Physiological Aspects Related to the Formation and Secretion of Thyroid Hormones
The formation and secretion of thyroid hormones involve several key steps:
- Iodine Absorption and Concentration:
Iodine, an essential component of thyroid hormones, is absorbed from the diet in the form of iodide (I⁻). It is then concentrated in the thyroid gland by the sodium/iodide symporter (NIS), which actively transports iodide into thyroid follicular cells. This process increases intracellular iodide concentration up to 30-40 times higher than plasma levels.
- Synthesis and Storage of Thyroglobulin:
Thyroglobulin, a large glycoprotein precursor for thyroid hormones, is synthesized within follicular cells under the stimulation of thyroid-stimulating hormone (TSH). It is secreted into the colloid within the follicle lumen via exocytosis.
- Iodination of Thyroglobulin:
Iodide ions are oxidized to iodine (I₂) by thyroid peroxidase at the apical membrane of follicular cells. The iodine is then covalently attached to tyrosine residues on thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). These iodinated tyrosines couple to form thyroxine (T4) or triiodothyronine (T3).
- Storage in Colloid:
The iodinated thyroglobulin remains stored in the colloid as a reservoir for future hormone synthesis. This storage mechanism allows for months-long buffering against dietary iodine deficiency.
- Reabsorption and Proteolysis:
When needed, iodinated thyroglobulin is reabsorbed into follicular cells via endocytosis. Lysosomal proteases cleave thyroglobulin to release T4 and T3.
- Secretion into Circulation:
The majority of released hormone is T4 (~80%), with a smaller proportion being T3 (~20%). These hormones are secreted into circulation where they bind to transport proteins.
Physiological Consequences of Thyroid Hormones Binding to Transporting Proteins
Thyroid hormones are highly bound to plasma proteins upon entering circulation:
- Transport Proteins Involved:
- Thyroxine-binding globulin (TBG): Binds ~70% of circulating T4 and T3.
- Transthyretin: Binds ~10-15%.
- Albumin: Binds ~15-20% but with lower affinity.
- Physiological Consequences:
- Prolonged Half-Life: Protein binding significantly extends the half-life of thyroid hormones, particularly T4, which has a half-life of 6-7 days compared to hours for unbound forms.
- Reservoir Function: Bound hormones act as a reservoir, ensuring stable concentrations in circulation despite fluctuations in secretion or metabolism.
- Regulation of Bioavailability: Only free (unbound) hormones are biologically active and can enter target cells. Protein binding regulates the availability of free hormone based on physiological needs.
- Prevention of Renal Loss: Binding prevents rapid renal clearance by reducing filtration through glomeruli.
Main Physiological Actions of Thyroid Hormones
Thyroid hormones exert widespread effects across multiple organ systems:
- Metabolic Effects:
- Increase basal metabolic rate by enhancing oxygen consumption.
- Stimulate gluconeogenesis, glycogenolysis, lipolysis, and protein turnover.
- Promote thermogenesis by decreasing mitochondrial efficiency during electron transport.
- Cardiovascular Effects:
- Increase cardiac output by enhancing heart rate and myocardial contractility.
- Decrease systemic vascular resistance through vasodilation.
- Neurological Effects:
- Essential for brain development during fetal life and infancy.
- Regulate mood, cognition, and reflexes in adults.
- Growth and Development:
- Promote skeletal growth by stimulating bone formation.
- Synergize with growth hormone for normal tissue development.
- Thermoregulation:
- Enhance heat production through shivering and non-shivering thermogenesis in brown adipose tissue.
- Gastrointestinal Effects:
- Increase gastrointestinal motility and appetite due to enhanced smooth muscle activity.
- Renal Effects:
- Increase renal blood flow and glomerular filtration rate, enhancing clearance rates for substances excreted renally.
- Lipid Metabolism:
- Promote reverse cholesterol transport.
- Enhance lipid utilization as an energy substrate while reducing serum cholesterol levels through increased hepatic uptake.
Regulation of Thyroid Hormone Secretion
Thyroid hormone secretion is tightly regulated by feedback mechanisms involving the hypothalamus-pituitary-thyroid axis:
- Hypothalamic Regulation via TRH:
The hypothalamus secretes thyrotropin-releasing hormone (TRH) in response to low circulating levels of T4/T3 or environmental stimuli like cold temperatures.
- Pituitary Regulation via TSH:
TRH stimulates the anterior pituitary gland to release thyroid-stimulating hormone (TSH). TSH acts directly on thyroid follicular cells to enhance all aspects of thyroid hormone synthesis—iodide uptake, thyroglobulin production, iodination, proteolysis—and secretion into circulation.
- Negative Feedback Mechanism:
High levels of circulating free T4/T3 inhibit TRH release from the hypothalamus and TSH secretion from the pituitary gland.
- Peripheral Regulation via Deiodinases:
Conversion of inactive prohormone T4 into active T3 occurs primarily in peripheral tissues like liver and kidney through deiodinase enzymes (DIOs). This step provides local control over bioactive hormone availability depending on tissue-specific demands.
- Inhibitory Factors on Secretion:
Certain factors such as somatostatin, dopamine, glucocorticoids (e.g., cortisol), or high iodine intake can suppress TRH/TSH release or inhibit specific steps in thyroid function directly.
