L2: Growth Hormone and IGFs

Growth hormone (GH= somatotropin): features

• 191 amino aid somatomammotropin

• secreted by somatotrophs

• similar to prolactin

Somatotrophs

• makes up around 40% of the anterior pituitary gland

GH release is stimulated by…

1. Hypothalamus→ growth hormone-releasing hormone

   • GHRH

2. Stomach→ Ghrelin

What is GH released inhibited by

• somatostatin

What does GH do?

1. promotes synthesis and release of somatostatin

   • → short-loop negative feedback

2. GHRH inhibits its own release

   • → ultra-short-loop feedback

How does GH circulate in the body

• in plasma

• bound to binding proteins

BUT:

• half life is still just 20 mins

this is unusual for a peptide hormone

How does the release of GH occur

• Erratic pulses

Men:

• consistently show a large peak in early hours of sleep

• driven by testosterone

Women:

• mean level is higher→ suggests there is other effects other than growth

• but more irregular

Childhood:

• high

• rising to a peak during puberty 

• declining but not zero over the preiod of adult life

exercise an other metabolic cues also promote release

GH levels in over the course of your life

What does GH act on?

1. activates membrane-based receptors

   • which occurs as pre-existiging dimers

2. When activated→ receptor activates JAK-2 (Janus kinase 2)

   • enzyme in the cytoplasm

3. This phosphorylates tyrosine residues on proteins

Metabolic role of GH in fasting: when is GH release

In response to:

1. hypoglycaemia

2. low free fatty acids (FFA) levels

Metabolic role of GH in fasting: these effects may be seen during…

• an overnight fast

• esp after several days of starvation

Metabolic role of GH in fasting: what does GH help to do

Preserve glucose for the brain:

1. by switching the metabolism of peripheral tissues towards the use of FFAs

2. promoting gluconeogenesis

Metabolic role of GH in fasting: how are GH effects antagonistic to insulin and analogous to cortisol

1. GH acts on adipose tissue→ to release FFAs

2. GH stimulates hepatic gluconeogenesis and glucose ouput

3. GH acts directly on insulin-sensitive target cells

   • such as muscles and adipocytes

   • to inhibit glucose uptake

   • → diabetogenic  effect→ ‘mimics what happens in diabetes’ but is not a pathology!

Growth hormone and growth: GH is also released in response to

• High amino acid levels:

  • arginine especially
    

Growth hormone and growth: what does GH do in this circumstanc?

• promotes uptake of amino acids into

  • muscle cells and chondrocytes

• Increases rates of protein synthesis

• cellular growth and differentiation is promoted in many other tissues

Therefore, GH helps to

1. Break down fat→ → Increase protein

• Used in dairy cows-. so promotes lactation

• Used to make animals leaner and more muscle

• Athletes?

  • if they alreayd have little fat→ will not make a differenece

Growth hormone and growth: why is control of growth complicated

• affected by environmental and genetic factors

  • → sex

Growth hormone and growth: other hormones and their connection with growth?

• e.g insulin and thyroid hormones

  • → NEEDED for growth

  • but

  • → do not CAUSE growth

Growth hormone and growth: significant deficiencies in growth are

• Dwarfism

Growth hormone and growth: possible causes of dwarfism

1. Pituitary dwarfism→ Failure to produce functional GH (for several reasons)

2. Dwarfism of Sindh→ defective GHRH receptor

3. Laron syndrome→ GH receptor mutations

   • lead to lack of IGF-1

4. Achondroplasia→ fibroblast growth factor receptor mutation

   • nothing to do with GH

   • most common form of dwarfism

   • Due to activating mutation of FGF recetpor

Note: the dwarfisms to do is GH→ rare and in proportion

Most common type of dwarfism→ limbs are smaller

Growth hormone and growth: what happens if in excess as a child>

Gigantism→ over secretion from a pituitray tumour

• Extreme height is due to overstimulation at the growth plates of the long bones

Growth hormone and growth: gigantism→ if growth hormone oversection occurs after the growth plates close…

1. height can no longer increase further

however:

• periosteal bone growth continues→ acromegaly

2. Anti-insulin effects of GH→ leads to diabetes

3. ALSO get poor eye sight→ due to tumour pressing on the Optic Chiasm

Effects of GH on growth plates: what does GH help to do

• control growth at the growth plates of long bones

  • e.g those in the limbs

1. chondrocytes there lay down catilage

2. becomes calcified

3. ultimately ossified→ allows the bone to elongate at these regions

4. As cartilage around them calcifies→ These cells themselves proliferate, hypotrophy and then die

5. Growth plates ‘close’ in late teens

   • fuse up, such that the bones cannot elongate any further

   • earlier in women than men

     • due to oestrogen

Description of growth plate strucutre/growth

1. Resting zone→ stem cells

2. Proliferate and get bigger_ .Proliferative zone→ chondrocytes

3. Bigger→ Hypertrophic zone→ chondrocytes

4. Get Calcified→ Calcifying cartilage→ bone

chonrocytes are cartilage cells

The thin layers of cartilage move away from eachother

oeastrogen induce closure of teh growth plates

Where does oestrogen come from in men?

• locally converted from testosterone

• Castrati→ castrated→ often taller because has more oestrogen

The somatomedin hypothesis: what is it

• most actions of GH on growth are mediated by insulin-like growth factor1

  • IGF-1→ somatomedin

• Released by the liver in response to GH

• IGF-1 stimulates elongation of long bones

The somatomedin hypothesis: why proposed?

