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SOMATROPIN
Disease diagnosis and treatment    

Synthesis:
GH is the most abundant anterior pituitary hormone and GH-secretion somatotrope cells constitute up to 50% of the total anterior pituitary cell population.
The pituitary GH gene produces two alternatively products that give rise 22-kDa GH(191 amino acids) and a less abundant, 20-kDa GH molecule, with similar biologic activity.

Secretion:
GH secretion is controlled by complex hypothalamic and a peripheral factor:
GHRH is stimulates GH synthesis and release Ghrelin or gastric-derived peptide, as well as synthetic agonists of the GHRP
    receptor stimulate GHRH and also directly stimulate GH release.
    GHRH is secreted as discrete spikes that elicit GH pulses whereas SRIF sets basal GH tone.
Somatostain" Somatotropin Release Inhibiting Factor (SRIF)" is synthesized in the medial preoptic area of the
    hypothalamus and inhibits GH secretion.
IGF-I, the peripheral target hormone for GH, feeds back to inhibit GH, estrogen induces GH, whereas glucocorticoid excess
    suppresses GH release.

GH secretion is pulsatile, with greatest levels at night. Generally correlating with the onset of sleep. GH secretory rates decline markedly with age so that hormone production in middle age is about 15% of production during puberty. These changes are paralleled by an age-related decline in lean muscle mass.

GH secretion is also reduced in obese individuals, though IGF-I levels are usually preserved, suggesting a change in the set point for the feed back control. Elevated GH levels occur within an hour of deep sleep onset as well as after exercise, physical stress, trauma and during sepsis.

Integrated 24-h GH secretion is higher in women and is also enhanced by estrogen replacement. Using standard essays, random GH measurements are undetectable in~50% of daytime samples obtained from healthy subjects and are undetectable in most obese and elderly subjects. Thus, single random GH measurements do not distinguish patients with adult GH deficiency from normal persons.

GH secretion is profoundly influenced by nutritional factors. Using newer ultra sensitive chemiluminescence's-based GH assays with a sensitivity of 0.002 µg/L, a glucose load can be shown to suppress GH to > 0.7µg/L in female and to > 0.07µg/L in male subjects. Increased GH pulse frequency and peak amplitudes occur with chronic malnutrition or prolonged fasting. GH is stimulated by high-protein meals and by L-arginine. GH secretion is induced dopamine and apomorphine ( a dopamine receptor agonist), as well as by α-adrenergic pathways, β-adrenergic blockage induces basal GH and enhances GHRH- and insulin-evoked GH release.

GH induces protein synthesis and nitrogen retention and impairs glucose tolerance by antagonizing insulin action. GH also stimulates lipolysis, leading to increased circulating fatty acid levels, reduced omental fat mass and enhanced lean body mass. GH promotes sodium, potassium and water retention and elevates serum levels of inorganic phosphate. Linear bone growth occurs as a result of complex hormonal and growth factor actions, including those of IGF-I.

Insulin-like growth factors:
Through GH exerts direct effects in target tissues, many of its physiological effects are mediated indirectly through IGF-I, a potent growth and differentiation factor. The major source of circulating IGF-I is hepatic in origin. Peripheral tissue IGF-I exerts local paracrine actions that appear to be both dependent and independent of GH. Thus, GH administration induces circulating IGF-I as well as stimulating IGF-I expression in multiple tissues.

Physiology:
Though IGF-I is not an approved drug. Investigational studies provide insight into its physiologic effects. Injected IGF-I
    (100µg/Kg) induces hypoglycemia and lower doses improve insulin sensitivity in patients with severe insulin resistance
    and diabetes. in IGF-I infusion enhances nitrogen retention and lowers cholesterol levels. Bone turn over may also be
    stimulated by IGF-I.
IGF-I side effects are dose-dependent, and overdose may result in hypoglycemia, hypotension, fluid retention,
    temporomandibular jaw pain and increased intracranial pressure. All of which are reversible.

Disorders of growth and development:
Skeletal maturation and somatic growth:
The growth plate is dependent on a variety of hormonal stimuli including GH, IGF-I, sex steroids, thyroid hormones, paracrine growth factors. The growth-promoting process also requires caloric energy, amino acids, vitamins and trace metals and consumers about 10% of normal energy production.
Bone age is delayed because of:
GH deficiency
Hypogonadism
Thyroid hormone deficiency
Elevated pubertal sex steroid levels.

GH deficiency in children:
GH deficiency isolated GH deficiency is characterized by:
Short stature
Micropenis
Increased fat
High-pitched voice

GHRH receptor mutations:
Recessive mutations of the GHRH receptor gene in subjects with severe proportionate dwarfism are associated with low basal GH levels that can’t be stimulated by exogenous GHRH, GHRP or insulin-induced hypoglycemia.

Growth hormone insensitivity:
This is caused by defects of GH receptor structure or signaling. homozygous or heterozygous mutationsof the GH receptor are associated with partial or complete GH insensitivity and growth failure (laron syndrome) this diagnosis is based on normal or high GH levels.

Nutritional short stature:
Caloric deprivation and malnutrition, uncontrolled diabetes and chronic renal failure represent secondary causes of GH receptor function. Children with these conditions typically exhibit features of acquired short stature with elevated GH and low IGF-I levels. Circulating GH receptor antibodies may rarely cause peripheral GH insensitivity.

Psychosocial short stature:
Emotional and social deprivation lead to growth retardation accompanied by delayed speech, discordant hyperphagia and attenuated response to administered GH.

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