G0G0 G1G1 S G2G2 M

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

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

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

Insulin-like Growth Factor Binding Proteins (IGFBPs) IGFBPs bind circulating IGF with high affinity & specificity Functions: 1. act as carriers of IGF in plasma 2. prolong the half-life of IGF in circulation 3. regulate IGF access to receptor in extracellular fluid (!)

IGFBPs—two main types 1.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 2.IGFBP-1 typically present in small amounts high IGFBP-1 associated w/ growth inhibition

IGFBP-3 IGF IGF receptor LIVER Cell Growth Functions

Cell IGF receptor LIVER IGFBP-1 IGF

Summary Growth factors move cell from G 0 to G 1 –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

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

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

Human Studies 1. low birth weight 2. slow weight gain 3. smaller head size 4. are delayed in their walking 5. reduced speech development

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

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

Effects of Cortisol on Plasma IGF Cortisol ↓ plasma IGF levels Effect takes 24 hours From Kajimura et al. (2003) JOE 178:91-99 control 2  g/g10  g/g Time (h) Plasma IGF (ng/ml)

Effects of Cortisol on Plasma IGFBPs ↓ plasma IGFBP-3 levels ↑ plasma IGFBP-1 levels Cortisol induces rapid changes in plasma IGFBPs From Kajimura et al. (2003) JOE 178:91-99 Tilapia control 2  g/g10  g/g IGFBP-3 ODU Time (h) ODU IGFBP-1

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

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

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

IGF levels

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

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

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

bGH in Dairy Cows?

Pygmies from Central Africa