Thyroid Hormones

Thyroid Hormones

Thyroid Hormones

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Development of the Thyroid Gland

  • Appears very early in life
  • Develops about 4 weeks after conception as an epithelial invagination of the tongue
  • Moves down the neck while forming bilobular structure, completed by third trimester
  • Composed of two large lobs, 20-25g, either side of the trachea, below the larynx, joined by the isthmus
  • 'Butterfly' shape
  • Pyramidal lobe often present
  • Rich blood supply from thyroid arteries
  • Innervated by the autonomic nervous system
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Anatomy of the Thyroid Gland

Cellular Structure

  • Thyroid gland has a very distinctive cellular organisation related to its function
  • Its cells are arranged in follicles
  • There are very a million follicles in your thyroid gland
  • Follicles are spherical bodies composed of epithelial cells surrounding a colloidal storage protein, thyroglobulin
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Histology

  • Epithelial cell height varies depending on the activity of the gland
    • inactive, epithelial cells are flattened, with a large colloidal mass
    • active, cells are columnar in shape, with a small colloidal lumen
  • Epithelial cells are exocrine, absorptive and endocrine
  • Larger epithelial cells lie between the follicles, parafollicular C cells, produce calcitonin
  • Connective tissue, blood vessels and nerves surround groups of follicles, forming the lobule
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Synthesis of Thyroid Hormones

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Thyroid Hormones

  • Dietary iodide (I-) taken up by iodide pump from the blood
  • I- concentrated to 25-50 times plasma concentration, 600ug/g tissue
  • Iodide uptake enhanced by thyroid stimulating hormone (TSH), iodine deficiency, TSH receptor antibodies
  • Iodide pump inhibited by I-, perchlorate (ClO4-), thiocyanate (SCN-), pertechnetate (TcO4-)
  • I- oxidised by H2O2 from thyroid peroxidase to I2 at apical surface
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Thyroid Hormones

  • I2 immediately incorporated into tyrosyl residues covalently bound to thyroglobulin (TG) molecules at apical border to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
  • MIT and DIT coupled by thyroid peroxidase to form T3 (3,5,3'-triiodothyronine, thyroxine)
  • T3 is the active hormone
  • Also get reverse T3, not active
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Thyroid Hormones

  • TG continually produced by cells as secretory vesicles and exocytosed into colloid
  • Thyroid hormones stored in colloid until secretion
  • TSH causes endocytosis and proteolysis by lysosomes of TG-hormone complex
  • T3 and T4 released into blood stream
  • MIT and DIT de-iodinated by halogenases and free iodine and tyrosine reused by gland
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Transport

  • Iodine not essential for biological activity
  • T4 ~90%, T3 ~10% of thyroid hormones, 80-100ug/day
  • T3 and T4 transported in plasma bound to proteins - thyroid binding globulin, transthyretin and albumin. T3 less avidly bound than T4
  • Only free hormone not bound to plasma proteins is biologically active
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Metabolism

  • T4 de-iodinated to T3 in the periphery (liver/kidney), most T3 is obtained via this route
  • T4 plasma, half-life 6-7 days, T3 24-36 hours
  • T3 ~10 times more potent than T4
  • T3 and T4 conjugated to glucuronide or sulphate in the liver and excreted in the bile
  • Iodide is excreted in the urine or re-circulated to the thyroid
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Regulation of Thyroid Hormone Release

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Control of Synthesis and Release

  • Thyrotrophin releasing hormone (TRH)
    • Tripeptide from the hypothalamus
    • Stimulates release of thyrotrophin or thyroid stimulating hormone (TSH) from the anterior pituitary 
    • Also releases prolactin
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Control of Synthesis and Release

  • Thyroid stimulating hormone (TSH)
    • TSH acts on specific receptors on basal membrane
    • Increases synthesis of iodide pumps
    • Increases synthesis of thyroglobulin
    • Increases synthesis and secretion of T3 and T4
    • Increases thickness of follicular epithelium and vascularity
    • Release of TSH inhibited by thyroid hormones, cortisol, growth hormone, oestrogens, dopamine and somatostatin
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Control of Synthesis and Release

Control of Synthesis and Release

  • Nuclear events
    • T3 and T4 enter cells by passive diffusion or by active uptake
    • T4 de-iodinated to T3 or rT3
    • T3 actively transported into the nucleus, also binds to cytosolic thyroid hormone binding protein (CTBP)
    • T3 binds to thyroid receptors (TR) in the nucleus already bound to regulatory thyroid hormone response elements (TREs)
    • Thyroid hormone receptor auxiliary protein (TRAP) necessary to stabilise TR binding to DNA
    • Stimulation of target genes
    • Several TR (alpha1-3, beta1-2) exist, different distributions
  • Cellular events
    • T3 binds to membrane-associated receptors to activate Na+/K+ ATPase pump. Increased uptake of glucose and amino acids
    • T3 directly activates mitochondria to increase energy production
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Physiological Actions of Thyroid Hormones

  • Thyroid hormones increase basal metabolic rate (BMR)
  • Calorigenesis
    • Increase O2 consumption in all tissues except brain, spleen, testes and anterior pituitary --> increased heat production
    • Important for thermoregulation
    • Take 4-5 days to occur, involves synthesis of new Na+/K+ ATPase pumps in cell membrane and direct activation of mitochondria
    • Blockers of Na+/K+ ATPase pumps such as cardiac glycosides (digoxin) inhibit actions of thyroid hormones
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Physiological Actions of Thyroid Hormones

  • Carbohydrate, protein and fat metabolism
    • Direct effect on carbohydrates involving increased GI glucose absorption and synthesis of metabolic enzymes
    • Indirect effect due to sensitising tissues to insulin, catecholamines and GH
    • Increase in gluconeogenesis and glycogenolysis in the liver and glucose utilisation in fat, liver and muscle cells
    • Synthesis and degradation of protein seen equally with low thyroid hormone levels, degradation predominates with abnormally high levels
    • Synthesis and lipolysis of fat occur, but lipolysis is more important. Potentisation of catecholamine activity on adipocytes
    • Increases oxidation of free fatty acids, calorigenic
    • Plasma cholesterol lowered by increasing liver uptake through increased synthesis of LDL receptors and increasing bile acid formation
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Physiological Actions of Thyroid Hormones

  • Maturation of the central nervous system
    • Essential for normal CNS development during foetal and early neonatal life. T3 and T4 do not cross the placenta
    • Growth of cortical and cerebellar neurones and myelination of nerve fibres
  • Skeletal growth and maturation
    • Synergistic effects with GH, essential for bone growth and development and normal stature
    • Also essential for normal functioning of nervous and cardiovascular systems, GI tract, development of teeth, skin and hair
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Why do we need thyroid hormones?

  • Responses to extremes of temperature
    • Body maintained 37.2 degrees
    • In the Arctic:
      • Body detects low temperature
      • Immediate release of T3 and T4 from the thyroid gland
      • More O2 used by tissues and mitochondria makes heat
    • Useful clinical sign
      • underactive thyroid gland - people feel cold
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