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Lect E3 - Endocrine growth Growth, Metabolism & Calcium Endocrine System Summary Lect # 3 Growth & Metabolism 1. Growth Hormone & Somatomedins (IGF’s) Prof Kumlesh K. Dev D Department off Physiology Ph i l 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon 6. Calcitonin, PTH & Vit D CRH TRH PRH PIH GnRH dopamine (LH releasing hormome LHRH) CorticotropinReleasing hormone ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone Gonadotropinreleasing hormone GHRH GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion Chapter 4 Principles of Neural and Hormonal Communication Human Physiology by Lauralee Sherwood ©2007 Brooks/Cole-Thomson Learning many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y The Glands Growth Factors & Hormones Summary Growth Hormone • Growth hormone & Somatomedins (IGFs) – from anterior pituitary gland – essential for normal growth – GH releases somatomedins (insulin like growth factors – IGF’s alter growth) • Thyroid hormone (Triiodothyronine – T3) – permissive for GH • Androgens/Estrogens (Oestrogns/Testosterone) – growth in puberty, stimulate protein synthesis in organs – effects ff t depend d d on presence off GH • Insulin – promotes protein synthesis, deficiency blocks growth – hyper-insulin spurs excessive growth • Calcitonin, PTH and Vit D 1 Lect E3 - Endocrine growth Other Growth Factors Growth Rate Growth Hormone Growth Hormone • Epidermal Growth Factor ─ polypeptide with mitogenic activity • Not continuous • different factors responsible for growth at different periods g • Platelet Derived Growth Factor ─ each human platelet contains ~1000 molecules, stimulates fibroblasts and glial cell growth Fetal growth • Promoted by placenta hormones • GH plays no role in fetal growth • Nerve Growth Factor ─ important for maintaining viability and promoting diff differentiation ti ti and d synaptic ti out-growth t th ffrom sensory and d sympathetic ganglionic neurones Postnatal growth spurt • first two years of life • Fibroblast Growth Factor ─ stimulates bone cell proliferation and collagen synthesis Growth Hormone Puberty growth spurt • Male: Androgens (testes) promote protein synthesis and bone growth • Female: Androgens (adrenal glands, less potent) promote protein synthesis and bone growth Related Growth Hormones & Receptors Growth Hormone ─ Also called somatotropin ─ Peptide hormone 191 amino acid ─ Mol wt approx. 20 kDa ─ 500µg made per day ((circulating g 0-30 ng/ml, g , t1/2 ~20min) ─ GH is encoded on chromosome 17 Normal Growth Curve Growth Hormone ─ Other members of GH family: ─ Placental Lactogens (somato-mammotropins) are 85% identical t GH to ─ Prolactin, less closely related to GH ─ evolved from a common ancestral gene ─ GH, Prolactin and PL can cross activate their receptors: ─ Growth hormone has weak prolactin-like, lactogenic activity ─ Prolactin has lactogenic activity, but no growth-promoting activity ─ Placental lactogen has weak growth-promoting activity 2 Lect E3 - Endocrine growth GH Release GHRH Receptor Signalling Growth Hormone Pulsed release ─ ─ ─ ─ released from anterior pituitary in several daily bursts peak secretion early morning before awakening and lowest in day secretion stimulated during deep sleep rhythm linked to sleep-wake not light/dark surges in first 2 hr sleep at night Deviation from 24h m mean (%) ─ Growth Hormone Diurnal variation in serum GH Growth Hormone 150 100 50 ─ terminated by somatostatin 0 -50 -100 Number/magnitude pulses depend on age ─ increased pulses during puberty ─ declines in adults ─ absent at 50yr+ ─ GH bursts initiated by bursting secretion of growth hormone releasing l i h hormone (GHRH) 0 6 12 18 Time (hr 24 ─ GHRH and somatostatin produced by hypothalamic neurons ─ GHRH receptor is a 7 transmembrane domain G-protein coupled receptor Age-related decrease in GH release ─ change in muscle:fat ratio ─ decreased bone density ─ GH sold as “anti-ageing” therapy? (but may actually speed ageing)…….. ─ GHRH stimulates GH synthesis and secretion Stimuli that regulate GH secretion Long term metabolic effects of GH Growth Hormone Stimulants Inhibitors ¾ low energy substrate ¾ REM sleep ¾ hypoglycemia ¾ hyperglycemia ¾ exercise and fasting ¾ cortisol ¾ increase in blood levels of certain