A. Growth Hormone

1. Regulation of Secretion

As shown in Figure 1, the neuroendocrine control of GH secretion is primarily under the control of the two hypothalamic hormones, GHRH and somatostatin, the release-inhibiting hormone. The synthesis and secretion of these peptides is discussed in section III.D. The balance between the secretion of GHRH and SST by the hypothalamus is determined by many inputs, including neuronal pathways which allow GH secretion to be responsive to stress and other environmental conditions. GHRH affects both the expression of the GH gene in the somatotrophs and the secretion of existing hormone, whereas somatostatin’s effects are predominantly on the secretion of existing GH.

Fig1. Control of GH secretion. The major contributors to GH secretion are the hypothalamic GH releasing hormone, GHRH, and the release inhibiting hormone, somatostatin, SST (also known as somatotropin release-inhibiting hormone, SRIH). The secretion of both GHRH and SST are under the influence of neural input, both positive (green arrows) and negative (red arrows), from other regions of the brain. Thus, GH secretion is responsive to stress and environmental conditions. The pituitary secretion of GH is also influenced by the stomach hormone ghrelin as well as by negative feedback from the peripherally produced mediator of GH action, IGF-1.

In addition to the hypothalamic hormones, somatotroph secretion of GH is under negative feedback control by insulin-like-growth factor 1, IGF-1, a peptide hormone that, as its name implies, shares considerable structural similarity with insulin (see below). The synthesis of IGF-1 (once known as somatomedin) is stimulated by GH in the liver; it mediates GH effects in several peripheral tissues as described further below, and exerts negative feedback control on GH secretion at the pituitary.

Growth hormone secretagogues (GHSs) have been recognized for more than three decades as small molecules that stimulate pituitary GH secretion independently of GHRH. Originally the two pathways were distinguished by the different second messengers involved in their action, cAMP for GHRH and intracellular Ca2+ for GHS. In the mid-1990s the receptor for these synthetic molecules was cloned, named GHS-R, and identified as an orphan G-protein coupled receptor since its natural ligand was unknown. In 1999 the natural ligand for this receptor was identified as a 28-amino acid peptide produced in the stomach. It was named ghrelin and found to play a role in the regulation of appetite (see section VI). As shown in Figure 1, it stimulates GHRH secretion by the hypothalamus and, in the pituitary, it synergizes with GHRH, stimulating release of GH in response to a maximal dose of the hypothalamic releasing hormone. In fact the effect of ghrelin on GH secretion requires an intact hypothalamic-pituitary system and it has no effect on patients with hypothalamic lesions.

The structure of mature ghrelin is shown in Figure 2. Its 28 amino acids are derived from a 117-amino acid prohormone and the active peptide is octanylated at the third position. Although only a small proportion of circulating ghrelin is acylated (1.8%), this posttranslational modification is required for its inter action with the GHS-R and stimulation of GH secretion. It is likely that the form lacking this modification, desacyl ghrelin, is an active peptide in ghrelin’s impact on metabolism and appetite and in the development of adipocytes.

Fig2. Amino acid sequence of ghrelin. The 28 amino acid sequence of ghrelin is shown, with acylated serine in the third position. The acyl group can be either 8 or 10 carbons long and is required for the growth hormone secretagogue activity of ghrelin, but not for many of its other biological activities.

Like many of the other pituitary hormones, the secretion of GH from the pituitary is pulsatile and, as shown in Figure 3, peaks of GH secretion occur throughout a 24-hr period. The magnitude of the peaks can vary with a number of factors, one of which is sleep, with which GH secretion is tightly linked, particularly in males. The sexually dimorphic pattern of GH secretion is characterized by the much more predominant nocturnal peak, relative to those during the day, in males than in females. This pattern, as well as the age-related decrease in the amplitude of GH pulses, is related to changes in GHRH secretion, indicating that endogenous GHRH secretion is the main regulator of pulsatile GH secretion in humans. Basal levels of GH are largely dependent on somatostatin’s influence on the somatotrophs.

Fig3. Patterns of GH secretion. Typical patterns of GH secretion are shown for a young male (top panel) and female (bottom panel) adult humans. The purple line at the bottom of the graph shows the pattern obtained in the presence of a GHRH antagonist which diminishes the amplitude of the GH pulses.

