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Gene Review

TRH  -  thyrotropin-releasing hormone

Homo sapiens

Synonyms: Pro-TRH, Pro-thyrotropin-releasing hormone, Prothyroliberin, TRF
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Disease relevance of TRH


Psychiatry related information on TRH


High impact information on TRH

  • METHODS: We enrolled 996 women at 13 North American centers who were in preterm labor at <30 weeks' gestation in a double-blind, placebo-controlled, randomized trial of antenatal thyrotropin-releasing hormone, given intravenously in four doses of 400 microg each at eight-hour intervals [10].
  • CONCLUSIONS: In preterm infants at risk for lung disease, antenatal administration of thyrotropin-releasing hormone and glucocorticoid is no more beneficial than glucocorticoid alone [10].
  • None of the 16 healthy women and none of the 10 women with secreting macroadenomas had LH beta, FSH, or LH responses to TRH [11].
  • Eleven of the 16 women with apparently nonsecreting adenomas had significant increases in serum LH beta in response to TRH, 3 had FSH responses, and 4 had LH responses [11].
  • The finding of increasing fetal serum concentrations of thyroid-stimulating hormone in the presence of increasing thyroid hormone concentrations suggests that the sensitivity of the fetal pituitary gland to negative feedback is limited or is counterbalanced by increasing stimulation by thyrotropin-releasing hormone from the hypothalamus [12].

Chemical compound and disease context of TRH


Biological context of TRH

  • Preincubation of AtT-C335Stop cells, but not AtT-WT cells, with CDE for several hours caused an increase in cell surface receptor number (up-regulation) that led to increased TRH stimulation of inositol phosphate formation and elevation of intracellular free Ca2+ [18].
  • To determine the binding site for a competitive inverse agonist, midazolam, three of the four residues that directly contact TRH and other residues that restrain TRH-R1 in an inactive conformation were screened by mutagenesis and binding assays [19].
  • In all cell contexts, TRH receptors on the plasma membrane underwent extensive ligand-driven endocytosis [20].
  • Alternatively, TRH inhibited PKC activity by reducing the EGF receptor serine/threonine phosphorylation, thereby enhancing tyrosine phosphorylation [21].
  • This study investigated the effect of TRH administration on the peripheral levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the early follicular and midluteal phases of the menstrual cycle in five ovulatory, euthyroid, and normoprolactinemic women [22].

Anatomical context of TRH

  • Thus, the TRH-TRHR complex is endocytosed via clathrin-coated vesicles and the receptor is recycled to the plasma membrane [23].
  • Infection with 100 AdCMVmTRHR particles/cell or more led to TRH responsiveness in > or = 90% of HeLa cells [1].
  • No significant correlations were found between basal or post-TRH PRL and cortisol, thyroid-stimulating hormone (TSH), thyroid hormones, gonadotropins, or estradiol in the patients [24].
  • The pattern of TRH receptor immunofluorescence was the same over a wide range of receptor expression in transiently transfected COS7 cells, and all cell lines bound similar amounts of 3H- and rhodamine-labeled TRH analogs, suggesting that cell-specific differences in TRH receptor localization were not simply the result of overexpression [20].
  • Maximum levels of response to TRH in oocytes expressing wild-type TRH-Rs were indistinguishable from those of oocytes expressing receptors mutated to Glu, Asn, or Asp in position 105 [25].

Associations of TRH with chemical compounds

  • Internalized TRHRs returned to the membrane within 20 min after removal of TRH, and cycloheximide did not block receptor recycling [23].
  • In cells infected with AdCMVmTRHR for 24 h, the size of the TRH-responsive phosphoinositide pool increased with increasing TRH-R expression [1].
  • Thrombin, endothelin, and carbachol, when combined, stimulated large increases in IP3 and [Ca2+]i, but did not block the IP3 or [Ca2+]i responses to TRH measured 10 min later [26].
  • Chlordiazepoxide (CDE), a known competitive inhibitor of TRH binding to wild-type (WT) TRH-Rs, is shown to compete for binding to C335Stop TRH-Rs also [18].
  • Human embryonic kidney 293 cells that had been transfected to express the long isoform of the rat thyrotropin-releasing hormone (TRH) receptor (clone E2) were further transfected with a cDNA encoding the murine version of G11alpha [27].

