Growth Hormone: Somatic Growth
Excessive GH in adults cause...
*Acromegaly*
Factors that Influence Secretion of GH (Inhibit/stimulate)
*GH regulated by GHRH & Somatostatin* -Inhibited by: obesity, insulin resistance, chronic hyperglycemia, elevated levels of free fatty acids -Stimulated by: >Stress: Traumatic and psychogenic >Exercise >Hypoglycemia, fasting: GH is one of the hormones that protect against fasting hypoglycemia >Some amino acids (Arginine, etc): IV infusion -> Arginine infusion: Stimulation test used to clinically assess GH production >Protein meal >First 2 hours of deep sleep >Sex Steroids >Ghrelin: Produced by stomach that stimulates hunger
The Hypothalamic-Pituitary-GH Axis
*Growth hormone-releasing hormone (GHRH)* stimulates, while *somatostatin* (SRIF) inhibits growth hormone (GH) secretion by acting directly on the *somatotropes*. -The ultra-short feedback loop consists of GHRH reducing hypothalamic release of GHRH. -The negative-feedback loops inhibit GHRH secretion and action on the somatotropes, causing a decrease in GH secretion. -The positive feedback loops (+) stimulate somatostatin secretion, causing a decrease in GH secretion, which ultimately can be considered a negative feedback system. -IGF,=insulin-like growth factor. -Negative feedback inhibition of GH secretion is exerted primarily by the actions of IGF-I (somatomedin C) on the pituitary and hypothalamus. -GH inhibits its own release by a short feedback loop to the hypothalamus. >It is thought to act by inhibiting GHRH secretion and by stimulating *somatostatin* release.
Anterior Pituitary Growth Hormone Release is Controlled by....
*Hypothalamic GHRH & Somatostatin* *Somatotropes* release GH
Factors Influencing Normal Postnatal Growth
-Adequate Nutrition -The principal extrinsic regulators of growth of particular importance are: >Dietary protein, essential vitamins, and minerals >Adequate caloric consumption >Malnutrition is the major cause of short stature world-wide. -Psychosocial Factors >Hormonal Influences: GH, IGF-I, thyroid hormones, sex steroids, insulin, and glucocorticoids -Asthmatics & high altitude also cause small stature due to low PaO2
Hypothyroidism and GH
-Circulating levels of GH and IGF-1 are low -GH secretion in response to provocative stimuli is diminished -Treatment of hypothyroid individuals with thyroid hormone restores GH and IGF-1 levels. >In hypothyroid children, there is a rapid catch-up in growth and an increase in skeletal maturation following the initiation of treatment with thyroid hormone. -Growth rate increases in hyperthyroid children but their maximum height doesn't increase because the epiphyseal cartilage plates CLOSE EARLY.
Physiological Actions of GH
-Effects of GH on metabolism are "diabetogenic" in respect to carbohydrate and lipid metabolism. >Fat mobilization and utilization: GH stimulates lipolysis ->GH in adipose tissue stimulates lipolysis= rise in circulating FFA levels >Conservation of blood carbohydrate: GH inhibits glucose uptake ->Decreases sensitivity to insulin ->Increase in circulating fatty acids inhibit glucose uptake. >Increases skeletal growth >Effects on soft tissue -Net effect is to *increase lean body mass* >GH increases amino acid uptake and protein synthesis -Effects occur ~2 hours after GH administration
Effects of GH on skeletal growth
-GH administration to hypopituitary subjects INCREASES chondrocyte proliferation in the cartilage growth plate. -This thickens the growth plate and ultimately leads to an INCREASE in the length of long bones. -The proliferation of osteoblastic progenitor cells from the periosteum that covers the bony surface is responsible for increases in bone diameter. -Experimental evidence indicates that the *effects of GH on bone are both direct and indirect.*
4 Causes of Dwarfism
-Gene defect for cartilage FGF (fibroblast growth factor) receptor: Achondroplasia -GHRH, GH, or IGF-I deficiency (pituitary dwarfism) >Hypothalamic= GHRH deficiency >Pituitary= Somatotrope destruction by tumor production of a defective GH molecules decreased GH production. -Unresponsive GH receptors (Laron dwarfism) >Caused by deletions or mutations for the GH receptor (type 1) >Patients have HIGH GH LEVELS >Do not produce IGF in response to GH administration. Post GH receptor defects (type 2) -Hypothyroidism (Cretinism) >Thyroid hormones are "permissive" for action of GH -Consequences of dwarfism: - Short stature -Delayed bone development -Delayed puberty -Mild obesity -Tendency toward hypoglycemia
Direct and Indirect Action of GH (Physiological actions)
-Growth hormone actions on target tissues may be direct or indirect Direct actions: GH stimulates IGF-I production and release by the liver and by target cells. -Other direct actions of GH include: >The stimulation of lipolysis by adipocytes >The stimulation of amino acid uptake and protein synthesis by the liver. -Indirect action: >The IGF-I produced in response to GH-stimulation induces most of the growth promoting actions of GH. ->There are 2 IGFs: IGF-I and IGF-II *IGF-I* is the principal mediator of GH actions on skeletal growth.
