Flashcards in L2 Growth Hormone Deck (24):
1
What is growth hormone?
- 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
2
Regulation of growth hormone secretion
- 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
3
Role of GHRH
- 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
4
Role of Ghrelin
- 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
5
Role of somatostatin on GH release
- Decreases pulse frequency
- Decrease pulse amplitude
- No impact on GH synthesis
- Inhibits GHRH release
- Synthesized by neurons in the periventricular region of the hypothalamus
6
How and when is growth hormone secreted?
- Pulsatile secretion, primarily at night and during strenuous exercise
- Larger amplitude during puberty
- # pulses/day stays constant
7
How does GHRH stimulate the release of GH?
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
8
How does somatostatin inhibit the release of GH?
Binds Gi coupled receptor --> inhibits adenylyl cyclase --> lowers [Ca2+]
9
What are the effects of GH on liver, adipose tissue, skeletal muscle, bone, and brain?
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
10
What stimulates GH secretion?
- 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)
11
What inhibits GH secretion?
- IGF-1
- Obesity
- Glucocorticoids
- Hyperglycemia
- Free fatty acids
- GH
- beta-adrenergic agonists
12
Effect of nutrient state on GH secretion
Fasting increases # and amplitude of GH pulses
Obesity decreases # and duration of GH pulses
13
GH activation of its receptor
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
14
IGF-1
- Stimulates growth
- Negative feedback to hypothalamus and pituitary to down-regulate GH secretion
- Clinical use: screen when considering GH deficiency
15
Signaling pathways activated by IGF-1 binding its receptor
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)
16
What causes the growth sprout at puberty?
Upregulation of GH/IGF-1
- Happens sooner for girls than boys
17
Growth hormone deficiency and replacement
- 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
18
Laron Syndrome
- 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
19
Gigantism
- Too much GH throughout life
- Typically have hyperglycemia
- 10% develop diabetes due to degeneration of beta cells of islets of Langerhans
20
Acromegaly
- Growth hormone excess in adults
- Protruision of the jaw, macroglossia (enlarged tongue), enlarged hands/feet, carpal tunnel, reduced strength
21
GH deficiency in adults
- 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
22
GH and aging
Decreases with age, thought to contribute to the loss of muscle mass and increased interstitial body fat that is seen with aging
23
What syndromes has the FDA approved the use of GH therapy for?
- Growth hormone deficiency
- Idiopathic short stature (ISS)
- Turner syndrome
- Prader-Willi syndrome
- Chronic renal insufficiency (DRI)
- Small for gestational age (SGA)
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