2. GH Receptor and Signaling

The growth hormone receptor, GHR, belongs to the class I cytokine/hematopoietin receptor superfamily. It contains 638 amino acids which comprise a glycosylated extracellular ligand-binding domain, a single membrane-spanning segment of 24 amino acids and the cytoplasmic signaling component. A soluble derivative of the extracellular domain is known as growth hormone binding protein, GHBP, which circulates in the blood. GH bound to GHBP is not available to bind to receptors on target tissues or for degradation, so that the binding protein levels can influence the pool of available hormone.

As shown by crystallization and other studies in the early 1990s, the active GH-GHR complex consists of one molecule of GH and two receptor monomers. Initially it was thought that GH binds to a monomer and brings about the dimerization to activate the receptor. More recent work, however, indicates that the binding of GH to the dimerized receptor causes an internal rotation of the receptor, activating the receptor com plex so that the intracellular domain initiates the signaling pathway outlined in Figure 4. Each monomer of the GHR dimer binds to a molecule of a tyrosine kinase of the Janus family, JAK2, which then phosphorylates several tyrosine residues on the intracellular domain of the dimeric GHR. These serve as docking sites for at least three different intracellular signaling pathways: STAT (signal transduction and activator of transcription); MAPK (mitogen activated kinase); and PI3K (phosphoinositide-3 kinase). The transcription of multiple genes is affected as a result of the activation of these pathways. One of these genes encodes the peripheral mediator of GH actions, IGF-1, described in the next section. Two others, IGF binding protein (IGFBP-3) and acid-labile subunit (ALS), are necessary for maintaining appropriate circulating levels of IGF-1.

Fig4. Growth hormone signaling. The binding of GH to a preformed GH receptor (GHR) dimer results in internal rotation leading to the activation of receptor-associated JAK2 (Janus kinase 2). Three major downstream signaling modules are shown. Through interaction with the insulin receptor substrate (IRS), the PI3 kinase/AKT pathway is activated, leading to changes in metabolic actions. Latent cytoplasmic STAT (signal transducer and activator of transcription) molecules (blue ovals) are recruited to the GHR where they are phosphorylated on tyrosine residues. Phosphorylated STAT molecules move to the nucleus where they bind to specific gene regulatory elements, altering gene expression. Activation of the ERK (extracellular signal regulated kinase) pathway also leads to changes in gene expression. Some of the genes whose expression is altered by these two pathways are indicated. GHRE, GHR enhancer; TF, transcription factor; IRS, insulin receptor substrate; IGF, insulin-like growth factor; IGFBP, IGF binding protein; ALS, acid labile subunit (see text).

3. GH–IGF-1 Axis

Many of the peripheral actions of GH are mediated by the peptide insulin-like growth factor-1, or IGF-1, the main source of which is the liver. As its name implies, IGF-1 (and its close relative, IGF-2) is structurally related to proinsulin. As shown in Figure 5 the single polypeptide IGF-1 has domains similar to those of pro insulin, including the A and B domains (the two subunits of the mature insulin, a C-domain (similar to the C-peptide released when proinsulin is converted to mature insulin), and a short carboxy terminal D-domain. In the A (blue) and B (pink) domains, the amino acids that are identical to those in the A and B subunits of insulin are shown in the darker color to emphasize the structural relationship between the two proteins. IGF-2 is very similar to IGF-1 structurally and in biological activity. The primary difference between the two is that IGF-2 is expressed predominantly in early embryonic and fetal life and IGF-1 is expressed in the adult. IGF-1, IGF-2, and insulin diverged from a common ancestral gene. In contrast to insulin, the IGFs circulate bound to specific IGF-binding proteins, a group of molecules that play an important role in the availability and plasma half-lives of the IGFs.

Fig5. Amino acid sequence of human insulin-like growth factor-1, IGF-1. The 70 amino acids in IGF-1 occur in four domains. From the N-terminus these are: B, pink; C, gray; A, blue; and D, yellow. Darker amino acids with white lettering are those that are identical in human pro-insulin. The A and B domains are homologous to the A and B chains of the insulin molecule and the C domain is the equivalent of the C-peptide in pro-insulin.

The Type I IGF receptor, which mediates the mitogenic and metabolic effects of both IGF-1 and IGF-2, is structurally similar to the insulin receptor, but distinct enough that there is little physiologically significant crossover in receptor binding between insulin and the two IGFs.

As shown in Figure 6, while some peripheral effects of GH in bone, muscle, and adipose tissue (some of the primary targets of GH) are the result of direct action of GH with its receptor in those tissues, IGF-1, interacting with its own distinct specific receptor is responsible for some of these actions, notably in muscle and liver for linear growth. Most of the circulating IGF-1 that mediates these effects is produced in the liver, although IGF-1 is also produced in target tissues locally and participates in autocrine and paracrine pathways. Both IGF-1 and IGF-2 are important participants in the differentiation and proliferation of many diverse cells in the body. These aspects of IGFs and their serum binding proteins will be discussed in more detail in Chapter 17.

