**3.3. TRH**

Thyrotropin-releasing hormone (TRH) is a tripeptide (pGlu-His-ProNH2) that was originally described to be synthesized in the mammalian hypothalamus, released into the hypothalamic–pituitary portal system and has the capability of inducing the release of thyroid-stimulating hormone (TSH) from the anterior pituitary [104, 105]. TRH binds to specific seven transmembrane domain, Gq/11-protein-coupled receptors of which, two subtypes have been cloned and characterized so far: TRHR1 and TRH-R2 [106, 107]. The two receptor subtypes exhibit similar affinities to TRH but different tissue distribution [108] and basal activities [109].

Besides stimulation of TSH secretion at the pituitary, main role of TRH as key factor in the hypothalamic-pituitary-thyroid axis, numerous morphological and pharmacological studies have described TRH as neurotransmitter or neuromodulator in the CNS affecting behaviour, temperature regulation, food intake, and nociception [110, 111]. Furthermore, as suggested by the wide tissue-distribution of TRH and TRH receptors, TRH is implicated in many physiological and pathological processes of prostate, pancreas, testis, adrenal gland, heart, skin and thyroid tissues [112-119].

In the case of thyroid, it has been well established that C cells express TRH at both mRNA and protein levels (see Figure 7) [36]. Furthermore, our research group have described that C-cell cultures express TRH-R1 and TRH-R2, whereas only TRH-R2 subtype is expressed by PC-Cl3 rat thyrocytes [60]. It has also been reported that TRH inhibits the TSH-induced increase of cAMP and subsequent release of thyroid hormones by the dog thyroid gland [120, 121], suggesting that TRH could participate in the regulation of thyroid hormone secretion as an antagonist to TSH [122].

In accordance to this point, Rausell et al. in 1999 [122] found that the levels of TRH and TRH-like peptides in the thyroid were strongly influenced by thyroid status. Furthermore, Rausell et al. demonstrated that TRH exerted a direct effect on thyroid hormone release in vitro [123] and administration of TRH to hyperthyroid patients with very low levels of TSH resulted in decreased levels of circulating thyroid hormones [124].

Although the effects of TRH on thyroid hormone secretion could, at least in part, be due to hypothalamic TRH, the results so far published in the literature and reviewed above would open the possibility of a paracrine regulation of follicular cell activity through C-cell released TRH as a putative additional mechanism for thyroid function.

**Figure 7.** Immunofluorescent staining for calcitonin (A) and TRH (B) in rat thyroid tissue. All calcitonin-immunopositive C cells are also immunopositive for TRH. (x400).
