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Physiology of Thyroid Gland

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The thyroid gland, located below the larynx on each side of and anterior to the trachea, is one of the largest of the endocrine glands.

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The thyroid gland contains numerous follicles, composed of epithelial follicle cells and colloid. The major constituent of colloid is the large glycoprotein thyroglobulin, which contains the thyroid hormones within its molecule. Also, between follicles are clear parafollicular cells, which produce calcitonin Histology of the Thyroid Gland

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O OH I I I I O NH 2 Thyroxine (T 4 ) O OH I I I O NH 2 3,5,3-Triiodothyronine (T 3 ) THYROID HORMONES Tyrosine There are two biologically active thyroid hormones: - tetraiodothyronine (T4; usually called thyroxine) - triiodothyronine (T3) Derived from modification of an amino acid (tyrosine)

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The thyroid secretes about 80 micrograms of T4, but only 5 micrograms of T3 per day. However, T3 has a much greater biological activity (about 10X) than T4. An additional 25 micrograms/day of T3 is produced by peripheral monodeiodination of T4. T4 thyroid I-I- T3 Differences between T4 and T3

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Thyroid hormones are unique biological molecules in that they incorporate iodine in their structure. Thus, adequate iodine intake (diet, water) is required for normal thyroid hormone production. Major sources of iodine: - iodized salt - iodated bread - dairy products Minimum requirement: 75 micrograms/day Why is Iodine Important in Thyroid Hormone Production?

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Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys). The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This is called iodide trapping. The transport of iodide into follicular cells is dependent upon a sodium/iodine cotransport system. Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen of the follicle (via pendrin receptor): Thyroid peroxidase I - I + Oxidized iodine ( I + ) can then be used in production of thyroid hormones. Iodine Metabolism

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The follicle cells of the thyroid produce thyroglobulin. Thyroglobulin is a very large glycoprotein. Thyroglobulin is released into the colloid space (via pendrin receptor), where its tyrosine residues are iodinated by I +. (organification) This results in monoiodotyrosine (MIT) or diiodotyrosine (DIT). Production of thyroglobulin

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Ion transport by the thyroid follicular cell I-I- I-I- organification Propylthiouracil (PTU) blocks iodination of thyroglobulin COLLOID BLOOD NaI symporter (NIS) Thyroid peroxidase (TPO) PTU, a thioamide drug used to treat hyperthyroidism

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follicle cell extracellular space colloid space I-I- I-I- thyroglobulin with monoiodotyrosines and diiodotyrosines iodination thyroglobulin gene I+I+ oxidation I-I- Na+ K+ Initial Steps in Thyroid Hormone Synthesis Pendrin

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The iodinated tyrosine residues on thyroglobulin are modified and joined to form T3 and T4, still attached to the thyroglobulin molecule. Second step: Production of Thyroid Hormones from Iodinated Thyroglobulin

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In order to secrete T3/T4, the thyroglobulin in the colloid space is internalized by endocytosis via megalin receptor back into the follicle cell. (receptor mediated endocytosis) This internalized vesicle joins with a lysosome, whose enzymes cause cleavage of T3 and T4 from thyroglobulin. Utilization of Thyroglobulin to Secrete Thyroid Hormones

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follicle cell colloid space Endocytosis (via megalin) thyroglobulin T3 T4 colloid droplet lysosome T3/T4 (deiodinated, recycled) extracellular space (T4 T3) T3 and T4 are then released into the extracellular space by diffusion. Only minute amounts of thyroglobulin are released into the circulation.

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Thyroid hormones are not very soluble in water (but are lipid soluble). Thus, they are found in the circulation associated with binding proteins: - Thyroid Hormone-Binding Globulin (~70% of hormone) - Pre-albumin (transthyretin), (~15%) - Albumin (~15%) Less than 1% of thyroid hormone is found free in the circulation. Only free and albumin-bound thyroid hormone is biologically available to tissues. Transport of Thyroid Hormones

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T3 has much greater biological activity than T4. A large amount of T4 (25%) is converted to T3 in peripheral tissues. This conversion takes place mainly in the liver and kidneys. The T3 formed is then released to the blood stream. In addition to T3, an equal amount of reverse T3 may also be formed. This has no biological activity. Conversion of T4 to T3

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In addition to T3, an equal amount of reverse T3 may also be formed. This has no biological activity.

