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• Thyroid gland


  Butterfly-shaped in the front of the neck, the larger endocrine gland in the body

  
• Thyroid secretions


  Metabolic hormones (T4 & T3), calcitonin (for calcium hemostasis)

  
• Thyroid metabolic hormones (T4 & T3)


  • Stimulate O2 consumption by body cells
  • Regulate lipids and carbohydrate metabolism
  • Influence body mass and mentation

  
• Thyroid dysfunctions


  • In fetal and neonatal life: absence or hypofunction cause severe mental retardation and dwarfism
  • In adult life: Hypothyroidism - mental and physical slowing; poor resistance to cold (cold intolerance)
  • In adult life: Hyperthyroidism - body wasting; nervousness, tachycardia; tremor; excess heat production

  
• Stimulus for thyroid hormones

  TSH (that regulated by TRH)

  
• Thyroid hormone regulation

  Negative feedback control: direct (hypothalamic) & indirect (pituitary) inhibition by T4

  
• Thyroid metabolic hormones

  • Iodinated hormones (T4 - 4 iodides; T3 - 3 iodides)
  • T4 called Thyroxine & T3 called triiodothyronine
  • T4 is the main secreted hormone
  • T3 is the biologically active
  • T4 converted to T3 in peripheral tissues by deiodination
  • Synthesized from tyrosine amino acid

  
• Steps in thyroid hormone synthesis

  1. Transport of iodine into colloid of the thyroid follicles (functional units)

  2. Iodine oxidation in the colloid

  3. Tyrosine iodination (tyrosine is in the thyroglobulin)

  4. Endocytosis of thyroglobulin-thyroid hormone into thyrocytes

  5. Thyroid hormone release by cleavage in lysosomes

  
• Thyroglobulin

  • Glycoprotein contains 10% carbohydrate by weight and 123 tyrosine residues (4 -8 ONLY used for hormone synthesis)
  • Synthesized in the thyrocytes
  • Secreted by exocytosis into the colloid
  • Thyroid peroxidases (membrane-bound enzymes in the apical membrane of thyrocytes) mediate oxidation and reaction of iodine with thyroglobulin
  • The produced thyroid hormone remain part of thyroglobulin until needed (colloid represent reservoir of the hormone for at least 2 months)
  • When needed colloid is internalized by endocytosis into thyrocytes and the hormone released by lysosomal cleavage

  
• Thyroid peroxidases

  Involved in iodination and coupling of iodinated tyrosine residues

  
• Synthetic steps in thyroid hormone production

  1. First step: iodination of tyrosine to give MIT

  2. Next step: iodination of MIT at C5 to give DIT

  3. Two DIT undergo oxidative condensation to form T4

  4. One DIT condense with one MIT to form T3 (major) and reverse T3 (RT3 - trace)

  
• % Distribution in the thyroid follicle


  • T4: 35%
  • T3: 7%
  • MIT: 3%
  • DIT: 33%

  
• Secretion rate


  • T4: 80 μg/day
  • T3: 4 μg/day
  • RT3: 2 μg/day
  • DIT & MIT: null

  
• Remaining DIT & MIT are deiodinated by iodotyrosine deiodinase to recover iodine and tyrosine for next round of hormone synthesis

  
• Plasma levels

  T4 = 8 μg/dL

  T3 = 0.15 μg/dL
• Thyroid hormone solubility

  Both are lipophilic

  
• Thyroid hormone in plasma

  • Present as bound form (bind to the plasma protein Thyroxine-binding globulin) + free form (biologically active)
  • The bound form acts as a reservoir when needed
  • The thyroid gland adds the free form to the circulation
  • Free hormone is biologically active and exerts an inhibitory feedback on pituitary TSH secretion

  
• Plasma proteins that bind thyroid hormones

  • Albumin (large capacity but bind only small amount; t1/2 = 13 days)
  • Prealbumin (Transthyretin but bind only small amount; t1/2 = 2 days)
  • Thyroxine binding globulin (TBG) (smallest capacity BUT bind most of T4; i.e., TBG has higher affinity to T4; t1/2 = 5 days)

  
• T4 Plasma protein binding

  99.98% bound and the free form = 0.02% (2 ng/dL)

  
• Urine concentration of thyroid hormones

  Very little and t1/2 = 6-7 days

  
• Metabolic pathway of T4

  • T4 deiodinated into T3 (catabolism & activation)
  • Site of metabolism: Liver, Kidneys and other tissues
  • Metabolism of T4: 1/3 to T3 & 45% to RT3

  
• T3 supply

  13% secreted by thyroid gland & 87% by deiodination