Qaly Wellness | Enhance Your Metabolic Function: The Life Cycle of Thyroid Hormone

1. Synthesis of Thyroid Hormones (T4 and T3)

The synthesis of thyroid hormones takes place in the thyroid gland, a butterfly-shaped organ located in the neck. The synthesis process involves several key steps:

a) Iodine Uptake

• The thyroid gland actively takes up iodide (I⁻) from the bloodstream via the sodium-iodide symporter (NIS), located on the basolateral membrane of thyroid follicular cells. This process is energy-dependent and facilitated by the electrochemical gradient maintained by sodium-potassium pumps.
• Iodine is transported into the thyroid follicular cells and then into the colloid (the gel-like substance inside thyroid follicles).

b) Iodination of Tyrosine Residues

• Thyroglobulin (TG), a large protein produced by thyroid follicular cells, contains tyrosine residues that serve as precursors for thyroid hormone synthesis.
• Iodide (I⁻) is oxidized to iodine (I₂) by the enzyme thyroid peroxidase (TPO), which is located on the apical membrane of the follicular cells.
• The iodine reacts with tyrosine residues on thyroglobulin, catalyzed by TPO, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).

c) Coupling of Iodotyrosines

• MIT and DIT are then coupled to form T3 (triiodothyronine), which consists of one MIT and one DIT, or T4 (thyroxine), which consists of two DIT molecules. This coupling reaction also occurs on the thyroglobulin backbone in the colloid.

d) Storage of Thyroid Hormone

• The iodinated thyroglobulin (which now contains T3 and T4) is stored in the colloid within the thyroid follicles until it is needed for secretion.

2. Secretion of Thyroid Hormones

a) Endocytosis and Cleavage of Thyroglobulin

• When thyroid hormones are needed, the thyroid gland undergoes a process known as endocytosis, in which the thyroglobulin-containing colloid is internalized into the thyroid follicular cells.
• Inside the follicular cells, lysosomal enzymes degrade the thyroglobulin, releasing the bound T3 and T4 into the cytoplasm.

b) Release into the Bloodstream

• The thyroid hormones (mainly T4, with a smaller amount of T3) are then transported out of the follicular cells into the bloodstream via membrane transporters, such as monocarboxylate transporters (MCT8).
• T4, the predominant hormone secreted, enters circulation and is carried in the blood bound to thyroid-binding globulin (TBG), transthyretin (TTR), and albumin. Only a small fraction (less than 1%) of the thyroid hormone is unbound and biologically active.

3. Peripheral Conversion of T4 to T3

Although the thyroid gland predominantly secretes T4, it is T3 that is primarily responsible for the biological effects of thyroid hormone. T4 is converted to T3 by deiodinase enzymes in various tissues, such as the liver, kidneys, and brain.

a) Types of Deiodinase Enzymes

• Type 1 deiodinase (D1): Found in the liver, kidney, and thyroid, this enzyme removes an iodine atom from T4 to convert it into the more active T3.
• Type 2 deiodinase (D2): Found in the brain, pituitary gland, and brown adipose tissue, D2 also converts T4 into T3, especially in the central nervous system.
• Type 3 deiodinase (D3): This enzyme inactivates T3 by converting it to an inactive form, reverse T3 (rT3), which has little to no biological activity.

4. Transport and Action of Thyroid Hormones in Target Tissues

Once in the bloodstream, thyroid hormones are transported to various target tissues. The thyroid hormones act primarily at the level of the nucleus, where they regulate gene expression. The mechanisms include:

a) Entry into Target Cells

• The unbound thyroid hormones (mainly T3) cross the plasma membrane of target cells via membrane transporters such as MCT8 (for T3), LAT1 (for T4), and possibly OATP1C1. These transporters allow the hormone to enter the cytoplasm and, in some cases, be converted to T3.

b) Thyroid Hormone Receptors (TRs)

• In the cytoplasm or nucleus, thyroid hormones bind to specific thyroid hormone receptors (TRs), which are part of the nuclear receptor superfamily. TRs are encoded by two main genes: TRα and TRβ. These receptors function as transcription factors that regulate the expression of target genes.
  • TRα is primarily expressed in the heart, skeletal muscle, and brain.
  • TRβ is more abundant in the liver, kidney, and pituitary gland.

c) Mechanism of Action

• In the absence of thyroid hormone, TRs usually exist as heterodimers with retinoid X receptors (RXRs) and are bound to DNA at thyroid hormone response elements (TREs). In this state, the receptor complex represses transcription.
• When T3 binds to TRs, the receptor undergoes a conformational change that promotes the dissociation of co-repressors and the recruitment of co-activators. This leads to the activation of transcription of genes involved in various cellular processes, such as metabolism, growth, and development.

5. Physiological Effects of Thyroid Hormones

Thyroid hormones regulate a wide range of physiological processes in almost every tissue in the body. The major effects include:

a) Metabolism

• Thyroid hormones increase the basal metabolic rate (BMR) by enhancing the activity of various enzymes involved in oxidative phosphorylation, glycolysis, and fatty acid oxidation. This leads to increased oxygen consumption and heat production, a process known as thermogenesis.
• They promote lipolysis (fat breakdown) and glycogenolysis (glycogen breakdown) to increase energy availability.

b) Cardiovascular System

• Thyroid hormones increase the heart rate (by enhancing beta-adrenergic signaling) and contractility, leading to increased cardiac output.
• They also promote vasodilation and can increase blood flow to various tissues.

c) Development and Growth

• Thyroid hormones are critical for the normal development of the brain, particularly during fetal development and early childhood.
• They influence the growth of bones and the maturation of tissues.

d) Central Nervous System

• In the brain, thyroid hormones regulate neurotransmitter metabolism, synapse formation, and neurogenesis, which are important for cognition and mood regulation. Thyroid hormone deficiency during early development can lead to cretinism (severe developmental delay).

e) Musculoskeletal System

• Thyroid hormones stimulate protein synthesis and bone resorption. They play a role in maintaining muscle strength and function.

6. Regulation of Thyroid Hormone Production

Thyroid hormone synthesis and secretion are tightly regulated by the hypothalamus-pituitary-thyroid (HPT) axis:

• Hypothalamus: Produces thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary.
• Pituitary Gland: Secretes thyroid-stimulating hormone (TSH) in response to TRH, which acts on the thyroid gland to stimulate the uptake of iodine and the synthesis and secretion of T3 and T4.
• Feedback Regulation: Elevated levels of T3 and T4 inhibit the release of TRH from the hypothalamus and TSH from the pituitary, thus maintaining a balance in thyroid hormone levels.

7. Deactivation and Clearance

• Metabolism: T3 and T4 are eventually metabolized in the liver and kidneys. T3 is converted into its inactive form, reverse T3 (rT3), by deiodinase enzymes, while both T3 and T4 are conjugated with glucuronic acid or sulfuric acid for excretion.
• Excretion: The conjugates are then excreted into the bile and eliminated in the feces, or they are filtered by the kidneys and excreted in urine.

In summary, the life cycle of thyroid hormone involves its synthesis from iodine and tyrosine in the thyroid gland, its secretion into the bloodstream, its conversion to the more active T3 in peripheral tissues, and its binding to thyroid hormone receptors to regulate gene expression in target tissues. This entire process is finely tuned by the hypothalamic-pituitary-thyroid