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Three deiodinases (D1, D2 & D3) catalyze the generation and/disposal of bioactive thyroid hormone. D1 & D2 bioactivate thyroid hormone by removing a single outer-ring iodine atom. D3 inactivates thyroid hormone by removing a single inner-ringiodine atom. All family members contain the novel amino acid selenocysteine (Se-Cys) in their catalytic center. Thyroid hormone deiodinases: THYROID HORMONE METABOLISM

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The thyroid gland is capable of storing many weeks worth of thyroid hormone (coupled to thyroglobulin). If no iodine is available for this period, thyroid hormone secretion will be maintained. One Major Advantage of this System

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Thyroid hormone synthesis and secretion is regulated by two main mechanisms: - an autoregulation mechanism, which reflects the available levels of iodine - regulation by the hypothalamus and anterior pituitary Regulation of Thyroid Hormone Levels

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The rate of iodine uptake and incorporation into thyroglobulin is influenced by the amount of iodide available: - low iodide levels increase iodine transport into follicular cells - high iodide levels decrease iodine transport into follicular cells Thus, there is negative feedback regulation of iodide transport by iodide. Autoregulation of Thyroid Hormone Production

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T3 & T4 Control Pathways Feedback regulation the hypothalamic-pituitary-thyroid axis Key players for the thyroid include: TRH TSH T3, T4

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TSH acts on follicular cells of the thyroid. TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP. - increases iodide transport into follicular cells - increases production and iodination of thyroglobulin - increases endocytosis of colloid from lumen into follicular cells Na+ I-I- thyroglobulinfollicle cell gene I-I- endocytosis thyroglobulin T3 T4 colloid droplet I-I- I+I+ iodination thyroglobulin Na+ K+ ATP Action of TSH on the Thyroid 1 2 3

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Mechanism of Action of T3 T3/T4 acts through the thyroid hormone receptor - intracellular, in steroid receptor superfamily - acts as a transcription factor - receptor binds to TRE on 5 flanking region of genes as homodimers and/or heterodimers. - multiple forms (alphas and betas) exist - one form (alpha-2) is an antagonist at the TRE hypervariable

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Expression and Regulation of Thyroid Hormone Receptors Thyroid hormone receptors are found in many tissues of the body, but not in adult brain, spleen, testes, uterus, and thyroid gland itself. Thyroid hormone inhibits thyroid hormone receptor expression (TRE on THR genes).

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One Major Target Gene of T3: The Na + /K + ATPase Pump Pumps sodium and potassium across cell membranes to maintain resting membrane potential Activity of the Na + /K + pump uses up energy, in the form of ATP About 1/3rd of all ATP in the body is used by the Na + /K + ATPase T3 increases the synthesis of Na + /K + pumps, markedly increasing ATP consumption. T3 also acts on mitochondria to increase ATP synthesis The resulting increased metabolic rate increases thermogenesis (heat production).

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Thyroid hormones: Key Points Held in storage Bound to mitochondria, thereby increasing ATP production Bound to receptors activating genes that control energy utilization Exert a calorigenic effect

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Required for GH and prolactin production & secretion Required for GH action Increases intestinal glucose reabsorption (glucose transporter) Increases mitochondrial oxidative phosphorylation (ATP production) Increases activity of adrenal medulla (sympathetic; glucose production) Induces enzyme synthesis Result: stimulation of growth of tissues and increased metabolic rate. Actions of Thyroid Hormones

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Thyroid hormones are essential for normal growth of tissues, including the nervous system. Lack of thyroid hormone during development results in short stature and mental deficits (cretinism). Thyroid hormone stimulates basal metabolic rate. What are the specific actions of thyroid hormone on body systems? Actions of Thyroid Hormones

