What is the function, regulation, and production of thyroid hormones?

Thyroid Gland: Hormones, Regulation, Production, and Function

The thyroid gland produces hormones that are essential for regulating metabolism, development, and cellular function throughout the body, with thyroid stimulating hormone (TSH) from the pituitary gland serving as the primary regulator of thyroid hormone synthesis and secretion. 1

Thyroid Hormone Production and Structure

• The thyroid gland primarily produces two hormones: thyroxine (T4) and triiodothyronine (T3), with T4 being the main hormone secreted by the thyroid gland 2
• T4 is a prohormone that is converted to the more biologically active T3 through deiodination in peripheral tissues, with approximately 80% of circulating T3 derived from peripheral T4 conversion 2, 3
• Thyroid hormones are synthesized from the amino acid tyrosine and require iodine for their production, with daily iodine requirements of 150 μg/day in adults 1
• The chemical structure of levothyroxine (synthetic T4) is C₁₅H₁₀I₄NNaO₄•H₂O, containing four iodine atoms that are essential for its biological activity 2

Regulation of Thyroid Hormone Production

• The hypothalamic-pituitary-thyroid axis regulates thyroid hormone production through a negative feedback loop involving the hypothalamus, pituitary, and thyroid gland 4
• Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH) 4
• TSH binds to receptors on thyroid follicular cells and stimulates multiple aspects of thyroid hormone synthesis, including iodide uptake, activation of thyroid peroxidase enzyme, oxidation and organification of iodide, and secretion of T4 and T3 into circulation 1
• Thyroid hormones exert negative feedback on both the hypothalamus and pituitary, inhibiting TRH and TSH production when thyroid hormone levels are adequate 4, 5
• TSH and free T3 show distinct circadian patterns that peak during nighttime hours, demonstrating the importance of timing in thyroid hormone regulation 6

Thyroid Hormone Transport and Metabolism

• Circulating thyroid hormones are more than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA) 2
• Only the unbound (free) hormone is metabolically active and available to tissues 2
• T4 has a longer half-life (6-7 days) compared to T3 (≤2 days), contributing to more stable serum levels 2
• The primary pathway of thyroid hormone metabolism is through sequential deiodination, with the liver being the major site of degradation for both T4 and T3 2, 3
• Iodothyronine deiodinases (types 1,2, and 3) regulate the activation and inactivation of thyroid hormones in peripheral tissues, controlling tissue-specific thyroid hormone availability 5, 3

Cellular Mechanism of Action

• Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis 2
• T3 and T4 diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA, forming a hormone-nuclear receptor complex that activates gene transcription 2
• The majority of biological effects are mediated by T3, which has approximately four times the biological potency of T4 2, 3
• Thyroid hormone receptors can regulate target gene expression differently depending on gene, tissue, and cellular context 5
• Thyroid hormone transporters and receptor coregulators can strongly control tissue-specific sensitivity to thyroid hormones 5

Physiological Functions of Thyroid Hormones

• Thyroid hormones regulate basal metabolic rate and are critical for thermogenesis and heat production 7
• They play essential roles in development, particularly neural development and brain function 5, 7
• Thyroid hormones regulate carbohydrate, protein, and lipid metabolism throughout the body 3, 7
• They control heart rate and cardiovascular function, with excess thyroid hormone potentially causing atrial arrhythmias, particularly in elderly patients 2
• Thyroid hormones regulate daily rhythms in glucose metabolism, with faster glucose clearance occurring during the early active phase 6
• They are essential for normal growth and skeletal development 1, 8

Thyroid Dysfunction

• Thyroid dysfunction represents a continuum from asymptomatic biochemical changes to clinically symptomatic disease 9
• Hypothyroidism results from insufficient thyroid hormone production and can range from subclinical (elevated TSH with normal T4) to overt (elevated TSH with low T4) 9
• Hyperthyroidism results from excess thyroid hormone production and can range from subclinical (low TSH with normal T4/T3) to overt (low TSH with elevated T4/T3) 9
• Both conditions can significantly impact metabolism, with hyperthyroidism increasing metabolic rate and hypothyroidism decreasing it 9, 6

Nutritional Requirements for Thyroid Function

• Adequate iodine intake is essential for proper thyroid hormone synthesis, with daily requirements of 150 μg/day in adults 1
• Iron and selenium are crucial for proper thyroid function, with iron deficiency impairing thyroid metabolism and selenium required for the deiodination of T4 to T3 via selenoenzymes 1
• Dietary factors can affect thyroid hormone absorption, with certain foods such as soybeans and dietary fiber decreasing bioavailability of T4 2

Clinical Assessment of Thyroid Function

• TSH is the most sensitive marker for thyroid dysfunction, but single time-point measurements may be influenced by circadian variations 6
• Free T4 and T3 measurements provide additional information about thyroid status 9
• TSH levels alone are not a sensitive indicator of iodine status, as concentrations are usually maintained within normal range despite frank iodine deficiency 1