Gene Expression Study of Thyrotropin Releasing Hormone (TRH) Receptor Using RT-PCR: Relationship to Clinical and Immunohistochemical Phenotypes in a Series of Human Pituitary Adenomas

Abstract

Abstract. Thyrotropin releasing hormone receptor 1 (TRHR1) and 2 (TRHR2) mRNAs were examined using reverse transcription polymerase chain reaction (RT-PCR). These data were then correlated with endocrinological and histological characteristics in 65 human pituitary adenomas including one non tumorous pituitary gland, to clarify the role of TRHR1 and 2 gene expression in human pituitary adenomas, especially as it relates to the paradoxical stimulatory effects of TRH found in pituitary adenomas. TRHR mRNA was not identified in four ACTH cell adenomas, whereas TRHR mRNA expression was found in 12/23 acromegaly specimens, 7/8 prolactinomas, 3/3 TSH cell adenomas, and 22/27 clinically nonfunctioning adenomas. Specimens obtained from patients expressing the TRHR gene were found to express TRHR1 and TRHR2 or TRHR1 alone, whereas no cases were identified in which TRHR2 alone was expressed. In examining the relationship between GH, PRL, TSH, or gonadotropin subunit response to TRH administration and TRHR gene expression, TRHR mRNA was found to be absent in 9 out of 10 GH cell adenomas without paradoxical GH response to TRH (non-responder), whereas TRHR genes were shown to be expressed in 10 out of 12 GH cell adenomas with paradoxical GH response to TRH (responders) (c 2 = 11.73, p = 0.0009). However, there was no significant correlation between TRHR gene expression and responsiveness to PRL or gonadotropins to TRH administration in PRL cell adenomas (c 2 = 0.16, p = 0.87) or gonadotroph cell adenomas (c 2 = 0.0006, p = 1), respectively. We concluded that the existence of the TRH receptor in adenoma cells plays an important role in the paradoxical GH response to TRH administration in GH cell adenomas. It should be noted that the PRL response to TRH in prolactinoma or an abnormal response of gonadotropin and/or its subunits to TRH in gonadotroph cell adenomas is considered to be due to a mechanism other than direct TRH action in adenoma cells. However, further studies are required to elucidate the role of TRHR2 in pituitary adenomas.

Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae

“…However, ectopically expressed TRH receptors cross-couple with cAMP and regulate GH secretion by somatotroph cells (34), and the abnormal GH response is more frequently observed in adenomae with gsp mutation than those without the mutation (35) as is in our series. As gsp mutation was more frequently encountered in non-DP adenomae in this study, it is thus rational to expect TRH receptor prevailed more frequently in DG GHomae than in SG ones (31). Ectopic expression of TRH receptors may couple with tumourigenesis of GHomae (triggered by gsp mutation) and amplified cAMP signalling (36,37).…”

“…In this study, the incidence of abnormal response to preoperative TRH or LHRH challenge test was significantly (P!0.05) lower in DP adenomae than in non-DP adenomae. Ectopic TRH receptors in GHomae cells play an important role in the abnormal GH response to TRH (31). Physiologically, TRH receptors act via the inositol 1,4,5-triphosphate pathway to release TSH and PRL (32,33).…”

Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis

“…A paradoxical TRH test in acromegaly is considered as non-diagnostic and thus clinically not useful, because it can be also present in other conditions, such as in children, anorexia nervosa, and serious liver disease [155]. Interestingly, acromegalic patients with a paradoxical response of GH to TRH express the TRH receptor in the adenoma, while TRH-negative patients do not [156], establishing the pathophysiological basis for this response. In a selected series of acromegalic patients who had a normal postoperative GH suppression (although differing in magnitude) and a normalized TRH test, only one recurrence was noted after a 14.3 years [160].…”

Association between polymorphisms in the TRHR gene, fat-free mass, and muscle strength in older women

“…The study by Liu et al (2009) is pointed by the catalog of the National Human Genome Research Institute (Hindorff et al 2010) as the only work that found the association of TRHR gene and body mass (lean). Until then, studies with this gene were associated with other outcomes such as pituitary adenoma (Igarashi-Migitaka et al 2003) and hypertension (García et al 2001;Ruixing et al 2008).…”