1. Physiological roles Influence on many aspects of body function –Direct action –Indirect action Early growth and development Deficiency –Abnormalities Growth Development Reproduction Behavior Metabolism

2. Thyroid hormones –Global implications Tissues Stage of life

3. Growth and development –Absence of thyroid hormones Growth retardation –Lack of bone elongation –Lack of bone maturation –Reduced GH secretion (No effects of replacement in the absence of thyroid hormones) –Tissue development in amphibians –Mammary gland development Ducts Alveoli Require prolactin

4. Growth and development –Brain development Protein synthesis Myelin production Axonal ramification/branching Irreversible effects –Mental deficiency

5. Generation of body heat –Majority of body heat Activity of Na transporter –Hydrolysis of ATP –Thyroid hormones Increased oxygen consumption Generation of ATP by mitochondria Increased Na/K-ATPase expression –Tissue-specific

7. Relationship between diet and thyroid hormone function Increase in energy intake –Total calories –Increased carbohydrate content –Increase in thermogenesis Increased T3 –Increased conversion of T4 to T3 Reduction in carbohydrate intake –Increased conversion of T3 to rT3 Increased metabolism of nutrients Sparing of nutrients from weight gain

8. Thyroid hormone concentrations during fasting –Decreased T3 –Decreased hepatic T3 receptors Independent from changes in T3 concentrations Effects of age –Reduced food intake Increased longevity –Frequency of diseases –Severity of diseases Potentially caused by alteration of thyroid hormone secretion

9. Permissive actions of thyroid hormones Thyroid hormones –Required for action of other hormones GH secretion and GH action –Increased GH secretion by thyroid hormones Synergizes with glucocorticoids –Increased ornithine decarboxylase (ODC) activity Regulation of nucleic acids and protein synthesis –GH plus thyroid hormones (tissue-specific)

10. Mechanism of action Analogous to steroid hormones –Two nuclear receptors (alpha and beta) Two isoforms within each receptor (1 and 2) Beta1, beta2, and alpha1 –High affinity to T3 Alpha2 –No binding to thyroid hormones –Negative regulator of other receptors –Specific expression within the CNS and pituitary gland

11. Dimerization –Homodimers –Heterodimers Retinoic acid receptor Retinoic acid X receptor Thyroid hormone receptor auxiliary proteins (TRAPs)

12. Process of signal transduction –Transport of T4 and T3 from circulation to cytoplasm Energy-dependent process –Conversion of T4 to T3 –Binding of T3 to TR –Formation of dimer –Interaction with DNA

14. Non-genomic action Plasma membrane –Increased red cell Ca-ATPase activity –Increased amino acid uptake –Increased glucose uptake Mitochondria –Increased ADP uptake by mitochondria –Increased oxygen consumption –Changes in mitochondria morphology Mitochondrial TR –Absent in thyroid hormone refractory tissues

15. Pathophysiology Hypersecretion/hyposecretion of thyroid hormones –Hypothyroidism –Hyperthyroidism Hypersecretion/hyposecretion of TRH/TSH –Secondary/tertiary hyperthyroidism –Secondary/tertiary hypothyroidism

16. Cause –Genetic Failure on thyroid growth and function Defects on thyroid hormone biosynthesis mechanism –Iodine trapping or organification –Thyroglobulin synthesis/secretion

17. Overstimulation of thyroid gland –Autoimmune disease against TSH receptor Excess secretion of TSH Grave’s disease –Goiter Loss of T3/T4 secretion –No negative feedback Swelling of thyroid glands Cause –Thyroiditis –Lack of iodine

18. Cretins –Absence of thyroid hormone Retarded development of thyroid gland or thyroiditis More prevalent in females Retarded growth and maturation of skeletons and muscles Mental retardation

19. Generalized tissue resistance to thyroid hormone –Variable clinical manifestation Tissue-dependent Elevated thyroid hormones Goiter Euthyroid –Cause Decreased binding affinity Decreased receptor number Abnormal postreceptor signal transduction