The discovery of thyrotropin releasing hormone (TRH) in 1969 was the definitive step in decoding the hypothalamic-pituitary thyroid (HPT) axis, thereby opening up the era of neuroendocrinology, while it also revolutionized the diagnostic and therapeutic approach to patients with thyroid diseases. TRH, produced in the hypothalamus, is the central regulator of the HPT. It functions via neurons originating in the paraventricular nucleus (PVN), which integrates multiple neuronal and humoral signals and resets the HPT axis according to variations of external and internal environmental conditions. The TRH activates TSH in the pituitary that stimulates the secretion of thyroxine from thyroid which, in turn, exerts a negative feedback on TSH and TRH secretion. However, various factors are involved in the regulation of the HPT axis. Leptin has both indirect and direct effects on TRH regulation, the former by regulating agouti-related peptide (AGRP) in the arcuate nucleus (ARN) that antagonizes the α-MSH stimulatory activity on pro-TRH gene expression in the PVN, and the latter by stimulating hypothalamic TRH expression, TRH transcription via stimulation of pro-convertase 1 and 2 expression, which lead to enhanced processing of pro-TRH into TRH. The interplay of TRH with leptin and the recently reported influence of ghrelin on the HPT axis can alter the setpoint of the axis. The polyphenol resveratrol, as recently observed, exerts an anxiolytic and antidepressant activity in subclinical hypothyroid (SCH) rats. Resveratrol, by decreasing both TSH and TRH mRNA expression, regulates the HPT axis, while in parallel it regulates the Wnt/β-catenin pathway in the hippocampus. These findings open up possibilities for the therapeutic use of resveratrol as coadjuvant, especially in overt and SCH states marked by anxiety and depression. The clinician should be aware of clinical changes that can invalidate the normal regulation of the HPT axis, the most commonly observed being medications and comorbidities.
Keywords: Hypothalamic-Pituitary Thyroid axis; TRH; TSH; tanycytes.