53: Growth Hormone Flashcards
Describe the relationship between GH and the insulin-like growth hormones
Overwhelming source of circulating IGF-1 is the liver. Some is made by kidney and skin but these sources do not contribute significantly to the circulation. IGF-1 circulates all day at a relatively constant level.
GH does not induce growth in animals that lack insulin; it also won’t stimulate growth in the absence of carbohydrates. Anorexia and other eating disorders will dramatically affect the growth of a child by curtailing IGF-1 production.
GH & food stimulate IGF-1 production in liver.
IGF-I stimulates growth:
– Endocrine: classic systemic effect through circulation
– Paracrine: affects neighboring cells
– Autocrine: affects producing cell
•Negative feedback to hypothalamus and pituitary to down-regulate GH secretion
•Clinical use: IGF-1 is the primary screening test when considering growth hormone deficiency, since its levels in the circulation are more stable and reflective of GH levels in normal individuals.
Insulin and insulin like growth factors are cleaved differently, But they share AA sequence homology.
Insulin and insulin like growth factor receptors are heterotetramers joined by disulfide bonds.
Dimerization of the IGF-1 receptor leads to autophosphorylation. This recruits two major phosphotyrosine binding proteins IRS-1 and Shc, which are phosphorylated by the IGF-1 receptor. This recruits other proteins to the membrane leading to the activation of the phosphoinositol-3-kinase (PI3K) and the Ras/MAP kinase pathways that regulate cellular transcription.
Describe the regulation of growth hormone secretion
Growth hormone releasing hormone stimulates GH secretion. Somatostatin inhibits GH secretion. Integration of the two gives episodic, pulsatile secretion.
Ghrelin is produced in stomach and pancreas & it stimulates hunger. Levels increase before meals and decrease after. Acts on growth hormone secretagogue receptor. It is likely more important for: feeding behavior, energy regulation, & (possibly) sleep, than for control of GH secretion. Target for design of anti-obesity drugs.
Pulses house secretion of growth hormone over lifespan. Pulses are primarily at night. Number of pulses per day stays constant. Larger pulse amplitude during puberty. Strenuous exercise causes a surge in growth hormone.
Typical variations in growth hormone secretion throughout the day, demonstrating the especially powerful effect of strenuous exercise and also the high rate of growth hormone secretion that occurs during the first few hours of deep sleep. Drugs that disrupt sleep in children can decrease growth, at least temporarily. Examples include drugs for ADHD (Ritalin). After 3 years on Ritalin, children are on average 1 inch shorter and 4 pounds lighter than their peers, however, they eventually catch up to a normal height if good nutrition is maintained.
Insulin induced hypoglycemia is used as a clinical test to provoke GH secretion in suspected GH-deficient individuals. Amino acids increase GH release primarily by decreasing somatostatin release. GH in the circulation is bound to GH-binding protein, which prolongs it half-life.
Stimulators of GH secretion: deep sleep, exercise, sex steroids, fasting/ hypoglycemia, amino acids, stress, a-adrenergic agonists, dopamine agonist (suppress acromegaly). Fasting increases the number of GH pulses and the amplitude of each pulse.
Inhibitors of GH secretion: IGF-I, obesity, glucocorticoids, hyperglycemia, free fatty acids, growth hormone, B-adrenergic agonists. Obesity decreases the number of GH pulses and the duration of each pulse.
Growth hormone release by the anterior pituitary is controlled by GHRH and somatostatin. Growth hormone has an important role in growth and development of children and regulation of metabolism. Some of GH’s effects are mediated by somatomedins (like IGF-1) produced by the liver or by specific target tissues.
Somatomedins inhibit the secretion of GH
Small-bodied neurons in the arcuate nucleus of the hypothalamus secrete GHRH, a 43-amino acid peptide that reaches the somatotrophs in the anterior pituitary via the long portal veins. GHRH stimulates G protein-coupled receptors on the somatotrophs to release GH stored in secretory granules by raising [cAMP]i and [Ca2+]i. cAMP activates protein kinase A to phosphorylate the transcription factor CREB, augmenting the transcription of Pit-1, a transcription factor that upregulates GH and the GHRH-receptor. Increased Ca2+ levels leads to secretion of GH.
