Growth Hormone – A Pituitary Hormone Lecture NO : 2nd MBBS Dr Muhammad Ramzan

Growth Hormone (GH ) – the definition Somatotropin A polypeptide hormone (191 AA) secreted by the anterior pituitary gland that promotes the body growth It is also called as Somatotropin GH influences the metabolism of proteins, lipids and carbohydrates www.medicinent.com

GH – the background Primary function of the GH is the promotion of linear growth especially of the long bones GH is present in intra uterine life as IGF-2 for faetal growth and continues as such independently Most of the growth promoting effects in adults are mediated by Insulin like Growth Factor-1(IGF-1) IGF-1 is a protein, synthesized in the liver and stimulated by GH www.Brittania.com – www.ncbi.nlm.nih.edu – www.ghr. Ncbi.nlm.nih.gov.

Target organs- tissues with GHR/RTK Target organs are the ones with GH hormone /Tyrosine Kinase receptors. (TRK) Major target organs/tissues are : Bones (Chondrocytes); Liver, Adipose tissues, Skeletal muscles and Kidneys

Target organs - GHR/RTK Demerization GHR are predominantly present as dimmer with 3 domains : Extracellular, membranous and Cytoplasmic These receptors are mobile and single chain The 2 receptors are held together by trans membrane helices. The process is called dimerization

GH – the receptors (GHR/RTK)/Enzyme 3 Domains

Factors that increase GH synthesis/secretion GH is also promoted by physical; chemical, traumatic and surgical stresses Young age in Children and adolescence Good nutrition Prolonged exercise and hypoglycemia Low levels of IGF-1 in blood www.vivo.colostate.edu

Factors that reduce GH synthesis/secretion Old /advanced age Malnutrition in children Chronic diseases especially of liver that ↓ IGF-1 synthesis Hyperglycemia / glucose given orally or I/V Emotional stress

Factors affecting GH synthesis

GH – Regulation of secretion/synthesis Major Regulators - 2 Secretion of GH is stimulated by the hypothalamic GH Releasing hormone – GHRH 1 Is inhibited by the GH Inhibitory hormone GHIH from 2 Hypothalamus and : Serum level of Insulin like Growth Factor – IGF-1 3 (IGF- I level is inversely proportional to GH level) www.vivo.colostate.edu

Regulation of GH synthesis There are 2 pathways for the regulation of GH synthesis Neuro endocrine /long loop/Indirect regulation Pituitary - somatic/direct/short loop regulation

Regulation of GH

Neuro endocrine regulation It is the interaction B/W the circulating level of GH/IGF-1 and hypothalamic – Pituitary axis Low GH/IGF-1 level stimulates the hypothalamus to release GnRH which activates ant.pitu.to ↑ GH/IGF-1 synthesis Opposite is true when GH/IGF-1 is high by ↑ the GHIH (Growth hormone Inhibiting hormone}

Pituitary- Somatic pathway Pituitary – GH axis It is the interaction B/W the circulating level of GH/IGF -! Low GH/IGF -1 stimulates Ant. pituitary to ↑ the synthesis of GH to ↑ the serum level of GH/IGF- 1 Opposite is true when circulating level is of GH/IGF -1 is high

GH - Mechanism of action 2 pathways GH is a protein hormone and its mechanism of action is similar to the like ones- 2nd messenger system It acts through 2 mechanisms: Genomic through activation of Genes – Delayed Non genomic via 2nd messenger - Rapid (minutes)

GH - Mechanism of action - Genomic Summary GH binds with the receptor RTK – causes Demerization and auto phorylation of the tyrosine residues of RTK – 1st step Phosphorylation of the JAK2 and the intracellular tyrosine residues near RTK takes place in the next /2nd step STAT proteins are generated by the RER of the target organs; get attracted, phosphorylated and forms dimmer STAT are transcription factors and are translocated to the DNA. Transcription of mRNA; move to cytoplasm and translates proteins and enzymes to execute the actions of GH

