Endocrine System.docx

The nervous system and the endocrine system work together to coordinate body functions and control homeostasis: ~ known as the neuroendocrine system • Nervous system releases neurotransmitters that act on neurons, muscle fibres and glands (endocrine / exocrine) ~ nerve AP’s produce their effects wit...

The nervous system and the endocrine system work together to coordinate body functions and control homeostasis: ~ known as the neuroendocrine system • Nervous system releases neurotransmitters that act on neurons, muscle fibres and glands (endocrine / exocrine) ~ nerve AP’s produce their effects within milliseconds • Endocrine system releases hormones into extracellular fluids / blood stream which delivers them to most body cells ~ hormones produce their effects within a few seconds to several hours • Organic chemical messengers / signalling molecules: – Amines – Eicosanoids (eg prostaglandins) – Steroids – Proteins, peptides, glycoproteins • Secreted by specialised glands, scattered cells and nerves • Transported in the blood stream or by simple diffusion • Categorised according to the of their target sites: – Endocrine – Neurohormone – Paracrine – Neurotransmitter – Autocrine – Pheromone • Regulate existing reactions within cells Distribution of hormones to Target cells Hormones can reach tissues/cells by diffusion or via blood • Hormone actions can be either: ➢ autocrine (on-self) ➢ paracrine (local) ➢ endocrine (distant) • Hormones exert targeted responses because cells have specific receptors Water Soluble (hydrophilic) ➢ cell surface receptors Lipid-soluble (hydrophobic) ➢ intracellular receptors The ability of cells to respond to hormones depends on the expression of specific receptors by the target cells ~ many hormones have different receptor sub-types which can be linked to different sub-types of G proteins eg: ~ adrenergic alpha-1(Gq), alpha-2(Gi), beta-1(Gs), beta-2(Gs) • Receptors are located on the plasma membrane or inside target cells: there are three main types: cell surface - peptides, adrenergic, histamine cytosolic / nuclear - steroid hormones nuclear - thyroid (triiodothyronine / T3) • Hormones must bind to their receptor(s) to form hormone-receptor complexes that produce their effects / actions Steroid Receptors • Steroid hormones diffuse into cells, bind to cytosolic ‘signal’ receptors & form receptor complexes ➢ cortisol, aldosterone, oestrogen, progesterone testosterone & vitamin D • receptor complexes bind to DNA acceptor sites • DNA binding starts mRNA and proteins synthesis • Receptors are recycled but the hormone is inactivated • Thyroid hormone (T3 ) has a similar mechanisms • Hormones must be distributed and bound to targets in the body • Once reaching a receptor, hormones can bind to targets in one of three ways; – Cell Surface – Cytosolic – Nuclear The hypothalamus and pituitary are very important parts of the neuroendocrine system that provide three important mechanisms of control: 1) Hypothalamus and Anterior Pituitary: ~ secretion of regulatory hormones (releasing & inhibitory) ~ these hormones control the secretary activity of the anterior lobe of the pituitary gland 2) Hypothalamus and Posterior Pituitary: ~ ADH and Oxytocin are formed in the hypothalamus ~ both are released from the posterior pituitary 3) Adrenal Gland: ~ sympathetic output to the adrenal medulla (adrenalin) ~ ACTH control of cortisol release from the adrenal cortex Hypothalamus and Pituitary Hormones Hypothalamic hormone secreting neurons secrete releasing hormones (RH) or inhibitory hormones (IH) into blood vessels to regulate anterior pituitary hormone secretion Stimuli for secretion of hormones Many types of stimulation can cause hormone release: action potentials → hypothalamic neurohormones hypothalamic neurohormones → anterior pituitary hormones TSH from the anterior pituitary → thyroid hormone acetylcholine neurotransmitter → adrenal medulla hormones glucose → insulin, glucagon low / high blood Ca++ → parathyroid / calcitonin hormones other (e.g., tissue injury) → histamine, cytokines • Many hormones are stored in vesicles which must fuse with the plasma membrane to be secreted: ➢ increased intracellular Ca2+ is required for the vesicles to fuse with the plasma membrane • Thyroid gland, in the neck, is 10-20 g and contains spherical follicles filled with colloid ➢ colloid contains thyroglobulin containing T3 & T4 hormone Thyroid gland releases thyroid hormones> T3 & T4 