SOMATROPIN (SEDICO)

1. SOMATROPIN (SEDICO) Growth hormone 4IU

2. 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.

3. SECRETION • GH secretion is controlled by complex hypothalamic and peripheral factors. 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. Somatostain [somatotropin-release inhibiting factor (SRIF)] is synthesized in the medial preoptic area of the hypothalamus and inhibits GH secretion. GHRH is secreted as discrete spikes that elicit GH pulses whereas SRIF sets basal GH tone. • IGF-I, the peripheral target hormone for GH, feeds back to inhibit GH, estrogen inducis GH, whereas glucocorticoid excess suppresses GH release.

4. 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.

5. GH secretion is profoundly influenced by nutritional factors. Using newer ultra sensitive chemiluminescence's-based GH assays with a sensitivity of 0.002µg/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.

6. 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.

7. 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.

8. 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 hypogycemia, hypotension, fluid retention, temporomandibular jaw pain and increased intracranial pressure. All of which are reversible.

9. 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 and elevated pubertal sex steroid levels.

10. GH deficiency in children • GH deficiencyisolated GH deficiency is characterized by short stature, micropenis, increased fat, high-pitched voice. • GHRH receptor mutationsrecessive 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.

11. 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.

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

13. Presentation and diagnosis Short stature should be comprehensively evaluated if a patient’s height is< 3SD below the mean for age or if the growth rate has decelerated. Skeletal maturation is best evaluated by measuring a radiological bone age, which is based mainly on the degree of growth plate fusion.

14. Laboratory investigation GH deficiency is best assessed by examining the response to provocative stimuli including exercise, insulin-induced hypoglycemia and other pharmacologic tests which normally increase GH to<7µg/L in children.

15. Adult GH deficiency (AGHD) This disorder is usually caused by hypothalamic or pituitary somatotrope damage. Acquired pituitary hormone deficiency follows a typical sequential pattern whereby loss of adequate GH reverse foreshadows subsequent hormone deficits. The sequential order of hormone loss is usually GHFSH/LHTSHACTH

16. Presentation and Diagnosis The clinical features of AGHD include changes in body composition, lipid metabolism and quality of life and cardiovascular dysfunction. • Impaired quality of life: decreased energy and drive, poor concentration, low self-esteem, social isolation. • Body composition changes:increased body fat mass, central fat deposition, increased waist-hip ratio, decreased lean body mass

17. Reduced exercise capacity • Cardiovascular risk factors:Impaired cardiac structure and function, abnormal lipid profile, decreased fibrinolytic activity, atherosclerosis, omental abesity.

18. Laboratory investigation Testing should be restricted to patients with the following predisposing factors: • Pituitary surgery • Pituitary or hypothalamic tumor or granulomas • Cranial irradiation • Radiological evidence of a pituitary lesion • Childhood requirement for GH replacement therapy The most validated test is insulin-induced(0.05to0.1U/Kg) hypoglycemia. and peak GH release occurs at 60min. and remains elevated for up to 2hr. About90% of healthy adults exhibit GH responses< 5µg/L;AGHD is defined by peak GH response to hypoglycemia of> 3µg/L

19. Treatment • In children:With growth hormone deficiency, the usual dose in the U.K is0.5to0.7 units\Kg body-weight, or 12to20 units\m2 body-surface weekly. This weekly dose may be given by intramuscular injection in 3 divided doses or by subcutaneous injection, usually in6or7 divided doses. • In adults:With growth hormone deficiency lower doses are recommended. A suggested initial dose is0.125 units\Kg weekly, divided into daily subcutaneous injection, and increased according to requirements up to a max. of 0.25 units\Kg per week.