Hormones: GH (Week 5--Howard) Flashcards
Pituitary gland
Two lobes: anterior (adenohypophysis), posterior (neurohypophysis)
Several pituitary hormones are endocrine-stimulating factors
Posterior lobe secretes neurohormones
Portal blood system connects hypothalamus to anterior pituitory
Neuronal and chemical regulation of hormone production and secretion
Anterior pituitary hormones in 3 groups
1) ACTH: ACTH (adrenocorticotropin), beta-endorphin, beta-LPH (beta-lipotropin), MSH (melanocyte stimulating hormone), CLIP (corticotropin-like intermediate peptide, not important) (note from histo, these are released by basophils)
2) Glycopeptides: FSH, LH, TSH (note from histo, these are released by basophils)
3) Growth stimulating: PRL (prolactin), GH (growth hormone, somatotropin) (note from histo, these are released by acidophils)
Posterior pituitary hormones (released by hypothalamic neurons)
Vasopressin (ADH)
Oxytocin
Hypothalamic peptides secreted into portal blood system to regulate release of anterior pituitary hormones
TRH stimulates TSH
GnRH stimulates FSH/LH
GHGH stimulates GH
Somatostatin (GHRIH) inhibits GH
CRH stimulates ACTH
Dopamine inhibits PRL (prolactin)
POMC (pro-opiomelanocortin)
Post-translational processing by proteolytic cleavage of POMC in anterior and intermediate lobes gives ACTH, beta-LPH (in anterior lobe) and MSH, CLIP, beta-END in intermediate lobe/CNS
2 subunits of glycopeptides
alpha: all glycopeptides have same alpha, and has biological activity
beta: different for each, and confers target specificity
(remember glycopeptides are FSH, LH, TSH)
GH (growth hormone)
Increases longitudinal growth by enhancing bone growth
Regulates metabolic activities
Can affect production or action of other endocrines, paracrines, autocrines
Effects vary with target tissue, duration of action (acute (< a few hr) vs. delayed or prolonged), anabolic vs. diabetogenic
Two mechanisms of action: (1) direct actions on target tissues; (2) indirect actions secondary to induction of insulin-like growth factor (IGF) at target tissue
General process of bone development
Extracellular matrix of collagen, glycoproteins becomes calcified by formation of crystalline complex of Ca2+ and phosphate hydroxide (hydroxyapatite)
Bone length increases by laying down bone to become calcified in epiphysial cartilage plate
What are the three cell types involved in bone development?
Chondrocytes (from mesenchymal stem cells)
Osteoblasts (from mesenchymal stem cells): recalcification
Osteoclasts (from promonocyte/macrophage cells): decalcification/resorption
Note: GH can regulate all of these bone cells!
What are the 2 types of bone formation?
Intramembranous: occurs in flat bones (skull, clavicle) and involves osteoblasts which secrete extracellular matrix and induce calcification
Endochondral: occurs in long bones and involves chondrocytes and osteoblasts, both of which secrete extracellular matrix; lengthening occurs at epiphysis, where cartilage chondroblasts of epihpyseal plate multiply to enlarge region that will become calcified
What happens to bone after it is formed?
Constant remodeling by resorption (decalcification) by osteoclasts and recalcification by osteoblasts
Note: impalance of this process can lead to osteoporosis
How does GH induce longitudinal growth at epiphyseal cartilage plate?
Induces chondrocyte proliferation, maturation, and secretion of matrix proteins and cartilage
After closure of epiphyseal cartilage plate, how does GH induce bone remodeling?
Induces osteoblast proliferation and activity
Induces osteoclast differentiation and activity
What can cause excessive secretion of GH?
Tumor in pituitary or hypothalamus (releases GHRH)
Ectopic tumor (releases GH)
Note: can also get excessive GH if tumor secretes GHRH
Acromegaly
Due to excessive secretion of GH that begins after closure of epiphyses of long bones
Thickening of skin (esp face, hands feet), enlarged organs, overgrowth of skeleton, lethargy, sweating, headaches, arthralgia
Increased incidence of diabetes and hypertension, increased mortality (respiratory disease, cardiovascular, malignancy)
Gigantism
Excessive secretion of GH that begins before closeure of epiphyses
Acromegaly develops if not treated
How do you diagnose acromegaly?
Increased level of IGF-1 in blood
Failure to supress blood GH levels by glucose (hyperglycemia should inhibit GH and hypoglycemia should stimulate GH!)
How do you treat acromegaly?
Surgery
Octreotride (somatostatin analog)
Beta-adrenergic agonists (stimulate somatostatin (GHRIH) in hypothalamus so less GH secretion)
What can cause GH deficiency (dwarfism)?
1) Congenital: defect of GH, GHRH, GH receptor (Laron Syndrome), IGF, IGF receptor (very difficult to treat if IGF receptor mutation), or developmental abnormality of pituitiary or hypothalamus
2) Acquired: tumors, pituitary trauma, psychosocial depravation
Clinical manifestations and treatment of GH deficiency (dwarfism)
Clinical manifestations: abnormally short, plumpness, retarded bone age in relation to chronological age
Treatment: periodic injection of GH (or IGF in the case of Laron Syndrome)
What else is GH used to treat?
Used to treat shortened growth in people with Turner’s syndrome (45, X) and renal failure
What is adult onset GH deficiency?
Clinical manifestations: low mood, reduced energy levels, obesity, reduced bone density
What is idiopathic short stature?
5th percentile or less for height
Normal response of serum GH level to stimuli
No other evident cause of short stature
Effects of hGH on normal adults (including elderly and athletes)
Increase in lean body mass and muscle mass
Decrease in adipose tissue mass
No increase in muscle strength, exercise endurance, exercise capacity, bone density
Adverse side effects include soft tissue edema, fatigue
No known effects on rate of healing
NOT recommended for anti-aging therapy!
