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

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

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

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

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

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

Thyroxine Binding Globulin

Peripheral Metabolism of Thyroxine

Thyroxine Binding Globulin

Thyroid Function Tests

Actions of Thyroid Hormones

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

Thyroid Function in Brain Development

Thyroid Function in Calorigenesis

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

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

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

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

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

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

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

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