Importance of charting growth
-Normal growth is a sign of good HEALTH in children. -Monitoring growth allows early detection of the causes of poor or accelerated growth. -Early recognition of growth abnormalities allows early intervention optimizing the possibility of achieving good health and a normal adult height.
Rate of growth in boys and girls from birth to 20 years of age
-Prenatal Growth >Factors controlling fetal growth are POORLY understood. >The role of GH in regulating in utero growth is unclear. >The observation that the mean birth weight for growth hormone deficient infants is one standard deviation below normal birth weight indicates that GH plays a role in PROMOTING fetal growth. -IGFs and IGFBPs play ESSENTIAL roles in stimulating fetal growth >However, not much is known about how IGF production is regulated in the fetus >Fetal IGF production appears to be INDEPENDENT of GH stimulation -The maternal environment: current research indicates that a woman's ability to meet the needs for fetal development is not related in any simple way to her current or immediate past dietary intake, but is rather more dependent upon her general state of health. >The maternal environment is a consequence of the mothers general state of health. -Postnatal Growth >The *growth rate decelerates after birth* >Two periods of rapid postnatal growth >Infancy (birth to 2 years of age). >By the end of the first year, length will increase by half and weight up to 3 fold. >By age 2, the rate of linear growth has stabilized to that characteristic of childhood. Picture (*): Corresponds to the peak serum IGF concentration
Growth hormones in pregnancy
-Principal growth hormone in pregnant women: hGH-V= placental GH -Chorionic somatomammotropin (hCS)/ placental lactogen (hPL) - 2 variants are transcribed by the placenta.
IGF-1 Mechanism of Action
-The IGF-1 receptor is a *receptor tyrosine kinase*. -Structurally: It is very similar to the insulin receptor -The binding of IGF‑I to its receptor induces allosteric interactions within the receptor that result in *receptor autophosphorylation* -Tyrosine kinase domains of the receptor also phosphorylate other cellular proteins to induce cellular responses. -Certain phosphotyrosines on the receptor and on specific intracellular substrates like IRS-1 (Insulin Receptor Substrate-1) provide docking sites for signaling proteins -On docking to a phosphotyrosine, a signaling protein can initiate a signaling cascade. -IGF-I and most other receptor tyrosine kinases receptors can activate the *Ras/Map kinase signaling pathway.* -An adapter protein docks with an IRS and activates a membrane-associated regulatory G protein (Ras). >Ras, in turn, initiates a signaling cascade that ultimately *phosphorylates transcription factors*. -Growth-promoting and mitogenic actions of IGF-1 are stimulated by this signaling pathway. -Target cells for IGFs include: >Fibroblasts >Adipocytes >Osteoblasts >Chondrocytes >Muscle cells -Specific effects of IGFs include: >Stimulation of RNA/DNA and protein synthesis >Cell proliferation >Insulin‑like effects on adipose tissue and muscle: IGFs are not as potent as insulin in inducing these effects.
Which of the following is both a direct action of GH and mediated by local IGF-1?
