G 0

1. S G1 G2 G0 M

2. GHIH (or) SST (somatostatin) Hypothalamus: GHRH (+) (+) (-) GH (somatotropin) Anterior Pituitary: (-) Liver: IGF (somatomedins) Control of Secretion

3. indirect effects direct effects + + + Insulin-like Growth Factor carbohydrate metabolism lipolysis in fat cells fat cells muscle Increases FFA, glycerol, and sugars in circulation chondrocytes Protein synthesis lipogenesis cartilage formation GROWTH HORMONE

4. IGF binding proteins (IGFBPs) GH/IGF/IGFBP Axis Brain Pituitary Growth Hormone (GH) Liver Growth IGF

5. Insulin-like Growth Factor Binding Proteins (IGFBPs) • IGFBPs bind circulating IGF with high affinity & specificity • Functions: • act as carriers of IGF in plasma • prolong the half-life of IGF in circulation • regulate IGF access to receptor in extracellular fluid (!)

6. IGFBPs—two main types • IGFBP-3 • most abundant form of IGFBP • main carrier of IGF in circulation • promotes IGF mediated somatic growth • high IGFBP-3 associated w/ growth stimulation • IGFBP-1 • typically present in small amounts • high IGFBP-1 associated w/ growth inhibition

7. LIVER IGF IGFBP-3 Cell IGF receptor Growth Functions

8. LIVER IGF IGFBP-1 Cell IGF receptor Growth Functions

9. Summary • Growth factors move cell from G0 to G1 • Initiate cell cycle • Growth Hormone • Direct effects: • Lipolysis • Carbohydrate metabolism • Increase IGF secretion from liver • Indirect effects through IGF • Increase lipogenesis in fat cells • Increase protein synthesis in muscle • Increase cartilage formation and growth in bone • IGFBPs • IGFBP3 enhances growth • IGFBP1 inhibits growth

10. Clinical Aspects • Stress effects on Growth • Overproduction of GH • Underproduction of GH • End-organ resistance

11. implants controls Days after implantation Maternal Effect: GC effect on Offspring Japanese quail From Hayward LS & Wingfield JC (2004) GCE 135:365-371

12. Human Studies • low birth weight • slow weight gain • smaller head size • are delayed in their walking • reduced speech development

13. brought into the hospital months later Direct Effect:Stress-induced dwarfism

14. IGF binding proteins (IGFBPs) GH/IGF/IGFBP Axis GCs Brain Pituitary Growth Hormone (GH) Liver Growth IGF

15. 2 mg/g 10 mg/g control Plasma IGF (ng/ml) 0 2 4 8 24 Time (h) Effects of Cortisol on Plasma IGF • Cortisol ↓ plasma IGF levels • Effect takes 24 hours From Kajimura et al. (2003) JOE 178:91-99

16. 2 mg/g 10 mg/g control IGFBP-3 ODU IGFBP-1 ODU 0 2 4 8 24 Time (h) Effects of Cortisol on Plasma IGFBPs • ↓ plasma IGFBP-3 levels • ↑ plasma IGFBP-1 levels • Cortisol induces rapid changes in plasma IGFBPs Tilapia From Kajimura et al. (2003) JOE 178:91-99

17. Clinical Aspects • Stress Effects on Growth • GCs decrease growth • GCs can act through IGF or IGF binding proteins • Overproduction of GH • Underproduction of GH • End-organ resistance

18. Acromegaly -overproduction of GH -before puberty: gigantism (excessive growth of long bones) -in adults: causes excessive growth of cartilage -symptoms

19. Clinical Aspects • Stress Effects on Growth • GCs decrease growth • GCs can act through IGF binding proteins • Overproduction of GH • Acromegaly • gigantism • Underproduction of GH • Hypo-pituitary dwarfism • End-organ resistance

20. IGF levels

21. Clinical Aspects • Overproduction of GH • Acromegaly • gigantism • Underproduction of GH • hypopituitary dwarfism • Stress-induced dwarfism • End-organ resistance

22. Laron’s Syndrome • Defective GH receptor • recessive gene • Lethal in males

23. Clinical Aspects • Overproduction of GH • Acromegaly • gigantism • Underproduction of GH • Hypopituitary dwarfism • Stress-induced dwarfism • End-organ resistance • Laron’s Syndrome

24. bGH in Dairy Cows?

25. Pygmies from Central Africa