Growth Hormone Flashcards
1
Q
growth hormone
A
- single chain polypeptide hormone
- produced in anterior pit
- half life of 20 minutes
- excess in childhood-gigantism
- adult- acromegaly
- deficiency during childhood-dwarism
2
Q
regulation of GH secretion
A
- hypothalamus- GHRH, somatostatin
- stomach and pancreas- ghrelin
- all activate G protein coupled receptors
- targets in most tissue
3
Q
hypothalamic control of GH secretion
A
- GHRH-dominant signal
- somatostatin inhibits
- integration results in episodic, pulsatile secretion
4
Q
GHRH
A
- increases GH gene transcription
- promotes GH release
- stimulates production of GHRH
- stimulates somatostatin release (brakes no out of control)
5
Q
somatostatin
A
- decreases pulse frequency
- decreases pulse amplitude
- no impact on GH synthesis
- inhibits GHRH release
6
Q
ghrelin
A
- stomach and pancreas
- stimulates hunger
- levels increase before meals and decrease after
- acts on growth hormone secretagogue receptor
- feeding behavior, energy regulation, sleep?
7
Q
pulsatile secretion of growth hormone over lifespan
A
- pulses primarily at night
- number of pulses per day stays nearly constant
- larger pulse amplitude during puberty
- strenuous exercise can cause surger
8
Q
ritalin
A
- can cause short stature
- because disrupts sleep and secretion of GH
- can catch up if good nutrition is maintained
9
Q
stimulation of GH secretion
A
- deep sleep
- exercise
- sex steroids
- fasting/ hypoglycemia
- amino acids
- stress-like severe stress/nutritional loss
- alpha adrenergic
- dopamin agonists (suppress in acromegaly)
10
Q
inhibitors of GH secretion
A
- IGF-I
- obesity
- glucocorticoids
- hyperglycemia
- free FA
- GH
- beta adrenergic agonists
11
Q
effect of nutrient state
A
- obesity decreases- number of GH pulses, duration of pulse
- fasting increases-number of pulses, amplitude of pulses
12
Q
insulin induced hypoglycemia
A
- used as a clinical test to provoke GH secretion in suspected GI-deficient individuals
- aa increase GH primarily by decreasing somatostatin release
- GH binds to GH binding protein which prolongs life
13
Q
GH Regulation/effects
A
- GHRH from hypothal increases GH, somatostatin decreases
- GH important in child development and metabolism
- some effects mediated by somatomedins-IGF1 produced by liver or target tissues
14
Q
actual release of GH
A
- GHRH stimulates Gs protein receptors in somatotroph cells
- increases cAMP and calcium, causes release of GH
- cAMP activates PKA, phosphorylates CREB, upregulates Pit-1 which upregulates GH
15
Q
paraventricular region
A
- synthesize somatostatin
- inhibits through Gi
16
Q
GH activation of its receptor
A
-transmembrane receptor in cytokine receptor family
-must dimerize for signal transduction
-major sites of action:
bone, liver adipocyte, muscle
-JAK/STAT
-binding causes dimerization of receptor and binding of JAK tyrosine kinase 1, induces phosphorylation of JAK kinases as well as receptor 2
-activated JAKs subsequently P the STATs- which go to the nucleus and act as TFs
-leads to expression of CISH and established GH target gene
17
Q
effects of GH
A
- postnatal longitudinal growth
- direct and indirect effects
18
Q
GH in liver
A
- stimulates IGF1
- stimulates hepatic glucose production
19
Q
adipose tissue
A
- GH stimulates release and oxidation of free FA, especially during fasting
- mediated by the reduction in activity of lipoprotein lipase
- lipogenesis reduced
20
Q
skeletal muscle-GH
A
- anabolic actions
- stimulates aa uptake and incorporation into protein
- suppresses protein degradation
- stimulates cell proliferation, increases metabolism and changes muscle fiber distribution
21
Q
brain effects of GH
A
-mood and behavior
22
Q
gh overall
A
counteracts action of insulin on lipid and glucose metabolism by decreasing skeletal muscle glucose use, increasing lipolysis and stimulating hepatic glucose production
23
Q
effect of GH on bone
A
- increase aa uptake
- increase protein syn
- inc DNA and RNA syn
- inc chondroitin sulfate
- inc collagen
- inc cell size and number
- supports differentiation of mesenchymal stem cells into chondrocytes
- local IGF1 induces clonal expansion of early chondrocytes and maturation of later
- leads to synthesis of ECM proteins including typ II collagen, hyaluronic acid and mucopolysaccharides
- as cells move toward trabecula they become calcified
24
Q
GH and food
A
- stimulate the liver to secrete IGF1
- some made by kidney and skin but don’t contribute to circulation
