Growth hormone (GH) secretion is subject to change in response to a wide variety of physiological situations, some of which are summarized in Table 1. Many, but not all, of these are mediated through the two major hypothalamic factors discussed below.

Table1. Factors That Affect Growth Hormone Secretion and Action

1. Growth Hormone-Releasing Hormone

Growth hormone-releasing hormone (GHRH) was originally isolated from ectopic tumors producing it (and thereby causing observable derangements in growth), rather than from the hypothalamus and its structure determined by two laboratories in 1982. GHRH is secreted by the arcuate nucleus of the hypothalamus and is derived from a 108 amino-acid pre-prohormone yielding either GHRH(1-44) shown in Figure 1 or GHRH(1-40), shortened at the carboxyl terminal. Both forms of GHRH are found in the human hypothalamus and since the full biological activity of GHRH lies in amino acid residues 1–29, the physiological differences between the two GHRH forms are likely minimal. Structurally, GHRH belongs to a family of proteins that includes secretin, glucagon, glucagon-like peptides (GLP-1 and GLP-2), and vasoactive intestinal peptide (VIP).

Fig1. Hypothalamic peptides that control anterior pituitary hormone secretion. The amino acid sequences of some important hypothalamic regulatory peptides are indicated schematically, reading left to right, N- terminal to C-terminal. TRH and GnRH, the smallest of the peptides, have modifications on both ends, with a pyroglutamyl moiety (red hexagon; see Figure 3-8 for structure) and amidation of the C-terminal carboxyl group (yellow diamond). CRH and GHRH have only the N-terminal modification, whereas somatostatin is not modified at either end. The sequence of somatostatin-28 is shown with both lightly and darkly shaded circles. The darker carboxyl terminal 14 amino acids are those of somatostatin-14.

Following secretion from its neurons into the portal circulation, GHRH binds to its receptor, GHRH-R, a G-protein coupled receptor on the somatrophs of the anterior pituitary. Increased cyclic AMP production leads to the increased synthesis of GH. Cyclic AMP also stimulates the opening of Ca2+ and K+ ion channels, which play roles in the secretion of existing GH from the cell, in its characteristic pulsatile fashion. Phospholipid signaling may also be involved in the exocytosis associated with the release of GH by the somatotroph when stimulated by GHRH. In addition to its effect on GH secretion and synthesis by somatotrophs, GHRH stimulates proliferation of these cells through the activation of the MAP kinase pathway.

GHRH and/or its receptor also occur outside the central nervous system in such tissues as the pancreas where it stimulates insulin, glucagon and somatostatin release; in the gastrointestinal tract where it stimulates gastrin release and stimulates epithelial cell division; and in tumors of many types.

2. Somatostatin

The stimulatory effect of GHRH on GH release from the anterior pituitary somatotroph is countered by the GH release-inhibiting hormone, somatostatin (SST), also known as somatotropin release inhibiting hormone (SRIH). The amino acid sequence of the two forms, somatostatin28 and somatostatin14, the forms that play the major role in the regulation of pituitary function in humans, are depicted in Figure 1. The periventricular nucleus (located rostral to the paraventricular nucleus) is the major site of somatostatin-producing neurons in the hypothalamus. In addition to its inhibitory effect on GH secretion by somatotrophs, for which it was named, somatostatin modulates a much broader range of peptides from the pituitary (e.g., TSH), as well as from the stomach, brain, intestine, and pancreas. For example, one of the somatostatin receptors (SSTR4) acts in the brain to decrease the Alzheimer’s related amyloid β peptide levels by increasing their rate of degradation.

There are five somatostatin receptors, designated SSTR1–SSTR5. These are encoded by separate genes on separate chromosomes. They differ in their tissue expression patterns, their affinities for various somatostatin agonists, and the G-proteins, and therefore the cell signaling pathways, to which they are coupled. Clearly this degree of variation allows somatostatin to have diverse effects in many different target tissues. Somatostatin14 has greatest affinity for SSTR2, which is responsible for the inhibition of the secretion of pituitary hormones, including GH. Upon ligand activation, SSTR2 binds the Gαi/o subunit, which inhibits adenylyl cyclase, diminshing cytoplasmic cAMP levels. SSTR2 activation also initiates opening of K+ channels and closure of Ca2+channels. Both of these mechanisms contribute to the suppression of pituitary growth hormone secretion.

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مواضيع ذات صلة

Regulation and Biological Actions of Growth Hormone and Prolactin

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