GH – Genomic mechanism of action

GH - Mechanism of action (Genomic) Delayed action The major players are the GH receptor, Janus Kinase 2 , Signal Transducers and Activators of Transcription (STAT) Binding of the GH with receptor causes its Dimerization and Activation of both the receptor and receptor associated enzyme- Janus Kinase2 (JAK2) There is Rotation of the Cytoplasmic domain of GHR to remove the inhibitory Pseudokinase domain of one of the JAK2

GH - Mechanism of action (Genomic) cont GH - Mechanism of action (Genomic) cont. Translocation of STAT to Nucleus This removal restores the Kinase activity of the other JAK2 and vice versa which promotes the Phosphorylation of : Intracellular enzymes and proteins including the STAT factors STATS are Tranalocated to the nuclear genes (HRE)for the transcription of mRNA which moves to the cytoplasm mRNA Translates a no of Proteins and enzyme to execute GH actions STATS are synthesized in RER of target cell and act as transcription factors for the STAT genes

GH – Genomic action

GH- Non genomic mechanism 1 2nd messenger cGMP. Binding of GH with the receptor, causes its activation (Phosphorylation of tyrosine) as well as that of RAS activating Protein Activation of RAS protein results in the conversion of GDP to GTP that activates Adenylate Cyclase It alter GTP to cGMP as 2nd messenger 1. cGMP alters the activity of the proteins and enzymes to execute the GH actions

GH- non genomic mechanism

GH - Non genomic mechanism cont. IP3.DAG and NO as 2nd messenger Phospholipase C is another Membranous enzyme that is also activated by the cGMP cGMP acts on the Phospho Inositol Diphosphate (PIP2 ) and convert it into Inositol Tri phosphate (IP3) , Diacyl glycerol (DAG)and Nitric Oxide(NO) – All of them act as 2nd messenger which execute the GH action

GH- Non genomic mechanism of action Quick/rapid action

GH – the Metabolic role in general GH is an anabolic hormone that promotes the body growth through its actions on the : Protein metabolism Lipid and Carbohydrate metabolism Growth of long bones and availability of Ca and Po4

GH – Metabolic actions

GH – Action on protein metabolism stimulates protein synthesis It ↑ proteogenesis by increasing the entry of AAs in the cells Promotes growth by ↑in the no of cells, muscle and bone mass It stimulates genetic expression; mRNA and its translation into proteins and enzymes GH inhibits protein degradation - Proteolysis

GH – effects on Lipid metabolism Promotes Lipolysis GH increases Lipolysis and enhances serum level of FAs Promotes the oxidation of FAs to satisfy the growing energy needs of the growth Reduces the Lipogenesis and Adipose tissue mass `

Effects on CHO metabolism Hyperglycemic GH prevents the entry of glucose in the cells and ↑increases blood glucose level, is hyperglycemic Its actions are antagonistic to the actions of Insulin and promotes Insulin Resistance GH promotes Glycogenolysis and : Reduces Glycogenesis

GH and bones – ↑ length and mass of long bones GH promotes retention of Ca and Po4 through increased GIT absorption and resorption by kidney It promotes Osteogenesis and Ossification Promotes the length and mass especially the long ones

GH – Secretion abnormalities GH may be secreted in excess or there may be deficiency of its secretion/synthesis The excess or deficiency may happen in children when epiphysis of long bones are not united or : It may occur in adults when epiphysis are closed Clinical manifestations are quite different in both the conditions

GH – the excess in children and adults Excess of GH in children results in : Gigantism or Giantism when epiphysis is not united and increases the length of long bones of limbs Acromegaly in Adults with closed epiphysis that increases the mass but not the length of long bones

GH – the Deficiency In Children/adults results in dwarfism Deficiency of GH in children results in short stature and is called Dwarfism or pituitary dwarfism All physical parts of the body are in appropriate proportion but the rate of growth is greatly reduced GH deficiency in adults is rare