- circulates all day at relatively constant level
- GH doesn’t induce growth in animals that lack insulin, also wont work without carbs, anorexia will curtail IGF 1 and decrease growth
25
IGF1
- stimulates growth
- endocrine, paracrine and autocrine
- negative feedback to hypothal and pit to downregulate GH
- clinical use-primary screening test fo GH def, more stable and reflective of GH
26
IGF I and II
- share 3 domains, aa seq homology (with insulin too)
- C region is cleaved from insulin, but not IGFs
- IGFs have D domain
27
IGF I and II receptors
- insulin and IGF1 are heterotetramers joined by disulfide bonds
- cytoplasmic portion of beta subunits have tyrosine kinase domains and auto-P sites
- IGFII-single polypeptide chain with no kinase domain, cellular function poorly understood
28
signaling pathways from IGF1
- dimerization of receptor leads to auto-P
- recruits two major phosphotyrosine binding proteins IRS-1 and SHC
- phosphorylated by IGF1 receptor
- recruits other proteins to the membrane leading to activation of the phosphoinositol 3 kinase and Ras/MAp kinase pathways that regulate transcription
29
pubertal growth spurt
- sex hormones contribute to rapid increase in stature
- girls earlier and boys later
- IGF peak in puberty
30
GH def and replacement
- several rare causes of def
- any defect affecting HPA
- mutation ins GH1 gene (can't treat because they've never seen it so they will have a rxn)
- children have extremely slow growth- less than 2 inches/year
- severe post natal growth factor
- giving extra hormone doesn't increase rate of growth to above normal levels
31
organic causes of GH def
congenital absence of pit stalk, TBI, cranial radiation therapy
32
idiopathic causes of GH def
-can be functional of developmental state, which resolves mid puberty
33
laron syndrome
- GH insensitivity
- point mutation/deletion in GH receptor
- low IGF concentration
- normal/elevated GH
- severe post natal growth failure
- treatable with IGF
- AR
- heterozygotes mild growth retardation
- out of 230 worldwide, none have cancer
- no diabetes/ acne
- mutation of Stat5b gene similar
- treatment with IGF before puberty can compensate for short stature
- ecuador
34
gigantism
- pituitary giants
- exposed to too much GH throughout life
- hyperglycemia/ diabetes
- degeneration of beta cells
35
acromegaly
- GH secreting adenomas
- effects vary depending on size and growth rate and invasiveness
- large tumors cause destruction of pit and deficiency of other pit hormones can affect optic chiasm and vision
- protrusion of jaw, macroglossia (big tongue), enlarged hands and feet, carpal tunnel, reduced strength
36
GH def in adults
- usually caused by pit probs
- can be result of surgery or radiation
- causes increase in interstitial fat
- reduced strength and bone loss
- feelings of anxiety and depression
- treatment with GH remediates issues
- found by using insulin to stimulate secretion
- increases visceral fat-carotid intima media thickness, IF markers of CV disease, clotting factors, insulin resistance
- decreases myocardial function- HDL
37
GH and aging
- 5-20, 5 ng/ml
- 20-40, 3
- 40-70, 1.6
- replacement therapy:
- restores muscle mass, reduces fat deposits, feeling of increased energy
- side effects include insulin resistance, diabetes, edema, carpal tunnel
38
FDA approved use of GH
- GH def, idiopathic short stature, turner syndrome
- prader willi syndrome
- chronic renal insufficiency
- small for gestational age
- nutrition- first few generations in america are taller because parents weren't nourished
39
other causes of growth problems
- celiac, hypothyroidism
- reduced levels of IGF
- replacement of thyroxin restore growth to normal height
- thyroid response element upstream of GH transcriptional start site- hypothyroid reduces GH
40
short stature with normal hormones
-turner, down syndrome
41
tuner syndrom
- haploinsufficiency of SHOX gene
- SHOX is developmentally regulated
- concentrated in the hypertrophic region of the growth plate zone during childhood
- pseudoautosomal region of Xp
- missing 1 X
- 45, X in about 50%
- isochomosome Xp or q, or mosaic
- 45X, 46XX
- slower velocity during childhood, scant pubertal growth spurt
- treated with GH and sex steroids- height improved but not restored
42
SHOX locus
- developmentally regulated
- expressed throughout fetal growth plate, concentrated in hypertrophic zone
- pseudoautosomal region of Xp
- can have mutation that causes short stature