Physical interactions of TRH

  • Prolactin molecular heterogeneity. Response to thyrotropin-releasing hormone stimulation of concanavalin A-bound and -unbound immunoassayable prolactin during human pregnancy [28].
  • In a single-blind placebo-controlled study, the effect of an iv bolus injection of 100 micrograms GHRH(1-29)NH2 on the response to 200 micrograms TRH was assessed in 10 untreated patients with acromegaly to determine whether GHRH interacts with TRH in acromegaly, as previously described in healthy subjects [29].
  • Pit-1/GHF-1 binds to TRH-sensitive regions of the rat thyrotropin beta gene [30].
  • Based on experimental data and the structural information acquired from computer simulations, we formulate a working hypothesis to describe the molecular events underlying the processes of TRH binding and TRH-R activation [31].
  • Treatment of pituitary GH4C1 cells with epidermal growth factor (EGF) caused up to a 60% reduction in the amount of [3H]MeTRH bound to specific TRH receptors [32].

Enzymatic interactions of TRH

  • Injection of 400 microgram TRH as a bolus induced in 7 out of 10 patients a clear-cut GH rise (larger than or equal 10 ng/ml) occurring 15-120 min after the injection, and no effect on GH levels in controls [4].

Regulatory relationships of TRH

  • The simultaneous administration of a low effective dose of GRF (0.05 micrograms/kg) plus a high dose of TRH (400 micrograms) was able to significantly inhibit the GH secretion elicited by GRF 0.05 micrograms/Kg alone [33].
  • Our data demonstrate that the paradoxical GH response to TRH in patients with type 1 diabetes mellitus is blocked by CRH administration [34].
  • In amphibians, the secretion of alpha-MSH by melanotrope cells is stimulated by TRH and inhibited by NPY [35].
  • We proposed that TRH directly stimulates the PI in normal and PPID-affected horses to release proopiomelanocortin (POMC) derived peptides [36].
  • It is concluded that TRH has a marked inhibitory effect on the enzymatic component of the pancreatic secretion stimulated by submaximal doses of secretin and cholecystokinin [37].

Other interactions of TRH


Analytical, diagnostic and therapeutic context of TRH

  • Testicular TRH mRNA was also detected; however, no significant differences in TRH mRNA levels were found between EDS-treated and control groups [40].
  • Prolactin and TSH responses to TRH and to haloperidol in schizophrenic patients before and after treatment [41].
  • Eight male subjects were studied in a balanced, crossover design with each subject receiving placebo-placebo, TRH-placebo, placebo-ethanol, and TRH-ethanol [6].
  • Messenger RNA levels of TRH and TRH-R in the testes were determined by Northern blot analyses quantitated with densitometry scanning [40].
  • As dopamine (DA) agonistic drugs notoriously increase both CNV areas and GH levels and experimental evidence for prodopaminergic properties of TRH has accumulated in animal models, a possible explanation of the results here presented might be the activation of DA pathways by TRH also in the human [42].