amino acids (e.g. Arg, Leu) ¾ free fatty acids ¾ glucagon ¾ hypothyroidism ¾ stress ¾ aging ¾ deep sleep ¾ dopamine receptor agonists Growth Hormone Carbohydrates ─ ─ ─ ─ increases blood glucose decreases peripheral insulin sensitivity increases hepatic glucose output increases serum insulin levels Proteins ─ ─ ─ ─ increases tissue amino acid uptake increases incorporation into proteins decreases urea production produces positive nitrogen balance ¾ growth hormone (feedback) Lipids IGF ─ is lipolytic - activates hormone sensitive lipase ─ stimulates IGF production ─ stimulates growth ─ mitogenic 3 Lect E3 - Endocrine growth Injection of GH into animals causes …….also don’t believe this Growth Hormone ─ Stimulation of bone growth ─ Stimulation of protein synthesis in many tissues Growth Hormone protein-building activity of GH does not promote athletic ability….. ability GH will not enlarge your….. MEN INCREASE SIZE!! ENLARGE YOUR PENIS WITH GROWTH VISION!! PENIS ENLARGEMENT AUDIO. Stimulate the Growth Hormone in your brain that determined the current size of your sex organ! Mind over Body visualization technique has been proven to work! 95% of all people tested report results within 30 days. Request your FREE copy of SIMPLE SECRETS with AMAZING Photos and complete details. Email your postal address to: [email protected] or snail mail your request to: RACA Box 819 - Perry, FL 32348-0819. ─ Stimulation of erythropoesis ─ Anti-insulin activity ─ increases hepatic glucose output ─ promotes lipolysis in adipocytes IGF-1A SAY NO TO STEROIDS ─ decreased glucose uptake by muscle GH releases IGF-1 IGF is on the streets right now….. AT LAST A SAFE ALTERNATIVE TO GROWTH HORMONE Accelerates bodies production of GH “..IGF-1 is out there on the streets right now….it’s the most wonderful stuff in the world for gaining muscle and losing fat.. Many athletes are comparing IGF-1A to Anabolic Steroids”. Quote From A Major Muscle Magazine GH mediates actions via IGFs Growth Hormone • GH stimulates – Liver production of somatomedins (insulin-like growth factor; IGF-1) IGF 1) – Acts on bone & soft tissues to promote growth – Stimulates protein synthesis, cell division (of condrocytes), lengthening, thickening of bones • metabolic effects – increases fatty acid levels in blood (enhances breakdown of triglyceride fat in adipose tissue) – increases blood glucose levels (decreases glucose uptake by muscles) Growth Hormone ─ main function of GH is to promote IGF-l production ─ GH stimulates liver to make IGF- 1 ─ GH requires i IGF IGF-1 1 tto promote t growth th ─ Mice genetically lacking GH are dwarfed; IGF-l gene overcomes GH defects ─ IGFs are structurally related to insulin ─ Insulin has weak somatomedin-like activity on some cells ─ Two different genes encode IGF- 1 and IGF-2 ─ IGF IGF- 1 stimulates ti l t b bone growth th and d cellll proliferation lif ti lleading di tto soft tissue growth ─ In some forms of dwarfism, GH production is normal, but IGF-I production is subnormal ─ African Pigmies lack pubertal surge of IGF-I 4 Lect E3 - Endocrine growth Pituitary Gigantism Acromegaly Growth Hormone Growth Hormone • GH hypersecretion after adolescence causes acromegaly • certain benign tumors (adenomas) in pituitary gland produces excess GH ─ GH excess caused by tumour cells of anterior pituitary producing GH Progression of acromegaly A - Age 9 (normal) B - Age 16 (coarsening features) C - Age 33 (established acromegaly) D - Age 52 (severe acromegaly) • Features include – Excessive thickening of bones – Coarsened facial features ─ in children this leads to gigantism • Brow/lower jaw protrusion (enlarge jaw) • Teeth spacing increase ─ in adults acromegaly results (growth in stature does not occur because adult long bones are unable to lengthen) – Soft tissue swelling of hands and feet • Enlarged hands & feet • Arthritis and carpal tunnel syndrome – Heart failure (major problem) – Vision loss (compressed optic chiasm) • Medication reduce GH secretion/tumor Robert Wadlow the “Alton Giant” He was 8 feet, 11 inches tall and weighed 475 pounds at the age of 22 – Bromocriptine (DA receptor agonist) – somatostatin, to stop GH production – GH receptor antagonists are emerging Dwarfism Feedback Loops of GH Growth Hormone Growth Hormone GH deficiency • treated by