Gonadotropin-releasing hormone receptor mRNA expression by human pituitary tumors in vitro.

Abstract

An important question in the pathogenesis and regulation of human gonadotroph adenomas is whether heterogeneous gonadotropin responses to gonadotropin-releasing hormone (GnRH) are due to dysregulation of GnRH receptor biosynthesis and/ or cell-signaling pathways. We investigated gonadotropin responsiveness to pulsatile GnRH in 13 gonadotroph adenomas. All tumors had evidence of follicle-stimulating hormone (FSH) ft and a subunit biosynthesis using reverse transcriptase/polymerase chain reaction (RTPCR) techniques. Four tumors significantly increased gonadotropin and/or free subunit secretion during pulsatile 10-8 M GnRH administration. The GnRH antagonist Antide (10-' to 108 M) blocked secretory increases in all GnRH-responsive tumors. Gonadotropin and/or free subunit secretion increased after 60 mM KCl, confirming that GnRH nonresponsiveness was not due to intracellular gonadotropin depletion. We hypothesized that GnRH nonresponsiveness in these tumors may be due to GnRH receptor (GnRHRc) biosynthetic defects. RTPCR analyses detected GnRH-Rc transcripts only in responsive tumors and normal human pituitary. This is the first demonstration of a cell-surface receptor biosynthetic defect in human pituitary tumors. We conclude (a) one third of gonadotroph tumors respond to pulsatile GnRH in vitro, (b) GnRH-Rc mRNA is detected in human gonadotroph adenomas and predicts GnRH responsiveness, and (c) GnRHRc biosynthetic defects may underlie GnRH nonresponsiveness in gonadotroph tumors. (J. Clin. Invest. 1994.93:2332-2339

Detection of gonadotropin-releasing hormone receptor in normal human pituitary cells and pituitary adenomas using immunohistochemistry

“…This distribution of GnRHR well reflects that found in normal pituitary cells, with the exception of thyrotroph adenomas. Our immunohistochemical results concerning the distribution of GnRHR correlate well with the expression of GnRHR mRNA in pituitary adenomas as detected by ISH, RT-PCR, and in situ RT-PCR (IS-RT-PCR), with the exception of ACTH-secreting tumors [1,24,26] (Table 3). In fact, the cases of functioning and nonfunctioning corticotroph adenomas that we examined did not show a GnRHR IR.…”

“…The high incidence of GnRH and GnRHR gene expression, found in pituitary adenomas with special reference to gonadotropin-secreting and nullcell adenomas, suggests that locally produced hypothalamic hormones and related receptors may play a role in the regulation of tumor cell growth and function, acting through a paracrine/autocrine mechanism. FSH/LH adenomas showing diffuse IR for GnRHR (7 of 12 of our cases) may correspond to those gonadotroph tumors that are responsive to pulsatile GnRH in vitro and show normal tumor receptor biosynthesis [1]. On the contrary, the FSH/LH adenomas lacking GnRHR IR (5/12 of our cases) may correspond to the subset of gonadotroph tumors with GnRHR biosynthetic defects and GnRH unresponsiveness, described by Alexander and Klibansky [1].…”

Gonadotropin-Releasing Hormone and Gonadotropin-Releasing Hormone Receptor Messenger Ribonucleic Acids Expression in Nontumorous and Neoplastic Pituitaries1

“…Alexander et al (13) and Miller et al (14) found GnRH and GnRH-R mRNAs in nontumorous and neoplastic human pituitaries by in vitro experiments and the PCR technique. These reports, however, did not investigate gene expression at the single-cell level.…”

“…Alexander et al (13) detected GnRH-R mRNA in human pituitary adenomas in vitro. In addition, using PCR techniques, Miller et al (14) reported both GnRH and GnRH-R mRNAs in gonadotroph tumors, as well as in the normal human pituitary.…”

Gene expression in pituitary adenomas: New insights

“…This theory has been given support by recent studies. Firstly, gonadotroph adenomas that did not respond to gonadotrophin-releasing hormone (GnRH) showed no evidence of expression of GnRH-receptor mRNA (Alexander and Klibanski, 1994). In addition, in patients with lactotroph adenomas, which are resistant to the dopamine agonist, bromocriptine (i.e., prolactin levels are not reduced by the drug), the level of D2 dopamine receptor expression is lower than in patients who do respond (Caccavelli et al, 1994;Pellegrini-Bouiller et al, 1996).…”