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Thyroid Hormone Actions which Increase Oxygen Consumption Increase mitochondrial size, number and key enzymes Increase plasma membrane Na-K ATPase activity Increase futile thermogenic energy cycles Decrease superoxide dismutase activity

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Stimulation of Carbohydrate Metabolism by Thyroid hormone Stimulates all of carbohydrate metabolism: including rapid uptake of glucose by the cells, increased glycolysis, increased gluconeogenesis, increased rate of absorption from the gastrointestinal tract, increased insulin secretion with its resultant secondary effects on carbohydrate metabolism. All these effects probably result from the overall increase in cellular metabolic enzymes caused by thyroid hormone.

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Stimulation of Fat Metabolism Lipids are mobilized rapidly from the fat tissue, which decreases the fat stores and increases the free fatty acid levels in the plasma. Increased thyroid hormone decreases the levels of cholesterol, phospholipids, and triglycerides in the plasma, and increases the free fatty acids. But, decreased thyroid secretion greatly increases the plasma levels of cholesterol, phospholipids, and triglycerides. TH decreases the plasma cholesterol concentration through increase the rate of cholesterol secretion in the bile and consequent loss in the feces.

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Increased Basal Metabolic Rate Because thyroid hormone increases metabolism in almost all cells of the body, excessive quantities of the hormone can increase the basal metabolic rate Conversely, when no thyroid hormone is produced, the basal metabolic rate falls.

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Effects of Thyroid Hormones on the Cardiovascular System Increased metabolism in the tissues causes more rapid utilization of oxygen than normal and release of greater than normal quantities of metabolic end products from the tissues. So, the increased blood flow leads to increased cardiac output and, Increase heart rate Increase force of cardiac contractions Increase stroke volume Up-regulate catecholamine receptors

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Effects of Thyroid Hormones on the Respiratory System Increase resting respiratory rate Increase minute ventilation Increase ventilatory response to hypercapnia and hypoxia

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Effects of Thyroid Hormones on the Renal System Increase blood flow Increase glomerular filtration rate

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Thyroid hormones affect renal function by both pre-renal and direct renal effects. 1. Pre-renal effects are mediated by the influence of thyroid hormones on the cardiovascular system and the renal blood flow (RBF). 2. The direct renal effects are mediated by the effect of thyroid hormones on glomerular filtration rate (GFR), tubular secretory and re-absorptive processes, as well as the hormonal influences on renal tubular physiology. Thyroid hormones influence Na reabsorption at the PCT primarily by increasing the activity of the Na/K ATPase and tubular potassium permeability

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Effects of Thyroid Hormones on Oxygen-Carrying Capacity Increase RBC mass Increase oxygen dissociation from hemoglobin

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Effects of Thyroid Hormones on Intermediary Metabolism Increase glucose absorption from the GI tract Increase carbohydrate, lipid and protein turnover Down-regulate insulin receptors Increase substrate availability

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Effects Thyroid Hormones in Growth and Tissue Development Increase growth and maturation of bone Increase tooth development and eruption Increase growth and maturation of epidermis,nhair follicles and nails Increase rate and force of skeletal muscle contraction Inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue

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Effects of Thyroid Hormones on the Nervous System Enhances wakefulness and alertness Enhances memory and learning capacity Required for normal emotional tone Increase speed and amplitude of peripheral nerve reflexes

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TH in Intrauterin and infantil periods: Critical for normal CNS neuronal development: Development of cerebral and cerebellar cortex Proliferation of axons Branching of dendrite Synaptogenesis Myelinization Migration of cells

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Deficiency of TH in infant or intrauterin periods (Cretenism) Mostly affected development of cerebral cortex, basal ganglia and cochlea, so: Loss of hearing CNS exitation, motor activity, learning capacity, memory, response to stimulus

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Effects of Thyroid Hormones on the Reproductive System Required for normal follicular development and ovulation in the female Required for the normal maintenance of pregnancy Required for normal spermatogenesis in the male