Neurons in the periventricular region of the hypothalamus synthesize somatostatin, a 14- amino acid neuropeptide. Somatostatin, which also travels to the anterior pituitary via the long portal vessels, is a potent inhibitor of GH secretion, through Gi-protein coupled receptors. Somatostatin acts by inhibiting adenylyl cyclase and thus lowers [Ca2+]i.
IGF-1 is a primary mediator of the effects of growth hormone (GH)—it is soo anabolic! Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis. Deficiency of either growth hormone or IGF-1 therefore results in diminished stature.
The receptors for growth hormone (and prolactin and most of the cytokines) activate the JAK/STAT pathway of signal transduction. Such hormone/cytokine receptors have no inherent tyrosine kinase activity as seen in the receptors for many growth factors. Instead binding of the hormones to their receptors causes receptor dimerization and the consequent binding of one or more associated JAK tyrosine kinases 1. This induces phosphorylation of the JAK kinases as well as the receptor 2. The activated JAKs subsequently phosphorylate the STATs, which as dimers, translocate to the nucleus and act as transcription activators.
Leads to the increased expression of CISH, a well established GH target gene.
Severe under expression of the GH receptor is a contributing cause of short stature in Pygmies.
GH receptos are present on many tissues and cell types including: liver, bone, kidney, adipose tissue, muscle, eye, brain, heart and cells of the immune system.
Identify the target organs or cell types for insulin-like growth factors that account for longitudinal growth
Growth hormone supports the differentiation of the mesenchymal stem cells (Prechondrocytes) into chondrocytes. Local IGF-I induces the clonal expansion of the early chondrocytes and the maturation of later chondrocytes.
This leads to the synthesis of extracelluar matrix proteins including type II collagen, hyaluronic acid, and mucopolysaccharides. As the cells move closer to the already formed trabecular bone it becomes calcified. Soon after this it begins to be remodeled by the action of osteoclasts and osteoblasts to form mature bone.
At puberty both sex hormones contribute to rapid increase in stature. For girls, growth spurts begin at the early stages of puberty, whereas for boys they usually occur well after puberty has begun. The pubertal peak rate of growth corresponds to the peak serum concentrations of IGF-I.
Describe the metabolic and growth promoting actions of growth hormone
A major role for GH is regulation of postnatal longitudinal growth. GH has direct and indirect effects (i.e. through somatomedians such as IGF-1). Effects of GH:
Liver- Stimulates the production of IGF-1, and stimulates hepatic glucose production.
Adipose tissue- GH stimulates the release and oxidation of free fatty acids particularly during fasting. This is mediated by the reduction of the activity of lipoprotein lipase, which clears lipoproteins and triglycerides from the bloodstream. Lipogenesis is reduced.
Skeletal Muscle- GH has anabolic actions on skeletal muscle– stimulates amino acid uptake and incorporation into protein– suppresses protein degradation. It also stimulates cell proliferation, increases metabolism and changes muscle fiber distribution.
Brain- affects mood and behavior.
Overall GH counteracts the action of insulin on lipid and glucose metabolism, by decreasing skeletal muscle glucose utilization, increasing lipolysis and stimulating hepatic glucose production.
Non objective important stuff
Growth hormone a.k.a. Somatotropin is a polypeptide hormone produced in anterior pituitary. Excess during childhood gives gigantism, deficiency in childhood gives dwarfism. Excess during adulthood gives acromegaly.
Growth hormone deficiency and replacement. Many rare causes of deficiency. Any defect affecting hypothalam-pituitary function. Mutations in GH–1 gene. Children have extremely slow growth less than 2 inches per year. Severe postnatal growth failure.
Giving extra hormone (hormone levels in access of normal) during treatment does not increase the rate of growth above what is attained with normal levels.