Note: DOES help with “power” in athletes, or anaerobic metabolism (something to help football players)
Effects of hGH on GH-deficient adults
Increase in lean body mass, muscle mass, muscle strength, athletic performance, bone density
Decrease in adipose tissue mass
Structure of GH
Single polypeptide chain with 191 AAs and 2 S-S bonds
Some minor GH isoforms present due to differential splicing etc (Note: can measure major 191-AA form vs. minor isoforms to see if an athlete has injected hGH bc if increased ratio of major to minor then must have injected! Must do blood test though, not urine)
Only primate GH is active in humans
Can we use recombinant DNA techniques to create GH?
Yes, cheaply and in an active and safe form for therapeutic use
What stimulates the synthesis of GH?
Transcription and translation are stimulated by GHRH
GHRH is in turn stimulated by sleep, stress, etc
What stimulates the release of GH from the anterior pituitary?
GHRH stimulates GH release
(Somatostatin inhibits GH release)
When is GH released the most?
GH released in episodic bursts, with largest amount occurring shortly after onset of deep sleep
How does GH inhibit its own release?
GH stimulates synthesis/release of somatostatin (which inhibits GH release)
GH induces IGF-1 (which inhibits GH release and stimulates somatostatin release)
How are thyroid hormones involved in GH activity?
Thyroid hormones stimulate GH release
Thuroid hormones are required for GH activity at target tissue
How does GH signal?
GH binds plasma membrane receptor in multiple tissues –> activation of cytosolic protein tyrosine kinase (JAK) –> JAK activates/phosphorylates other proteins including TF called STAT –> transcription of target genes for metabolism, growth (proliferation and differentiation)
Note: it is believed that one protein in (an offshoot of) this pathway is IRS (insulin receptor substrate) which may be one way GH can mimic or inhibit insulin activity. GH can stimulate JAK to phosphorylate IRS to have effects but if too much phosphorylation, IRS will be inactivated so insulin cannot have its effects.
IGF-I (insulin-like growth factor I)
Has two insulin-like domains
Produced by the liver and other tissues
Can act as endocrines, paracrines, autocrines
Functions in prenatal and postnatal growth
Causes effects formerly attributed to GH (cartilage growth)
Binds to cell receptors distinct from but similar to insulin receptor; can also activate insulin receptor
Synthesis is induced by GH
IGF-II (insulin-like growth factor II)
Produced by liver
Functions primarily in fetal growth
Synthesis not induced by GH
How are circulating levels of GH regulated after GH has been produced?
There are GH receptor proteins that are soluble (arose due to differential splicing/proteolysis of membrane bound GH receptor)
These GH binding proteins (GHBP) regulate level of active GH in circulation because they (1) protect circulating GH from being degraded but also (2) reduce level of free GH able to bind/activate membrane bound GH receptor
How are circulating levels of IGF regulated after IGF has been made?
Similar to GH!
There are IGF receptor proteins that are soluble (arose due to differential splicing/proteolysis of membrane bound IGF receptor)
These IGF binding proteins (IGFBP) regulate level of active IGF-I and IGF-II in circulation because they (1) protect circulating IGF from being degraded but also (2) reduce level of free IGF able to bind/activate membrane bound GH receptor
There are specific proteases that degrade IGFBP
Short term (< a few hours) effects of GH
Stimulation of AA uptake into cells and protein synthesis (insulin-like)
Decrease blood level of glucose (glucose uptake) (insulin-like)
Decrease blood level of fatty acids (TG synthesis) (insulin-like)
Long term (> a few hours) effects of GH
Stimulation of AA uptake into cells and protein synthesis (insulin-like)
Stimulation of synthesis of DNA and RNA (insulin-like)
Stimulation of lipolysis (TG breakdown) in adipose tissue and increase blood level of FAs (anti-insulin-like)
Decrease glucose uptake and utilization (anti-insulin-like)
Retention of cheif intracellular minerals (K+, Mg2+)
Note: long term effects increase muscle mass but don’t increase strength or performance
Placental lactogen
Hormone secreted by placenta
Homology to GH but acts more like prolactin (or, long-term, anti-insulin-like GH)
GH-like anti-insulin activity: impairs carbohydrate uptake and utilization (glucose metabolism) in the mother so the fetus gets more glucose than the mother
Placental lactogen may contribute to gestational diabetes
Pitocin
Synthetic peptide used to induce labor and stop postpartum uterine bleeding
Somatotropin vs. somatostatin
Somatotropin is GH (growth!)
Somatostatin is GHRIH (inhibits release of GH!)
Anabolic vs. diabetogenic
Anabolic: increase protein synthesis, lipid storage, glucose utilization
Diabetogenic: decrease protein synthesis, lipid storage, glucose utilization
Can GH help in wound healing?
If administered after wound is made (in surgery?) then it can help, but giving GH before the wound is made does NOT help healing
Effect of giving GH to children with GH deficiency
Child will now grow!
Possible side effects of GH
Soft tissue edema, arthralgias, carpal tunnel syndrome, gynecomastia, diabetes
What secretes IGF-I?
Liver (endocrine)
Target tissues (paracrine, autocrine)
Two ways you can tell if someone has been taking hGH
1) Ratio of major 191-AA form vs. minor isoforms
2) Presence of increased IGF-I
Note: hard to measure GH directly because of pulsatile release
Things that stimulate GH
“Type-A personality!”
Deep sleep
alpha-adrenergic
Fasting
Hypoglycemia
ACh
Sex steroids
Stress
AAs
Things that inihibit GH
“Lazy person”
Obesity
beta-adrenergic
GCs
High FFAs
Hyperglycemia
Hypothyroidism
IGF-I
