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OST 529 Systems Biology: Endocrinology

OST 529 Systems Biology: Endocrinology. Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology. Organization of the Endocrine System. Peripheral Substrate-Regulated Systems Hormone Negative Feedback-Regulated Systems Hypothalamic-Pituitary Neuroendocrine Reflex Systems.

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OST 529 Systems Biology: Endocrinology

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  1. OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology

  2. Organization of the Endocrine System • Peripheral Substrate-Regulated Systems • Hormone Negative Feedback-Regulated Systems • Hypothalamic-Pituitary Neuroendocrine Reflex Systems

  3. Hormone Negative Feedback Hypothalamic-Pituitary Systems • Thyroid Axis (Thyroid Hormones) • Adrenocortical Axis (Glucocorticoids) • Ovarian Axis (Estrogen/Progesterone) • Testicular Axis (Testosterone)

  4. Thyroid Hormones and Antithyroid Agents Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” 10th Edition Chapter 57: 1563-1596

  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. Synthesis of T3 + T4 Iodide Trapping Organification • thyroperoxidase-catalyzed iodination of tyrosine • MIT & DIT Coupling T3 triiodothyronine (MIT + DIT) T4 tyroxine (DIT + DIT)

  7. Release of T3 +T4 Colloid resorption Thyroglobulin proteolysis T4/T3 release ratio 5:1

  8. Thyroxine Binding Globulin

  9. Peripheral Metabolism of Thyroxine

  10. Thyroxine Binding Globulin

  11. Thyroid Function Tests

  12. Actions of Thyroid Hormones

  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. Thyroid Function in Brain Development

  15. Thyroid Function in Calorigenesis

  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. Non-Toxic Goiter Thyroid hyperplasia, hypertrophy Chronic TSH, TSH-like goitrogens Inactive T3/T4 iodide deficiency enzyme deficiency inflammation

  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. Adult Hypothyroidism (Myxedema) • Generalized slowing of metabolic processes • Etiology • surgical thyroidectomy • radioactive iodine • inflammation • autoimmune destruction (Hashimoto’s thyroiditis)

  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. 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. Anti-Thyroid Agents • Propylthiouracil • blocks iodine organification & coupling • Potassium iodide solutions • inhibits iodide uptake and trapping • Radioactive iodine • destroys thyrocytes

  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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