The hypothalamic-pituitary-thyroid axis. TRH can be seen in green.
TRH is synthesized within parvocellular neurons of the paraventricular nucleus of the hypothalamus.[2] It is translated as a 242-amino acid precursor polypeptide that contains 6 copies of the sequence -Gln-His-Pro-Gly-, with both ends of the sequence flanked by Lys-Arg or Arg-Arg sequences.
To produce the mature form, a series of enzymes are required. First, a protease cleaves to the C-terminal side of the flanking Lys-Arg or Arg-Arg. Second, a carboxypeptidase removes the Lys/Arg residues leaving Gly as the C-terminal residue. Then, this Gly is converted into an amide residue by a series of enzymes collectively known as peptidylglycine-alpha-amidating monooxygenase. Concurrently with these processing steps, the N-terminal Gln (glutamine) is converted into pyroglutamate (a cyclic residue). These multiple steps produce 6 copies of the mature TRH molecule per precursor molecule for human TRH (5 for mouse TRH).
TRH is a tripeptide, with an amino acid sequence of pyroglutamyl-histidyl-proline amide.
History
The structure of TRH was first determined, and the hormone synthesized, by Roger Guillemin and Andrew V. Schally in 1969.[4][5] Both parties insisted their labs determined the sequence first: Schally first suggested the possibility in 1966, but abandoned it after Guillemin proposed TRH was not actually a peptide. Guillemin's chemist began concurring with these results in 1969, as NIH threatened to cut off funding for the project, leading both parties to return to work on synthesis.[6]
Schally and Guillemin shared the 1977 Nobel Prize in Medicine"for their discoveries concerning the peptide hormone production of the brain."[7] News accounts of their work often focused on their "fierce competition" and use of a very large amount of sheep and pig brains to locate the hormone.[6]
Clinical significance
TRH is used clinically by intravenous injection (brand name Relefact TRH) to test the response of the anterior pituitary gland; this procedure is known as a TRH test. This is done as diagnostic test of thyroid disorders such as secondary hypothyroidism and in acromegaly.
TRH has anti-depressant and anti-suicidal properties,[8] and in 2012 the U.S. Army awarded a research grant to develop a TRH nasal spray in order to prevent suicide amongst its ranks.[9][10] The antidepressant properties of TRH are present when TRH is administered intrathecally, or administration into the spine, and the effects are short-lived.[8] Some researchers are testing a prodrug approach to administer TRH orally and have TRH reach the brain without being degraded in the stomach or blood.[11]
TRH has been shown in mice to be an anti-aging agent with a broad spectrum of activities that, because of their actions, suggest that TRH has a fundamental role in the regulation of metabolic and hormonal functions.[12]
Side effects
Side effects after intravenous TRH administration are minimal.[13] Nausea, flushing, urinary urgency, and mild rise in blood pressure have been reported.[14] After intrathecal administration, shaking, sweating, shivering, restlessness, and mild rise in blood pressure were observed.[8]
^Urayama A, Yamada S, Kimura R, Zhang J, Watanabe Y (December 2002). "Neuroprotective effect and brain receptor binding of taltirelin, a novel thyrotropin-releasing hormone (TRH) analogue, in transient forebrain ischemia of C57BL/6J mice". Life Sciences. 72 (4–5): 601–607. doi:10.1016/S0024-3205(02)02268-3. PMID12467901.
^Bowen R (1998-09-20). "Thyroid-Stimulating Hormone". Pathophysiology of the Endocrine System. Colorado State University. Retrieved 2009-03-04.
^Boler J, Enzmann F, Folkers K, Bowers CY, Schally AV (November 1969). "The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide". Biochemical and Biophysical Research Communications. 37 (4): 705–710. doi:10.1016/0006-291X(69)90868-7. PMID4982117.
^Burgus R, Dunn TF, Desiderio D, Guillemin R (November 1969). "[Molecular structure of the hypothalamic hypophysiotropic TRF factor of ovine origin: mass spectrometry demonstration of the PCA-His-Pro-NH2 sequence]". Comptes Rendus de l'Académie des Sciences, Série D (in French). 269 (19): 1870–1873. PMID4983502.
^ abWoolgar S, Latour B (1979). "Chapter 3: The Case of TRF(H)". Laboratory life: the social construction of scientific facts. Thousand Oaks: Sage Publications. ISBN0-8039-0993-4.
^ abcMarangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia PJ, L'Herrou TA, et al. (March 1997). "Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients". Archives of General Psychiatry. 54 (3): 214–222. doi:10.1001/archpsyc.1997.01830150034007. PMID9075462.