  1. Thyrotropin-releasing hormone (TRH) receptor number determines the size of the TRH-responsive phosphoinositide pool. Demonstration using controlled expression of TRH receptors by adenovirus mediated gene transfer. Gershengorn, M.C., Heinflink, M., Nussenzveig, D.R., Hinkle, P.M., Falck-Pedersen, E. J. Biol. Chem. (1994) [Pubmed]
  2. Increase in plasma growth hormone levels following thyrotropin-releasing hormone injection in children with primary hypothyroidism. Collu, R., Leboeuf, G., Letarte, J., Ducharme, J.R. J. Clin. Endocrinol. Metab. (1977) [Pubmed]
  3. Effects of hypophysiotropic factors on growth hormone and prolactin secretion from somatotroph adenomas in culture. Ishibashi, M., Yamaji, T. J. Clin. Endocrinol. Metab. (1985) [Pubmed]
  4. Growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with severe liver disease. Panerai, A.E., Salerno, F., Manneschi, M., Cocchi, D., Müller, E.E. J. Clin. Endocrinol. Metab. (1977) [Pubmed]
  5. Prolactin in patients with major depressive disorder and in healthy subjects. III. Investigation of basal and post-TRH prolactin during different forms of acute and chronic psychological stress. Baumgartner, A., Gräf, K.J., Kürten, I. Biol. Psychiatry (1988) [Pubmed]
  6. Behavioral and endocrine interactions between thyrotropin-releasing hormone and ethanol in normal human subjects. Garbutt, J.C., Hicks, R.E., Clayton, C.J., Andrews, R.T., Mason, G.A. Alcohol. Clin. Exp. Res. (1991) [Pubmed]
  7. Orexis, anorexia, and thyrotropin-releasing hormone. Karydis, I., Tolis, G. Thyroid (1998) [Pubmed]
  8. Effect of TRH on TSH and prolactin levels in affective disorders. Kjellman, B.F., Ljunggren, J.G., Beck-Friis, J., Wetterberg, L. Psychiatry research. (1985) [Pubmed]
  9. Stimulation and inhibition of food intake in sheep by centrally-administered hypothalamic releasing factors. Ruckebusch, Y., Malbert, C.H. Life Sci. (1986) [Pubmed]
  10. Antenatal thyrotropin-releasing hormone to prevent lung disease in preterm infants. North American Thyrotropin-Releasing Hormone Study Group. Ballard, R.A., Ballard, P.L., Cnaan, A., Pinto-Martin, J., Davis, D.J., Padbury, J.F., Phibbs, R.H., Parer, J.T., Hart, M.C., Mannino, F.L., Sawai, S.K. N. Engl. J. Med. (1998) [Pubmed]
  11. Recognition of gonadotroph adenomas in women. Daneshdoost, L., Gennarelli, T.A., Bashey, H.M., Savino, P.J., Sergott, R.C., Bosley, T.M., Snyder, P.J. N. Engl. J. Med. (1991) [Pubmed]
  12. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. Thorpe-Beeston, J.G., Nicolaides, K.H., Felton, C.V., Butler, J., McGregor, A.M. N. Engl. J. Med. (1991) [Pubmed]
  13. Effects of disodium EDTA and calcium infusion on prolactin and thyrotropin responses to thyrotropin-releasing hormone in healthy man. Dudczak, R., Waldhäusl, W.K., Bratusch-Marrain, P. J. Clin. Endocrinol. Metab. (1983) [Pubmed]
  14. Prolactin and TSH response to TRH and metoclopramide before and after l-thyroxine therapy in subclinical hypothyroidism. Lombardi, G., Iodice, M., Miletto, P., Merola, B., Panza, N., Annunziato, L. Neuroendocrinology (1986) [Pubmed]
  15. Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamic-pituitary disease. Barbieri, R.L., Cooper, D.S., Daniels, G.H., Nathan, D., Klibanski, A., Ridgway, E.C. Fertil. Steril. (1985) [Pubmed]
  16. Prolactin secretion after surgery or bromocriptine treatment of prolactinoma. De Leo, V., Petraglia, F., Sardelli, S., Danero, S., Genazzani, A.R., D'Antona, N. Obstetrics and gynecology. (1987) [Pubmed]
  17. Reproductive functions in obese women. Kumar, A., Mittal, S., Buckshee, K., Farooq, A. Progress in food & nutrition science. (1993) [Pubmed]
  18. A constitutively active mutant thyrotropin-releasing hormone receptor is chronically down-regulated in pituitary cells: evidence using chlordiazepoxide as a negative antagonist. Heinflink, M., Nussenzveig, D.R., Grimberg, H., Lupu-Meiri, M., Oron, Y., Gershengorn, M.C. Mol. Endocrinol. (1995) [Pubmed]
  19. A model of inverse agonist action at thyrotropin-releasing hormone receptor type 1: role of a conserved tryptophan in helix 6. Lu, X., Huang, W., Worthington, S., Drabik, P., Osman, R., Gershengorn, M.C. Mol. Pharmacol. (2004) [Pubmed]
  20. Effect of cell type on the subcellular localization of the thyrotropin-releasing hormone receptor. Yu, R., Hinkle, P.M. Mol. Pharmacol. (1997) [Pubmed]
  21. The molecular mechanism of EGF receptor activation in pancreatic beta-cells by thyrotropin-releasing hormone. Luo, L., Yano, N., Luo, J.Z. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  22. The effect of thyrotropin-releasing hormone stimulation on serum levels of gonadotropins in women during the follicular and luteal phases of the menstrual cycle. Colon, J.M., Lessing, J.B., Yavetz, C., Peyser, M.R., Ganguly, M., Weiss, G. Fertil. Steril. (1988) [Pubmed]
