Growth Hormone and IGF-1 Flashcards
Mediates growth and metabolic functions to include cell proliferation and differentiation, and serum glucose concentrations
Growth Hormone
GH is an anabolic hormone. In so doing, it
- ) Increases
- ) Lowers
- ) Urinary nitrogen retention
2. ) Serum urea
Target tissues for GH expression express a cell surface receptor consisting of an extracellular ligand binding and cytoplasmic signaling domains. This receptor is the
GH receptor
The anabolic actions of GH result from its stimulatory effects on which three things?
- ) Cellular amino acid uptake
- ) Increased gene transcription
- ) De novo protein synthesis
GH is an antagonist to the catabolic effects of
Glucocorticoids
Promotes lipolysis and this increases the availability of glycerol and free fatty acids as fuel for muscle work
GH
During periods of metabolic demand, GH shunts the matabolic pathways from glycogenolysis to the metabolism of FFA into
Acetyl-CoA
This increased production of acetyl-CoA is used to produce
ATP
GH thus supports the conservation of glycogen stores while decreasing the cellular uptake of
Glucose
There are strong relationships between GH and
Glycemic status and insuln
GH is the only
Proglycemic hormone
Designed to preserve plasma glucose levels by 1) directly blocking glucose uptake by skeletal muscle (promoting insulin resistance), and 2) shunting muscle energy expenditure away from the utilization (oxidation) of glucose to the oxidation of FFA
GH
This glucose conservation is of benefit during periods of fasting/starvation when muscle catabolism would be generated by
Glucocorticoids
Promote muscle catabolism during periods of fasting/starvation to free up amino acids that can be used to generate ATP
Glucocorticoids
Thus acts as a counter modulator to the catabolic actions of glucocorticoids in skeletal muscle
GH
GH secretion is suppressed by
Acute hyperglycemia
After a meal, insulin is released to promote glucose uptake. The insulin-induced drop in blood glucose in turn stimulates
GH secretion
GH tends to slightly raise
Blood glucose levels
Should GH remain elevated, we will likely see an increase in the secretion of
Insulin
Antagonizes insulin sensitivity in the liver and especially in skeletal muscle
GH
This induces an insulin resistant state which maintains
Blood glucose
Since elevated GH impairs insulin sensitivity, a subsequent glucose challenge during this insulin resistant period would result in
Hyperinsulinemia
Chronic elevation of GH can result in a pathologic condition of
Insulin resistance and accompanying hyperglycemia
Work in conjunction under physiologic conditions to stimulate anabolism in bone and muscle tissue
GH and Insulin
Insulin and GH each stimulate the cellular uptake of
Amino acids and subsequent protein synthesis
A member of the insulin family, and mediates the growth-promoting effect of GH
Insulin-like growth factor (IGF-I)
Regulates IGF-I gene transcription
GH
Exerts negative feedback on GH secretion
IGF-I
Circulating isoforms of truncated IGF-I and GH respectively
IGF binding proteins (IGFBPs) and GH binding proteins (GHBPs)
These are produced mainly in the liver, are carrier proteins which extend the half-life of circulating GH and IGF-I, and aid in the delivery of these hormones to target tissues
IGFBPs and GHBPs
By extending the half-life of GH, GHBP dampens acute changes in serum GH levels, in part by reducing
Renal clearance of GH
Are GH and IGF-I bioactive when they are bound to their respective binding proteins?
No
Have been observed with malnutrition, chronic liver disease, and short stature
Low GHBP levels
Together, stimulate skeletal muscle growth and proliferation, as well as the growth and deposition of bone
GH and IGF-I
In long bones, GH/IGF-I exert mitogenic effects in chondrocytes within the
Epiphyseal cartilages (epiphyseal lengthening)
Also promote osteoblast activity, and in so doing, support the deposition of Ca2+ phosphate salts in bone
GH and IGF-I
Epiphyseal lengthening has a limited life span, and stops late in adolescence when epiphyseal plates fuse due to rising
Estradiol-17B production
The neuroendocrine control of GH secretion resides within the
Hypothalamus and anterior pituitary
The ventromedial nucleus of the hypothalamus houses neurons which produce
Growth Hormone Releasing Hormone (GHRH)
A stimulatory factor that is secreted into the hypophyseal portal vessels
GHRH
GHRH stimulates the production and release of GH by the
Somatotropes (in the anterior pituitary)
Express receptors for GHRH, GH secretagogue (stimulatory), dopamine (stimulatory), and somatotroph-release inhibiting factor (SRIF, aka somatostatin, inhibitory), which together represent a few of the central factors that control the secretion of GH
Somatotropes
GH secretogues and dopamine stimulate the secretion of
GH
What inhibits the secretion of GH?
