Growth hormone

Growth hormone (GH) is a peptide hormone that is made in and secreted from the somatotroph cells of the anterior pituitary gland, and which is essential for regulating post-natal growth in all mammals. In somatrotrophs, GH is stored in large, dense-cored secretory granules, which are secreted by calcium-dependent exocytosis. GH secretion from the pituitary depends on many factors, including stress, exercise, and the stage of the menstrual cycle.

GH exerts its effects by interacting with the GH receptor – a G-protein coupled receptor that is expressed by many cell types. GH increases bone mineral density, especially in longitudinal bones, but also influences many other processes that influence body composition, such as lipid metabolism. Many of the actions of GH are mediated by insulin-like growth factor-I (IGF-I) secreted from the liver in response to GH. GH secretion declines progressively during adulthood, and this decline becomes especially marked in elderly subjects. In individuals with severe GH deficiency, muscle mass, muscle strength and bone mass are all decreased, and the relative proportion of total and visceral fat is increased. Thus, GH promotes skeletal growth, increases catabolic rate, and promotes muscle growth rather than fat deposition.

Growth hormone deficiency

Short stature can be caused by impairments of either GH secretion or GH receptor function. Short stature in children with Prader-Willi syndrome, which is explained in part by a decreased GH secretory capacity, can be effectively treated with exogenous GH for one year. GH treatment to correct physical abnormality has to be continued indefinitely. In children with idiopathic short stature, growth failure may have any of several different causes. Some children with idiopathic short stature have low levels of plasma GH binding protein; this is a soluble form of theGH receptor which can bind GH, and the decreased GH binding protein activity in children suggests that they may present a degree of GH insensitivity because of a defect in the GH-receptor.

GH secretion in dwarfism

Dwarfism can arise by defects in GH production and release, or by defects in downstream signalling, and there are several animal models that exemplify this. For example, in dwarf (dw/dw) chickens, the overall GH mean, amplitude, and baseline concentrations are significantly higher than those of control normal-sized (Dw/dw) chickens, and no differences in peak length or peak frequency between genotypes are observed. By contrast, in the dwarf mouse strain (lit/lit), anterior pituitaries do not release GH or accumulate cyclic adenosine 3’ monophosphate (cyclic AMP) in response to human or rat GH releasing hormone (GHRH), whereas dibutyryl cyclic AMP, as well as the adenylate cyclase stimulators forskolin and cholera toxin, markedly stimulate GH release. Thus the basis of the GH deficiency in the little mouse may be a defect in an early stage of GHRH-stimulated GH release, related either to receptor binding or to the function of the hormone-receptor complex, while the defect in the dwarf chickens is a failure to respond to GH.

Pulsatile GH secretion

In all species studied to date, GH is released episodically. This pulsatile pattern of secretion is particularly marked in male rats, which show large pulses of GH secretion at approximately 3-h intervals with peak values higher than 200 ng/ml and basal values lower than 1 ng/ml. More continuous secretion and substantially higher basal concentrations are evident in female rats. This difference is an important contributor to the higher growth rate in males of most mammalian species.

Pulsatile GH secretion is governed mainly by two hypothalamic peptides: a stimulatory factor, GHRH (for GH releasing hormone, sometimes called GRF, GH releasing factor), and an inhibitory factor, somatostatin (sometimes called SRIF- somatotropin release inhibitory factor). These peptide factors reach the anterior pituitary gland via the hypophysial portal circulation after release from nerve endings in the median eminence. Measurement of immunoreactive GHRH and somatostatin concentrations in portal blood found episodic secretion of immunoreactive GHRH, with maximal concentrations during GH secretory episodes, and secretion of immunoreactive GHRH was accompanied by a reduction in portal plasma concentrations of immunoreactive somatostatin.

Hypothalamic control of GH secretion

GHRH is synthesised by a sub-population of neuroendocrine neurones in the arcuate nucleus of the hypothalamus, and somatostatin by a sub-population of neurones in the periventricular nucleus. These peptides are transported along axons to neurosecretory nerve endings in the median eminence, and released from nerve terminals into the hypothalamo-hypophysial portal blood circulation to influence the anterior pituitary gland.

In the rat there is a striking difference in the pattern of GH release between males and females. The male rat secretes GH in large 3-hourly pulses, and levels between pulses are very low. The female rat secretes more frequent pulses, but of lower amplitude, and these pulses are superimposed upon a constant background level of secretion. This sexually dimorphic pattern of secretion may be mediated by actions of oestrogen on the somatostatin neurones, since these cells are known to possess oestrogen receptors.

The pulsatile secretion of GH is of considerable biological significance, as has been clearly demonstrated by studies on a dwarf rat strain whose genes have given it an insufficiency of GH. Although normal growth may be induced in a dwarf rat by continuous exposure to GH, the same effect can be induced by much less GH if the normal endogenous pattern of secretion is mimicked. Thus for GH, pulses are a biologically efficient signal.

Physiological stimuli for GH release

Exercise is a potent stimulator of GH secretion in most species and has been studied extensively in man. The magnitude of the GH response depends upon several factors including the intensity and duration of acute exercise, the muscle mass used during exercise, and the degree of training.Food deprivation induces a dramatic alteration in GH secretion in all species studied. In rats, food deprivation inhibits pulsatile GH secretion, and refeeding results initially in low-amplitude pulses (at a higher frequency than the endogenous rhythm) giving way to normal 3h high-amplitude pulses within 6-8h. Exercise and diet have a major physiological influence upon the hypothalamic regulation of GH secretion, but the pathways involved in these influences are poorly understood.

New hormones regulating GH secretion?

An important new class of growth-hormone secretagogues came to the fore in the 1990's as agents of considerable therapeutic potential. These agents are mimetics of the synthetic hexapeptide GHRP-6, and now include orally active non-peptidyl compounds. GHRP-6 releases GH by a direct action at the pituitary: an action mediated by different receptors, and by a separate second messenger pathway, from those which mediate the actions of GRF. GHRP-6 also acts in the hypothalamus; following central or peripheral administration it increases the electrical activity of neurones in the arcuate nucleus, the principal location of the GRF cell bodies. GHRP-6 also induces expression of the immediate-early gene product Fos in the arcuate nucleus, but at no other hypothalamic or forebrain site (in many neuronal systems Fos expression is a marker of electrical activation, and Fos is thought to be involved as a transcription factor linking electrical activity to changes in gene expression). These characteristics of GHRP-6, that it is a selective secretagogue for GH, acting selectively at both hypothalamic and pituitary sites to stimulate GRF and GH release respectively, suggest that GHRP-6 is mimicking an endogenous ligand whose physiological role is specifically concerned with regulation of GH secretion. The receptor for these secretagogues was sequenced and cloned in 1996, and localised to the anterior pituitary and the hypothalamus, including in particular the arcuate nucleus and nentromedial nucleus. A peptide named “ghrelin”, originally purified from rat stomach but found also in humans, was reported in 1999, and identified as an endogenous ligand at this receptor. Ghrelin appears to be secreted from the stomach in considerable amounts – and may also be present in a small subset of neurones in the arcuate nucleus.