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
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
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
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.
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