Pituitary Physiology

Question 1

Growth hormone - general notes on structure/function

Answer 1

• Starts as prohormone
• Contains many introns and exons, can be spliced for different types of GH
• Most important type is 191 AA long
• Signal peptide cleaved, stored in secretory granules of somatotrophs of adenohypophysis
• Secretion controlled primarily by GHRH & somatostatin (GH feeds back on both of these)
  
  • GHRH –> increased GH –> increased cAMP
  • Somatostatin –> decreased GH –> decreased cAMP
• Increased serum AA –> increased GH
  
  • Test by injecting arginine
• Decreased serum glucose –> increased GH
  
  • Significant counter-regulatory hormone for insulin action
• Metabolically GH dominates; with growth IGF dominates

Question 2

Effects of GH malfunction (table)

Answer 2

Question 3

Prolactin: actions and MOA

Answer 3

• Tonically inhibited by hypothalamic secretion of prolactin inhibitory hormone (PIH) aka dopamine
• If hypothalamus is inhibited: adenohypophysis secretes larger amounts of PRL, other pituitary hormones
  
  • Lactotrophs secrete PRL
• Principal target (and main site of action): breast (mammary gland)
  
  • Plays role in production of milk
• High levels of PRL inhibit pulsatile secretion of GnRH by hypothalamic neurons
• Specific receptors in: breast, liver, ovary, testis, prostate
• Prolactin receptors –> members of growth hormone/cytokine receptor families
  
  • Long form of receptor: 620 AA’s in length
  • Single chain proteins, cross the membrane only once
  • Ligand binding causes receptor dimerization –> activation of JAK/STAT pathway
• PRL/GH share structural homology (so do their receptors)
• PRL receptors well-stimulated by GH

Question 4

Direct action of growth hormones on organs and systems

Answer 4

• Adipose tissue
  
  • Increases lipolysis, leads to mobilization of lipids and increased FFAs in plasma
  • Leads to eventual loss of subcutaneous fat
  • GH is counter-regulatory to insulin
• Muscle –> strong anabolic effect
  
  • Increases amino acid transport and protein synthesis
• Liver –> increases RNA, protein, glucose synthesis
  
  • Increases IGF-1 secretion in presence of insulin, mediates indirect effects
  • Increases glucose due to increase in gluconeogenesis and glycogenolysis (small extent)
• General –> GH is anti-insulin-like (decrease glucose uptake/increase glucose in plasma)
  
  • FFAs in plasma provide energy source
  • Glucose preserved for CNS
  • Protein sparing

Question 5

Other effects of growth hormone on organs and systems

Answer 5

• Fundamental for postnatal growth
  
  • Stimulates somatic growth
  • Regulates metabolism
• Indirect actions: mediated via IGF-1
  
  • Powerful mitogen and growth-promoting agent

Question 6

MOA of growth hormone through binding to its receptor

Answer 6

• Cytokine receptor
• Dimerizes on GH binding
• Activates JAK/STAT pathway –> gene expression

Question 7

Effects of IGF-1: bone/cartilage

Answer 7

• Stimulates proliferation of epiphyseal plate
• After puberty, linear growth at plate stops (growth plates close)

Question 8

Effects of IGF-1: muscle

Answer 8

• Stimulates proliferation, differentiation, protein synthesis
• Particularly post-puberty

Question 9

Effects of IGF-1: adipose tissue

Answer 9

• Stimulates uptake of glucose and inhibits lipolysis
• Function is insulin-like and antagonizes GH

Question 10

Effects of diet on IGF-1 function

Answer 10

• Production of IGF-1 requires GH and insulin –> only grow in times of plenty!
  
  • Normal diet –> nice balance
  • Eating lots: increased serum AA –> increased GH and increased glucose –> increased insulin –> increased IGF
  • Starvation: decreased serum AA –> increased GH and decreased glucose –> decreased insulin –> no IGF
• Thus in times of fasting: GH elevated but IGF-1 levels are depressed
  
  • Safety mechanism for body saying not to waste energy on growth

Question 11

MOA of IGF-1

Answer 11

• Receptors are EGF/Insulin receptor family
• Inherent tyrosine kinase activity
• Upon ligand binding, can readily phosphorylate themselves (autophosphorylation) and other proteins of signal transduction pathway
• Major pathway –> IGF binds to insulin receptor associated proteins 1 and 2 (IRS I & II) –> IRS then bind other moelcules to activate either:
  
  • MAP kinase pathway, or
  • Transduction mediated by PI-3 kinase