hormones and growth - notes Flashcards
hormones most relevant in growth
GH thyroid hormones insulin androgens estrogens glucocortocoids peptide growth factors
why would malnutrition prevent growth?
malnourished tissues are refractory to the actions of many hormones
growth hormone
1: promotion of skeletal growth
2: stimulation of soft tissue growth
GH on linear growth
affects chondrogenesis
GH on soft tissue growth
increases cell number and size
HGH and insulin
antagonizes effects of insulin on liver and muscle
directly or indirectly via somatomedins
forms of HGH
major forms: one of 22000 D and one of 20000 D
produced by anterior pituitary
also larger form and several smaller forms in pit
big and big-big in plasma
somatotrope cells
produce HGH
most numerous in anterior pituitary
predominate in lateral wings where lactotrope cells also found
acidophiles
GH on metabolism
1: increased protein synthesis and AA uptake by tissues (promotes positive N2 balance)
2: increased RNA and DNA synthesis
3: increased connective tissue growth and skeletal growth
4: increased acid mucopolysaccharide formation in skin and cartilage
5: hyperglycemia via antiinsulin or diabetogenic action
6: increased retention of Na, K, Cl, Mg, PO4, and Ca
7: increased lipolysis => increased fat mobilization
changes in GH effects on metabolism over time
for first few minutes, exhibits insulin-like activities on glucose uptake and on free FA utilization
then changes to anti-insulin effects such as increasing plasma glucose levels and increasing circulating FFA
initial effects due to somatomedins
what effect would removal of the pituitary have on adolescents with juvenile diabetes
would reduce insulin requirements
how is commercially available HGH produced?
recombinant technology
stimulatory factors in HGH release
hypoglycemia
1: hypothalamus is directly responsive to circulating glucose levels - produce GHrH, somatotropin releasing factor, somatocrinin => GH release
2: increased blood levels of AA, esp. arginine - GH levels increase 2-4 hours after a meal
3: deep sleep (stage 3 and 4) - turned off by REM sleep
4: diurnal variation in GH release - peak levels in evening and early morning
5: exercise - likely correlates with FFA utilization for energy
6: GHRH from hypothalamus
7: brain GHRP/gerlin (growth hormone releasing peptide) => increased GHRH, decreased somatostatin
what are provocative tests for hGH?
insulin, arginine, L-dopa, conidine
must use at least two and take multiple samples throughout day because levels fluctuate so much
inhibitory factors in HGH release
1: REM sleep
2: somatomedins (IGFs) - hGH increases production - mediate effects of hGH on tissues - ones released by liver are mainly responsible for circulating levels - negative feedback
3: primary hypothyroidism via inhibitory effects of excessive TRH on somatotropes
4: high FFA levels
growth hormone deficiency
usually associated with deficiencies of other pituitary hormones too
pubertal development delayed
growth stunted => dwarfism
must treat before full bone maturation
usually due to hypothalamic dysfunction or pituitary lesion or failure of tissues to respond to GH (s.a. laron dwarfism and african pigmyism
laron dwarfism and african pigmyism
GH deficiency syndromes
HGH levels are high and somatomedin leves are subnormal
either receptor or post-receptor defect leading to the symptoms of GH deficiency (ie tissues aren’t responding properly to GH)
somatomedin C levels low in hypopituitary dwarfs
can use it to treat this sometimes
growth hormone hypersecretion
usually due to tumor of pituitary
can cause pituitary gigantism if before epiphyseal plates sealed
if after bone maturation, acromegaly
plasma HGH and somatomedin C levels elevated in both
treat with microhypophysectormy, radiation, or drugs that inhibit HGH secretion (s.a. bromocriptine)
acrogmegaly
pituitary tumor after epiphyseal plates have fused
connective tissue proliferation
dermal overgrowth
enlargement of extermities
plasma HGH and somatomedin C levels elevated
treat with microhypophysectormy, radiation, or drugs that inhibit HGH secretion (s.a. bromocriptine)
somatomedin C levels elevated
insulin in growth
hyperinsulin before or after birth => excessive growth
deficiency => growth failure
fills permissive role
affects possible due to its structural similarity to somatomedin C (IGF-1)
nerve growth factor
may mediate role of thyroid hormones in development of brain during last part of gestation and for several months of postnatal development (for growth of ganglia in fetal life, maintaining sympathetic nervous system postnatally)
118 AA, derived from dimer with 3 subunits
beta subunit is biologically active
produced by number of tissues
differentiating factor
production stimulated by androgens and thyroid hormones
thyroid hormones in neural development
required for brain development during last part of gestation and for several months of postnatal development
may be mediated by NGF
hypothyroidism and growth
children with this have severely retarded growth
increase protein and RNA synthesis, possibly increase in DNA synthesis
could have permissive role
since HPA mechanisms controlling GH and TH release are interrelated, problems in TH may reduce stores and release of GH
also appear to prime tissues to respond to somatomedins
sex hormones in growth
promote protein synthesis and hence N2 retention
androgens responsible for adolescent growth spurt
androgenation associated with muscular growth
but need GH to have effect - act synergistically to enhance linear growth
promote bone maturation that ultimately leads to closure of plates
estrogen on growth
may have some inhibitory effect, possible mediated by reduction of somatomedin release in response to GH
glucocorticoids in growth
hormones of adrenal cortex
