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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; .

   (13)   Argente J, Pozo J, Chowen JA. The growth hormone axis: control and effects. Horm Res 1996; 45 Suppl 1:9-11.

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

 

 

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