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Schematic illustration of the feedback system regulating the hypothalamic-pituitary-thyroid axis. Thyroid hormones exert negative feedback effect at the level of hypothalamic TRH neurons and of pituitary gland. The central feedback effect of thyroid hormones depends on the circulating T4 levels. In the hypothalamus, T4 is converted to T3 by D2 in tanycytes. By volume transmission, T3 secreted from tanycytes reaches the hypophysiotropic TRH neurons, where T3 inhibits the proTRH gene expression via TR-β2 receptors. The set point of the feedback regulation can be altered by two mechanisms: (i) regulation of D2 activity in tanycytes may alter the hypothalamic T3 availability independently from the peripheral T4 concentration. (ii) Neuronal afferents can alter the PCREB concentration in the hypophysiotropic TRH neurons that can change the set point of feedback regulation through competition of PCREB and thyroid hormone receptors for the multifunctional binding site (Site 4) of the TRH promoter. ARC, hypothalamic arcuate nucleus; C1-3, C1-3 adrenergic area of the brainstem; CSF, cerebrospinal fluid; DMN, hypothalamic dorsomedial nucleus; ME, median eminence; NTS, nucleus tractus solitarius; PVN, hypothalamic paraventricular nucleus; py, pyramidal tract; sp5, spinal trigeminal tract. (From Fekete & Lechan (128) with permission)