Download Physiological roles

Physiological roles
• Influence on many aspects of body function
– Direct action
– Indirect action
• Early growth and development
• Deficiency
– Abnormalities
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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
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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
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Tissue-dependent
Elevated thyroid hormones
Goiter
Euthyroid
– Cause
• Decreased binding affinity
• Decreased receptor number
• Abnormal postreceptor signal transduction