Laron syndrome is growth hormone insensitivity. There’s a point mutation or deletion in the growth hormone receptor. There is a low IGF-I concentration. There is normal or elevated GH concentration & severe post natal growth failure. It is treatable with rh-IGF-1. Laron syndrome is autosomal recessive; heterozygotes show mild growth retardation. The disease is rare. The insulin/IGF-1 pathway is thought to promote aging.
Many Guinness World Record giants are likely pituitary giants, individuals who have been exposed to too much GH throughout life. Typically has hyperglycemia and 10% of giants develop full-blown diabetes mellitus due to degeneration of beta cells of the islets of Langerhans.
Growth hormone-secreting adenomas cause acromegaly (6/100,000 individuals): The effects of growth hormone-secreting adenomas vary depending on size and growth rate as well as invasiveness. Large tumors cause destruction of the pituitary and deficiency of other pituitary hormones and may affect the optic chiasm and vision. Growth hormone excess produces acromegaly in adults (right panel), with protrusion of the jaw, macroglossia (enlarged tongue), enlarged hands and feet, carpal tunnel syndrome, reduced strength and other effects.
GH deficiency is identified by provocative pharmacological tests to stimulate GH secretion. For instance insulin treatment to lower blood sugar is followed 20-30 min later with a blood test for GH.
Growth hormone deficiency in adults is usually caused by pituitary problems. It can be the result of surgery or radiation. It causes increased intestinal fat. It causes reduce strength and bone loss. It can cause feelings of anxiety and depression. Treatment with rhGH remediates many of these issues.
Implications of GH- Deficiency for Cardiovascular Disease: Increases:- visceral adipose tissue- carotid intima-media thickness - Inflammatory markers of cardiovascular disease- clotting factors -insulin resistance – LDL
Decreases:-myocardial function – HDL – “Get up and go”. GH-deficiency is not as impactful as being grossly over weight and sedentary but has the same trend.
Reduced levels of GH are thought to contribute to some normal effects of aging such as loss of muscle mass, increase in interstitial body fat.
Growth hormone replacement therapy restores muscle mass, reduces fat deposits, gives you feeling of increased energy. Side effects include insulin resistance, diabetes, edema, & carpal tunnels syndrome.
GH is approved for use in: Growth hormone deficiency, idiopathic short stature (ISS), Turner syndrome, Prader-Willi syndrome (PWS), chronic renal insufficiency (DRI), small for gestational age (SGA)
In families moving to the U.S. from a developing country, the first two generations grow a little taller than predicted by the formula.
Growth charts are used by medical professionals to follow a child’s growth over time. In general, children follow a fairly constant percentile. Deviation from this percentile may indicate a chronic illness such as inflammatory bowel syndrome (for instance Celiac’s disease), Lupus and other collagen-vascular diseases, renal failure, and thalassemia.
Nutritional deficiency leads to reduced levels of IGF-1 and slower growth in Celiac disease children. Effectively treating the disease can restore normal growth.
Replacement doses of thyroxin restored his growth to normal and the height expected for his family. There is a thyroid hormone response element upstream of the Growth Hormone transcriptional start site. Therefore hypothyroidism reduces growth hormone production with very dramatic consequences.
Turner and Down syndrome are the most common genetic syndromes that cause short stature in the U.S.
Turner syndrome (only 1 x chromosome in female) Absence of one X-Chromosome -45, X in about 50% -Remainder are other karyotypes: Isochromosome Xp or Xq Mosaic, e.g. 45,X/46,XX. Slower velocity during childhood, plus scant pubertal growth spurt. They are treated with GH, although they make their own, and also given sex steroids. Height is improved but not completely restored (low 5-foot range).
Patients with extra sex chromosomes have extra copies of SHOX and are taller than normal. For instance, in Klinefelter’s syndrome (XXY), individuals are taller than average partly due to an extra copy of SHOX and partly due to a gonadotropin deficiency. In addition they don’t go into puberty and don’t fuse their bones and thus continue to grow for longer than normal.
SHOX Locus: SHOX is in the pseudoautosomal (PAR) region of X chromosome.
Deletion of the pseudoautosomal region of either sex chromosome will result in short stature.
