L2 Growth Hormone

Question 1

What is growth hormone?

Answer 1

• Polypeptide hormone made in the anterior pituitary
• Increases cell size and proliferation
• Important role in growth and development, regulates metabolism
• Half life ~20 minutes (bound to GH binding protein)
• Excess during childhood = gigantism
• Deficiency during childhood = dwarfism
• Excess during adulthood = acromegaly

Question 2

Regulation of growth hormone secretion

Answer 2

• Stimulated by GHRH and Ghrelin
• Inhibited by Somatostatin (inhibits anterior pituitary)
• Negative feedback from IGF-I (produced by liver in response to GH) –> inhibits GHRH and activates somatostatin

Question 3

Role of GHRH

Answer 3

• Increases GH gene transcription
• Promotes GH release
• Stimulates production of GHRH receptor
• Stimulates somatostatin release via negative feedback loop
• Synthesized by neurons in the arcuate nucleus of the hypothalamus

Question 4

Role of Ghrelin

Answer 4

• Stimulates hunger
• Produced in stomach and pancreas
• Levels increase before meals and decrease after
• Acts on growth hormone secretagogue receptor
• Likely more important for feeding behavior, energy reg, sleep than GH secretion
• Target for anti-obesity drugs

Question 5

Role of somatostatin on GH release

Answer 5

• Decreases pulse frequency
• Decrease pulse amplitude
• No impact on GH synthesis
• Inhibits GHRH release
• Synthesized by neurons in the periventricular region of the hypothalamus

Question 6

How and when is growth hormone secreted?

Answer 6

• Pulsatile secretion, primarily at night and during strenuous exercise
• Larger amplitude during puberty
• # pulses/day stays constant

Question 7

How does GHRH stimulate the release of GH?

Answer 7

GHRH binds Gs receptor –> raises [cAMP] –> activates PKA –> phosphorylates CREB –> changes transcription of Pit-1 –> upregulates GH and GHRH receptor.
- Increase [Ca2+] levels leads to secretion of GH

Question 8

How does somatostatin inhibit the release of GH?

Answer 8

Binds Gi coupled receptor –> inhibits adenylyl cyclase –> lowers [Ca2+]

Question 9

What are the effects of GH on liver, adipose tissue, skeletal muscle, bone, and brain?

Answer 9

Liver: stimulates production of IGF-1 and hepatic glucose production
Adipose: release of FA during fasting. Mediated by reduction of lipoprotein lipase. Reduces lipogenesis
Skeletal muscle: Stimulates amino acid uptake, suppresses protein degradation, stimulates cell proliferation, increases metabolism
Bone: supports stem cell differentiation into chondrocytes
Brain: affects mood and behavior

Question 10

What stimulates GH secretion?

Answer 10

• Deep sleep
• Exercise
• Sex steroids
• Fasting/hypoglycemia (clinical test)
• Amino acids (decrease somatostatin release)
• Stress
• alpha-adrenergic agonists
• Dopamine agonists (reduced in pts with acromegaly)

Question 11

What inhibits GH secretion?

Answer 11

• IGF-1
• Obesity
• Glucocorticoids
• Hyperglycemia
• Free fatty acids
• GH
• beta-adrenergic agonists

Question 12

Effect of nutrient state on GH secretion

Answer 12

Fasting increases # and amplitude of GH pulses

Obesity decreases # and duration of GH pulses

Question 13

GH activation of its receptor

Answer 13

GH binds transmembrane receptor –> changes dimer –> activates JAK2 by autophosphorylation –> phosphorylates/activates STAT transcription factors –> translocate to nucleus and activate transcription
- Under-expression of receptor contributes to short stature of Pygmies

Question 14

IGF-1

Answer 14

• Stimulates growth
• Negative feedback to hypothalamus and pituitary to down-regulate GH secretion
• Clinical use: screen when considering GH deficiency

Question 15

Signaling pathways activated by IGF-1 binding its receptor

Answer 15

Binds –> dimerization –> autophosphorylation –> recruits and phosphorylate binding proteins IRS-1 and Shc –> recruits other proteins to membrane –> activation of PI3K and Ras/MAP kinase pathways (reg. transcription)

Question 16

What causes the growth sprout at puberty?

Answer 16

Upregulation of GH/IGF-1

- Happens sooner for girls than boys

Question 17

Growth hormone deficiency and replacement

Answer 17

• Causes: congenital absence of pituitary stalk, TBI, cranial radiation, mutations in GH-1 gene (can’t be treated with rhGH - will make AB against)
• Children have extremely slow growth <2 inches/year

Question 18

Laron Syndrome

Answer 18

• Growth hormone insensitivity, causes severe post-natal growth failure
• Point mutation or deletion in GH receptor
• Low IGF-1 concentration
• Normal or elevated GH concentration
• Autosomal recessive - heterozygotes show mild growth retardation
• Tx with rhIGF-1

Question 19

Gigantism

Answer 19

• Too much GH throughout life
• Typically have hyperglycemia
• 10% develop diabetes due to degeneration of beta cells of islets of Langerhans

Question 20

Acromegaly

Answer 20

• Growth hormone excess in adults

- Protruision of the jaw, macroglossia (enlarged tongue), enlarged hands/feet, carpal tunnel, reduced strength

Question 21

GH deficiency in adults

Answer 21

• Usually caused by pituitary problems, can be from surgery or radiation
• Causes increased interstitial fat, reduced strength, bone loss, anxiety and depression
• Tx with rhGH
• Test by trying to stimulate GH secretion pharmacologically

Question 22

GH and aging

Answer 22

Decreases with age, thought to contribute to the loss of muscle mass and increased interstitial body fat that is seen with aging

Question 23

What syndromes has the FDA approved the use of GH therapy for?

Answer 23

• Growth hormone deficiency
• Idiopathic short stature (ISS)
• Turner syndrome
• Prader-Willi syndrome
• Chronic renal insufficiency (DRI)
• Small for gestational age (SGA)

Question 24

What causes the short stature seen in Turner Syndrome?

Answer 24

• Haploinsufficiency of the SHOX gene
• SHOX is expressed throughout the fetal growth plate, most concentrated in hypertrophic zone during childhood
• SHOX locus in pseudoautosomal region of Xp