1. Fat mobilization 2. Inhibition of glucose uptake 3. Increased amino acid uptake 4. Bone growth ---- Bone growth is answer -Fat mob, glucose uptake is direct of GH (IGF promotes uptake of both); amino acid uptake promoted by IGF
Exercise causes an increase in GH secretion. After the finish of exercise, homeostasis is restored because circulating GHRH would
1. Increase 2. Decrease 3. Not change ---- Decrease as normal regulation
The GH Receptor
1.) GH has 2 hormone receptor binding sites: each site binds a GH receptor to form a *receptor homodimer* 2.) As the associated *JAKs* are brought closer together, they phosphorylate each other. (JAK-STAT pathway) Mechanism of GH Action: The GH receptor is a transmembrane protein that belongs to the cytokine/GH/PRL/erythropoietin receptor family. -The cytoplasmic domain of the receptor has NO intrinsic catalytic activity. >Instead, an intracellular kinase belonging to the Janus kinase family, usually JAK 2, is tightly bound to the cytoplasmic domain of the receptor. -About half of the GH in circulation is bound to a binding protein. >The GH binding protein has the same molecular structure of the external portion of the GH receptor and is formed by proteolytic cleavage of the GH receptor on the external surface of target cells. -Model of signal transduction for the direct effects of GH -GH binding induces *receptor dimerization* -The receptor dimer brings two JAKs into close proximity so that the JAK associated with one receptor can phosphorylate the JAK associated with the other receptor. -This is followed by the JAK-mediated phosphorylation of the GH receptors. -Phosphotyrosine residues on the GH receptor serve as docking sites for other signaling proteins such as STAT (signal transducers & activators of transcription) proteins. -Upon docking to specific phosphotyrosine residues in the GH receptors, the *STAT proteins* are phosphorylated by the receptor-associated JAKs. -Phosphorylated STAT proteins form dimers and migrate to the nucleus where they *activate gene transcription.* -GH can activate additional intracellular signaling pathways because JAK 2 can phosphorylate other signaling proteins besides STAT. -Moreover, other signaling proteins that dock with phosphotyrosines on the GH receptor can initiate ADDITIONAL signaling cascades.
In a patient with a genetic defect in GH receptors making them partially unresponsive, you would expect the level of IGFs to be:
A. Higher than normal B. Lower than normal C. Normal ---- B GH are unresponsive then not capable of making IGFs (Insulin-like growth factors)
A 4'11" 17-yo male is tested for a growth hormone disorder and is found to have elevated GHRH and GH but normal thyroid function. His most likely disorder is?
A. achondroplasia B. pituitary dwarfism C. Laron dwarfism D. cretinism ------ C as don't have receptors to respond to GH so produce MORE GHRH and GH; thyroid is not affected at all
A medical student volunteered to be a subject for a research project on growth hormone. Blood samples were taken each day at midnight and noon. Her GH level was consistently much higher at midnight than it was at noon. The endocrine control system responsible for this is:
A. negative feedback. B. positive feedback. C. stress-related. D. exercise-related. E. circadian ----- circadian
Gigantism
Abnormal height caused by excessive GH secretion before the epiphyses close Growth Hormone Excess= -Primary cause is a pituitary adenoma -Gigantism if it occurs during childhood -Acromegaly (affects hands, feet, face) if it occurs in an adult >Acromegaly is characterized by: -Local effects of the tumor (enlargement of sella turcica, headache, visual problems, destruction of other pituitary cells) -Conditions associated with GH excess -An increase in periosteal bone growth (results in enlarged digits, hands, face, and feet and in deformities of the skull) -Connective tissue proliferation >Entrapment of nerves in connective tissue and bone (may cause peripheral neuropathy) -Impaired glucose tolerance -Enlargement of some visceral organs
Relation Between Age and Integrated GH Concentration
Above diagram. The "integrated concentration" is the average concentration over a 24 hour period. -Multiple samples, taken during a 24-hour period, are pooled and the GH concentration of the pooled sample is measured. -Circulating IGF levels decline with age in proportion to the integrated 24 hour GH output.
Growth Hormone
GH -Pituitary Hormone members of the Somatomammotropin Family >Growth hormone (GH) - 2 equally potent forms (Differential splicing of mRNA makes 2 different products from same gene) ->Most abundant secretory product of the APG. >Prolactin (PRL) -GH modulates metabolism and body composition -Stimulates linear growth and development via IGF-1 >GH also known as somatotropin >IGF-1 also known as somatomedin
Actions of GH and IGF-1
GH causes acute metabolic effects - "diabetogenic" actions -Provides "fuel" and raw materials for growth, an indirect effect on growth. -IGF-1 causes growth: a direct effect on bone and soft tissue. -The net effect of GH is to *increase lean body mass* -GH stimulates the uptake of amino acids and protein synthesis and inhibits proteolysis in skeletal muscle and other GH-responsive tissues. -Blood urea content & urinary nitrogen excretion *decrease as amino acids are converted to protein.* -Age-related muscle WASTING may be due to the DECREASE in GH secretion that occurs with aging. -Administration of exogenous GH REDUCES body fat by mobilizing fat stores and decreasing fat deposition. -GH promotes the growth of connective tissue -GH increases the mass of some organs such as the liver and spleen; however, most tissues grow in proportion to body size.
