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