W3 L9: Growth hormones 

  • It’s a somatotrope → secreted by somatotroph cells of anterior pituitary
  • Exerts it’s effects directly on most tissues in the body
  • Has 2 main types of effects:
    • stim. tissue growth
    • influences metabolism
  • Neurons in hypothalamus - release stim. hormone into portal circulation - acts on anterior pituitary cells - e.g. somatotrophs - will release 2nd hormone that acts on target organ
Human Growth Hormone (hGH)
  • Peptide hormone consisting of 191 amino acids
  • Signals by binding to tyrosine kinase receptors on outside of cells
  • Stimulates:
    • body growth
    • secretion of insulin-like growth factor (IGF)-1
    • stim. lipid breakdown
    • counteracts actions of insulin → prevents uptake of glucose

 

  • Tyrosine kinase receptor
  • Stimulation of growth factor receptor by growth hormone - so binds to receptor
  • Dimerisation (partnering) → leads to accessory proteins coming & allowing phosphorylation of receptor
  • Δ in shape that recruits additional kinase proteins → which phosphorylate to next substrate (kinase cascade)
  • Leads to migration of protein to nucleus to associate w/ other transcription factors & induce expression via transcription
  • Nuclear phosphatases remove phosphate gps → inactivates protein & return to cytoplasm
Control of Growth Hormone Release
  • GHRH is released by neurones in hypothalamus
  • GRHR is carried directly to anterior pituitary in the portal circulation → binds to specific receptors on somatotroph cells of anterior pituitary
  • Somatotroph cells release growth factor hormone into general circulation
  • GH binds to GH receptors in many tissues
  • In liver, binding of GH to GHR causes release of insulin like growth factor 1 (IGF-1)
  • IGF-1 binds to IGF-1 receptors on chondrocytes & osteoblasts in bone

 

  • Induces growth→ GH binds to GHR will induce expression of genes that ↑ proliferation & ↑ cell size & ↑ AA uptake to make more proteins ∴ cells ÷
Effects of growth hormone
  • ↑ tissue size by ↑ protein synthesis, RNA & DNA synthesis & ↑ mitosis
  • In liver - stim. IGF-1 production

On bone

  • ↑ protein deposition by chondrocytes & osteogenic cells
  • Differentiation of osteogenic cells into osteoblasts
  • Epiphyseal line → under line is where growth occurs - chondrocytes & osteolineage cells
  • Stim. from growth hormone - ↑ protein deposition e.g. ↑ collagen
    • cartilage cells → osteogenic cells → osteoblasts
    • osteoblasts ↑ bone length by ↑ calcium deposition
Insulin-like Growth Factors (IGFs)
  • Peptide growth factors, act via G protein coupled receptor signalling (via adenylyl clyclase)
  • 2 rel. factors IGF-1 & IGF-2
  • Synthesised in growing tissues e.g. bone, adipose & liver

Function

  • IGF-1 is important part of growth Hormone (GH) feedback control
    • stim. growth
  • IGF-2 most active in the embryonic phase of development where it stim. embryonic growth

In bone

  • All aspects of chondrocyte function (e.g. collagen/bone matrix production)
  • Formation & maturation of osteoblasts

   

Metabolic effects of growth hormone

In fasted state:

  • Drives for maintenance of blood glucose levels
    • in adipose & muscle - ↓ glucose uptake
    • in liver & adipose drives glycogenesis, gluconeogenesis (liver) & lipolysis (adipose)

     

Both direct & indirect (through IGF-1) effects on bone exist

 

Regulation & pathologies
When do we need GH?
  • It’s regulated based on physiological state:
    • Stress hormone - ↑ w/ neurogenic or physiological stress
    • acute hypoglycaemia is a trigger for release of GH
    • ↑ amino acids in blood stim. GH release
    • ↑[glucose]blood & ↑ free fatty acids → leads to inhibition of GH release
Feedback & physiological stim. of growth hormone
  • Low at birth as can’t walk- less stress on bones, which stim. GH secretion
  • Large peak before puberty due to high activity
  • Low in senescence due to sedentary lifestyle

 

 

  • Peak at 12 as you hit REM cycle & 3 when blood glucose drops
  • Male GH reference range: <3 μg/L
  • Female GH reference range: <8 μg/L

 

Pituitary Dwarfism
  • GH deficiency in children
  • Slow bone growth - fairly normal body proportions
  • If untreated, max. height ~ 4 ft
  • Associated w/ deficiencies in other pituitary hormones e.g. TSH gonadotrophins
    • result in abnormal body proportions, failure of sexual maturity
  • Treatment w/ GH replacement
    • GH deficiency ~ not life threatening
    • must be human GH (hGH)

Variants of dwarfism

  • Laron dwarfism
    • mutation of GH receptor gene (GHR)
    • single-base pair change Δ in GH receptor
    • reduced GH sensitivity
    • often low IGF-1 too

Pituitary Gigantism

  • hGH hypersecretion in children
  • rapid bone growth - fairly normal body proportions
  • individuals may reach ~ 8 ft
  • rare clinically, only happens in children
  • e.g. benign tumour that excessively secretes GH
Acromegaly
  • ↑ hGH secretion during adulthood
    • only some bones responsive to GH
    • more common than gigantism
  • Enlargement/thickening of hands, feet, jaw & face
  • Thickening of soft tissues
    • e.g. coarsening of facial features
  • Treatment usually surgical
    • anatomical changes are irreversible