TRH

**Structure and source:** Tripeptide (pyroGlu-His-Pro-NH2) produced by parvocellular neurons of the hypothalamic paraventricular nucleus. It travels through the hypophyseal portal system to the anterior pituitary.

**Mechanism:** TRH binds the TRH receptor (a Gq-coupled GPCR) on pituitary thyrotrophs. This activates PLC, which generates IP3 and DAG, increasing intracellular Ca2+ and activating PKC. The result is TSH synthesis and release. TSH then acts on the thyroid (Gs/cAMP) to increase T3/T4 synthesis and release.

**Other actions:** TRH also stimulates prolactin release from lactotrophs. This explains why primary hypothyroidism (high TRH) can cause hyperprolactinemia, galactorrhea, and amenorrhea. TRH is also found in the CNS, where it acts as a neuromodulator with mild arousal and antidepressant-like effects.

**Regulation (negative feedback):** - T3 and T4 (mainly free T3, generated by type 2 deiodinase in the pituitary) inhibit TRH and TSH. Pituitary TSH suppression is the more sensitive feedback site. - Somatostatin, dopamine, and glucocorticoids inhibit TSH release. - Cold exposure increases TRH, particularly in neonates.

**Clinical correlations (HPT axis interpretation):** - Primary hypothyroidism (e.g., Hashimoto): low T4, high TSH, high TRH. - Primary hyperthyroidism (e.g., Graves): high T4, low TSH, low TRH. - Secondary (pituitary) hypothyroidism: low T4, low TSH, high TRH from loss of feedback. - Tertiary (hypothalamic) hypothyroidism: low T4, low TSH, low TRH. A TRH stimulation test restores TSH response in hypothalamic disease but not in pituitary disease. This test is rarely used now because sensitive TSH assays are available. - Dopamine and glucocorticoids suppress TSH. Hyperprolactinemia from hypothyroidism resolves with levothyroxine.

**Pharmacology:** Protirelin (synthetic TRH) was used diagnostically. Taltirelin is a TRH analog used in Japan for spinocerebellar degeneration.

**High-yield pearls:** - TRH is the only hypothalamic releasing hormone that is a tripeptide. - The TRH/TSH/thyroid axis uses Gq for TRH and Gs for TSH receptors. - Mnemonic: TRH raises TSH and prolactin. Dopamine lowers prolactin and TSH.