The discovery of the tripeptide thyrotropin-releasing hormone (TRH) in 1970 (Burgus et al. 1970; Nair et al. 1970) facilitated expanded understanding of the regulation of the HPT axis. Like CRH, TRH is widely distributed within extrahypothalamic regions of the brain where it acts as a neurotransmitter quite distinct from its role as a hypothalamic–hypophysiotropic hormone. Also similar to CRH, TRH is released by parvocellular neurons of the hypothalamic paraventricular nucleus, whose fibers project to the median eminence where they secrete TRH into the hypothalamo-hypophyseal portal system (Greer 1952; Swanson and Kuypers 1980). TRH is then transported to the anterior pituitary where it acts upon TRH receptors located on pituitary thyrotrophs to cause the release of thyroid-stimulating hormone (TSH), also known as thyrotropin. TSH released from the pituitary is transported within the systemic circulation to the thyroid gland where activation of TSH receptors results in increased iodine uptake, follicle cell metabolism, and the release of the two major thyroid hormones, T₃ and thyroxine (T₄). Once released into the general circulation, T₃ and T₄ are bound to plasma proteins, including transthyretin and thyroxine-binding globulin. Thyroid hormones regulate a wide variety of metabolic activities and provide negative feedback at the level of the hypothalamus and pituitary to regulate, respectively, the release of TRH and TSH.