NEW INSIGHTS INTO THE HYPOTHALAMIC-PITUITARY-THYROID AXIS

Abstract

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.

Figure 1.

In the posttranslational process, TRH is degraded by the pyroglutamyl-peptidases I and II to its main metabolite His-Pro-NH2, which can be spontaneously metabolized to cyclo (His-Pro), and by the action of prolyl endopeptidase (TRH desamidase) to desamidated pyro-Glu-His-Pro-OH. TRH is released by hypophysiotopic neurons in the median eminence from where it is transported by the portal plexus in the anterior pituitary where it stimulates TSH secretion that stimulates the secretion of T4 and T3 from the thyroid cells. Potent orexigenic peptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), that are projected from the arcuate nucleus (ARN) to the paraventricular nucleus (PVN) and innervate TRH neurons, are inhibited by leptin. In contrast, the neuronal group that synthesizes the anorectic peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine- and amphetamine regulated transcript (CART), is stimulated by leptin. Thus, leptin, by inhibiting NPY and AGRP, which antagonizes the α-MSH stimulatory activity on pro-TRH gene expression in the PVN, activates pro-TRH expression.

Figure 2.

Ghrelin is secreted in the stomach and in turn stimulates the secretion of T4. It is not clear whether the reported inhibition of TSH following ghrelin administration is the result of a direct effect of ghrelin at the pituitary level or comes about via the inhibition by the thyroid hormones (negative feedback). Ghrelin can activate the orexigenic peptides AGRP and NPY in the ARN, thus exhibiting an antagonistic action to leptin.