Medical Physiology Block 7 Week 3 Flashcards
What happens to children with excessive GH secretion? deficiency in GH secretion?
Individuals with excessive GH secretion during childhood develop gigantism (lengthening of long bones)
those with a deficiency of GH develop pituitary dwarfism
Does deficiency of GH beginning in adult life result in a major clinical illness?
No
What happens to adults who have excessive GH secretion (after puberty?)
acromegaly: Characterized by the growth of bone (increased diameter; growth plate has already fused; increased bone density) and many other somatic tissues, including skin, muscle, heart, liver, and the gastrointestinal tract
Progressive thickening of bones and soft tissues of the head, hands, and feet
Cause morbidity as a result of joint deformity, hypertension, pulmonary insufficiency, and heart failure
Describe synthesis of growth hormone.
Synthesized as a larger preprohormone
Cleaved to a prohormone while being transported between RER and Golgi
Cleavage of the pro-sequence and disulfide bond formation occur during transit through the Golgi bodies
Stored in secretory granules in the cytosol of the somatotrophs until it is secreted
What hormones have homology to growth hormone?
human placental lactogens, placental-variant GH, and prolactin
Describe daily profile of GH secretion.
Over 70% of total daily GH secretion occurs during the induction of slow-wave sleep
Exercise, stress, high-protein meals, and fasting cause a rise in the mean GH level in humans (increased frequency, not amplitude)
The integrated amount of GH secreted each day is higher during pubertal growth than in younger children or in adults
Describe GHRH modulation of somatotrophs.
GHRH binds to a G protein–coupled receptor (GPCR) on the somatotrophs and activates Gα s , which, in turn, stimulates adenylyl cyclase
What hormone increases growth hormone secretion? decreases?
ghrelin (acylated; growth hormone secretagogue receptor), estradiol, and testosterone; triggerd by high dietary protein intake
somatostatin (Galpha i)
What is the effect of GH?
GH triggers the secretion of IGF-1 from GH target tissues throughout the body.
Describe negative feedback of GH and GHRH.
IGF-1 inhibits GH secretion, increases secretion of somatostain, and suppresses GHRH release from the arcuate nucleus in the hypothalmaus
growth hormone inhibits its own secretions via short loop feedback
How is growth hormone transported in plasma?
Significant fraction is complexed to GH-binding protein (formed by proteolytic cleavage of the extracellular domain of GH receptors in GH target tissues; high affinity); most circulates freely
Describe growth hormone receptor.
monomeric, single membrane spanning segment; extensively glycosylated, tyrosine kinase-associated receptor (dimerizes; JAK2/STAT3); modulates apoptosis (trophic signal?)
What are acute effects of growth hormone?
Stimulation of lipolysis in adipose tissue, inhibition of glucose uptake by muscle, and stimulation of gluconeogenesis by hepatocytes; stimulates chondrocyte proliferation (stimulating formation of cartilaginous ECM) and promotes longitudinal bone growth
long term effect is production of IGF-1
How is IGF-1 transported in the blood? Where does most of it come from?
bound to binding proteins; produced by the liver (IGF-1 is secreted into the extracellular space, where they act locally in a paracrine fashion; binding to proteins inhibits the entry of IGFs into the vascular system)
Describe the IGF-1 receptor.
tyrosine kinase (heterotetramer that is structuarally related to the insulin receptor)
two completely extracellular alpha chains (linked to one another by disulfide bonds) and two transmembrane beta chains
Can insulin bind to IGF-1 receptor? Can IGF-1 bind to insulin receptor?
Yes to both; lower affinity (hybrid receptors exist in the body)
Describe IGF-2 signaling.
Although IGF-2 also binds to the IGF-1 receptor (most important function), it preferentially binds to IGF-2 receptor, a single-chain polypeptide distinct from IGF-1 receptor)
if expressed on the plasma membrane, it is suggested that the receptor recruits JAK2/STAT3 or 5 (nuclear signaling)
may bind to mannose-6-phosphate (if located in the ER): Physiological role appears to be in processing mannosylated proteins by targeting them for lysosomal degradation
When do IGF-1 levels and growth rate diverge? Why?
During adulthood, longitudinal growth essentially ceases, yet secretion of GH and of IGF-1 continues to be highly regulated (hormones decline with age)
Early childhood is characterized by very rapid growth but quite low IGF-1 levels (IGF-2 concentration is greater during fetal life and peaks just before birth; peaks to adult levels at age 1)
Is insulin signaling required for IGF-1 production?
Yes; Increased insulin appears to be required, at least in some tissues, for GH to stimulate IGF-1 effectively
What other hormones promote growth?
Hyperinsulinemia results in increased fetal growth
An excess of adrenal glucocorticoids inhibits growth
Androgen or estrogen excess occurring before the pubertal growth spurt accelerates bone growth (narrows longitudinal growth window)
What is a stimulus for decrease in growth rate?
Growth levels off in accordance with the development of secondary sexual characteristics
What is longitudinal growth?
Longitudinal growth involve lengthening of the somatic tissues (including bone, muscle, tendons, and skin) through a combination of tissue hyperplasia and hypertrophy
Describe longitudinal growth of bone.
For bone, longitudinal growth occurs by hyperplasia of chondrocytes at the growth plates of the long bones, followed by endochondral ossification; the calcified cartilage is remodeled as it moves toward the metaphyses of the bone, where it is eventually replaced by true lamellar and trabecular bone
When does bone growth stop?
epiphyseal closure occurs toward the completion of puberty (calcification of the cartilaginous surrounding matrix also occurs)