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 GoiterThyroid hyperplasia, hypertrophy

Chronic TSH, TSH-like goitrogens

Inactive T3/T4iodide 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