Basic Physiology of Growth Hormone and its Secretion

[Spook]

Basic Physiology of Growth Hormone and its Secretion

Robert Bennett MD, FRCP




Growth hormone is essential for normal linear growth and the attainment of an adult mature height. It also plays an important role in the cartilage growth and the attainment of normal bone mass. There is only one rheumatic disorder, namely acromegaly, in which abnormalities of growth hormone production play a major etiological role. However, there is increasing appreciation that suboptimal growth hormone secretion, leading to a state of adult growth hormone deficiency, may occur in the setting of chronic inflammatory disease, chronic corticosteroid use and fibromyalgia..



Regulation and activities of the hypothalamic pituitary IGF 1 axis

GH secretion is pulsatile due to a tonic inhibition by the hypothalamic secretion of somatostatin in conjunction with a pulsatile secretion of GHRH (1;2). Serum GH levels are usually undetectable between pulses. There are approximately 10 pulses of GH secretion per day, lasting about 90 minutes, and separated by about 128 minutes (3). Peak GH secretory activity occurs within an hour after the onset of deep sleep (4;5). Exercise, physical activity and sepsis are associated with increased GH secretion. In general, women have any increased daily integrated growth hormone secretion compared to men. But on the other hand, men have an increased pulsatility compared to women; this is thought to be an important determinant to linear growth, as the tissue response to GH appears to be determined by the pulsatility of GH secretion rather than the absolute amount of GH that is secreted. Peak serum GH concentrations are 4.3 ± 0.7 ng/ml at night and 2.7 ± 0.5 ng/ml during the day. Besides, the critical actions of GHRH and somatostatin in controlling GH, its secretion is also influenced by several other factors. For instance, serotonin, dopamine, enhanced a2-adrenergic tone and GABA receptor stimulation all lead to an increase in GH secretion. Whereas GH itself, IGF-1, enhanced b-adrenergic tone, IGF-1 and cortisol, all inhibit GH secretion. Furthermore several drugs, fasting, estrogen levels, and exercise, all modulate GH production (6;7). GH secretion is lower in elderly, postmenopausal and obese subjects. Estrogen replacement improves GH secretion.



Over the past few years this classical view of growth hormone secretion was been complicated in 1996 by the identification and cloning of an endogenous GH secretagogue receptor. This is structurally different from the receptor for GHRH and its ligand, ghrelin, was discovered in 1999. Ghrelin is a 28 amino acid peptide produced by endocrine cells within the stomach that increases appetite and stimulates GH secretion. Ghrelin secreting cells have also been reported in the intestine, pancreas, hypothalamus and testis. There is inverse relationship between body weight and plasma ghrelin levels. However, its precise role in modulating the pulsatile release of GH is not yet fully elucidated. It is increasingly evident that ghrelin has other actions which include increased gastric motility and acid secretion, stimulation of endocrine and exocrine pancreatic function, modulation of the pituitary gonadal axis and stimulation of slow wave sleep (8-11). Ghrelin levels are reduced by about 80% after total gastrectomy and to a lesser extent by gastric bypass surgery. So far the only rheumatic disorder which has been studied as regards ghrelin is fibromyalgia. In a report on 19 patients with fibromyalgia and 14 healthy controls there was no significant difference in plasma ghrelin levels (12).



Physiology and actions of GH and IGF-1

Growth hormone has multiple actions which serve to promote linear growth, increased muscle mass and reduce fat stores (see table 1) (13). These actions are in part due to direct effects of GH, but most are mediated via the effects of IGF 1 (see table 2). With increased availability of supplemental growth hormone therapy it has become increasingly apparent that GH has subtle but important effects on the general sense of well-being.

