LECTURE 4: Thyroid Hormones

### Thyroid Hormones: Synthesis and Secretion Process The thyroid gland is responsible for the production of three main hormones: **thyroxine (T4)**, **triiodothyronine (T3)**, and **calcitonin**. Of these, T4 and T3 are collectively referred to as **thyroid hormones** and are primarily involved in regulating the body's metabolism, while calcitonin plays a role in calcium homeostasis. #### Thyroid Hormone Synthesis - **Role of Thyroglobulin**: - Thyroid hormone synthesis begins with **thyroglobulin**, a large glycoprotein synthesized by **thyroid epithelial cells** (follicular cells) and secreted into the **follicle lumen** (colloid) of the thyroid gland. - **Thyroglobulin** serves as a precursor to thyroid hormones and contains **134 tyrosine residues**. Only a small portion of these tyrosines is used for hormone synthesis, specifically to form T3 and T4. - **Iodide Uptake and Transport**: - **Iodine**, in the form of **iodide (I⁻)**, is essential for thyroid hormone production. The thyroid follicular cells actively take up iodide from the bloodstream through a specialized **sodium-iodide symporter (NIS)** located on the plasma membrane. This process is known as the **"iodine trap."** - Once iodide is inside the follicular cell, it is transported to the colloid, where it interacts with thyroglobulin to facilitate hormone synthesis. - **Thyroid Peroxidase (TPO) Catalyzed Reactions**: - **Thyroid peroxidase (TPO)** is a critical enzyme that catalyzes two essential steps in thyroid hormone synthesis:**Iodination (Organification)**: TPO mediates the addition of iodine to the tyrosine residues on thyroglobulin, forming **monoiodotyrosine (MIT)** and **diiodotyrosine (DIT)**. This step is also referred to as **organification of iodide**. - **Coupling Reaction**: TPO also catalyzes the coupling of iodinated tyrosine molecules to form T4 and T3: - **T4 (Thyroxine)** is created by coupling two molecules of DIT. - **T3 (Triiodothyronine)** is created by coupling one molecule of MIT and one molecule of DIT. - **Storage of Thyroid Hormones**: - Through TPO's action, thyroid hormones accumulate in the **colloid**, bound to thyroglobulin. They are stored here until the body signals the need for their release. #### Thyroid Hormone Release - **Endocytosis of Colloid**: - When thyroid hormones are required, **thyroid epithelial cells** ingest the colloid containing thyroglobulin-bound T3 and T4 by **endocytosis** at their apical surface. - **Lysosomal Digestion**: - The colloid-containing endosomes merge with **lysosomes** within the follicular cell. Lysosomes contain hydrolytic enzymes that digest thyroglobulin, freeing T3 and T4 molecules from the protein scaffold. - **Release into the Bloodstream**: - The liberated T3 and T4 diffuse out of the lysosome and pass through the **basal plasma membrane** of the follicular cell into the bloodstream. - Once in circulation, T3 and T4 bind to carrier proteins, such as **thyroxine-binding globulin (TBG)**, **transthyretin**, and **albumin**. These proteins transport thyroid hormones to various tissues throughout the body, where they regulate metabolic processes. --- #### Additional Information on Thyroid Hormones and Their Actions - **T3 and T4 Activity**: - **T3** is the more potent of the two hormones and is primarily responsible for the metabolic effects of thyroid hormone. Although T4 is produced in higher quantities, it is largely converted to T3 in peripheral tissues by deiodination. - **Thyroid hormone receptors (TRs)** in target cells primarily bind T3, which then activates or suppresses specific genes involved in metabolic regulation. - **Role in Growth and Development**: - Thyroid hormones are essential for normal **growth**, **neural development**, and **metabolic function**. They are particularly important during fetal development and infancy, where they support brain development and proper body growth. - **Transport Mechanism and Regulation**: - In the bloodstream, thyroid hormones are primarily bound to TBG, which maintains hormone solubility and prolongs its half-life. - The release and synthesis of T3 and T4 are tightly regulated by the **Hypothalamus-Pituitary-Thyroid (HPT) Axis**. ### Mechanism of Thyroid Hormone Action in the Body - **Cellular Entry and Activation**: - Thyroid hormones, mainly **T4** and **T3**, enter the body’s cells through specific transport proteins or passive diffusion across the cell membrane. - Within the cell, **T4 is converted to T3** by enzymes known as **deiodinases**. This conversion is crucial as **T3** is the more potent and biologically active form of thyroid hormone. - **Binding to Thyroid Hormone Receptor (TR)**: - Once inside the cell, **T3** binds to the **thyroid hormone receptor (TR)** located in the **cell nucleus**. - These TRs are part of a family of nuclear receptors that regulate gene expression by interacting with specific DNA sequences, particularly **thyroid response elements (TREs)** on t