Somatotroph release inhibiting factor (SRIF)
A hormone secreted by the gastric mucosal neuroendocrine cells and the hypothalamus which stimulates GH secretion
Ghrelin
Hypoglycemia and depressed serum concentrations of certain amino acids also signal the neuroendocrine release of
GH
Acute hyperglycemia lowers GH secretion, however, GH secretion is stimulated by
Chronic Hyperglycemia
GH secretion can also be transiently stimulated by high protein meals and the amino acids
Arginine and Lysine
In general, metabolic and/or physical stress (to include trauma, hypovolemic shock, sepsis, and exercise) stimulate
GH secretion
Will control GH secretion based upon the central (i.e. hypothalamic) receptor isoform that is most activated
Heightened SNS tone
Results in stimulation of GH secretion, likely by inhibiting the secretion of somatostatin while increasing seratonin
a2 adrenergic response
Are coupled to the release of somatostatin and thus down-regulate GH secretion
B2 adrenoreceptors
There is also a circadian rythm for GH secretion, and this results in an increase in serum GH concentrations during the first hours of
Deep (REM) sleep
The production of GH is greatest in the child (and through puberty), and following age 20, GH production begins to wane by about
14% per decade
By approximately 50-60 years of age. GH secretion can be reduced by 60%. This process is called
Somatopause
Has a short half-life; thus, catching peak versus nadir levels is tricky
GH
Testing for abnormalities in the GH system relies upon the principles of stimulation and suppression; these are forms of
Endocrine dynamic testing
Has been shown to be a fairly reliable marker of GH excess
Serum IGF-I
If GH excess is suspected, we rely upon the suppression of GH by glucose as a form of
Suppression testing
To conduct this evaluation, the patient is given an oral glucose load (the oral glucose tolerance test, OGGT), and blood GH is drawn at timed intervals after the
Glucose load
Failure to lower GH below 2ng/mL shows
Loss of negative feedback (indicates positive test for GH excess)
If GH deficiency is suspected, testing relies upon known mechanisms for the stimulation of GH, so called
Stimulation testing
Uses insulin tolerance, arginine, GHRH, and exercise to test for GH deficiency
Stimulation testing
A disease resulting from the abnormal production of GH/IGF-I
Acromegaly (hypersomatotrophism)
Affects roughly equal numbers of men and women and is often diagnosed in the early-mid4th decade of life
Acromegaly
Presenting symptoms often include headache and visual field defects (resulting from compression of the neural visual tracts by expanding pituitary mass), and/or a host of reproductive endocrine manifestations ranging from amenorrhea, oligomenorrhea, or galactorrhea to loss of libido and impotence
Acromegaly
The pathogenesis of acromegaly most commonly results from a
GH-producing pituitary tumor
Disproportionate thickening of bone tissue can occur,
and this is especially apparent in the jaw (mandible overgrowth), forehead (frontal skull bossing, cranial
ridging), nose, hands, and feet of the adult if there is
Abnormally elevated levels of GH in acromegaly
Often times, the first signs of acromegaly are
-caused by excess GH targeting essentially all systems with GH and IGF-I receptors
Metabolic and cardiovascular problems
Can include enlargement of organs, glands, and soft tissues such as the heart, thyroid, spleen, tongue, liver, and kidneys
Acromegaly
Can increase cardiomyocyte contractility by enhancing intracellular Ca2+
-also induces cardiomyocyte hypertrophy
Excess GH
GH increases lean body mass by promoting the expansion of total body water (i.e. fluid retention). Second, GH alters vasomotor function, likely due to changes in endothelial structure and function which increase vascular resistance. Thus, GH excess often results in
Hypertension
Early on in acromegaly, GH-induced increases in HR raise
Cardiac output
Over time, GH can stimulate the formation of
-leads to Heart failure
Biventricular hypertrophy
Owing to its stimulatory effect on blood glucose levels, chronic GH in acromegaly can lead to impaired
Glucose tolerance, insulin resistance, and diabetes mellitus
GH induces volume expansion, resulting in reduced
PRA
Increases in total body water may be linked with a GH-directed rise in aldosterone levels that has been observed in
Acromegaly
Results from abnormally elevated levels of GH and IGF-I during childhood and puberty
-essentially the development of acromegaly in children
Gigantism
Often caused by GH secreting tumores and is linked with insulin resistance and hyperglycemia
Gigantism
What are two non surgical options to treat gigantism or acromegaly?
- ) Somatostatin analogue (octreotide)
2. ) GH-R antagonist (pregvisomant)
In about 20-30% of certain somatotroph adenomas, GH secretion can be reduced by
Dopamine agonism
Dopamine receptor agonists which can be effective in the management of some forms of acromegaly
Bromocriptine and cabergoline
It is believed this mechanism results from a common embryonic lineage of these tumors which couples the mechanism of GH secretion to that of
Prolactin (PRL)
Dopamine is a potent inhibitor of
Prolactin (PRL)
Realize though that under normal physiologic conditions, dopamine STIMULATES
GH secretion
In children, short stature, central obesity, and high pitched voice are signs of
GH deficiency
In adults, decreased bone density, central obesity, depression, and an abnormal lipid profile are clues to the presence of
-also comes with cardiovascular consequences
GH deficiency
Conditions of isolated GH deficiency are very rare. Rather GH deficiency is usually associated with
Hypopituitarism
This condition often manifests with signs resembling
that of metabolic syndrome: central obesity, insulin resistance, dyslipidemia, and atherosclerosis
Hypopituitarism
When present in children and/or for prolonged duration, GH deficiency can lead to decreased
Left ventricular wall thickness and ejection fraction
In additional to its purported performance-enhancing actions, GH has been historically difficult to detect since some exogenous GH preparations have a chemical signature that is virtually indistinguishable from that of
Endogenous GH
What is the half-life of GH?
15-20 minutes
Data show that while GH replacement does improve physical performance parameters in GH-deficient
adults (e.g., muscle mass; strength; and aerobic capacity, VO2max), studies have indicated that it
probably has no significant performance-enhancing effect in
Healthy individuals
Increased by GH
Lean body mass (LBM)
The main performance enhancing benefit of GH
It’s lipolytic properties
Thus GH is really only beneficial to
Body builders