GH acts by binding to a specific receptor in the liver leading to the production and secretion of IGF-1. The GH receptor is a 70 kd protein which is dimerized by interaction with GH. This is followed by a complex second signaling cascade that involves phosphorylation through various protein kinases. Mutations of the GH receptor are associated with partial or complete GH insensitivity and growth failure (Laron dwarfism)

Insulin like-growth factor I (IGF-I) is a small protein of molecular weight 7,647 that is secreted into the blood under the control of growth hormone (14). Some 75% of IGF 1 is secreted by the liver the other 25% is synthesized and peripheral tissues resulting in both autocrine and paracrine responses. It is 99% protein-bound to one of six IGF binding proteins (IGFBPs). These function to transport IGF and control access to extra-vascular spaces. IGFBP-3 has the highest affinity for IGF-1 and is the most abundant of the binding proteins. However, it is usually fully saturated and the second most abundant binding protein, IGFBP-2 accounts for the greatest changes in the levels of free IGF-1. The levels of are IGF binding proteins are positively influenced by the magnitude of growth hormone secretion and reduced by deficiency states of testosterone, estrogen and thyroxine (14).



The blood levels of IGF 1 very greatly over the lifespan. Peak values are reached in early puberty (300 – 500 ng/ml) and fall rapidly to about 40% of the peak value by age 20. Thereafter, they decline by about 3 ng/ml/year. Twin studies have indicated that about 40% an individual's IGF 1 is related to undefined genetic factors. Nutritional status significantly affects blood IGF one levels. For instance, a seven-day fast decreases the IGF-1 level by about 50%. Disorders associated with malnutrition such as renal failure, severe liver dysfunction and chronic inflammatory disorders such as Crohn's disease also result in reduced IGF 1 levels. There is a strong inverse correlation between growth hormone secretion and obesity, especially intra-abdominal fat deposits. However, there is often a paradoxical effect of obesity on IGF 1 levels, as in some obese subjects the IGF 1 level is normal whereas in others it maybe elevated or depressed. This discrepancy between growth hormone secretion and IGF 1 levels is probably due to increased levels of IGFB-3 in obese patients.





References



(1) Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998; 19(6):717-797.

(2) Muller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone secretion. Physiol Rev 1999; 79(2):511-607.

(3) Tannenbaum GS. Genesis of episodic growth hormone secretion. J Pediatr Endocrinol 1993; 6(3-4):273-282.

(4) Veldhuis JD, Iranmanesh A. Physiological regulation of the human growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis: predominant impact of age, obesity, gonadal function, and sleep. Sleep 1996; 19(10 Suppl):S221-S224.

(5) Van Cauter E, Plat L, Copinschi G. Interrelations between sleep and the somatotropic axis. Sleep 1998; 21(6):553-566.

(6) al Damluji S. Adrenergic control of the secretion of anterior pituitary hormones. Baillieres Clin Endocrinol Metab 1993; 7(2):355-392.

(7) Cordido F, Casanueva FF, Dieguez C. Cholinergic receptor activation by pyridostigmine restores growth hormone (GH) responsiveness to GH-releasing hormone administration in obese subjects: evidence for hypothalamic somatostatinergic participation in the blunted GH release of obesity. J Clin Endocrinol Metab 1989; 68(2):290-293.

(8) Gualillo O, Lago F, Gomez-Reino J, Casanueva FF, Dieguez C. Ghrelin, a widespread hormone: insights into molecular and cellular regulation of its expression and mechanism of action. FEBS Lett 2003; 552(2-3):105-109.

(9) Lazarczyk MA, Lazarczyk M, Grzela T. Ghrelin: a recently discovered gut-brain peptide (review). Int J Mol Med 2003; 12(3):279-287.

(10) Broglio F, Gottero C, Arvat E, Ghigo E. Endocrine and non-endocrine actions of ghrelin. Horm Res 2003; 59(3):109-117.

(11) Weikel JC, Wichniak A, Ising M, Brunner H, Friess E, Held K et al. Ghrelin promotes slow-wave sleep in humans. Am J Physiol Endocrinol Metab 2003; 284(2):E407-E415.

(12) Otero M, Nogueiras R, Lago F, Meijide J, Amarelo J, Mera A et al. Ghrelin plasmatic levels in patients with fibromyalgia. Rheumatol Int 2003; .