  23. Visualization of the thyrotropin-releasing hormone receptor and its ligand during endocytosis and recycling. Ashworth, R., Yu, R., Nelson, E.J., Dermer, S., Gershengorn, M.C., Hinkle, P.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  24. Prolactin in patients with major depressive disorder and in healthy subjects. I. Cross-sectional study of basal and post-TRH and postdexamethasone prolactin levels. Baumgartner, A., Gräf, K.J., Kürten, I. Biol. Psychiatry (1988) [Pubmed]
  25. Altered ligand dissociation rates in thyrotropin-releasing hormone receptors mutated in glutamine 105 of transmembrane helix III. del Camino, D., Barros, F., Pardo, L.A., de la Peña, P. Biochemistry (1997) [Pubmed]
  26. Desensitization of thyrotropin-releasing hormone receptor-mediated responses involves multiple steps. Yu, R., Hinkle, P.M. J. Biol. Chem. (1997) [Pubmed]
  27. Thyrotropin-releasing hormone-induced subcellular redistribution and down-regulation of G11alpha: analysis of agonist regulation of coexpressed G11alpha species variants. Svoboda, P., Kim, G.D., Grassie, M.A., Eidne, K.A., Milligan, G. Mol. Pharmacol. (1996) [Pubmed]
  28. Prolactin molecular heterogeneity. Response to thyrotropin-releasing hormone stimulation of concanavalin A-bound and -unbound immunoassayable prolactin during human pregnancy. Shoupe, D., Montz, F.J., Kletzky, O.A., diZerega, G.S. Am. J. Obstet. Gynecol. (1983) [Pubmed]
  29. The interaction of GHRH with TRH in acromegaly: a controlled study. Looij, B.J., Roelfsema, F., Frölich, M., Nieuwenhuijzen Kruseman, A.C. Acta Endocrinol. (1991) [Pubmed]
  30. Pit-1/GHF-1 binds to TRH-sensitive regions of the rat thyrotropin beta gene. Mason, M.E., Friend, K.E., Copper, J., Shupnik, M.A. Biochemistry (1993) [Pubmed]
  31. Thyrotropin-releasing hormone and its receptors - A hypothesis for binding and receptor activation. Engel, S., Gershengorn, M.C. Pharmacol. Ther. (2007) [Pubmed]
  32. Epidermal growth factor decreases the concentration of thyrotropin-releasing hormone (TRH) receptors and TRH responses in pituitary GH4C1 cells. Hinkle, P.M., Shanshala, E.D., Yan, Z.F. Endocrinology (1991) [Pubmed]
  33. Inhibitory influence of thyrotropin releasing hormone administration on growth hormone response to low doses of growth hormone-releasing hormone in normal man. Zanoboni, A., Gibillini, M., Cucchi, M.R., Zanoboni Muciaccia, W., Zanussi, C. J. Endocrinol. Invest. (1988) [Pubmed]
  34. Corticotropin-releasing hormone inhibition of paradoxical growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics. Barbarino, A., Corsello, S.M., Tofani, A., Sciuto, R., Della Casa, S., Rota, C.A., Colasanti, S., Barini, A. Metab. Clin. Exp. (1992) [Pubmed]
  35. Neuropeptide Y inhibits spontaneous alpha-melanocyte-stimulating hormone (alpha-MSH) release via a Y(5) receptor and suppresses thyrotropin-releasing hormone-induced alpha-MSH secretion via a Y(1) receptor in frog melanotrope cells. Galas, L., Tonon, M.C., Beaujean, D., Fredriksson, R., Larhammar, D., Lihrmann, I., Jegou, S., Fournier, A., Chartrel, N., Vaudry, H. Endocrinology (2002) [Pubmed]
  36. Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with pituitary pars intermedia dysfunction and equine pars intermedia explants. McFarlane, D., Beech, J., Cribb, A. Domest. Anim. Endocrinol. (2006) [Pubmed]
  37. Thyrotropin-releasing hormone inhibits pancreatic enzyme secretion in humans. Gullo, L., Labò, G. Gastroenterology (1981) [Pubmed]
  38. Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms. Weiss, S.R., Clark, M., Rosen, J.B., Smith, M.A., Post, R.M. Brain Res. Brain Res. Rev. (1995) [Pubmed]
  39. Neuropeptides and human sleep. Steiger, A., Holsboer, F. Sleep. (1997) [Pubmed]
  40. The detection of thyrotropin-releasing hormone (TRH) and TRH receptor gene expression in Siberian hamster testes. Rao, J.N., Debeljuk, L., Bartke, A., Gao, Y.P., Wilber, J.F., Feng, P. Peptides (1997) [Pubmed]
  41. Prolactin and TSH responses to TRH and to haloperidol in schizophrenic patients before and after treatment. Markianos, M., Hatzimanolis, J., Stefanis, C. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (1994) [Pubmed]
  42. Thyrotropin-releasing hormone enhances event-related brain potentials and growth hormone release in man. Strollo, F., Amabile, G., Fattapposta, F., Strollo, G., More, M., Riondino, G. Neurosci. Lett. (1988) [Pubmed]
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