E6

• Thyroid gland


  Endocrine gland that secretes hormones directly into the bloodstream
• Thyroid hormones


  • T3 - triiodothyronine
  • T4 - thyroxine
• Thyroid gland


  • Development
  • Regulation of growth
  • Control of basal metabolic
• 200 million people have thyroid disease
• Thyroid diseases


  • Hyperthyroidism - TOO MUCH
  • Hypothyroidism - TOO LITTLE
  • Goitre - SWELLING
  • Cancer
• Thyroid gland anatomy


  • Located in neck
  • Butterfly-shaped gland
  • Two lobes united by a narrow isthmus
  • Brownish-red, highly vascular
  • Thin fibrous capsule containing
• Parafollicular cells/C cells


  • Minority of thyroid cells (<10%)
  • Involved in control of serum calcium homeostasis
  • Secrete calcitonin
  • Inhibits osteoclasts from resorbing/breaking down bone resulting in decrease in calcium in the blood
  • Other tissues also produce calcitonin so replacement is not required in the absence of a thyroid gland
• Thyroid follicular epithelial cells

  • Majority of thyroid cells
  • Line the spherical follicles and surround a follicular lumen filled with colloid (thyroid hormone store)
  • Controlled by thyroid-stimulating hormone (TSH)
  • Responsible for the production of T3 and T4
• Thyroid hormone structure


  • Tyrosine-based hormones that contain iodine
  • Triiodothyronine (T3) contains 3 iodine atoms
  • Thyroxine (T4) contains 4 iodine atoms
  • Iodine essential for thyroid hormone biosynthesis
• Iodide transport into the thyroid


  1. Iodide must be transported into the cell from the bloodstream

  2. First, rate-limiting step in thyroid hormone biosynthesis

  3. Occurs against a concentration gradient (high level of intracellular iodide)

  4. Iodide uptake mediated by the sodium/iodide symporter (NIS), located on the basolateral cell membrane
• Sodium iodide symporter (NIS)

  2Na in, 1 I in
• Iodide transport into the follicular lumen

  1. Iodide then moves across and out of the cell by passive transport into the follicular lumen (site of hormone biosynthesis)

  2. Mediated in part by pendrin, an anion transporter located on the apical/luminal cell membrane
• Thyroglobulin (Tg)


  • Thyroid-specific protein
  • Most highly expressed protein in the thyroid gland
  • Large glycoprotein dimer that is secreted into the follicular lumen
  • Serves as a scaffold for hormone synthesis and storage
  • 132 tyrosine residues - up to 1/2 can become iodinated (store for iodine) while only 7 molecules of thyroid hormone are generated
• Thyroid peroxidase (TPO)


  • Thyroid-specific protein
  • Located on apical/luminal membrane
  • Enzyme that catalyses oxidation of iodide to facilitate the iodination of Tg tyrosine residues and coupling of the iodotyrosines to form thyroid hormone
• Iodination of thyroglobulin


  TPO catalyses oxidation of iodide -> iodination of Tg tyrosine residues
• Final steps of thyroid hormone synthesis


  1. Iodinated Tg is stored in the follicular lumen as colloid

  2. When thyroid hormone is required, the colloid is endocytosed from lumen into vesicles

  3. Through fusion of these vesicles with lysosomes, Tg is digested by proteolytic enzymes to release the T3 and T4

  4. T3 and T4 are secreted into the bloodstream via thyroid hormone transporters such as MCT8
• TSH receptor (TSHR)


  • TSHR is a G protein-coupled receptor (GPCR)
  • Located in the basolateral membrane of thyroid cells
  • TSH binding causes a conformational change in the TSHR
  • TSHR then replaces the GDP on the G protein with a GTP
• Almost all effects of TSH on thyroid hormone biosynthesis are mediated by adenylyl cyclase/cAMP
• Changes in gene transcription


  1. Activated PKA enters through nuclear pore

  2. Activated phosphorylated CREN binds to CREB-binding protein on CREB binding-element

  3. Transcription and translation of new protein
• Thyroid binding proteins


  • T3 and T4- hydrophobic
  • About 70% bound to thyroxine binding globulin
  • 15-20% bound to Transthyretin
  • 10-15% bound to albumin
  • Free T4- 0.03%
  • Free T3- 0.3%
  • Unbound/free hormone enters the target cells
• Circulating thyroid hormones


  • Majority of secreted thyroid hormone is T4
  • T4 is a prohormone
  • T3 is biologically active hormone
  • 20% of T3 produced each day is secreted from the thyroid
  • Remaining 80% is generated by conversion of T4
• Conversion of T4 to T3


  1. Amount of active hormone (i.e. T3) is regulated by the peripheral tissues

  2. Thyroid hormone transporters such as MCT8 take up T3 and T4 into the tissues

  3. T4 is then converted to active T3 by enzymes called deiodinases

  4. T3 passes back into bloodstream - controls serum T3 levels as well as 'local' tissue T3 levels

  5. The presence of transporters and deiodinases in peripheral tissues represent further levels of hormone regulation
• Metabolism of iodothyronines


  • Deiodinase 1/D1: Inner and outer ring deiodinase, can activate and inactivate TH, secondary activator of T3, liver, kidney
  • Deiodinase 2/D2: Outer ring deiodinase, main activator of T3, main source of serum T3 and local T3, CNS, pituitary, BAT, skeletal muscle, placenta
  • Deiodinase 3/D3: Inner ring deiodinase, inactivates T3 and T4, clearance of T3 and T4- protective role, CNS, placenta
• Thyroid hormone action


  • Thyroid hormone acts on almost all tissues
  • Development
  • Regulation of growth
  • Control of basal metabolic rate
• Without immediate treatment (hormone replacement), humans born without a functioning thyroid gland (congenital hypothyroidism) become severely mentally deficient
• Thyroid hormone is essential for early brain development - a lack of hormone causes irreversible motor and cognitive impairment
• Lack of hormone in childhood and adolescence results in short stature and delayed skeletal maturation
• Basal metabolic rate


  • The minimum energy expenditure required for the basic functions of the body while at rest
  • Thyroid hormone increases BMR through oxygen consumption and heat production
  • Alters mitochondrial activity, the major site of oxidative processes in the cell
  • T3 in excess can increase BMR by 60-100%. In its absence BMR is reduced to 50%
• Effects of T3 on bodily mechanisms


  • Increases carbohydrate metabolism (glycogenolysis, gluconeogenesis)
  • Increases lipid metabolism by mobilising lipids and circulating free fatty acids
  • Decreases circulating cholesterol and triglycerides by increasing cholesterol secretion in bile
  • Regulates cardiovascular contractility and heart rate
• Thyroid hormone receptors


  • Nuclear hormone receptors
  • Ligand (T3)-activated transcription factors
  • Bind to thyroid hormone response elements (TREs)
  • 2 receptor genes, α & β; and 2 splice variants of each
• Non-genomic effects of T3 and T4


  • Effects of thyroid hormone that are independent of nuclear binding of T3
  • Rapid effects, mostly at the plasma membrane, that are not blocked by inhibitors of mRNA or protein synthesis
  • Induction of signal transduction pathways e.g. MAPK, PI3K
  • Modulation of plasma membrane ion pumps or channels
  • Rapid uptake of glucose and amino acids
• Regulation of Thyroid Hormone

  • HPT (hypothalamic-pituitary-thyroid) axis - TSH regulation - negative feedback
  • Thyroid hormone transporters
  • Deiodinase enzymes - metabolism
  • Thyroid hormone receptor