"Medical Physiology Growth Hormone Brian Howell" 3/17

Question 1

Excess GH during childhood causes what pathology?

Answer 1

Excess GH in childhood (usually continues into adulthood) causes gigantism.

Excess GH in adulthood causes acromegaly. This can be from a GH secreting adenoma. These people have enlarged, protruding jaw, big hands, feet, carpal tunnel syndrome and reduced strength. Vision (from optic chiasm) and other hormonal effects may occur if the source is a pituitary tumor.

Question 2

What is dwarfism?

Answer 2

A childhood deficiency in GH.

Question 3

T/F: GH activates GPCRs because it is a polypeptide hormone.

Answer 3

True

Question 4

What is somatostatin’s effect on GH synthesis?

Answer 4

No effect. Somatostatin only inhibits GHRH release.

Question 5

What effect do drugs like ritalin have on GH?

Answer 5

Drugs like ritalin can stunt growth temporarily because they disrupt the GH surge which normally occurs during the first few hours of sleep.

Question 6

Name 3 positive mediators of GH.

Answer 6

Deep sleep
Strenuous exercise
puberty
stress
amino acids
fasting/hypoglycemia
sex steroids
alpha-adrenergic agonists
dopamine agonists

Question 7

Name 3 negative mediators of GH.

Answer 7

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

Question 8

How do amino acids increase GH release?

Answer 8

Amino acids increase GH release primarily by decreasing somatostatin release.

Question 9

What is GH-binding protein?

Answer 9

GH-binding protein binds GH in the circulation and prolongs its half life (normally about 20 min).

Question 10

What pathway does GH binding to its cytokine receptor induce?

Answer 10

GH activates the JAK2/STAT pathway of signal transduction.

Question 11

Why are Pygmies short?

Answer 11

Severe underexpression of the GH receptor.

Question 12

Where are GH receptors found?

Answer 12

GH receptors are found on many tissues, such as liver, bone, kidney, adipose tissue, muscle, eye, brain, heart and immune system cells.

Question 13

By what pathway does GHRH stimulate GH production?

Answer 13

GHRH acts on somatotrophs via GPCR and cAMP/Ca+ pathway. The transcription factor CREB is activates by protein kinase A, and augments transcription of Pit-1, which is another TF. Pit-1 upregulates GH and the GHRH receptor. Increased Ca levels lead to secretion of GH.

Question 14

Where is somatostatin synthesized?

Answer 14

Somatostatin and GHRH are both made in the hypothalamus, but by different cells. Neurons in the periventricular region of the hypothalamus synthesize somatostatin.

Neurons in the arcuate nucleus of the hypothalamus make GHRH.

Question 15

What is the action of somatostatin to precent GH secretion?

Answer 15

Somatostatin, which also uses the portal system to reach the anterior pituitary, inhibits adenyl cyclase, which lowers Ca levels, and thus prevents secretion of GH.

Question 16

What are the DIRECT effects of GH?

Answer 16

1. GH acts on the liver to produce IFG-1, and stimulates hepatic glucose production
2. GH acts on adipose tissue to stimulate the release and oxidation of free fatty acids, especially during fasting. GH mediates the reduced action of lipoprotein lipase, so less TGs and lipoproteins are removed from the bloodstream.

Question 17

What is the effect of GH on insulin?

Answer 17

GH blocks the action of insulin on lipid and glucose metabolism by decreasing skeletal muscle glucose utilization, increasing lipolysis, and stimulating hepatic glucose production.

Think of GH as an anabolic hormone, a starvation hormone.

Question 18

Why will people with acromegaly or gigantism develop type II diabetes?

Answer 18

GH’s effects on insulin (anti-insulin) lead to high circulating levels of blood glucose. Eventually, destruction of the beta cells in the islets of Langherhans occurs.

Question 19

Why does GH stimulate both osteoblasts and osteoclasts?

Answer 19

Osteoblasts for bone formation, and osteoclasts for bone remodeling.

GH supports the differential on prechondrocytes to chondrocytes, which influences the ossification process.
GH does this by acting directly on prechondrocyte (stem) cells, then IGF-1 gets involved with autocrine and paracrine stimulation of those cells to help them mature, make ECM etc.

Question 20

What are the roles of IGF-1 (insulin like growth factor-1)?

Answer 20

IGF-1 is made in the liver mostly. Some is made in the kidney and skin. IGF-1 circulates all day at a constant level.

IGF-1 feeds back to the hypothalamus to downregulate GH secretion.

IGF-1 is the primary screening test for GH deficiency since it is more detectable than GH (longer half life in blood) and more reflective of GH levels in normal individuals.

Question 21

T/F: Both carbohydrates and GH are needed for the liver to produce IGF-1

Answer 21

True

Question 22

What kind of receptors do insulin and IGF-1 have?

Answer 22

They both have tyrosine kinase receptors with similar structures.

Question 23

What signaling pathways are activated by IGF-1?

Answer 23

IGF-1 binding influences the IRS and Shc pathways, which leads to the IP3 pathway and Ras/MAP-k pathways which regulate celluluar transcription.

Question 24

Why can children with mutations in GH-1 gene not be given rhGH as replacement therapy?

Answer 24

The child will make antibodies to what is considered a foreign protein.
Children with even minimal levels of GH can be treated with rhGH because the body will recognize the hormone.

Question 25

What is the defect in Laron syndrome?

Answer 25

The defect in Laron syndrome is a point mutation or deletion in the GH receptor gene.
Symptoms are short stature, high (or normal) GH but low IGF-1.
Children are treated with rhIGH-1.
Laron syndrome is protective against cancer.
People with a Stat5b gene mutation have a similar phenotype.

Question 26

T/F: The insulin/IGF-1 pathway is thought to promote aging.

Answer 26

True

Question 27

T/F: Both high and low GH cause insulin resistance, vis different mechanisms.

Answer 27

True

Question 28

What is the most severe effect of GH deficiency in adulthood?

Answer 28

Increased interstitial fat, such as increasing carotid-media thickness, leading to cardiovascular disease (visceral adipose tissue deposition)

GH deficiency can be treated with exogenous GH.

Question 29

What diseases might inhibit normal growth of a child?

Answer 29

Inflammatory diseases ie celiac, IBS, Lupus, renal failure, collagen-vascular diseases, thalassemia, hypothyroidism

Chronic illness in general

Question 30

What accounts for the short stature in Turner Syndrome?

Answer 30

Haploinsufficiency of the SHOX gene, which is on the x-chromosome in the pseudoautosomal region.

Deletion of the SHOX gene causes short stature.

Patients with extra copies of X, like XXY Kinefelter’s, are taller than normal.

Question 31

T/F: Deletion of the pseudoautosomal region of either sex chromosome will result in short stature.

Answer 31

True