Download Thyroid Lecture

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: 1563-1596
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