enter blood and circulate to target >Increased cellular metabolism 1. T3 enters nucleus 2. T3 binding releases the corepressor (CoR) from the thyroid hormone receptor (TR) 3. Co-activator (CoA) assists T3 gene activation 4. Gene expression is regulated by T3 • Thyroid gland releases T3 and T4 hormones • T3 and T4 hormone production requires iodine • The effect of T3 and T4 is an increased metabolic rate – Thermogenesis – Increased basal metabolic rate – Increased O2 consumption – Increased Cardiac Output and Ventilation Stress Responses • Stress responses are adaptive responses that: ~ enable individuals to cope more effectively with stress ~ maintain / re-establish homeostasis through physiological or behavioural changes • 1915: Walter Cannon used the term ‘Fight or Flight Response’ to explain the acute stress response: ~ animals react to threats via activation of the sympathetic nervous system (involves adrenalin & noradrenalin) • 1946: Hans Selye described a ‘General Adaptation Syndrome’ with 3 stages: Alarm, Resistance, Exhaustion ~ he observed that stress also increases infection / illness Stress and the Hypothalamus-Pituitary-Adrenal Axis • Stress involves increased levels of arousal / activation: ~ generalised activation of the nervous system and secretion of stress hormones (adrenalin & cortisol) • Acute ‘fight or flight’ stress response involves: ~ increased sympathetic activity (adrenergic) ~ adrenal gland secretion of adrenaline & noradrenaline ~ decreased parasympathetic activity (cholinergic) • Hypothalamus-pituitary-adrenal (HPA) axis releases: ~ corticotrophin-releasing factor (CRF) by the hypothalamus ~ adrenocorticotrophic hormone release by the pituitary gland ~ cortisol release by the cortex of the adrenal gland Short-term Biological Stress Responses Combined effects of noradrenaline (nor-epinephrine) and adrenaline (epinephrine) act within seconds or minutes: ~ increased blood pressure ~ increased breathing rate ~ increased metabolic rate ~ glycogen broken down to glucose causing increased blood glucose • Change in blood flow (vasodilatation / constriction) leading to: ~ increased alertness and muscle function ~ decreased digestive, excretory, reproductive function Adrenal Secretion includes: 80% adrenaline Iodine and Thyroid Hormones • Iodine requirement: 100 – 250 μg / day • Dietary iodine is trapped by the thyroid gland to synthesise thyroid hormones: ~ T4: Thyroxine (4 x iodine) ~ T3: Triiodothyronine (3 x iodine) • T3 & T4 are stored in colloid • TSH binding causes T3 and T4 to re-enter thyroid follicle cells and be released into blood • T4 & T3 circulate in blood bound to thyroxine binding protein • T4 & T3 diffuse into cells where T4 is converted to T3 (the active form) T3 & T4 Synthesis 1. Iodine is transported into the colloid 2. TSH promotes thyroglobulin synthesis 3. Thyroglobulin is iodinated 4. Thyroglobulin containing T3 & T4 stored for 3 months 5. TG-hormone complex taken up by cells 6. Fusion with lysosome 7. Secretion of T3 & T4 Distribution of Thyroid Hormones • Thyroid hormone levels in plasma are very stable and vary little: ~ they maintain their effects rather than ‘trigger’ effects • T4 and T3 circulate bound to thyroxine binding protein ~ T4 & T3 diffuse into tissue cells where T4 is converted to T3 which is the more biologically active form • T3 enters the nucleus and binds to high affinity T3 receptors on DNA to regulate mRNA and protein synthesis ~ TR-α1 receptors widely distributed throughout the body ~ TR-β1 receptors mainly in liver but also in kidney ~ TR-β2 receptors in hypothalamus and pituitary Thyroid Hormones and Metabolism • Cold, particularly in children, stimulates TRH (thyroid releasing hormone) release from hypothalamus paraventricular nucleus: • TRH promotes thyroid hormone synthesis and release: ~ increases basal metabolic rate and heat production ~ heat is produced by muscle and brown adipose tissue • Metabolic rate is the rate at which cells use oxygen to release energy (via ATP) by oxidation of food molecules: ~ energy release is about 20 k joules / litre of 02 used • Glucose oxidation releases CO2, metabolic H2 0 and ATP: ~ C6H1206 + 602 → 6C02 + 6H20 + 36 ATP molecules glycolysis + Citric acid cycle + oxidative phosphorylation Thyroid Actions in Cells 1. T3 enters nucleus 2. T3 binding releases the corepressor (CoR) from the thyroid hormone receptor (TR) 3. Co-activator (CoA) assists T3 gene activation 4. Gene expression is regulated by T3 Hyper