Fig6. The GH-IGF-1 axis. In the liver GH interacts with its receptor to stimulate the production of its major mediator, insulin-like growth factor-1 (IGF-1; somatomedin). Through its receptor, IGF-1R (blue), IGF-1 mediates effects at several target tissues, including bone and muscle necessary for body growth and adipose tissue. These tissues also respond directly to GH, as indicated by the presence of the GH receptor, GHR (green).

Normal growth charts, in terms of both the rate of growth and actual height, are shown in Figure 7. Prenatal bone growth is largely dependent on IGF-1 and IGF-2 and is independent of GH. Postnatal skeletal growth requires GH and IGF-1, both of which have receptors on the epiphyseal growth plate where long bone growth occurs. Thus individuals with a defect in the GH receptor or in its signaling pathway show subnormal growth rates only after birth. A defect in either IGF-1 synthesis or in the IGF-1 receptor results in growth abnormalities both pre- and postnatally. Both GH and IGF-1 continue to have effects on bone through childhood and during the peripubertal periods of skeletal maturation and acquisition of peak bone mineral density. Some portions of the adult skeleton remains sensitive to GH and IGF-1 in adulthood resulting in the GH excess condition of acromegaly (see section VII).

Fig7. Growth curves from birth through adolescence. The left panel shows the changes in rate of growth and depicts the prepubertal growth spurt, which begins and ends earlier in girls than in boys. This difference is reflected in the earlier flattening of the absolute growth curve for girls in the panel on the right.

In addition to its skeletal effects, GH influences several aspects of fuel metabolism. These effects, which are a direct response to GH or a response to IGF-1, include increased lipolysis in adipose tissue leading to increased circulating free fatty acids; increased triglyceride uptake by liver and muscle through stimulation of lipoprotein lipase. GH effects on carbohydrate metabolism are, in the short term, insulin-like but chronically oppose insulin action. The overall effect of GH on protein metabolism is an anabolic one.

B. Prolactin

1. Regulation of PRL Secretion

As discussed in section III.E and shown in Figure 8, PRL secretion from pituitary lactotrophs is predominantly under the negative control of dopamine from hypothalamic neurons. Stimulation of release by other hypothalamic factors, including VIP and TRH, also occurs, often in concert with decreased dopamine levels. This attribute, i.e., high constitutive secretion of PRL when not under hypothalamic control, is unique to mammals; in other species, the more commonly observed balance between negative and positive regulatory factors is observed.

Fig8. Feedback regulation of prolactin secretion. The hypothalamic influences on prolactin secretion described in Figure 3-11 are shown here, as well as the positive effects of estrogen and, during pregnancy, other hormones (see Chapter 14). The powerful positive neural influence of suckling on prolactin release is also indicated, as is the short-loop negative feedback exerted by prolactin at the hypothalamus.

In mammals, peripheral feedback effects on PRL secretion include the neuroendocrine reflex that is established in response to suckling, a positive feedback loop that serves the lactational function of mammals. In this reflex, impulses resulting from the stimulation of nerve endings in the nipple are transmitted via the spinal cord to the brain stem and hypothalamus.

Extensive experimental data indicate that in rats estrogen stimulates PRL secretion at the hypothalamus through effects on DA secretion and at the pituitary through effects on gene expression. In humans the rise in the number of lactotrophs in the pituitary correlates with increased serum estrogen levels and, in hypogonadal situations, a clear effect of estrogen on prolactin secretion can be demonstrated. At the same time, a rise in PRL levels does not accompany the mid-cycle estro gen peak in women nor are basal levels of the hormone decreased when ovaries are removed. Thus, it is likely that although estrogen stimulation of PRL secretion may be important under some circumstances, in most women estrogens do not play a significant role in the day-to-day control of prolactin secretion.

PRL itself can also participate in the regulation of its own secretion through the short feedback loop to the hypothalamus, where it exerts PRL receptor-mediated inhibitory effects on dopamine synthesis, secretion and turnover, all leading to decreased levels of dopamine and increased pituitary secretion of PRL.

