itmKKU^t^tF a somatotroph. GHRH binds to membrane receptors that are coupled to adenylyl cyclase (AC) by stimulatory G proteins (Gs). Cyclic AMP (cAMP) rises in the cell and activates protein kinase A (PKA), which then phosphorylates proteins (P proteins) involved in stimulating GH secretion and the expression of the gene for GH. Ca2+ is also involved in the action of GHRH on GH secretion. The possible involvement of the phosphatidylinositol pathway in GHRH action is not shown. Somatostatin (SRIF) binds to membrane receptors that are coupled to adenylyl cyclase by inhibitory G proteins (Gi). This action inhibits the ability of GHRH to stimulate adenylyl cyclase, blocking its action on GH secretion.

^NGUREIHn^ The actions of GHRH and somatostatin on itmKKU^t^tF a somatotroph. GHRH binds to membrane receptors that are coupled to adenylyl cyclase (AC) by stimulatory G proteins (Gs). Cyclic AMP (cAMP) rises in the cell and activates protein kinase A (PKA), which then phosphorylates proteins (P proteins) involved in stimulating GH secretion and the expression of the gene for GH. Ca2+ is also involved in the action of GHRH on GH secretion. The possible involvement of the phosphatidylinositol pathway in GHRH action is not shown. Somatostatin (SRIF) binds to membrane receptors that are coupled to adenylyl cyclase by inhibitory G proteins (Gi). This action inhibits the ability of GHRH to stimulate adenylyl cyclase, blocking its action on GH secretion.

drolysis of membrane PIP2 in the somatotroph. The importance of this phospholipid pathway for the stimulation of GH secretion by GHRH is not established.

Somatostatin is a small peptide consisting of 14 amino acid residues. Although made by neurosecretory neurons in various parts of the hypothalamus, somatostatin neurons are especially abundant in the anterior periventricular region (i.e., close to the third ventricle). The axons of these cells terminate on the capillary networks giving rise to the hypophyseal portal circulation, where they release somato-statin into the blood.

Somatostatin binds to receptors in the plasma membranes of somatotrophs. These receptors, like those for GHRH, are also coupled to adenylyl cyclase, but they are coupled by an inhibitory G protein (see Fig. 32.10). The binding of somatostatin to its receptor decreases adenylyl cyclase activity, reducing intracellular cAMP. Somatostatin binding to its receptor also lowers intracellular Ca2+, reducing GH secretion. When the somatroph is exposed to both somatostatin and GHRH, the effects of somatostatin are dominant and intracellular cAMP and Ca2 + are reduced. Thus, somatostatin has a negative modulating influence on the action of GHRH.

GH and Insulin-Like Growth Factor I. GH is not considered a traditional trophic hormone,- however, it does stimulate the production of a trophic hormone called insulinlike growth factor I (IGF-I). IGF-I is a potent mitogenic agent that mediates the growth-promoting action of GH. IGF-I was originally called somatomedin C or soma-totropin-mediating hormone because of its role in promoting growth. Somatomedin C was renamed IGF-I because of its structural similarity to proinsulin.

Insulin-like growth factor II (IGF-II), an additional growth factor induced by GH, is structurally similar to IGF-I and has many of the same metabolic and mitogenic actions. However, IGF-I appears to be the more important mediator of GH action.

IGF-I is a 7.5 kDa protein consisting of a single chain of 70 amino acids. Because of its structural similarity to proinsulin, IGF-I can produce some of the effects of insulin. IGF-I is produced by many cells of the body,- however, the liver is the main source of IGF-I in the blood. Most IGF-I in the blood is bound to specific IGF-I-bind-ing proteins, only a small amount circulates in the free form. The bound form of circulating IGF-I has little insulin-like activity, so it does not play a physiological role in the regulation of blood glucose level.

GH increases the expression of the genes for IGF-I in various tissues and organs, such as the liver, and stimulates the production and release of IGF-I. Excessive secretion of GH results in a greater than normal amount of IGF-I in the blood. Individuals with GH deficiency have lower than normal levels of IGF-I, but there is still some present, since the production of IGF-I by cells is regulated by a variety of hormones and factors in addition to GH.