• observation that cartilage from rates did not proliferate when incubated with GH alone

The somatomedin hypothesis: IGF features

• so-called because of their structural similarity to proinsulin

• forms a negative feedback mechanism:

The somatomedin hypothesis: how does it form a negative feedback mechanism

• increases somatostatin released

• by hypothalamus

• → inhibits GH production by the pituitary

The somatomedin hypothesis: IGF-1 plasma levels throughout lifetime

• increase with age

• peaking at puberty

• falling off in adulthood concomitatnt with decrased GH

The somatomedin hypothesis: how does it circulate the blood

• plasma binding proteins

  • → IGFBP₁ to IGFBP₆

• half like is 20 hours

  • compared to under 20 mins for GH

The somatomedin hypothesis: levels of these binding proteins are controlled by

• hormonal control of:

  • GH

  • Insulin

Challenging the somatomedin hypothesis 1: GH injection in growth plate

1. GH injection into a growth plate of a long bone in ONE LIMB

2. simtulates growth in the growth plate of this ONE LIMB

RESULT→ Local action of GH

Challenging the somatomedin hypothesis 2: GH injection in growth plate with IGF-1 removed 

removed by immunization with IGF-1 antiserium

1. GH to growth plate of ONE LIMB as before

2. But add IGF antiserum (removes IGF-1)

RESULT→ BOTH limbs grow similarly

Conclusion: GH actions within the growth plate requires IGF-1

Challenging the somatomedin hypothesis 3: if liver-derived (endocrine) IGF-1 is specifically knocked out

RESULT→ body growth is normal

These experiments suggest…

• IGF-1 is produced locally in target tissues

• under the influence of GH

→ Liver-derived IGF-1 may not be important for growth

this developed the→ Dual effector hypothesis

What is the dual effector hypothesis

• GH stimulates the differentiation of chondrocytes in the growth plate

• from precursors

and also

• the local formation of IGFs

→ drives further growth

IGF-1 (endocrine and paracrine) acts as a second affector→ promoting the proliferation of chondrocytes

What did experiment 3 suggest?

• that the endocrine IGF-1 is unimportant for growth

but this has been challenged!

Challenge to the results of experiment 3: is enocrine IGF-1 really unimportant?

• there was still some IGF-1 circulating in the plasma

• so, a reduction in IGFBPs might have resulted in higher effective IGF-1 levels than previously believed

→ later studies removing all circulating IGF-1 do show an effect on growth

In fact, IGF-1 is likely to be invovled both as…

1. Paracrine 

and

2. Endocrine signal

an ever-expanding number of endocrine, paracrine and autocrine factors are being implicated as promoting intracellular growth regulatory pathways

→ very complicated!

e.g thyroid hormones, leptin (tells the body there are availbale fat stores)

Experiment in IGF-1 knockout showed

• The bone has the SAME NUMBER of cells as the wild type

• → just smaller

• → so IGF doesn’t affect the number

Overall feedback of the GH

Why does GH not promote growth during starvation?: paradox?

• why would a hormones released during fasting

ALSO

• promote growth?

→ how can the body dissociate the catabolic and anabolic effects of GH and ensure that growth is not promoted when resources are not availabel?

Important note: hormones have different affects depending on other hormone interactions and environmental conditions/states

1. When Fed→ Insulin has permissive  effects on growth

2. When Fasting→ FGF21 promotes ‘GH resistance’

Why does GH not promote growth during starvation?: role of insulin in this question

• insulin has important permissive effects on growth:

  • IGF-1 production by the liver

  • reducing leverls of some IGF binding proteins

    • → increases the level of free and effective IGF-1

Why does GH not promote growth during starvation?: role of thyroid hormone in this question

• also required for normal growth

  • Levels of thyroid hormone decline when fasting

Why does GH not promote growth during starvation?: role of Fibroblast growth factor 21 (FGF21) in this question

• Released from the liver when fasting

  • in response to elevated free fatty acids levels

• promotes ‘growth hormone resistance’

  • e.g by reducing the amount of IGF-1 produced in reponse to GH

Why does GH not promote growth during starvation?: Therefore, combined effect of

• High GH

• low FGF21

• sufficient levels of insulin and thyroid hormone

→ required to promote growth

although many other factors are also involved

Interplay between GH and insulin

• GH release is promoted by high amino acid levels

but

• byt low glucose and FFA levels

Pathway when Glucose injection

1. High glucose, low amino s

2. Promote inculin

3. glucose uptake and use

   1. No growth coz growth hormone not PERMITTED by insulin co not enough aas

Pathway when fasting

1. Glucose low and aminos low

2. Hypoglycerimia promotes GH and is permissed by low insluin

3. Low gluose→ low insulin

4. GH promotes use of fat

5. FGF21 STOPS the GH growth effect

pathway when balanced meal

1. High glucose and aminos

2. Promotes insulin

3. AND promotes GH

4. FGF21 has no effect

5. Allows growth

Growth in utero: what is needed?

• Pituitary growth hormones→ not necessary

• IGF-1 and IGF-2→ important

  • imprinted genes

  • get paternal gene→ evolutionary arms race?

Growth in utero: production of IGF-1/2 are regulated before birth by…

• hormones 

  • inc: somatomammotropins and insulin

  This is why:

  • → pituitary growth hormone is not required

Example essay questions

1. Discuss the theoretical problems that you might encounter in designing and interpreting an experiment to investigate the effects of a hormone on the body.

2. Discuss the actions of the hormones in the growth hormone / prolactin family (NST 1B 1999: you’ll learn more about prolactin next term)

3. Is growth hormone inappropriately named?