University:
West Coast University
Course:
PHAR 837 | IPC Infectious Diseases I
Academic year:

2024
Views:

489

Pages:

22
Author:

Asal A.

3 preorgimdow CacoB and knowneed to trail Asking Growth Hormone Disorders Fred Farris, PhD Andenohypophysis Histology Am I Growth Hormone protain • 191 amino acid peptide with 2 disulfide linkages • Structure closely resembles that of prolactin • Human cadaver pituitaries (past) • Recombinant DNA (identical amino acid sequence as endogenous GH) Growth Hormone • Main Function – to promote linear growth • Increases lean muscle mass • Promotes lipolysis • Increase bone mineralization • Promotes gluconeogenesis and reduces hepatic uptake of glucose • Promotes organ growth • Supports immune system S GH and Insulin-Like Growth Factor – 1 (IGF-1) • Main functions of GH is to promote linear growth • Growth promotion effects primarily mediated by IGF-1 or Somatomedin C • Endocrine IGF-1 mainly secreted by liver • Bone, cartilage, muscles, kidney secrete autocrines or paracrines to stimulate local growth • Unlike GH effects on body growth, its effects on metabolism are direct • Direct binding to cell receptors 6 Insulin-Like Growth Factor - 1 • Member of the insulin related peptides • Peptide of 70 amino acids with MW 7,649 Da • Similar to insulin with A and B chains connected by two disulphide bonds • The C-peptide is 12 amino acids • Binds with low affinity to insulin receptor and elicit at least partial agonist response Growth Hormone Pharmacodynamics • Mediate effects via cell surface receptors of the JAK/STST cytokine receptor superfamily • JAK – Just Another Kinase; Janus Kinase • STAT – Signal Transducer and Activator of Transcription Growth Hormone Release •Secreted in pulsatile fashion •In response to blood glucose levels •Highest levels following onset of deep sleep •Secretion high in children, peaks during puberty, decrease in adults in age related manner •Circulating half-life of 20 min for endogenous GH •Exogenously administered GH given QD •Persists for ~ 36 hr with peak at 2-4 hr Regulation of GH Secretion 1. Secretion or GHRH from the hypothalamus 2. GHRH stimulates somatotropic cells to secrete GH 3. GH acts on cells to promote metabolic Rxns or to release IGFs 4. Elevated GH and IGFs inhibit release of GHRH and GH 5. GHIH secreted from hypothalamus 6. GHIH inhibits somatotropic cells from secreting GH Growth Hormone Effects •In both adults and children GH has: •Anabolic effects on muscle •Catabolic effects on adipose tissue •Shift balance of body mass to increase muscle and decrease adiposity •GH and IGF-1 have opposite effects on carbohydrate metabolism •GH reduces insulin sensitivity  mild hyperinsulinemia and increased blood glucose levels •IGF-1 has insulin-like effects on glucose transport Growth Hormone Deficiency •Deficiency may result from genetic, congenital or acquired etiology •Neonates with isolated GH deficiency are typically normal size – prenatal growth is not GH-dependent • In contrast, IGF-1 is essential for normal prenatal growth •IGF-1 expression and growth become GH-dependent during the first year of life •In childhood, GH deficiency typically presents as, shortstature, often with mild adiposity, and mild hypoglycemia Pathophysiology of GH Deficiency Dwarfism • Prader-Willi Syndrome • Turner’s Syndrome – Genetic • Failure to thrive • Psychosocial dwarfism • Nutritional deficiency • Could be reversible without GH therapy if intervened early Rx for GH Deficiency Pathophysiology of GH Excess • GH excess generally results from somatotroph adenoma • Giantism – Excess linear growth • If GH excess is experienced before epiphyseal plate closure • Difference between tall/pituitary giantism • Bones grow longer but not necessarily stronger • Weakness in muscles, ligaments, soft tissues • Reduction in mobility (awkward and slow movements) • Low life expectancy • Acromegaly • Excess GH after adult height is reached • Excessive growth of bones, cartilage, and other organs • Surgery is Rx of choice for adenomas • If inoperable, then pharmacotherapy Giantism/Gigantism Acromegaly Rx of Growth Hormone Excess • If surgery does not bring GH levels low enough • Somatostatin (GHIH) analogs • GH receptor antagonists • Dopamine receptor antagonists • Somatostatin (GHIH) • Inhibits release of GH but also insulin • Hyperglycemia • Very short half-life = 2-3 minutes • Octreotide – Somatostatin analog • 45X potent than GHIH but only 2X as potent against pancreatic islets • Less hyperglycemia at therapeutic dose • Plasma half-life 80 minutes; given q8h • Octreotide acetate – longer actin formulation • IM depot; Given Q4weeks • Lanreotide – half-life 23-30 days; Given q4weeks Rx of Growth Hormone Excess • Pegvisomant is a GH receptor antagonist • PEG derivative of mutant GH • Reduces circulating IGF-1 levels by 97% • Does not inhibit GH secretion • Rebound increase in circulating GH • May affect liver enzymes – monitoring needed • Dopamine agonists – bromocriptine and cabergoline (ergot alkaloids) • Approved for acromegaly with surgery, radiation, and octreotide • Dopaminergic effects – nausea, vomiting, anxiety, headaches, lightheadedness • Psychiatric effects can also happen Growth Hormone Excesss Acromegaly and Giantism Acknowledgements ◦ The contents of many of the slides used in this presentation were adapted from material originally prepared by Dr. Gauri Sabnis – Many Thanks for her assistance

Growth Hormone Disorders

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