Thyroid Hormone Synthesis and Release

Thyroid Hormone Synthesis, Storage and Release

• Thyroid hormones are produced by the thyroid gland and are essential for regulating metabolism, growth, and development.
• Thyroid hormones are synthesized from tyrosine, an amino acid found in thyroglobulin.
• The thyroid gland has follicles, lined with follicular cells, which produce thyroglobulin and secrete it into the colloid.
• Colloid is a viscous fluid, stored in the follicles, and contains thyroglobulin.
• Thyroid hormones T3 (triiodothyronine) and T4 (thyroxine) are synthesized and stored in the colloid as part of the thyroglobulin molecule.
• T4 is the main hormone secreted (~90%).
• T3 is about 4 times more potent than T4 on target tissues.
• T3 and T4 are predominantly transported in the circulation bound to carrier molecules.

Steps involved in the synthesis and release of thyroid hormones:

• Step 1. Uptake of Iodide: Iodide ions are actively transported from the circulation into the follicular cells, creating a higher concentration inside the cells compared to surrounding fluid.
• Step 2. Oxidation of Iodide: Iodide ions are oxidized inside the follicular cells by thyroid peroxidase to generate either iodinium ions (I+) or iodide free radicals.
• Step 3. Iodination of Tyrosine: The iodinium ions are attached to the tyrosine ring of tyrosines within the thyroglobulin molecule via thyroid peroxidase.
• Step 4. Coupling of Iodotyrosines: Monoiodotyrosine (T1) and Diiodotyrosine (T2) are coupled via covalent bonds on thyroglobulin to form T4 and T3.
• Step 5. Proteolytic Cleavage of Thyroglobulin: The iodinated thyroglobulin is taken into the follicular cells by pinocytosis, where it fuses with a lysosome.
• Step 6. Release of T3 and T4: Lysosomal enzymes break down thyroglobulin, releasing T3 and T4 and any remaining T1 and T2. T1 and T2 are recycled, and T3 and T4 are released into the circulation.

Regulation of T3 and T4 Secretion

• Thyroid-stimulating hormone (TSH) from the anterior pituitary gland regulates the synthesis and release of T3 and T4.
• Increased demand for T3 and T4 triggers signals in the hypothalamus, leading to the release of thyrotropin-releasing hormone (TRH).
• TRH stimulates the anterior pituitary to increase TSH secretion.
• TSH binds to receptors on the follicular cells of the thyroid gland, increasing iodide uptake, thyroglobulin synthesis and thyroid peroxidase levels.
• Increased circulating levels of T3 and T4 provide negative feedback to the hypothalamus and anterior pituitary, decreasing TRH and TSH release.
• Some circulating T4 is converted to T3 by the liver.
• In children, cold temperatures stimulate TRH secretion, helping them adapt to changes in environmental temperatures.

Actions of T3 and T4 on Metabolism

• T3 and T4 increase protein synthesis, building and repairing muscle, which requires more energy and oxygen.
• T3 and T4 increase basal metabolic rate: increased oxygen consumption and energy expenditure at rest. This also generates more heat.
• T3 and T4 alter metabolism:
  • Increase vitamin demand
  • Enhance the lipolytic action of adrenaline and glucagon, releasing lipids for energy.
  • Increase insulin-dependent glucose utilization in target tissues (like skeletal muscle) to meet increased energy demand and stimulate glycogen synthesis.
• T3 and T4 are lipophilic and cross cell membranes freely.
• T3 and T4 bind to receptors in the nucleus of cells, increasing DNA-dependent RNA polymerase. This increases gene transcription and mRNA production, leading to increased protein synthesis of enzymes such as respiratory enzymes.
• T3 and T4 also increase the production of sodium-potassium ATPase. This pump expels sodium ions from cells in exchange for potassium ions, increasing ATP use and overall metabolism.