L4 Growth Hormone PDF

Growth
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GROWTH HORMONE
O GH (Somatotropin), synthesized
by somatotrophs of
Adenohypophysis
O Function: Required for normal
growth (linear growth)
O Stimulates production of IGFs
(somatomedins) in the liver
O IGF-1 (Somatomedin-C) mediates
growth-promoting effect of GH
O Peak of GH & IGF-1: During
adolescence - >50 yo
GH control: IGFs and Insulin
O Under GH control: IGFs are released from liver,
O Because there are insulin-like GFs from liver, it
suppresses the insulin and its effect (from pancreas).
O Such mechanism, decreases the sensitivity of insulin
receptors and therefore,
O under GH control leads to insulin resistance, and
promotes hyperglycemia rather than glucose uptake by
the cells.
O IGFs (I and II) have proinsulin molecules
O Lowers insulin effect (diabetogenic): suppressed by
hyperglycemia & stimulated by hypoglycemia.
GH:Mechanism of Action
O GH exerts its effects on growth mainly through the IGFs
and their binding proteins:
O IGFs (I and II) have proinsulin molecules but differs from
insulin.
O Binding of IGF-I to type I receptors stimulates tyrosine
kinase activity and autophosphorylation of tyrosine
residues in the receptor. This leads to cell differentiation or
division (or both).
O IGF-I is produced in most tissues and is exported to
neighboring cells to act on them in a paracrine manner or
on the cell of origin in an autocrine manner.
Cont…
O IGF-I is a progression factor, so that a cell which has
been exposed to a competence factor can progress
to another stage like in cellular life cycle from G0 to
G1 to S-phases.
O Thereby, IGFs (under GH influence) promotes cellular
proliferation and cellular division (especially mitosis).
O Stimulatory effects of IGF-I on cartilage growth,
hematopoiesis, ovarian steroidogenesis, myoblast
proliferation and differentiation, and differentiation
of the lens (eyes).
Cont…
O This hormone stimulates growth in general especially,
growth of epiphyseal cartilage and bone. It acts
directly on osteoprogenitor cells, stimulating them to
divide and differentiate.
O Chondrocytes in epiphyseal growth plates are
regulated by IGF-I, which is primarily produced by the
liver in response to GH.
O In addition to IGF-I, insulin and thyroid hormones also
stimulate chondrocyte activity.
Normal Physiology
O GH, via IGF-I, increases protein synthesis by enhancing
amino acid uptake and directly accelerating the
transcription and translation of mRNA.
O GH tends to decrease protein catabolism by mobilizing
fat as a more efficient fuel source: it directly causes the
release of fatty acids from adipose tissue and enhances
their conversion to acetyl-CoA
O This protein-sparing effect is an important mechanism by
which GH promotes growth and development.
Insulin Effect
O GH also affects carbohydrate metabolism. In excess,
it decreases carbohydrate utilization and impairs
glucose uptake into cells.
O This GH-induced insulin resistance appears to be
due to a post-receptor impairment in insulin action.
These events result in glucose intolerance and
secondary hyperinsulinism.
Fetal GH
O The number of available receptors is important in
GH effect
O Laron’s Syndrome: Low receptors: GH resistance
(elevated GH with low serum IGFs)
O IUGR (Intrauterine growth retardation) – fetal
deficiency of GH
O Excess IGFBP-1 stunts fetal growth
O Excess IGFBP-3 leads to selective organomegaly.
O The secretion of GH is
mediated by two
hypothalamic hormones
contributing to pattern of
GH secretion:
O GHRH
O Somatostatin (GH-inhibiting
hormone)
GH Secretion
O GH is secreted in a pulsatile manner, so that serum
concentrations are low much of the day but peak
during short intervals.
O Episodic Secretion: Values are higher in the
immediate neonatal period, decrease through
childhood, and rise again as a result of increased
pulse amplitude (but not frequency) during puberty.
O GH secretion falls again during aging.
Growth Hormone Releasing
Hormone (GHRH)
O From Hypothalamus: GHRH binds to specific receptors,
stimulating cAMP production by somatotrophs and stimulating
both GH synthesis and secretion.
O The effects of GHRH are partially blocked by somatostatin. The
administration of
O GHRH to normal humans leads to rapid release of GH (within
minutes); levels peak at 30 minutes and are sustained for 60–
120 minutes.
O Other peptide hormones such as ADH, ACTH, and α-MSH may act
as GH-releasing factors when present in pharmacologic amounts.
Even TSH- and gonadotropin- releasing hormones (TRH and
GnRH) often cause GH secretion in patients with acromegaly.
O Regulation of GHRH is primarily under neural control, but there is
also short-loop negative feedback by GHRH itself.
Somatostatin
O A potent inhibitor of GH secretion. It decreases
cAMP production in GH-secreting cells and
inhibits both basal and stimulated GH secretion.
O Somatostatin secretion is increased by elevated
levels of GH and IGF-I.
O Long-acting analogs of somatostatin have been
used therapeutically in the management of
excessive GH and conditions such as pancreatic
and carcinoid tumors that cause diarrhea.
Neural Control of GH
O Basal GH secretion results in irregular and intermittent
release associated with sleep and varying with age.
O Peak levels occur 1–4 hours after the onset of sleep (during
Sleep stage 3 and 4). These nocturnal sleep bursts accounts
for nearly 70% of daily GH secretion, are greater in children
and tend to decrease with age.
O Glucose infusion does not suppress this episodic release.
O Emotional; physical; and chemical stress; including surgery,
trauma, exercise, electroshock therapy, and pyrogen
administration, provoke GH release.
O In addition, impairment of secretion leading to growth failure
has been well documented in children with severe emotional
deprivation.
Metabolic Control of GH
O Glucose administration, orally or IV, lowers GH and
provides a simple physiologic maneuver useful in the
diagnosis of acromegaly. Hypoglycemia stimulates
GH release.
O Protein meal or IV infusion of amino acids (eg,
arginine) causes GH release. But, in states of
protein-calorie malnutrition also increase GH, as a
result of decreased IGF-I production and lack of
inhibitory feedback.
Cont…
O Fatty acids suppress GH responses to certain
stimuli, including arginine and hypoglycemia.
O Fasting stimulates GH secretion, possibly as a
means of mobilizing fat as an energy source and
preventing protein loss.
Neuropharmacologic Control
O Neurotransmitters and neuropharmacologic agents
affect GH secretion.
O Biogenic amine agonists and antagonists act at the
hypothalamic level and alter GHRH or somatostatin
release.
O Dopaminergic, alpha-adrenergic, and serotonergic
agents all stimulate GH release.
Direct GH effect (not
mediated by IGFs)
O Lipolysis
O Increased amino acid transport into tissues
O Increased protein and glucose synthesis in liver
O Cartilage growth.
O GH in excess causes insulin resistance and is a
diabetogenic substance, increasing blood sugar.
O GH secretion is decreased significantly in obesity but
rises in states of starvation.
Effects of Other Hormones
O THYROID HORMONE: Delay in Bone age advancement:
Newborns with congenital hypothyroidism are of normal
length, but if untreated, they manifest exceedingly poor
growth soon after birth. Infants untreated can also suffer
permanent mental retardation.
O SEX STEROIDS: Gonadal sex steroids like estrogen

