Cairo University Faculty of Pharmacy Department of Pharmacology & Toxicology

1. Growth Hormone (somatotrophin) Cairo University Faculty of Pharmacy Department of Pharmacology & Toxicology Pharmacology III Practical Sessions

2. Hormones Pharma-III Practical • GH is the most abundant anterior pituitary hormone which is synthesized and secreted by somatotrophs. “Somatotrophs are cells in the anterior pituitary These cells constitute 40-50% of anterior pituitary cells. They respond by releasing GH in response to GHRH (somatocrinin) or are inhibited by GHIH (somatostatin), both received from the hypothalamus”

3. Hormones Pharma-III Practical Daily GH secretion varies throughout life; - secretion is high in children - it reaches maximal levels at puberty and then decreases in an age-related manner in adulthood. GH release is PULSATILE; GH is secreted in discrete but irregular pulses. Between these pulses, circulating GH falls to levels that are undetectable with most current assays . The amplitude of secretory pulses is maximal at night, and the most consistent period of GH secretion is after the onset of deep sleep.

4. Sleep Emotional Factors Exercise, fasting Neurotransmitters (DA, 5-HT & NE) Drugs (dopamine agonists) GH Release Hormones Pharma-III Practical Regulation of secretion Hypothalamus GHRH + SST ̶ ̶ ̶ AnteriorPituitary GH GH liver Target tissues ̶ Liver, muscle, bone, adipose and other tissues IGF-1

5. Hormones Pharma-III Practical • Insulin-like growth factor 1 (IGF-1) (somatomedin C) is one of the mediators of GH action. It plays an important role in childhood growth and continues to have anabolic effects in adults. • IGF-1 is produced primarily by the liver as an endocrine hormone as well as other target tissues. Its production is stimulated by GH. • Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin and lungs. IGF-1 regulates cell growth and development, especially in nerve cells as well as cellular DNA synthesis.

6. Hormones Pharma-III Practical Physiologic Effects of Growth Hormone it has two distinct types of effects: • Direct effects: are the result of growth hormone binding to its receptor on target cells. For example on Fat cells (adipocytes). • Indirect effects: are mediated primarily by IGF-1. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.

7. Hormones Pharma-III Practical Pharmacological actions of GH

8. Hormones Pharma-III Practical 1- Effects on Growth • GH stimulates the liver and other tissues to secrete IGF-I. • IGF-I stimulates differentiation and proliferation of chondrocytes(cartilage cells), resulting in bone growth. • IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts.

9. Hormones Pharma-III Practical 2- Metabolic Effects of GH • Protein metabolism: GH stimulates protein anabolism in many tissues, increases amino acid uptake, increases protein synthesis and decreases oxidation of proteins. • Fat metabolism: GH enhances the utilization of fat by stimulating lipolysis and mobilization of FFA from adipose tissues.

10. Hormones Pharma-III Practical • Carbohydrate metabolism: GH is one of the hormones that serves to maintain blood glucose within a normal range. GH has anti-insulin activity utilization of glucose by peripheral tissues GH also gluconeogenesis hepatic glucose output Bothhyperglycemia insulin secretion(hyperinsulinemia).

11. Hormones Pharma-III Practical Clinical DisordersI) GH Deficiency Causes: ↓GHRH -Pituitary hypoplasia (↓GH ) - ↓IGF-1 (generation/actions) - Receptor defects Children Dwarfism “Short stature with normal body proportion Adults  Hypopituitarism “↓ GH + other pituitary hormones (ACTH, TSH, FSH, LH, PRL) ” Treatment: Synthetic GH (Somatrophin) Synthetic GHRH(Sermorelin)

12. Hormones Pharma-III Practical GH Deficiency

13. Hormones Pharma-III Practical II) GH overproduction Mainly benign pituitary tumor (↑GH) Other rare causes: ↑GHRH (hypothalamus) Children Gigantism “increased longitudinal growth”

14. Hormones Pharma-III Practical Adults (after epiphyseal closure) Acromegaly • enlargement of hands and feets (acral parts)  paresthesias and joint pain • coarsening of facial features, protrusion of lower jaw (prognathism) • soft tissue overgrowth, cardiomegaly • Gynecomastia and galactorrhea (hyperprolactinemia)

15. Hormones Pharma-III Practical Mortality rate is high in untreated acromegaly patients mainly due to tissues overgrowth causing: cardiomegaly, upper airway obstruction and GIT malignancies. Treatment of excess GH disorders: - Synthetic Somatostatin (Octreotide) - DA agonists (Bromocriptine) - Surgical removal / Radiotherapy of the tumor - GH Antagonists (Pegvisomant)

16. Hormones Pharma-III Practical Diagnosis of GH disorders * Magnetic resonance imaging (MRI) is useful to confirm pituitary adenoma

17. Hormones Pharma-III Practical GH Deficiency GH Excess Following aProvocative test (provoke GH releasee.g. insulin-induced hypoglycemia - agents as: arginine, L-dopa) • Serum GH level < 10 ng/ml  GH deficiency • Serum GH level < 5 ng/ml Severe GH deficiency OGTT Oral glucose tolerance test ↓ In response to a 75g glucose challenge: - Normal subjects: suppress GH level <1 ng/ml - Patients with excess GH either: fail to suppress or further increase GH level.

18. Hormones Pharma-III Practical Assessment • LARON SYNDROME. • What is carpal tunnel syndrome ? • Mention the relation between acromegaly &this syndrome.

19. *LARON SYNDROME : is an autosomalrecessive disorder characterized by an insensitivity to growth hormone (GH), caused by a variant of the growth hormone receptor. It causes short stature . this disorder is mainly associated with mutations in the gene for the GH receptor. These can result in defective hormone binding to the receptor its action after hormone occupancy. There are exceptionally low levels of insulin-like growth factor (IGF-1) and its principal carrier protein, insulin-like growth factor binding protein 3. Administration of GH has no effect on IGF-1 production, therefore treatment is mainly by biosynthetic IGF-1. IGF-1 must be taken before puberty to be effective.

20. What is carpal tunnel syndrome? Mention the relation between acromegaly &this syndrome. Carpus means "wrist." The wrist is surrounded by a band of fibrous tissue . The tight space between this fibrous band and the wrist bone is called the carpal tunnel. The median nerve passes through the carpal tunnel to receive sensations from the thumb, index, and middle fingers of the hand. Any condition that causes swelling or a change in position of the tissue within the carpal tunnel can squeeze and irritate the median nerve. Irritation of the median nerve in this manner causes tingling and numbness of the thumb, index, and the middle fingers -- a condition known as "carpal tunnel syndrome." Xss GH (acromegaly )cause enlargement in acral part that presses on nerve causing parathesia.

21. Hormones Pharma-III Practical