and Hypo Thyroidism Hyper- • Increased HR • Increased Ventilation • Increased Vascularization • Decrease Body Fat • Increased Cardiac Hypertrophy (Size increase) • Decreased Thyroid Size (Due to reduced stimulation) • Reduced TSH (no stimulus to release more!) Hypo- • Decreased HR • Decreased Ventilation • Decreased Vascularization • Increased Body Fat • Decreased Cardiac Size • Increased Thyroid Size (due to increased stimulation) • Increased TSH (Thyroid gland being stimulated to release more!) • Thyroid gland releases T3 and T4 hormones • T3 and T4 hormone production requires iodine • The effect of T3 and T4 is an increased metabolic rate – Thermogenesis – Increased basal metabolic rate – Increased O2 consumption – Increased Cardiac Output and Ventilation Other Actions of Thyroid Hormones • Thyroid hormone is necessary for normal growth and development, particularly in babies and children ~ foetal thyroid hormone is released from week 11-12 of gestation to promote growth and development of the foetal skeleton and nervous system • Some effects of thyroid hormone result from its stimulation of growth hormone release • Lack of T3 & T4 (often due to dietary iodine deficiency) causes: ~ irreversible brain damage in children ~ impaired brain function in adults (low mood / mood swings) • All UK children are tested for thyroid function soon after birth Clinical Features of Congenital Iodine Deficiency Syndrome • Caused by foetal and lifetime thyroid /iodine deficiency: ~ hearing loss ~ poor cochlea development ~ dysarthria (poor speech) ~ Muscle rigidity ~ Mental development & low IQ ~ bradykinesia (slow movement) ~ All other hypothyroidism effects Myxoedema and Grave’s Disease • Myxoedema (postnatal hypothyroidism) ~ due to thyroid / iodine deficiency / iodine transporter deficiency ~ autoimmune Hashimoto’s thyroiditis ~ causes facial swelling, hair loss, dry cold skin, cold sensitivity, weight gain, loss of appetite, constipation, poor memory & lethargy • Grave’s disease (hyperthyroidism) ~ autoimmune disorder in which an antibody mimics TSH and stimulates T4 & T3 release ~ causes enlarged thyroid (diffuse goitre) with bulging eyes (exophthalmos), heat intolerance, sweating & anxiety • Thyroid hormone deficiency can cause a number of developmental issues in children – Often due to iodine deficiency (congenital or dietary) • Thyroid hormone deficiency could cause – Impaired brain development – Hearing loss – Muscle rigidity – Mood changes Hormones that Regulate Blood Calcium Levels • Daily calcium requirements are about 1g per day; however, net dietary calcium absorption is only about 150 mg / day: ~ renal calcium losses are also about 150mg/day • Normal blood calcium levels are 2.3 – 2.4 mmol / l • Minute to minute regulation of plasma calcium levels is achieved by the combined effects of three different hormones: ~ 1,25-dIhydroxyvitamin D3 ~ parathyroid hormone (PTH) ~ calcitonin Calcium plays a vital role in many aspects of cellular function: ~ neurotransmitter / hormone secretion ~ muscle contraction (actin / myosin interactions) • Calcium hydroxyapatite forms bone ~ Ca10(PO4)6(OH)2 Synthesis of 1,25-dihydroxyvitamin D3 • 1,25-dihydroxyvitamin D3 (calcitriol) is formed from skin cholesterol and dietary vitamin D • U-V light through skin is required to form Vitamin D • Vitamin D forms 25-hydroxyvitamin D in liver • Parathyroid hormone stimulates renal proximal tubule cells in kidney to form 1,25-dihydroxyvitamin D3 Functions of Vitamin D (1,25-dihydroxyvitaminD3) • Vitamin D can be provided in the diet, particularly by oily fish and eggs, but is mainly formed in skin during U-V light exposure ~ vitamin D3 is converted to 25-hydroxylvitamin D3 in liver • 1,25-dihydroxyvitamin D3 (calcitriol) is then synthesised from 25-hydroxyvitamin D3 by proximal tubule cells in the kidney • The main actions of 1,25-dihydroxyvitamin D3 include: ~ absorption of Ca2+ by small intestine mucosa cells via calbindin ~ acts like a steroid hormone binding to specific nuclear receptors on DNA that produce calcium transport calbindin ~ also increases phosphate uptake ~ increased calcification of bone via osteoblasts & osteoclasts • Calcium required for bone remodelling and growth- Blood concentration regulated by Vitamin D, PTH and Calcitonin – Vitamin D; Required for Ca absorption into bone – PTH; Promotes Ca release from bone when serum Ca is low (bone breakdown) – Calcitonin; Opposes PTH- Reduced blood Ca Low plasma calcium is