Thyroid Regulation

Thyroid hormone regulation operates through the hypothalamic-pituitary-thyroid (HPT) axis with precise negative feedback control. The hypothalamus secretes thyrotropin-releasing hormone (TRH) from the paraventricular nucleus, which travels via the hypophyseal portal system to the anterior pituitary, stimulating thyrotrophs to synthesize and secrete thyroid-stimulating hormone (TSH, thyrotropin). TSH binds to TSH receptors on thyroid follicular cells, activating Gs-coupled adenylyl cyclase and cAMP signaling, which stimulates all steps of thyroid hormone biosynthesis: iodide trapping via the sodium-iodide symporter (NIS), iodide oxidation and organification by thyroid peroxidase (TPO), coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT) to form T3 (MIT + DIT) and T4 (DIT + DIT), thyroglobulin endocytosis and proteolysis, and hormone secretion. Circulating T4 (the predominant secretory product, 80-90%) is converted to active T3 by type 1 and type 2 deiodinase enzymes in peripheral tissues, or to inactive reverse T3 (rT3) by type 3 deiodinase (which increases during illness, contributing to sick euthyroid syndrome). Free T3 and T4 exert negative feedback at the anterior pituitary (suppressing TSH) and hypothalamus (suppressing TRH), completing the regulatory loop. Only free (unbound) thyroid hormones are biologically active;...