S
G0
G1
G2
M
Control of Secretion
Hypothalamus:
GHIH (or)
SST (somatostatin)
GHRH
(+)
GH
Anterior Pituitary:
(-)
Liver:
(-)
(somatotropin)
IGF (somatomedins)
(+)
GROWTH HORMONE
indirect effects
direct effects
+
+
Insulin-like Growth Factor
lipolysis in fat cells
fat cells
+
carbohydrate
metabolism
muscle
Increases FFA, glycerol, and sugars
in circulation
chondrocytes
lipogenesis
cartilage formation
Protein synthesis
GH/IGF/IGFBP Axis
Brain
Pituitary
Growth Hormone (GH)
IGF binding proteins (IGFBPs)
Liver
Growth
IGF
Insulin-like Growth Factor Binding Proteins
(IGFBPs)
IGFBPs bind circulating IGF with high
affinity & specificity
Functions:
1.
2.
3.
act as carriers of IGF in plasma
prolong the half-life of IGF in circulation
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
LIVER
IGF
IGFBP-3
Cell
IGF receptor
Growth Functions
LIVER
IGF
IGFBP-1
Cell
IGF receptor
Growth Functions
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
Clinical Aspects
•
•
•
•
Stress effects on Growth
Overproduction of GH
Underproduction of GH
End-organ resistance
Maternal Effect: GC effect on Offspring
Japanese quail
implants
controls
Days after implantation
From Hayward LS & Wingfield JC (2004) GCE 135:365-371
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
GH/IGF/IGFBP Axis
GCs
Brain
Pituitary
Growth Hormone (GH)
IGF binding proteins (IGFBPs)
Liver
Growth
IGF
Effects of Cortisol on Plasma IGF
Plasma IGF (ng/ml)
0
2
4
Time (h)
Cortisol ↓ plasma IGF levels
Effect takes 24 hours
10 mg/g
8
24
From Kajimura et al. (2003) JOE 178:91-99
2 mg/g
control
Effects of Cortisol on Plasma IGFBPs
2 mg/g
control
10 mg/g
ODU
IGFBP-3
↓ plasma IGFBP-3 levels
plasma IGFBP-1 levels
Cortisol induces rapid
changes in plasma IGFBPs
ODU
↑
IGFBP-1
0
2
4
Time (h)
8
24
From Kajimura et al. (2003) JOE 178:91-99
Tilapia
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