IGF-I has a negative-feedback effect on the secretion of GH (Fig. 32.11). It acts directly on somatotrophs to inhibit the stimulatory action of GHRH on GH secretion. It also inhibits GHRH secretion and stimulates the secretion of somatostatin by neurons in the hypothalamus. The net ef-

Dehydration Negative Feedback

^NGUREESin^ The hypothalamic-pituitary-GH axis.

^■■■■■■■Ir Growth hormone-releasing hormone (GHRH) stimulates, and somatostatin inhibits, GH secretion by acting directly on the somatotroph. The negative-feedback loops ( —), shown in red, inhibit GHRH secretion and action on the somatotroph, causing a decrease in GH secretion. The feedback loops ( + ), shown in gray, stimulate somatostatin secretion, causing a decrease in GH secretion. IGF-I, insulin-like growth factor I.

^NGUREESin^ The hypothalamic-pituitary-GH axis.

^■■■■■■■Ir Growth hormone-releasing hormone (GHRH) stimulates, and somatostatin inhibits, GH secretion by acting directly on the somatotroph. The negative-feedback loops ( —), shown in red, inhibit GHRH secretion and action on the somatotroph, causing a decrease in GH secretion. The feedback loops ( + ), shown in gray, stimulate somatostatin secretion, causing a decrease in GH secretion. IGF-I, insulin-like growth factor I.

fect of these actions is the inhibition of GH secretion. By stimulating IGF-I production, GH inhibits its own secretion. This mechanism is analogous to the way ACTH and TSH regulate their own secretion through the respective negative-feedback effects of the glucocorticoid and thyroid hormones. This interactive relationship involving GHRH, somatostatin, GH, and IGF-I comprises the hypothalamic-pituitary-GH axis.

Feedback Effects of GH on Its Own Secretion. An increase in the blood concentration of GH has direct feedback effects on its own secretion, independent of the production of IGF-I. These effects of GH are due to the inhibition of GHRH secretion and the stimulation of somatostatin secretion by hypothalamic neurons (see Fig. 32.11). GH circulating in the blood can enter the interstitial spaces of the median eminence of the hypothalamus because there is no blood-brain barrier in this area.

Pulsatile Secretion of GH. In humans, GH is secreted in periodic bursts, which produce large but short-lived peaks in GH concentration in the blood. Between these episodes of high GH secretion, somatotrophs release little GH,- as a result, the blood concentration of GH falls to very low levels. It is believed that these periodic bursts of GH secretion are caused by an increase in the rate of GHRH secretion and a fall in the rate of somatostatin secretion. The intervals between bursts, when GH secretion is suppressed, are thought to be caused by increased somatostatin secretion. These changes in GHRH and somatostatin secretion result from neural activity generated in higher levels of the CNS, which affects the secretory activity of GHRH and somato-statin producing neurons in the hypothalamus.

Bursts of GH secretion occur during both awake and sleep periods of the day, however, GH secretion is maximal at night. The bursts of GH secretion during sleep usually occur within the first hour after the onset of deep sleep (stages 3 and 4 of slow-wave sleep). Mean GH levels in the blood are highest during adolescence (peaking in late puberty) and decline in adults. The reduction in blood GH with aging is mainly due to decrease in the size of the GH secretory burst but not the number of pulses (Fig 32.12).

A variety of factors affect the rate of GH secretion in humans. These factors are thought to work by changing the secretion of GHRH and somatostatin by neurons in the hypothalamus. For example, emotional or physical stress causes a great increase in the rate of GH secretion. Vigorous exercise also stimulates GH secretion. Obesity results in reduced GH secretion.

Changes in the circulating levels of metabolites also affect GH secretion. A decrease in blood glucose concentration stimulates GH secretion, whereas hyperglycemia inhibits it. Growth hormone secretion is also stimulated by an

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