promote pubertal growth spurt but is not a major
influence in prepubertal growth. Increased sex steroids
mediated by Estrogen will cause advancement of skeletal
age, premature epiphysial fusion, and short adult stature.
O GLUCOCORTICOIDS: Endogenous or
exogenous glucocorticoids in excess quickly
stop growth; this effect occurs more quickly
than weight gain.
O The absence of glucocorticoids has little
effect on growth if the individual is clinically
well in other respects (ie, if hypotension and
hypoglycemia are absent).
Psychologic Factors
O Aberrant intrafamilial dynamics, psychologic stress,
or psychiatric disease can inhibit growth either by
altering endocrine function or by secondary effects
on nutrition (psychosocial dwarfism or maternal
deprivation).
Nutritional Imbalance
O Feeding problems in infants, resulting from inexperience
of parents or poor child-parent interactions (maternal
deprivation), may account for poor growth.
O Fad diets, such as poorly constructed vegan diets that
put children at risk for vitamin B12 or iron deficiency as
well as dietary manipulation for expected benefit, such
as a severely low fat diet, may place children at risk for
deficiency of fat-soluble vitamins.
O Deliberate starvation of children by caregivers is an
extreme form of child abuse that may be first discovered
because of poor growth.
O Oversecretion in childhood, caused by a defect in the mechanism
regulating GH secretion or a GH-secreting tumor in the pituitary
gland, leads to gigantism, an abnormal increase in the length of
bones.
O Absence or hyposecretion of GH in childhood leads to failure of
growth of the long bones, resulting in pituitary dwarfism.
O Absence or severe hyposecretion of thyroid hormone during
development and infancy leads to failure of bone growth and
dwarfism, a condition known as congenital hypothyroidism.
O ACROMEGALY: Increased activity of osteoblasts in bone
surface.When oversecretion of GH occurs in an adult, bones do not
grow in length as a result of epiphyseal closure. Instead, abnormal
thickening and selective overgrowth of hands, feet, mandible, nose,
and intramembranous bones of the skull occurs.
Diseases
Syndromes of Tall Stature
O BECKWITH-WIEDEMANN SYNDROME
O Patients demonstrate macrosomia (birth weight >
90th percentile) increased postnatal growth,
omphalocele in 80%, macroglossia in 97%, and
hypoglycemia due to the hyperinsulinism of
pancreatic hyperplasia in 63%. Other reported
features include fetal adrenocortical cytomegaly,
and large kidneys with medullary dysplasia.
Pituitary Gigantism
O Patients—besides growing excessively rapidly—have
coarse features, large hands and feet with thick fingers
and toes, and often frontal bossing and large jaws.
Racial Dwarfism
O Pygmies of Africa: congenital inability to synthesize significant

amounts of somatomedins, even if plasma GH amount is high
or low.
O GH as ―youth serum‖: treatment for
osteoporosis, weakness, premature skin aging

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Growth

O SEX STEROIDS: Gonadal sex steroids like estrogen

O Pygmies of Africa: congenital inability to synthesize significant

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