Thyroid Hormones


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Thyroid Hormones

  1. 1. THYROID HORMONES Chairperson Dr. F.A Sattar HOD, Dept of Psychiatry VIMS n RC Dr. Soumya Nath Maiti IMO
  2. 2. Overview  Introduction  Production, transport and conversion of thyroid hormones  Regulation of thyroid hormones  Mechanism of Action and actions of thyroid hormones  Effect of thyroid hormone on various systems  Hypo and hyperthyroidism  Summary
  3. 3. Introduction - Thyroid Gland  The thyroid gland, located immediately below the larynx on each side of and anterior to trachea, is one of the largest of endocrine glands.  It secretes two major hormonesThyroxine and triidothyronine.  It also secretes calcitonin, an important hormone for calcium meatabolism
  4. 4. Introduction - Thyroid Hormones  There are two biologically active thyroid hormones: - tetraiodothyronine (T4; usually called thyroxine) - triiodothyronine (T3)  Derived from modification of tyrosine.
  5. 5. Differences between T4 and T3  The thyroid secretes about 80 microg ofT4, but only 5 microg ofT3 per day.  However,T3 has a much greater biological activity (about 10 X) thanT4. T4 thyroid I- T3
  6. 6. Importance of Iodine • 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 micrograms/day
  7. 7. Iodine Metabolism • Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland.The basal membrane of the thyroid cell has the specific ability to pump iodine actively to the interior of the cell.This is called iodide trapping. • Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen of the follicle: peroxidas eI- I+ • Oxidized iodine can then be used in production of thyroid hormones.
  8. 8. Production of Thyroglobulin  Pituitary producesTSH, which binds to follicle cell receptors.  The follicle cells of the thyroid produce thyroglobulin.  Thyroglobulin is released into the colloid space, where it’s tyrosine residues are iodinated by I+.  This results in tyrosine residues which have one or two iodines attached (monoiodotyrosine or diiodotyrosine).
  9. 9. More and more of iodotyrosine residues become coupled with one another. The major production of this coupling reaction is thyroxine molecule. One molecule of monoiodotyrosine couples with diidotyrosine to form tridotyrosine (T3).
  10. 10. 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), (~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.
  11. 11. Conversion of T4 to T3  T3 has much greater biological activity thanT4.  A large amount ofT4 (25%) is converted toT3 in peripheral tissues.  This conversion takes place mainly in the liver and kidneys. TheT3 formed is then released to the blood stream.  In addition toT3, an equal amount of “reverseT3” may also be formed. This has no biological activity.
  12. 12.  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. Storage of thyroglobulin
  13. 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 - Neuroendocrine regulation by the hypothalamus and anterior pituitary
  14. 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. 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
  16. 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. 17. Regulation of TSH Release from the Anterior Pituitary  TSH release is influenced by hypothalamicTRH, and by thyroid hormones themselves.  Thyroid hormones exert negative feedback onTSH release at the level of the anterior pituitary. - inhibition ofTSH synthesis - decrease in pituitary receptors forTRH hypothalamus TRH TRH receptor TSH synthesis pituitary T3/T4 + - -
  18. 18. 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 phospholipase C G protein-coupled receptor IP3 calcium DAG PKC calmodulin • Thyroid hormones also inhibit TRH synthesis.
  19. 19. 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
  20. 20. Other Factors Regulating Thyroid Hormone Levels  Diet: a high carbohydrate diet increasesT3 levels, resulting in increased metabolic rate (diet- induced thermogenesis).  Low carbohydrate diets decreaseT3 levels, resulting in decreased metabolic rate.  Cold Stress: increasesT3 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)
  21. 21. Mechanism of Action of Thyroid hormones  The general effect of thyroid hormone is to activate nuclear transcrpition of large numbers of genes.  Therefore in virtually all cells of the body, great numbers of protein enzymes, structural proteins, transport proteins are synthesized.  The net result is generalized increase in functional activity throughout the body.
  22. 22. T3/T4 acts through the thyroid hormone receptor, which are attached to the DNA. When not bound to hormone, the thyroid hormone receptor binds to target DNA. It is associated with corepressor proteins that cause DNA to be tightly wound and inhibit transcription. Binding of hormone causes a conformational change, resulting in loss of corepressor binding and association with coactivator proteins, which loosen DNA structure and stimulate transcription.
  23. 23. 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).
  24. 24. 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.
  25. 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. 26. 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
  27. 27. 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
  28. 28. Effects of Thyroid Hormones on the Respiratory System  Increase resting respiratory rate  Increase minute ventilation  Increase ventilatory response to hypercapnia and hypoxia
  29. 29. Effects of Thyroid Hormones on the Renal System  Increase blood flow  Increase glomerular filtration rate
  30. 30. Effects of Thyroid Hormones on Oxygen-Carrying Capacity  Increase RBC mass  Increase oxygen dissociation from hemoglobin
  31. 31. 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
  32. 32. Effect of Thyroid Hormone on growth  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)
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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 ofTH binding globulin)
  37. 37. Hypothyroidism and Goiter  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.
  38. 38. Thyroid Hormone Excess: Hyperthyroidism  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 (excessiveTSH release, autoimmune disorders,)
  39. 39. Cretinism  Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. Commonly due to Congenital lack of thyroid gland or failure of gland to produce hormone due to genetic defect.  This condition Is characterized by failure of body growth and mental retardation
  40. 40.  A neonate without a thyroid gland may have normal appearance as it was supplied with thyroid hormones by the mother in utero.  But within a few weeks neonates movements become sluggish and growth begin to be greatly retarded.  Treatment with adequate iodine or thyroxine usually causes return to normal growth. But unless it is treated within a few weeks after birth mental retardation becomes permanent.
  41. 41. 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
  42. 42. References  Textbook of Medical Physiology 11th edition by GUYTON & HALL  Principals of Pharmacology by BENNET & BROWN.
  43. 43. Thank You