Thyroid Lecture

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Thyroid Lecture

  1. 1. OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology
  2. 2. Organization of the Endocrine System • Peripheral Substrate-Regulated Systems • Hormone Negative Feedback-Regulated Systems • Hypothalamic-Pituitary Neuroendocrine Reflex Systems
  3. 3. Hormone Negative Feedback Hypothalamic-Pituitary Systems • Thyroid Axis (Thyroid Hormones) • Adrenocortical Axis (Glucocorticoids) • Ovarian Axis (Estrogen/Progesterone) • Testicular Axis (Testosterone)
  4. 4. Thyroid Hormones and Antithyroid Agents Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” 10th Edition Chapter 57: 1563-1596
  5. 5. Thyroid Hormones & Antithyroid Agents • Thyroid Hormones (T3, T4) – Synthesis and metabolism – Secretion – Actions • Hypothyroidism – Non-toxic goiter – Cretinism (Neonatal); Myxedema (Adult) • Hyperthyroidism – Toxic goiter – Thyrotoxicosis • Thyroid Resistance
  6. 6. Synthesis of T3 + T4 Iodide Trapping Organification – thyroperoxidase-catalyzed iodination of tyrosine – MIT & DIT Coupling T3 triiodothyronine (MIT + DIT) T4 tyroxine (DIT + DIT)
  7. 7. Release of T3 +T4 Colloid resorption Thyroglobulin proteolysis T4/T3 release ratio 5:1
  8. 8. Thyroxine Binding Globulin
  9. 9. Peripheral Metabolism of Thyroxine
  10. 10. Thyroxine Binding Globulin
  11. 11. Thyroid Function Tests
  12. 12. Actions of Thyroid Hormones
  13. 13. Metabolic Actions of Thyroid Hormones • Essential for normal growth and development – promotes protein synthesis – neuronal proliferation + myelination • Maintenance of body temperature and energy – increase basal metabolic rate (calorigenesis) – increase oxygen consumption + heat production • Slow onset, prolonged duration of action
  14. 14. Thyroid Function in Brain Development
  15. 15. Thyroid Function in Calorigenesis
  16. 16. Hypothyroidism • Thyroid hormone deficiency – retardation of growth (children) – generalized slowing of metabolism (adult) • Primary hypothyroidism – defect in thyroid gland • Secondary hypothyroidism – defect in hypothalamic-pituitary axis • Non-toxic goiter
  17. 17. Non-Toxic Goiter Thyroid hyperplasia, hypertrophy Chronic TSH, TSH-like goitrogens Inactive T3/T4 iodide deficiency enzyme deficiency inflammation
  18. 18. Neonatal Hypothyroidism (Cretinism) • Delayed development of nervous and skeletal systems – moderate to severe mental retardation – dwarfism • Prognosis dependent upon diagnosis and initiation of thyroid hormone replacement therapy – prenatal (maternal) and neonatal thyroid screening
  19. 19. Adult Hypothyroidism (Myxedema) • Generalized slowing of metabolic processes • Etiology – surgical thyroidectomy – radioactive iodine – inflammation – autoimmune destruction (Hashimoto’s thyroiditis)
  20. 20. Thyroid Hormone Preparations • Levothyroxine (Thyroxine) – T4 salt of natural L-isomer – hormone replacement for hypothyroidism • Liothyronine – T3 salt – diagnostic (TSH suppression test) • Liotrix – T4:T3 mixture 4:1 ratio
  21. 21. Hyperthyroidism • Thyroid hormone excess – generalized hyperstimulation of metabolism • Grave’s disease – autoimmune disorder – thyroid-stimulating antibody directed against TSH receptor on thyroid cells • Toxic goiter – thyrotoxicosis
  22. 22. Anti-Thyroid Agents • Propylthiouracil – blocks iodine organification & coupling • Potassium iodide solutions – inhibits iodide uptake and trapping • Radioactive iodine – destroys thyrocytes
  23. 23. Thyroid Resistance • Thyroid hormone resistance – thyroid hormone receptor defect – target cells – thyrotrophs (loss of negative feedback) – elevated TSH and T3/T4 • Thyrotropin resistance – TSH receptor defect – elevated TSH; hyposecretion of T3/T4

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