Physiological roles
• Influence on many aspects of body function– Direct action– Indirect action
• Early growth and development
• Deficiency– Abnormalities
• Growth• Development• Reproduction• Behavior• Metabolism
• Thyroid hormones– Global implications
• Tissues• Stage of life
• 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
• Growth and development– Brain development
• Protein synthesis• Myelin production• Axonal ramification/branching• Irreversible effects
– Mental deficiency
• 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
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
• 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
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)
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
• Dimerization– Homodimers– Heterodimers
• Retinoic acid receptor• Retinoic acid X receptor• Thyroid hormone receptor auxiliary proteins
(TRAPs)
• 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
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
Pathophysiology
• Hypersecretion/hyposecretion of thyroid hormones– Hypothyroidism– Hyperthyroidism
• Hypersecretion/hyposecretion of TRH/TSH– Secondary/tertiary hyperthyroidism– Secondary/tertiary hypothyroidism
• Cause– Genetic
• Failure on thyroid growth and function• Defects on thyroid hormone biosynthesis
mechanism– Iodine trapping or organification– Thyroglobulin synthesis/secretion
• 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
• 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
• 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