2. Prolactin Receptor and Signaling

The human PRL receptor, PRLR, is closely related to the GHR and both are members of a subfamily of hemapoietic cytokine receptors that includes erythropoietin and most interleukins. The monomeric form of this type of receptor is characterized by a single-pass transmembrane region and a cytoplasmic tail that has no intrinsic tyrosine kinase activity but can be phosphorylated by cytoplasmic kinases. The cytoplasmic tail contains two regions, Box 1 and Box 2, which are highly conserved across the cytokine receptor super family. The gene for the PRL receptor contains 10 exons and alternative splicing leads to the presence of isoforms that differ by their abundance and structure in the intracellular domain, within different species. In humans, the long form is the most abundantly expressed and mediates many of the biological effects of PRL on its target tissues. Shorter forms have been identified and studied but their physiological roles have not yet been clarified.

As depicted in Figure 9, a PRLR dimer with one ligand bound is the activated form of the prolactin receptor. Although evidence exists for involvement of PRL binding in the dimerization, it is now thought that, as with GHR, the dimer is formed in the absence of ligand. The best understood signaling path way of the occupied dimerized PRLR is that initiated by JAK2, a nonreceptor tyrosine kinase that is associated with Box 1 of the intracellular domain of the PRLR. Activated JAK2 phosphorylates Stat5, a latent cytoplasmic transcription factor that translocates to the nucleus where it activates transcription of specific genes, whose expression brings about the biological response of the target cells or tissues.

Fig9. The human prolactin receptor, hPRLR. The human prolactin receptor monomer (upper right) is characterized by two distinct extracellular domains (ECD), a transmembrane domain and an intracellular domain (ICD). Each of the domain types has highly conserved motifs, indicated by bands from the top of ECD (beige and blue) to the bottom of ICD (purple). Two segments of the ICD, Box 1 and Box 2, carry out differing signaling functions within the cell. The remainder of this figure depicts the two possibilities of the order of PRL binding and dimerization to form the active receptor. In the upper portion PRL binds a monomer, then dimerization occurs while in the bottom panel, dimerization of two unliganded monomers of hPRLR takes place prior to the binding of one molecule of prolactin. It is now believed that, as is the case with the GH-GHR complex, dimerization takes place prior to hormone binding. The JAK/Stat pathway is the major signaling mechanism for PRL in target tissues.

3. Prolactin Biological Actions

Prolactin is present in all vertebrate species and its activities vary widely between classes of vertebrates. The biological actions of prolactin can be grouped into six general categories: reproduction; metabolism; water and electrolyte balance; growth and development; immunoprotection; behavior. For example, in teleosts certain gill ion transport systems are the targets of prolactin as is the nasal salt gland in birds. Prolactin is involved in skin sloughing in reptiles and feather growth in birds.

Many actions of prolactin are broadly supportive of successful reproduction. Since reproductive strategies vary with species so do the specific biological actions of prolactin. In mammals, prolactin’s most important actions (and the source of the name of the hormone) have to do with its indispensable role in lactation. This includes the growth and development of the mammary gland and the changes it undergoes during pregnancy; the production of milk; and the delivery of milk to the young. The role of suckling in prolactin secretion has already been touched upon and the actions of prolactin in mammary gland growth and development and lactogenesis will be discussed in more detail in Chapter 14.

In rodents, but not in most other mammalian species, including humans, prolactin is necessary for maintenance of the corpus luteum, which secretes the steroid hormones required for the maintenance of pregnancy in mammals. Prolactin does play a role in human pregnancy, in addition to preparing the breasts for lactation, but it generally acts in con cert with other hormones in this regard. It acts alone, however, in the stimulation of the size and number of lactotrophs in the pituitary gland which accounts for a large part of pituitary growth during human pregnancy.

High levels of prolactin, such as in the hyperprolactemia resulting from prolactin secretion from an ectopic or pituitary tumor, inhibits gonadal function in both males and females and can lead to infertility or impotence. This antigonadal effect of prolactin is one of the most highly conserved of its actions across classes and species. However, the role of normal levels of prolactin in gonadal function in males and nonpregnant females is not yet fully understood.

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مواضيع ذات صلة

Hypothalamic Control of Growth Hormone Secretion

Corticotropin-Releasing Hormone

The Physiology of Vasopressin

Gonadotropin-Releasing Hormone

Thyrotropin-Releasing Hormone

Biosynthesis of Adrenal Cortex Mineralocorticoids, Glucocorticoids, and Some Androgens

Mechanisms of hormone action: Cell Signaling by Membrane Receptors

Biosynthesis of Peptide and Protein Hormones

Hormones and Their Communication Systems

Stepwise development of tissue- specific insulin resistance

Insulin resistance in adipose tissue Adipose tissue

Insulin resistance in the liver