Download Hormonal Control of Growth

Hormonal Control of
Growth
• Growth of an individual or an organ involves:
– Increase both in cell number and cell size
– Differentiation of cells to perform highly specialized
functions
– and tissue remodeling that may require apoptosis as
well as new cell formation
• Most of these processes depend on locally
produced growth factors that operate through
paracrine or autocrine mechanisms
• Many continue to operate throughout life
providing not only cell renewal, but also for
adaptations to meet changing physiological
demands
Dr. M. Alzaharna (2014)
Growth Hormone
• Growth hormone, which is also called
somatotropin (STH), is the single most
important hormone required for normal
growth
• Attainment of adult size is absolutely
dependent on GH; in its absence growth is
severely limited
Dr. M. Alzaharna (2014)
Synthesis, secretion, and metabolism
• Although the anterior pituitary gland produces at
least six hormones, more than one-third of its
cells synthesize and secrete GH
• 90% of the GH produced by somatotropes is
comprised of 191 amino acids and has a
molecular weight of ~ 22,000
• The remaining 10% has a molecular weight of
20,000 and comprised of 176 amino acids
• Both forms are products of the same gene
• Both forms of hormone are secreted and have
similar growth-promoting activity, although
metabolic effects of the 20K form are reduced
Dr. M. Alzaharna (2014)
Synthesis, secretion, and metabolism
• About half the GH in blood
circulates bound to a protein that
has the same amino acid sequence
as the extracellular domain of the
GH receptor
• GH that crosses the glomerular membrane is
reabsorbed and destroyed in the kidney, which is the
major site of GH degradation
• GH also is degraded in its various target cells
following uptake by receptor mediated endocytosis
Dr. M. Alzaharna (2014)
Mode of action
• Like other peptide and protein hormones GH
binds to its receptor on the surface of target
cells
• GH produces its effects in various cells by
stimulating the transcription of specific genes
Dr. M. Alzaharna (2014)
Physiological actions of growth hormone
• Effects on skeletal growth
– The ultimate height attained by an individual is
determined by the length of the skeleton and, in
particular, the vertebral column and long bones of
the legs
• The somatomedin hypothesis
– GH may not act directly to promote growth but,
instead, stimulates the liver to produce an
intermediate, blood borne substance
(somatomedin) that activates chondrogenesis and
perhaps other GH-dependent growth processes in
other tissues
Dr. M. Alzaharna (2014)
Physiological actions of growth hormone
• Somatomedin was found to consist of
two closely related substances that also
produce the insulin-like activity
– These substances now are called
insulin-like growth factors , or IGF-I and
IGF-II
– IGF-I is more important mediator of the
actions of GH
– Children whose growth is more rapid
than average have higher than average
concentrations of IGF-I
⁻ It is now apparent that GH stimulates secretion of IGFs, which act
locally in an autocrine or paracrine manner to stimulate:
⁻ cell division, chondrocyte maturation, secretion of extracellular
matrix proteins, and bone growth
Dr. M. Alzaharna (2014)
Physiological actions of growth hormone
• Effects of GH/IGF-I on body composition
– The bodies of growth hormone-deficient animals
and human subjects have a relatively high
proportion of fat, compared to water and protein,
in their bodies
– Most internal organs grow in proportion to body
size, except liver and spleen, which may be
disproportionally enlarged by prolonged
treatment with GH
– When human subjects or experimental animals
are given GH repeatedly for several days, there is
net retention of nitrogen, reflecting increased
protein synthesis
Dr. M. Alzaharna (2014)
Regulation of GH secretion
• In humans, GH secretion is pulsatile
• Frequent bursts of secretion occur
throughout the day, with the largest
being associated with the early
hours of sleep
• In addition, stressful changes in the
internal and external environment
can produce brief episodes of
hormone secretion
• Effects of age
– GH secretion, though most active
during the adolescent growth spurt,
persists throughout life, long after
growth has stopped
Dr. M. Alzaharna (2014)
Regulation of GH secretion
• In addition to spontaneous pulses, secretory episodes
are induced by such metabolic signals as:
– a rapid fall in blood glucose concentration
– or an increase in certain amino acids
• Traumatic and psychogenic stresses are also powerful
inducers of GH secretion in humans
– whether increased secretion of GH is beneficial for coping
with stress is not established
• Three hormones are involved in regulation and
somatotropes express receptors for all three
hormones:
– GH-releasing hormone (GHRH)
– Somatostatin
– And ghrelin
Dr. M. Alzaharna (2014)
Regulation of GH secretion
• Growth hormone releasing
hormone provides the primary
drive for GH synthesis and
secretion
• Somatostatin reduces or blocks
secretion of GH in response to
GHRH, but has little or no
influence on GH synthesis
– constant secretion of somatostatin
restrains secretion of GH
– Periodic interruptions in secretion
produces a rebound release of GH
PVN: periventricular nuclei; ARC: arcuate
nuclei; SST: somatostatin; GHRH growth
hormone releasing hormone; IGF-I insulin-like
growth factor-I; (+) stimulation. (─) inhibition
Dr. M. Alzaharna (2014)
Regulation of GH secretion
• Ghrelin increases responses of somatotropes
to GHRH
– stimulation of GH secretion by ghrelin requires
costimulation by GHRH
• Negative feedback control sets the overall
level of GH secretion by regulating the
amounts of GH secreted in each pulse
Dr. M. Alzaharna (2014)
Role of Thyroid Hormones
• Growth is stunted in children suffering
from deficiency of thyroid hormones
• Treatment of hypothyroid children with
thyroid hormone results in rapid “catch
up” growth and accelerated
• The effects of thyroid hormones on
growth are closely entwined with GH
• T3 and T4 have little, if any, growthpromoting effect in the absence of GH
• Thyroid hormones affect synthesis of
human GH indirectly by increasing the
expression GHRH receptors by
somatotropes
Dr. M. Alzaharna (2014)
Role of Insulin
• insulin may serve as a growth-promoting
hormone during the fetal period
• Infants born of diabetic mothers often are larger
than normal, especially when the diabetes is
poorly controlled
• Because glucose readily crosses the placenta,
high concentrations of glucose in maternal blood
increase fetal blood glucose and stimulate the
fetal pancreas to secrete insulin
• Structurally, insulin is closely related to IGF -I and
IGF-II and when present in adequate
concentrations can activate IGF-I receptors
Dr. M. Alzaharna (2014)
Role of Gonadal Hormones
• Awakening of the gonads at the onset
of sexual maturation is accompanied by
a dramatic acceleration of growth
• At the same time that gonadal steroids
promote linear growth, they accelerate
closure of the epiphyses and therefore
limit the final height that can be
attained
• Most, and possibly all, of the increase
in height stimulated by estrogens or
androgens at puberty is due to
increased secretion of GH
Dr. M. Alzaharna (2014)
Role of Glucocorticoids
• Glucocorticoids are required for synthesis of GH and
have complex effects on GH secretion
• When given acutely, they may enhance GH gene
transcription and increase responsiveness of
somatotropes to GHRH
• However, GH secretion is reduced by excessive
glucocorticoids, probably as a result of increased
somatostatin production
• Impairment of growth is seen in children treated
chronically with high doses of glucocorticoids to
control asthma or inflammatory disorders
• Consistent with their catabolic effects in muscle and
lymphoid tissues, glucocorticoids also antagonize the
actions of GH
Dr. M. Alzaharna (2014)