replacing GH • GH was extracted from human pituitary glands at autopsy • now made by recombinant tech Hypothalamus GHRH GHRH Hereditary • underproduction of GHRH • incapable of manufacturing GH Laron dwarf • circulating GH levels ok but GH receptors unable to bind Long Loop GrowthGrowth hormone inhibiting hormone Ant. Pituitary GH Growth Hormone GH The Dwarf Sebastian de Morra The Dwarf Francisco Lezcano, Called "El Nino de Vallecas“ many target organs Short Loop African Pygmy • unresponsiveness to IGF • defect in IGF1 receptor GHIH somatostatin Growthhormone releasing hormone Liver growth, anabolic actions IGF-I 5 Lect E3 - Endocrine growth Growth, Metabolism & Calcium The Glands Summary Summary 1. Growth Hormone & Somatomedins (IGF’s) 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon 6. Calcitonin, PTH & Vit D CRH TRH PRH PIH GnRH dopamine (LH releasing hormome LHRH) CorticotropinReleasing hormone ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone Gonadotropinreleasing hormone GHRH GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y Thyroid Gland T3 and T4 Hormones Thyroid Thyroid Gland • front of upper part of trachea • encapsulaed p by y a fiborous capsule p • develops from epithelial outgrowth of tongue TRACHEA Types of thyroid hormones • Thyroxine (T4) (t1/2 ~7 days) in follicles • Triiodotyronine (T3) (t1/2 ~1.5 days) in follicles • Calcitonin by C cells Function of T3 and T4 • T3 and T4 accelerate metabolism • increase carbohydrate, fat and protein turnover • increase oxygen consumption & heat production • important during development, essential between wk 11 and birth Thyroid Thyroxine (T4) Structure of T3 and T4 • T4 & T3 are tyrosine-based hormones • T3 has 3 iodine atoms,, T4 contains 4 • T3 more effective, but T4 more abundant Levels of T3 and T4 • levels controlled by anterior pituitary TSH • negative feed back loop operates for T3 and T4 secretion • transported in blood, blood bound to thyroxine-binding globulin (TBG) • only made by follicular cells when iodide available • iodide actively absorbed from blood to thyroid follicles • deficiency dietary iodine, thyroid enlarges to trap more iodine, i.e. goitre I T3 I -O- HO- -CH2-CH-COOH NH2 I I I rT3 -O- HO- -CH2-CH-COOH NH2 I 6 Lect E3 - Endocrine growth Goiter & Hashimoto’s disease Hypothyroidism Thyroid Thyroid Hypothyrodism - Infants • stunted growth • bone formation • skeletal abnormalities • severe mental retardation Goiter - low idoine uptake ─ no T3/T4 made because not enough i did iingested iodides t d ─ "iodide pump" of thyroid gland is very effective, i.e. 30% of ingested iodide may be taken up by thyroid ─ when dietary iodide insufficient to produce thyroxine, efficiency of iodide uptake increases due to thyroid cell proliferation ─ normall h human th thyroid id gland l d off 25 g may grow to 250 g during goiter Hypothyrodism - Adults • low metabolic rate & decreased energy • always cold, cold sensitivity, tolerance • excess sleep, sluggishness, fatigue, tired, cant finish tasks, weight gain • constipation, dry skin Hashimoto’s - autoimmune disease ─ autoimmune (autoantibodies destroy follicular cells) Hyperthyroidism Feedback Loops of Thyroid Hormone Thyroid Symptoms • high metabolic rate • protruding eyes • hyperactivity, insomnia, palpitations, nervousness, tremor, can’t concentrate • heat sensitivity, heat intolerance, weight loss, always hot, warm, smooth, moist skin Thyroid Hypothalamus TRH TRH Long Loop Ant. Pituitary TSH Grave’s disease • hyperthyroidism due autoimmune problem (TSH is mimicked by autoantibodies) • Treatments – Beta blockers help some symptoms – Anti-thyroid medications – Radioactive iodine treatment destroys overactive thyroid cells – Surgery thyroidectomy Thyrotropiny p Releasing hormone Thyroid stimulating hormone TSH Thyroid gland Short Loop Thyroid Thyroid Hormone (T3.T4) Thyroid Hormone 7 Lect E3 - Endocrine growth Growth, Metabolism & Calcium Summary 1. Growth Hormone & Somatomedins (IGF’s) 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon 6. Calcitonin, PTH & Vit D CRH TRH PRH PIH GnRH dopamine (LH releasing hormome LHRH) CorticotropinReleasing hormone ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone Gonadotropinreleasing hormone GHRH GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y 8