mainly due to low dietary calcium Parathyroid Chief Cells • Low blood Ca2+ stimulate PTH secretion by Chief cells • PTH raises blood Ca2+ via: ~ 1,25-dihydroxyvitamin D3 in gut ~ renal tubular reabsorption ~ osteoblast stimulation osteoclast bone resorption Calcitonin • Calcitonin (thyrocalcitonin) is secreted by parafollicular Chief-cells • Calcitonin lowers blood Ca2+ levels in two ways: ~ major effect: Inhibits osteoclast activity in bones ~ minor effect: Inhibits renal reabsorption of Ca2+ and phosphate, allowing them to be excreted in the urine • Calcitonin receptors expressed by bone osteoclasts, kidney cells and parts of the brain: ~ calcitonin can be used therapeutically in post-menopausal osteoporosis in women High plasma calcium is mainly due to absorption of dietary calcium Hypocalcaemia Disorders (low blood Calcium) • Hypocalcaemia (Ca2+ < 2.1 mmol / l): can be caused by: ~ dietary calcium and vitamin D deficiency ~ vitamin D deficiency due to low UV-light exposure ~ hypoparathyroidism (may be due to thyroid surgery) • Effects of hypocalcaemia if severe: CATs go numb ~ Convulsions; Arrythmias; Tetany and numbness in the hands and feet and around the mouth ~ mainly due to increased nerve and muscle excitability • Hypocalcaemia combined with vitamin D deficiency also causes poor bone formation and mineralisation resulting in: ~ rickets in children ~ osteomalacia (bone softening) in adults • Normally treated with calcium and vitamin D Hypercalcaemia Disorders (high blood Calcium) • Hypercalcaemia (Ca2+ > 2.6 mmol / l): can be caused by: ~ parathyroid tumours that secrete excess PTH ~ malignancy due to PTH-like peptide secretion ~ very large doses of Vitamin D (Vitamin D intoxication) ~ extra-renal 1,25-dihydroxyvitamin D3 synthesis by macrophages, particularly in sarcoidosis • Effects of hypercalcaemia if severe and rapid in onset: ~ abdominal pain, nausea, vomiting and dehydration ~ demineralisation of bone if PTH is raised ~ calcification of soft tissues and blood vessels, kidney stones ~ increased blood pressure due to impaired renal function ~ anxiety, confusion; depression; weakness; coma • Treatment of hypercalcaemia will depend on the cause • Blood concentration of Calcium regulated by Vitamin D, PTH and Calcitonin – Vitamin D; Required for Ca absorption into bone – PTH; Promotes Ca release from bone when serum Ca is low (bone breakdown) – Calcitonin; Opposes PTH- Reduced blood Ca • Hypocalcaemia: Usually deficiency of Vitamin D – CATs go numb- Convulsion, Arrhythmia, Tetany and numbness – Poor bone formation • Hypercalcaemia: – Abdominal pain, nausea, vomiting – Calcification of soft tissues (eg, kidney stone formation) Characteristic of the Human Skeleton and Bone • The human skeleton contains 10 – 12 kg of bone: ~ 1 – 2 kg of calcium (99% of the body total) ~ 0.5 – 0.75 kg of phosphorus (88% of the body total) ~ we require about 1 gram of each per day in the diet ~ 70% of bone is hydroxyapatite (calcium phosphate) hydroxyapatite is Ca10(PO4)6(OH)2 ~ 30% of bone is osteoid which is a matrix of collagen, hyaluronate, chondroitin sulphate, osteocalcin • Bone is a connective tissue that is highly metabolically active: ~ receives 12% of the cardiac output at rest (600 ml / min) Functions the Skeleton • Mineral storage: ~ calcium and phosphate • Support: ~ framework that supports the body and cradles soft organs • Protection: ~ for delicate organs - brain, spinal cord, heart & lungs • Movement: ~ bones act as attachment points and levers for muscles • Blood cell formation: ~ bone marrow haematopoiesis Types of Bones • Long bones: ~ metacarpals, metatarsals phalanges, humerus, ulna, radius, tibia fibula • Short bones: ~ carpals and tarsals • Flat bones: ~ rib, scapula, skull, sternum • Irregular bones: ~ vertebrae and some facial bones • Sesamoid bones: ~ patella Parts of Bone • Cartilage protects the ends of long bones • An epiphysis/ metaphysis is found at each end • The epiphyseal line is a layer of growing cartilage • Trabecular bone is on each side of an Epiphyseal line • The shaft is cortical bone • The shaft contains bone marrow where red and white blood cells form Bone Cell Types Osteogenic: form osteoblasts Osteoblasts: form new bone Osteocytes: entrapped ‘osteoblasts’-Mature bone cells Osteoclasts: multinucleated cells that reabsorb bone using acids and enzymes Bone has a multitude of function and different structures to fulfil these functions • Bone split into epiphysis and diaphysis – Epiphysis: Porous, high blood flow and high turnover – Diaphysis: Shaft of bone. Lower turnover, less porous • Bone is layered with numerous specialist cells and its own blood supply • Osteoblasts- Bone building cells • Osteoclasts- Bone resorption (breakdown) cells • Osteocytes- Mature bone cells which maintain bone homeostasis- “Trapped” osteoblasts Bone Growth in the Epiphyseal Plate (Bone Ends) • Growing epiphyseal cartilage contain chondrocytes ➢ epiphyseal bone growth is promoted by growth hormone (mainly during sleep) ➢ sex steroid fuse the epiphysis towards the end of puberty preventing further growth • Osteoblasts replace the chondrocytes and calcify the new bone matrix (osteoid) • Osteoblasts become trapped in new calcified bone (osteoid) and become osteocytes with cellular inter-connexions Trabecular bone and Osteoporosis • Trabecular / cancellous bone contains thin struts of bone: ~ in osteoporosis trabeculae bone is reabsorbed faster by osteoclasts than it is reformed by osteoblasts causing bone thinning and greater fracture risks (e.g., neck of femur) Bone Marrow • Contains stem cells • Produces osteoprogenitors • Red bone marrow produces red and white blood cells ~ haematopoiesis forms 2.5 x 106 red blood cells per second (2.5million) ~ stimulated by erythropoietin (hormone secreted by kidney) ~ survive 100 – 120 days • Yellow bone marrow contains fat cells (more with age) • Leukaemia is over production of white cells (several types) • Bone growth stimulated by growth hormone • Bone goes through continuous remodelling • Osteoporosis caused by increased reabsorption of bone without reformation – Osteoclasts reabsorbed and not reformed into Osteoblasts Muscle Comparisons Cardiac Muscle- Single/Bi-Nucleated Skeletal Muscle- Multi-Nucleated Smooth Muscle- Single-Nucleated Anatomy of Muscle Skeletal Muscle- Spindle shaped cells (fusiform), cross striations Smooth Muscle- Nuclei, smooth muscle cells Cardiac Muscle- Relatively short Length: 30-200µm, Diameter: 5-10µm, No striations Function of skeletal muscles Movement of the skeleton Posture Support of visceral organs Body temperature Energy storage The smallest anatomical structure in skeletal muscle is myofibril. Acetylcholine is a neurotransmitter which causes a propagation of the action potential through an NMJ. Excitation- contraction coupling I. Calcium ions link action potentials in a muscle fibre to contraction. Calcium ions are stored in sarcoplasmic reticulum. T-tubules key in permeating action potential -Contains ion channels -Found in both skeletal and cardiac muscles Excitation coupling II. Actin-Muscle thin filament Tropomyosin- Stiffens and stabilises actin; prevents actin binding at rest Troponin- 3 sub-units, each with a specific role Skeletal muscle contraction requires calcium from the Sarcoplasmic reticulum Actin is referred to as the thin filament The contraction of muscle at the molecular level is called the power stroke. In order to cause the power, stoke, ATP must hydrolyse to form ADP and Inorganic Phosphate (Pi) Isotonic contraction means the muscle contracts, shortening in length. An example is lifting an object which is easy to move etc. Type 1- Slow twitch oxidative fibres Type 2A- Fast twitch oxidative glycolytic fatigue resistant fibres Type 2B- Fast twitch glycolytic fatigable fibres The fastest contracting muscles in skeletal muscle are Type 2B. Smooth muscle is found in large intestine, stomach, bladder, eyes. The intestinal smooth muscle undergoes phasic contraction (contracts and relaxes continuously). Smooth muscle contraction primarily relies on calcium from outside the cell. The difference between skeletal muscle and smooth muscle contraction initiation by an action potential is that smooth muscle needs calcium and skeletal muscle uses calcium and skeletal muscle uses sodium. Cardiac Muscle • Function- Similar to smooth muscle in being involuntary • Structure- Striated as in skeletal muscle • Contraction-Mechanical mechanism similar to that of Skeletal Muscle • Has a “Pacemaker Potential”- Skeletal Muscle does not • Activation of cardiac muscle can be excitatory, inhibitory or induced by hormones Cardiac Excitation-Contraction Coupling Action potential propagated along tubule Ca influx Ryanodine receptor activated, allowing Ca efflux from Sarcoplasmic reticulum Calcium bound to Troponin, causing conformational change to allow Myosin to bind to actin POWER STROKE Cardiac muscle has t-tubules and gap junctions.