Lecture 13 - Pathophysiology of GH/IGF axis in postnatal life 1

Question 1

IGF-1 production: what is the process?

Answer 1

Hypothalamus - GHRH
Anterior pituitary (somatotrophs) - GH
Liver - IGF-1

Question 2

Somatostatin: what is it and what does it do?

Answer 2

Growth hormone inhibiting hormone

Inhibits growth hormone

Question 3

GH: what is it, what does it do, what tissues does it affect

Answer 3

Growth hormone

• Affects tissues directly
• Produces IGF-1 - indirect effect

Adipose - lipolysis
Muscle - protein synthesis (anabolism)
Liver - gluconeogenesis/glycogenolysis to increase glucose output

Question 4

IGF-1: what is it, what does it do, where is it produced, how does it exist in the body

Answer 4

Insulin-like growth factor-I

• Stimulate bone growth - may also stimulate more IGF-1 production
• Adipose - lipogenesis
• Muscle - protein synthesis (anabolism)
• Liver - decreases glucose output, increases tissue glucose uptake
• Insulin sensitivity - increases

Liver mostly (~75%) but also peripheral tissues too

IGF binding proteins mostly, less than 5% is free in circulation

Question 5

Endocrine IGF: what is it, how much IGF-1 does it produce, and what does it do?

Answer 5

Liver-derived IGF-1 (endocrine) IGF-I

~75%

Can increase bone growth in the absence of local IGF-I

Question 6

GH signalling pathways: how does it affect tissues, what is its structure, how does it become activated, what are pathways, and what decides what pathway occurs?

Answer 6

• Directly acting on tissues
• Indirectly acting on tissues (IGF-1)

Homodimer
Site 1 and 2

Site 1 and 2 binding causes a conformational change, allowing intracellular signalling binding (through Box1)

Pathway 1:
* Jak2 phosphorylates key tyrosine residues
* Allows STAT TFs to be phosphorylated and dimers (both homo and heterodimers)
* Dimer STAT TFs bind to promoter regions of genes and cause activation

Pathway 2:
* Src - MAPK/ERK pathway - gene TFs downstream (ER? or look at image again and take more notes)

Question 7

IGF1 receptor: what is the structure, what is it similar to, what pathways does its signalling have downstream, and what decides which pathway occurs?

Answer 7

2α2β

Similar to insulin receptor - hybrid receptors may occur

IRS1/SHIP phosphorylation - MAPK pathway (mitogenic functions)
IRS1 - PI3K/Akt pathway (cell survival/metabolism)

• Which signal molecules are expressed
• Number of contacts IGF-1 interacts with receptor?
• How long IGF-1 interacts with the receptor? (long time to dissociate - mitogenic pathway promoted)

Question 8

IGF-1: what receptors may it bind to and at what affinity does it bind to them?

Answer 8

IGFR - highest affinity
IGFR/IR hybrid - medium affinity
IR - lower affinity

Question 9

IGF binding proteins: what are they, what do they do, how do they release IGF-1, and what are the types?

Answer 9

Proteins that bind to IGF-1

Bind with higher affinity to IGF-1 than receptor - may help regulate IGF-1 activity

Post-translational modification affecting affinity (cleaving, (de)phosphorylation, glycosylation, etc (additional reading))

<5% IGF-free in the circulation

• IGFBP-1
• IGFBP-2
• IGFBP-3
• IGFBP-4
• IGFBP-5
• IGFBP-6

Question 10

IGFBP-1/2/4/6: what is their half life and how much of circulating IGF is found within them?

Answer 10

Short half-life (~0.5h)

15% in small (50kDa) binary complex

Question 11

IGFBP-3 + ALS and IGFBP-5: what is their half life and how much of circulating IGF is found within them?

Answer 11

Long half-life (10-16h)

80% in 150kDa ternary complex

Question 12

Bones: how are they affected by IGF-1 and GH, what are the layers, what do they do, and which are affected by GH/IGF-1?

