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Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
Thyroid hormone
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Thyroid hormone

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  • 1. Production, Regulation, and Action
  • 2. Histology of the Thyroid Gland • The thyroid gland contains numerous follicles, composed of epithelial follicle cells and colloid. • Between follicles are clear parafollicular cells, which produce calcitonin.
  • 3. The Thyroid Gland – Histology I
  • 4. Why is Iodine Important in Thyroid Hormone Production? • 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 - shellfish • Minimum requirement: 75- 80 micrograms/day
  • 5. Iodine Metabolism • Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys). • The transport of iodide into follicular cells is dependent upon a Na+/I- cotransport system. • Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen of the follicle: peroxidase I- I+ • Oxidized iodine can then be used in production of thyroid hormones.
  • 6. Production of Thyroglobulin  Pituitary produces TSH, which binds to follicle cell receptors.  The follicle cells of the thyroid produce thyroglobulin.  Thyroglobulin is a very large glycoprotein.  Thyroglobulin is released into the colloid space, where its tyrosine residues are iodinated by I+.  This results in tyrosine residues which have one or two iodines attached (monoiodotyrosine or diiodotyrosine).
  • 7. Thyroid Hormone Synthesis
  • 8. Thyroid Hormones  There are two biologically active thyroid hormones: - tetraiodothyronine (T4; usually called thyroxine) - triiodothyronine (T3)  Derived from modification of tyrosine.
  • 9. Differences between T4 and T3  The thyroid secretes about 80 micro gm of T4, but only 5 micro gm of T3 per day.  However, T3 has a much greater biological activity (about 10 X) than T4.  An additional 25 microg/day of T3 is produced by peripheral monodeiodination of T4. T4 thyroid I- T3
  • 10. TRIIODOTHYRONINE TETRAIODOTYROSINE RAPID ACTION AND DEGRADATION SLOW TO RESPOND 10 x MORE RAPIDLY BINDS TO RECEPTORS SLOW BINDING METABOLICALLY ACTIVE INACTIVE,CONVERTS TO T3 DIFFERENCE IN ACTIONS OF T3 & T4
  • 11. Transport of Thyroid Hormones • 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), (~14%) - 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.
  • 12. One Major Advantage of this System  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.
  • 13. Regulation of Thyroid Hormone Levels  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.
  • 14. Autoregulation of Thyroid Hormone Production  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.
  • 15. Neuroendocrine Regulation of Thyroid Hormones: Role of TSH  Thyroid-stimulating hormone (TSH) is produced by thyrotroph cells of the anterior pituitary.  TSH is a glycoprotein hormone composed of two subunits: - alpha subunit (common to LH, FSH, TSH) - TSH beta subunit, which gives specificity of receptor binding and biological activity a LHb FSHb TSHb LH FSH TSH
  • 16. Action of TSH on the Thyroid  TSH acts on follicular cells of the thyroid. - increases iodide transport into follicular cells - increases production and iodination of thyroglobulin - increases endocytosis of colloid from lumen into follicular cells Na+ I- thyroglobulinfollicle cell gene I- endocytosis thyroglobulin T3 T4 colloid droplet I-I+ iodination thyroglobulin Na+ K+ ATP
  • 17. Mechanism of Action of TSH  TSH binds to a plasma membrane-bound, G protein-coupled receptor on thyroid follicle cells.  Specifically, it activates a Gs-coupled receptor, resulting in increased cAMP production and PKA activation. TSH Gsa Adenylyl Cyclase ATP cyclic AMP Protein kinase A Follicle cell
  • 18. Thyroid Follicles
  • 19. Influence of TRH on TSH Release • Thyrotropin-releasing hormone (TRH) is a hypothalamic releasing factor which travels through the pituitary portal system to act on anterior pituitary thyrotroph cells. • TRH acts through G protein-coupled receptors, activating the IP3 (Ca2+) and DAG (PKC) pathways to cause increased production and release of TSH. TRH phospholipase C G protein-coupled receptor IP3 calcium DAG PKC calmodulin • Thyroid hormones also inhibit TRH synthesis.
  • 20. Negative Feedback Actions of Thyroid Hormones on TSH Synthesis and Release hypothalamus TRH TRH receptor TSH synthesis pituitary T3/T4 + - - - TRH synthesis Thyroid gland follicle cell receptors TSH binds
  • 21. Other Factors Regulating Thyroid Hormone Levels  Diet: a high carbohydrate diet increase 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.  Any condition that increases body energy requirements (e.g., pregnancy, prolonged cold) stimulates hypothalamus  TRH  TSH (Pit)
  • 22. conversion  T4 can convert to T3 through deniodenation in peripheral tissues as well as in the thyroid.  (catalyzed by deiodinase).
