Thyroid hormone


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Thyroid hormone

  1. 1. Production, Regulation, and Action
  2. 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. 3. The Thyroid Gland – Histology I
  4. 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. 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. 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. 7. Thyroid Hormone Synthesis
  8. 8. Thyroid Hormones  There are two biologically active thyroid hormones: - tetraiodothyronine (T4; usually called thyroxine) - triiodothyronine (T3)  Derived from modification of tyrosine.
  9. 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
  11. 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. 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. 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. 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 a LHb FSHb TSHb LH FSH TSH
  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. 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. 18. Thyroid Follicles
  19. 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. 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. 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. 22. conversion  T4 can convert to T3 through deniodenation in peripheral tissues as well as in the thyroid.  (catalyzed by deiodinase).
  23. 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. 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. 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. 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. 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. 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. 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. 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. 31. Effects of Thyroid Hormones on the Respiratory System  Increase resting respiratory rate  Increase minute ventilation  Increase ventilatory response to hypercapnia and hypoxia
  32. 32. Effects of Thyroid Hormones on the Renal System  Increase blood flow  Increase glomerular filtration rate
  33. 33. Effects of Thyroid Hormones on Oxygen-Carrying Capacity  Increase RBC mass  Increase oxygen dissociation from hemoglobin
  34. 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. 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. 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. 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. 38.  Calcium metabolism.  Adrenal cortex.
  39. 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. 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. 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. 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. 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. 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. 45. Hyperthyroidism Signs  Tachycardia (AF)  Tremor  Goiter  Warm moist skin  Proximal muscle weakness  Lid retraction or lag  Gynecomastia