Changes in the pattern of GH secretion with Age
GH is released in a circadian pattern characterized by a LARGE BURST of secretory activity occurring approximately *1 to 2 hours after the onset of deep sleep* -Effects of age on GH production Daily pituitary output of GH is *highest during the adolescent growth spurt* Growth hormone secretion DECLINES gradually during the third and fourth decades. -In middle-age, GH release in response to GHRH administration or insulin‑induced hypoglycemia is diminished. -GH secretion is low in elderly individuals. >This decline in GH production may be responsible for the age-related decline in lean body mass. -The age-related decrease in GH output is characterized by a decrease in the size of the secretory pulses. -To accurately assess circulating levels of hormones that are released in short secretory pulses, it is preferable to obtain multiple samples at timed intervals and then make a single determination from a pool containing an aliquot from each sample.
Hypothalamic Control of GH Secretion
Hypothalamic releasing/inhibiting hormones that modulate the secretory activity of somatotropes GHRH: a peptide that stimulates the synthesis and release of GH. -The mechanism of action involves a G protein-mediated activation (Gs) of adenylyl cyclase and a PKA-mediated activation of voltage-gated Ca2+ channels. -PKA also activates transcription factors that induce the transcription of GH and the GHRH receptor. -The actions of GHRH on GH release are *enhanced by ghrelin*, a peptide secreted by neurons in the arcuate nucleus of the hypothalamus. >The physiological relevance of this effect has yet to be determined. -*Somatostatin:* a peptide that blocks basal and GHRH‑stimulated GH release. >The actions of somatostatin are mediated by a *Gi protein* that inhibits adenylyl cyclase activity and activates K+ channels that hyperpolarize the cell membrane (less secretion).
Insulin-like Growth Factors (IGFs)
IGF-1 is the principal IGF responsible for the indirect actions of GH -Indirect effects of GH are mediated primarily by a GH-dependent peptide called Insulin‑like Growth Factor I (IGF‑I). -Most circulating IGF-I is transported in a large molecular weight complex that includes: >IGF >IGFBP-3 (The major IGF binding protein in humans) provides a circulating reservoir of IGF -> Main IGFBP in human plasma ->Increases IGF's half life >ALS (acid-labile subunit) -GH stimulates the synthesis of IGFBP-3, IGF-1 and ALS -Major source of IGF-1 is the liver but made at other local productions which is important in mediating many actions of GH. -*Chondrocytes in the epiphyseal growth plate express receptors for both GH and IGF-1.* -Prechondrocytes & other GH target cells in the epiphyseal growth plate synthesize and release IGF-1 in response to GH stimulation. -The affinity of IGFBPs for IGF-I is greater than its affinity for the IGF-I receptor >However, the affinity of IGFBP for IGF-I decreases when the IGFBP binds to the surface of target cells or is degraded by IGFBP proteases. >These properties may be critical for the regulation of IGF-I bioavailability and targeting IGF action to specific target cells. CLINICAL NOTE: there are some cancers that overexpress IGFBP proteases.
Sex Steroids and GH
Stimulating growth hormone secretion is a major mechanism through which *sex steroids increase growth velocity at puberty*. -Multiple clinical observations support the conclusion that many of the sex steroid actions on linear growth at puberty are mediated by *estradiol* RATHER THAN testosterone in both boys and girls. -The increase in GH secretion at puberty in males has traditionally been attributed testosterone; however, more recent evidence indicates that estradiol is the principal hormone that stimulates the increase in GH secretion that *drives the pubertal growth spurt in both girls and boys.* -Longitudinal growth terminates when the epiphyseal growth plate FUSES. -Estradiol (E2) is the principal hormone responsible for stimulating *growth plate maturation and fusion in both males and females.* *Sex steroids stimulate the pubertal growth spurt and fusion of the epiphyseal growth plates*
Thyroid hormone and GH
Thyroid Hormones -Thyroid hormones also play a major role in promoting *postnatal somatic growth.* -Although required for normal linear growth in children, thyroid hormones *will not promote growth in the absence of GH.* -A SYNERGISM between these two hormones is also indicated by the observation that the *maximal stimulation of growth by GH requires permissive amounts of thyroid hormones.* Thyroid hormones appear to promote linear growth by increasing GH secretion