  • 23. Actions of Thyroid Hormones  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.
  • 24. Actions of Thyroid Hormone  Required for GH and prolactin production and 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. Increased heat production (calorigenic effect)
  • 25. Effects of Thyroid Hormone on Nutrient Sources • Effects on protein synthesis and degradation: -increased protein synthesis at low thyroid hormone levels (low metabolic rate; growth) -increased protein degradation at high thyroid hormone levels (high metabolic rate; energy) • Effects on carbohydrates: -low doses of thyroid hormone increase glycogen synthesis (low metabolic rate; storage of energy) - high doses increase glycogen breakdown (high metabolic rate; glucose production)
  • 26. 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).
  • 27. 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).
  • 28. 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
  • 29. Thyroid Hormone Actions which Increase Oxygen Consumption  Increase mitochondrial size, number and key enzymes  Increase plasma membrane Na-K ATPase activity  Decrease superoxide dismutase activity  T3 /T4 can increase oxygen consumption, promote metabolism and BMR(basal metabolic rate) ,↓utility.
  • 30. Effects of Thyroid Hormones on the Cardiovascular System  Increase heart rate  Increase force of cardiac contractions  Increase stroke volume  Increase Cardiac output  Up-regulate catecholamine receptors
  • 31. Effects of Thyroid Hormones on the Respiratory System  Increase resting respiratory rate  Increase minute ventilation  Increase ventilatory response to hypercapnia and hypoxia
  • 32. Effects of Thyroid Hormones on the Renal System  Increase blood flow  Increase glomerular filtration rate
  • 33. Effects of Thyroid Hormones on Oxygen-Carrying Capacity  Increase RBC mass  Increase oxygen dissociation from hemoglobin
  • 34. 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
  • 35. 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,hair follicles and nails  Increase rate and force of skeletal muscle contraction  Inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue
  • 36. Effects of Thyroid Hormones on the Nervous System  Critical for normal CNS neuronal development  Enhances wakefulness and alertness  Enhances memory and learning capacity  Required for normal emotional tone  Increase speed and amplitude of peripheral nerve reflexes
  • 37. 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
  • 38.  Calcium metabolism.  Adrenal cortex.
  • 39. Thyroid Hormone Deficiency: Hypothyroidism  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 TH binding globulin….)
  • 40. Hypothyroidism Symptoms  Tiredness and weakness  Dry skin  Feeling cold  Hair loss  Difficulty in concentrating and poor memory  Constipation  Weight gain with poor appetite  Hoarse voice  Menorrhagia, later oligo and amenorrhoea  Paresthesias  Impaired hearing
  • 41. Hypothyroidism Signs  Dry skin, cool extremities  Puffy face, hands and feet  Delayed tendon reflex relaxation  Carpal tunnel syndrome  Bradycardia  Diffuse alopecia  Serous cavity effusions
  • 42. Causes of Hypothyroidism  Autoimmune hypothyroidism (Hashimoto’s, atrophic thyroiditis)  Iatrogenic (I123treatment, thyroidectomy, external irradiation of the neck)  Drugs: iodine excess, lithium, antithyroid drugs, etc  Iodine deficiency  Infiltrative disorders of the thyroid: amyloidosis, sarcoidosis,haemochroma tosis, scleroderma
  • 43. Causes of Hyperthyroidism Most common causes  Graves disease  Toxic multinodular goiter  Autonomously functioning nodule Rarer causes  Thyroiditis or other causes of destruction  Thyrotoxicosis factitia  Iodine excess (Jod-Basedow phenomenon)  Struma ovarii  Secondary causes (TSH or ßHCG)
  • 44. Hyperthyroidism Symptoms  Hyperactivity/ irritability/ dysphoria  Heat intolerance and sweating  Palpitations  Fatigue and weakness  Weight loss with increase of appetite  Diarrhoea  Polyuria  Oligomenorrhoea, loss of libido
  • 45. Hyperthyroidism Signs  Tachycardia (AF)  Tremor  Goiter  Warm moist skin  Proximal muscle weakness  Lid retraction or lag  Gynecomastia

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