Answer 12

During fetal growth, human growth rate is highest, requires high levels of IGF-1 and GH - IGF-1/GH act on the growth plate to cause bone growth

Epiphyseal bone - growth plate - metaphyseal bone

• Epiphyseal bone - near top of bone that connects to other bones
• Reserve zone - progenitor cells,
• Proliferative zone - GH/IGF-1
• Maturation zone - maturation into chondrocytes
• Hypertrophic zone - GH/IGF-1, produce
• Invasion zone
• Metaphyseal bone - located in the ‘neck’ of the bone

Growth plate is located between the neck (metaphyseal) and head (epiphyseal) of the bone

Question 13

Dual Effector Hypothesis: what is it?

Answer 13

Growth hormone causes bones to produce IGF-1 which causes bone growth

Question 14

Somatomedin Hypothesis: what is it and what were the issues with the hypothesis?

Answer 14

GH needed to stimulate IGF-1 in order to affect bones

Bone expresses GHR - why the receptor if not used? Dual effector hypothesis

Question 15

GH defects: what are the types and what do they result in?

Answer 15

• GH deficiency
• GH insensitivity - Laron, STAT5
• IGF deficiency/insensitivity

Short stature

Question 16

GH/IGF-1 diagnosis

Answer 16

• General investigations - karyotype, nutrition, bone age, etc
• Endocrine investigation - GH stimulation test and IGF-1 measurement
• Arginine - promoted GH production, used to detect if the issue is a GH or IGF-1 issue
• IGF-1 measurement - if low

Question 17

GH deficiency treatment: how does it work, what are the limitations, and how do people respond to the treatment?

Answer 17

Doses traditionally based on weight:
* Children - 25-50 μg/kg/day
* Adolescents – 25-100 μg/kg/day
* Adults – 6-25 μg/kg/day

Needs careful monitoring through IGF-I - (GH dose that maintains IGF-I at +2 SDS)

Response variable:
* Age - younger respond better
* Severity of GH deficiency - those with worse deficiencies respond better
* Response in the first year - better response is typically better and may even result in a normal end height

Question 18

Laron syndrome: what is it, what is it caused by, what does it result in, and what clinical features are there?

Answer 18

GHR loss-of-functions that result in a lack of effect of growth hormone

> 60 types of GHR LoF mutations (mostly nonsense or splicing mutations in extracellular domain but some disrupt dimerisation & signaling rather than hormone binding)

High circulating GH and IGF-1 + IGFBP-3 levels

• Facial features – protruding forehead, saddle nose
• Impaired muscle development
• Obesity
• Growth restriction – typically >5 S.D below normal adult height

Question 19

Laron syndrome treatment: what are the types, are there any adverse effects of these treatments, and if there are any why do they exist?

Answer 19

hrIGF-1 (mecasermin) at 40-120μg/kg

• Hyperglycaemia (49%)
• Lipohypertrophy (32%)
• Tonsillar/adenoid hypertrophy (22%)

Low IGF-1 means IGFBP-3 deficiency so ay IGF-1 used for treatment has a short half life so IGF-1 must be administered in very high amounts

Question 20

IGF deficiency/insensitivity defects: how common are they, what are the types, how severe are they, and how are they treated?

Answer 20

Rare (1 in a million globally)

Exon 4 deletion - inactivating mutation

• Severe intrauterine growth restriction
• Postnatal growth restriction

hrIGF-1 (mecasermin) at 40-120μg/kg

Question 21

GH excess: what is it most frequently caused by, what does it cause to occur,

Answer 21

Usually due to pituitary adenoma

Children/adolescents - gigantism
Adults - acromegaly

Question 22

Growth plates: when do they close, what promotes the closing, and what is their relation to conditions caused by GH excess?

Answer 22

End of puberty typically

Progenitors in the reserve zone apoptose due to estrogen

• GH excess before they close (children/adolescents) - gigantism
• GH excess after they close (adults) - acromegaly