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(14) Hall K, Hilding A, Thoren M. Determinants of circulating insulin-like growth factor-I. J Endocrinol Invest 1999; 22(5 Suppl):48-57.

[Spook]

Growth hormone, also known as somatotropin, 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.

Physiologic Effects of Growth Hormone
A critical concept in understanding growth hormone activity is that it has two distinct types of effects:


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-1 (IGF-1), 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-1 acting on its target cells.
Keeping this distinction in mind, we can discuss two major roles of growth hormone and its minion IGF-1 in physiology.

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-1. IGF-1 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-1 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
Growth hormone 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-1 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, growth hormone stimulates protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis and decreased oxidation of proteins.


Fat metabolism: Growth hormone enhances the utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes.


Carbohydrate metabolism: Growth hormone 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 growth hormone 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 growth hormone.
Growth hormone secretion is also part of a negative feedback loop involving IGF-1. High blood levels of IGF-1 lead to decreased secretion of growth hormone not only by directly suppressing the somatotroph, but by stimulating release of somatostatin from the hypothalamus.

Growth hormone also feeds back to inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph.

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. In children and young adults, the most intense period of growth hormone release is shortly after the onset of deep sleep.

Disease States
States of both growth hormone deficiency and excess provide very visible testaments to the role of this hormone in normal physiology. Such disorders can reflect lesions in either the hypothalamus, the pituitary or in target cells. A deficiency state can result not only from a deficiency in production of the hormone, but in the target cell's response to the hormone.

Clinically, deficiency in growth hormone or receptor defects are as growth retardation or dwarfism. The manifestation of growth hormone deficiency depends upon the age of onset of the disorder and can result from either heritable or acquired disease.

The effect of excessive secretion of growth hormone is also very dependent on the age of onset and is seen as two distinctive disorders:

Giantism is the result of excessive growth hormone secretion that begins in young children or adolescents. It is a very rare disorder, usually resulting from a tumor of somatotropes. One of the most famous giants was a man named Robert Wadlow. He weighed 8.5 pounds at birth, but by 5 years of age was 105 pounds and 5 feet 4 inches tall. Robert reached an adult weight of 490 pounds and 8 feet 11 inches in height. He died at age 22.


Acromegaly results from excessive secretion of growth hormone in adults. The onset of this disorder is typically insideous. Clinically, an overgrowth of bone and connective tissue leads to a change in appearance that might be described as having "coarse features". The excessive growth hormone and IGF-1 also lead to metabolic derangements, including glucose intolerance.
Pharmaceutical and Biotechnological Uses of Growth Hormone
In years past, growth hormone purified from human cadaver pituitaries was used to treat children with severe growth retardation. More recently, the virtually unlimited supply of recombinant growth hormone has lead to several other applications to human and animal populations.

Human growth hormone is commonly used to treat children of pathologically short stature. There is concern that this practice will be extended to treatment of essentially normal children - so called "enhancement therapy" or growth hormone on demand. Similarly, growth hormone has been used by some to enhance atheletic performance. Although growth hormone therapy is generally safe, it is not as safe as no therapy and does entail unpredictable health risks. Parents that request growth hormone therapy for children of essentially-normal stature are clearly misguided.


The role of growth hormone in normal aging remains poorly understood, but some of the cosmetic symptoms of aging appear to be amenable to growth hormone therapy. This is an active area of research, and additional information and recommendations about risks and benefits will undoubtedly surface in the near future.


Growth hormone is currently approved and marketed for enhancing milk production in dairy cattle. There is no doubt that administration of bovine somatotropin to lactating cows results in increased milk yield, and, depending on the way the cows are managed, can be an economically-viable therapy. However, this treatment engenders abundant controversy, even among dairy farmers. One thing that appears clear is that drinking milk from cattle treated with bovine growth hormone does not pose a risk to human health.

Another application of growth hormone in animal agriculture is treatment of growing pigs with porcine growth hormone. Such treatment has been demonstrated to significantly stimulate muscle growth and reduce deposition of fat.