when in high amounts, catabolic effect on peripheral growth
but cortisol has anabolic effects on liver and is required as permissive agent in some processes
interferes with action of somatomedin C on cartilage
normally negative effects on protein synthesis can become synthesis-enhancing when the hormones given together with certain tissue growth factors
cortisol in growth
has anabolic effects on liver and is required as permissive agent in some processes
interferes with action of somatomedin C on cartilage
adrenal virilizing hyperplasia
one condition in which glucocorticoids can be used to promote growth, despite the fact that glucocorticoids are generally catabolic
somatomedins
peptide growth factor
mediate growth-promoting actions of GH
5: A, B, C, IGF-1, IGF-2
somatomedin B
not regulated by GH
promotes thymidine incorporation in culture, but is essentially an antiprotease
somatomedin A
release regulated by GH
neutral peptide with no disulphide bonds
promotes growth of cartilage and thymidine incorporation by cells
somatomedin C and IGF-1
now thought identical
structurally related to proinsulin
70 aa, can be divided into 3 domains (A, B, C)
A and B about 50% identical with proinsulin
structure remains intact (A, B, and C not divided)
serum levels provide some index of GH activity on tissue targets - leves rise with age in prepubertal children, peak during puberty, and fall in adulthood
levels low in hypopituitary dwarfs, elevated in acromegaly
IGF-1 and IGF-2
whats though of as somatomedins
structurally related to proinsulin
released from liver by GH
likely mainly responsible for circulating levels of peptides
tissues levels increase dramatically in response to hGH (more so than plasma levels) - may chiefly be paracrine
IGFBPs
bind somatomedins in plasma - 85% bound
produced by liver and GH target tissues
plasma levels of IGF-1 and IGF-2
in normal adults:
IGF-1 levels average about 200 ng/mL
IGF-2 levels average about 650 ng/mL
IGF-2 receptor (type 1)
on cell membranes
alpha and beta subunits linked by disulfide bonds
insulin can also bind, but with low affinity (IGF-1 also has weak affinity for insulin receptors)
actions of IGF-1 in cells
1: stimulates DNA synthesis and cell division
2: promotes sulphate incorporation into proteoglylcans of cartilage and connective tissue
3: differntiation of myoblasts into myotubules in muscle
4: myoblast proliferation
5: can also have insulin-like actions
6: in adipose tissue can stimulate glucose oxidation and the synthesis of lipids
IGF-2 receptor
type 2 receptor
insulin has no binding affinity
actions of IGF-2 in cells
1: IGF-2 has higher binding affinity for insulin receptor than does IGF-1 so has more potent insulin-like actions on muscle and adiopse
2: promotes cell division
3: promotes RNA synthesis
4: promotes protein synthesis
platelet derived growth factor (PDGF)
basic peptide
2 chains (a, B) united by disulphide bridge
may be involved in development of atherosclerosis
actions of PDGF on growth
1: promotes growth of fibroblasts and SMCs by acting as a competence factor - once cells competent, they can undergo mitosis in response to appropriate stimuli (s.a. that from IGF-1 or EGF)
PDGF receptor
membrane protein
activation leads to increased tyrosine kinase activity and increased conversion of membrane phospholipid to IP3 and DAG
fibroblast growth factor (FGF)
peptide
isolated from pituitary and brain
seems to stimulate cell proliferation by acting as a competence factor
epidermal growth factor (EGF) structure
53 aa, 3 disulphide bridges
derived from 1200 AA precursor (2 molecules of EGF and 2 molecules of a binding subunit)
binding subunit cleaves precursor to form an active peptide that has paracrine or autocrine role
produced by many different tissues throughout body
EGF actions
paracrine or autocrine role
stimulates cell proliferation in epithelial cells and in cells of mesodermal origin
EGF receptor
membrane glycoprotein with extracellular and intracellular components
intracellular is tyrosine kinase - autophosphorylates
when EGF binds, entire hormone-receptor complex becomes internalized
erythropoietin
produced by kidneys
stimulates proliferation of primitive hematopoietic stem cells
promotes conversion of proerythrocytes to erythrocytes
regulated by states of tissue oxygenation, stimulated by hypoxia
interleukins
peptide products of lymphocytes
IL-1
single-chain product of monocyte macrophages stimulates: 1: thymocyte mitosis 2: growth of activated T-lymph 3: T-lymph reactivity
IL-2
produced by lymphoid and spleen cells
formation stimulated by IL-1
stimulates growth and differentiation of lymphocytes
IL-3
glycoprotein
stimulates growth and differentiation of lymphocytes
GH effects on bone growth
1: widening of epiphyseal plate
2: growth of cartilage (chondrogenesis)
3: increased incorporation of sulphate into chondriotin sulphate and of proline into collagen
4: stimulates osteocyte activity => increased ossification
most activity attributed to somatomedins, but has some direct effects
TH effects on bone growth
1: stimulate cartilage breakdown and bone deposition - promote bone maturation/osteogenesis
androgens in gone growth
responsible for pubertal growth spurt
initially produces linear growth but then leads to increase in bone maturation and speed up closure of epiphyseal plate - cartilage formation can’t keep up with bone deposition
early maturation under influence of androgens => stunted growth
some actions indirect via peptide growth factors
estrogens on bone growth
inhibit bone growth
promote closure of epiphyseal plates
insulin on bone growth
necessary, but role not known
glucocorticoids on bone growth
direct action - inhibitory
promote osteoporosis through decreased bone formation and increased bone resorption
directly inhibit actions of somatomedins on bone