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Diet: a high carbohydrate diet increases T3 levels, resulting in increased metabolic rate (diet-induced thermogenesis). Low carbohydrate diets decrease T3 levels, resulting in decreased metabolic rate. Cold Stress: increases T3 levels in other animals, but not in humans. Other Factors Regulating Thyroid Hormone Levels

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Early onset: delayed/incomplete physical and mental development Later onset (youth): Impaired physical growth Adult onset (myxedema) : gradual changes occur. Tiredness, lethargy, decreased metabolic rate, slowing of mental function and motor activity, cold intolerance, weight gain, goiter, hair loss, dry skin. Eventually may result in coma. Many causes (insufficient iodine, lack of thyroid gland, lack of hormone receptors, lack of TBG.) Thyroid Hormone Deficiency: Hypothyroidism

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During iodine deficiency, thyroid hormone production decreases. This results in increased TSH release (less negative feedback). TSH acts on thyroid, increasing blood flow, and stimulating follicular cells and increasing colloid production. How is Hypothyroidism Related to Goiter?

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Emotional symptoms (nervousness, irritability), fatigue, heat intolerance, elevated metabolic rate, weight loss, tachycardia, goiter, muscle wasting, apparent bulging of eyes, may develop congestive heart failure. Also due to many causes (excessive TSH release, autoimmune disorders,) Thyroid Hormone Excess: Hyperthyroidism

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Graves' disease:A condition usually caused by excessive production of thyroid hormone and characterized by an enlarged thyroid gland, protrusion of the eyeballs, a rapid heartbeat, and nervous excitability. Also called exophthalmic goiter.

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Calcitonin Calcitonin is a 32-amino acid polypeptide hormone that is produced in humans primarily by the parafollicular (also known as C-cells) of the thyroid. It acts to reduce blood calcium (Ca 2+ ), opposing the effects of parathyroid hormone(PTH).

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Biosynthesis Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA). The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin. The calcitonin receptor, found primarily on osteoclasts, is a G protein-coupled receptor, which is coupled by G s to adenyl cyclase and thereby to the generation of cAMP in target cells.

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Physiology The hormone participates in calcium(Ca 2+ ) and phosphorus metabolism. In many ways, calcitonin has the counter effects of parathyroid hormone(PTH). To be specific, reduces blood Ca 2+ levels in three ways: 1) Decreasing Ca 2+ absorption by the intestines. 2) Decreasing osteoclast activity in bones. 3) Decreasing Ca 2+ and phosphate reabsorption by the kidney tubules.

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These stimulate secretion of calcitonin: Increased plasma Ca levels Feeding ( Gis hormones, especially gastrin) -adrenergic agonist drugs Dopamine Estrogens

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High levels of blood Ca (>11mg) When blood Ca levels are high, Calcitonin is released. Causes bone deposit to occur Ca from the blood is stored into bone. (Osteoblasts and Osteocytes are working.) 99% of all Ca is found in bone.

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Osteoclasts cause bone resorption Controlled by PTH Osteoblasts cause bone deposit Controlled by calcitonin

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Action 1) Bone mineral metabolism: - Prevent postprandial hypercalcemia resulting from absorption of Ca 2+ from foods during a meal - Promote mineralization of skeletal bone. - Protect against Ca 2+ loss from skeleton during periods of Ca 2+ stress such as pregnancy and lactation. - It have hypophostatemic effects: *inhibits of bone resorption * stimulates of phosphate deposition in bone * increases excretion of phosphate in tubules

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2) Vitamin D regulation 3) A satiety hormone: - Inhibit food intake in rats and monkeys - May have CNS action involving the regulation of feeding and appetite.

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In human, CT increases gastric acid and pepsin secretion and decreases pancreatic amylase and pancreatic polypeptide. The kidney is the principal site of CT degradation by neutral endopeptidase (NEP). The effect of CT on the kidney is to stimulate diuresis and increase the fractional excretion rate of sodium and chloride. In addition, in urine a calcium and phosphate excretion increases.