Thyroid Regulation

The hypothalamic-pituitary-thyroid (HPT) axis regulates thyroid hormone through negative feedback. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates pituitary thyrotrophs to release thyroid-stimulating hormone (TSH). TSH then activates receptors on thyroid follicular cells, increasing iodide uptake, thyroid peroxidase activity, thyroglobulin processing, and secretion of predominantly thyroxine (T4) with a smaller amount of triiodothyronine (T3). Most circulating T3 is produced outside the thyroid when deiodinase enzymes convert T4 to T3. T3 is more biologically active; T4 functions largely as a circulating reservoir. Free, unbound hormone enters cells and exerts the physiologic effects of thyroid hormone. The pituitary and hypothalamus sense circulating free hormone and reduce TSH and TRH secretion when free T4 and T3 rise. This feedback system explains why TSH is such a sensitive test. The pituitary changes TSH substantially in response to a relatively small change in free T4. In primary hypothyroidism, falling thyroid output therefore causes TSH to rise before free T4 necessarily falls below the laboratory reference interval. In early hyperthyroidism, even a small increase in free hormone can suppress TSH. Pregnancy, estrogen therapy, and liver disease can change thyroxine-binding...