Growth Hormones & Growth Factors

Synthesis & Structure of Growth Hormone

Synthesized by somatotropes ( a subclass of anterior pituitary cells). It’s a single polypeptide hormone (191 amino acids), with 2 disulphide linkages.

GH, prolactin, chorionic somatomammotropin have similar sequence homology, therefore all have growth and lactating effects.

Growth Hormone Receptor

All receptors are proteins.

When GH binds to a cell surface receptor (receptor no.1), it will pull another cell surface receptor (receptor no. 2) and binds with it, causing dimerization of 2 GH receptors, forming a dimeric complex. The GH-dimeric receptor complex associates with and activates the JAK-2 protein (a tyrosine kinase) causing phosphorylation of the receptor and autophosphorylation of JAK-2 on tyrosine residues. This event will activate a number of signal pathways:

1) State protein activation & gene transcription

2) MAP kinase pathway activation

3) PI 3 kinase pathway activation

4) PLC activation, production of diacylglycerol & protein kinase C activation

The activation of these signal pathways will bring about actions of the growth hormone.

Control of Growth Hormone secretion

Growth hormone synthesis and secretion is regulated by GHRH / GHIH (Somatostatin).

When there are high levels of growth hormones – hypothalamus will release GHIH and decrease release of GHRH – therefore, growth hormone release will be lowered.

Besides the feedback mechanism regulating the secretion of GH, it is also influenced by plasma levels of:

1. Metabolic fuels
2. Stress
3. Sleep rhythms
4. Exercise
5. High glucose: Supress GH release
6. Low glucose: Increase GH release
7. High amino acid: Increase GH release
8. High fatty acids: Increase GH release

Actions of Growth Hormones

1) Growth

This growth effect is mediated by insulin-like growth factors (IGF/Somatomedins –Mediate), which are a family of growth promoting proteins produced by liver cells. It is produced when GH binds to it’s receptors. There are 4 IGFs:

• IGF-1 (somatomedin C) being the active factor.

Binds membrane receptors 70aa. Growth effects.

• IGF-II

Binds membrane receptors 67aa. 2 times higher in plasma levels than IGF-I

Only IGF-1 gives off growth effects, therefore one lack in IGF-1, but have IGF-2, will fail to grow normally –> GH deficient dwarfs & pygmies.

It is structurally similar to proinsulin (insulin-like). IGF is also originally known as ‘sulfation factor’ as it enhances the incorporation of sulfate into cartilage.

Growth effects are seen in: cartilage growth, linear bone growth (act on epiphyseal growth plates of long bones), width of bone (enhanced periosteal growth), visceral & endocrine organs, skeletal & smooth muscles, skin, C/T. Basically, growth in all aspects.

2) Protein Synthesis

GH increases transport of amino acids into muscle cells, increase protein synthesis (anabolic), and increases synthesis of RNA & DNA (also proteins) in some tissues.

Resembles some actions of insulin.

3) Carbohydrate metabolisme

• Increase hepatic glucose production (glyconeogenesis)
• Decrease tissue glucose uptake (more glucose in blood)
• Decreased rate of glycolysis (not used)
• Increased glycogen synthesis in liver (for storage, from increased glucose)

Oppose effect of insulin.

Therefore, prolonged administration of GH will result in diabetes mellitus.

4) Lipid metabolisme

• Promotes lipolysis (release of free FA & glycerol from adipose)
• Reduced synthesis of TG (in adipose)
• Increase free FA
• Increased oxidation of free FA in liver when taken into tissue (ketogenic – form ketone bodies)

GH favours usage of FA as fuel. Therefore, glucose remains high/conserved.

5) Stimulate production & release of IGFs in liver.

6) Mineral metabolisme

Promotes positive Calcium, Magnesium & Phosphate balance.

Bone growth:

• Promotes growth of long bones at epiphyseal plates in growing children.
• Promotes appositional/ acral growth in adults.

Causes retention of Na+, K+ & Cl-

7) Prolactin-like effect

Due to it’s similar structure, it can bind to lactogenic receptors. Causes stimulation of mammary gland (lactogenesis).

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Hyposecretion of GH

	GH	IGF-1	IGF-2	Response to GH Stimulation
GH- deficient dwarfs	Low	Low	Low/ Normal	YES
Pygmies	Normal	Low	Normal	No
Laron type dwarfs	High	Low	Low	No

GH-deficient dwarfs: Eventhough it responds to GH normally, but there is no GH. No GH, no IGF-1. Even in hypoglycemia, GH levels will fail to increase.

Pygmies: They lack IGF-1 eventhough there is normal GH. This is because IGF-1 is not produced when GH binds to GH receptor. Therefore, there is no growth. They have a post-GH receptor defect.

Laron type dwarfs: They have high amounts of GH, but it cannot bind to the GH receptor. They lack functional hepatic GH receptors.

Therefore, pygmies & Laron type dwarfs are due to target organ resistance.

Hypersecretion of Growth Hormones

Excess of GH is most often due to pituitary tumour.

In children:

Gigantism. It occurs before the epiphyseal plate closes, therefore there is accelerated growth of long bones.

In adults:

Acromegaly. It occurs after the epiphyseal plate closes, therefore there is cessation of long bone growth. Instead there is acral bone growth. Acral bone growth can be seen characteristically in facial changes (protruding jaw, enlarged nose) and enlargement of hands, feet and skull.

 

Even with hyperglycemia, patients with excessive GH from a tumor, will not be able to suppress GH levels.