thyroxine

Thyroxine (T4) is synthesized in thyroid follicular cells through iodide trapping, oxidation, organification onto tyrosine residues of thyroglobulin, and coupling of iodotyrosines (catalyzed by thyroid peroxidase) to form T4 and T3. Most circulating T4 is bound to thyroxine-binding globulin (TBG), with only free T4 being biologically active. In peripheral tissues, T4 is deiodinated by 5'-deiodinase to the more potent T3 (or to inactive reverse T3). Thyroid hormone acts via nuclear receptors to increase basal metabolic rate, stimulate Na+/K+-ATPase activity, enhance beta-adrenergic receptor sensitivity, promote glycogenolysis, lipolysis, and protein synthesis, and is essential for normal CNS and skeletal development in infants (deficiency causes cretinism). Regulation occurs via negative feedback: hypothalamic TRH stimulates pituitary TSH release, which stimulates thyroid follicular cells to produce and release T4/T3; elevated T4/T3 suppresses TRH and TSH. Clinically, TSH and free T4 levels are used to diagnose thyroid disorders: primary hypothyroidism (low T4, high TSH; e.g., Hashimoto thyroiditis), primary hyperthyroidism (high T4, low TSH; e.g., Graves disease), secondary hypothyroidism (low T4, low TSH; pituitary failure). Synthetic levothyroxine (T4) is the standard treatment for hypothyroidism. Drugs like amiodarone, lithium, and iodine excess/deficiency can disrupt thyroid hormone synthesis. Thyroid hormone measurement is also affected by pregnancy and estrogen (increased TBG) versus nephrotic syndrome/steroids (decreased TBG), altering total but not free hormone levels.