Presence of Growth Hormone Secretagogue Receptor Messenger Ribonucleic Acid in Human Pituitary Tumors and Rat GH 3 Cells 1 (original) (raw)
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Synthetic GH secretagogues (GHSs; GH-releasing peptides and their nonpeptide mimetics) stimulate GH release, activate the hypothalamo-pituitary-adrenal axis, and release PRL in vivo. Patients with acromegaly show an exuberant GH response to GHSs, whereas patients with pituitary-dependent ACTH-secreting tumors show an exaggerated rise in ACTH and cortisol. We, therefore, studied the presence of GHS receptor (GHS-R) messenger ribonucleic acid (RNA) in 38 human pituitary tumors of different cell types, 3 ectopic ACTHsecreting tumors, a pancreatic gastrinoma, 3 insulinomas, and a nonsecreting thymic carcinoid as well as in 7 normal pituitary glands. Certain pituitary tumors were also studied by in vitro cell culture with measurement of secreted GH, ACTH, PRL, FSH, LH, ␣-subunit, and TSH. RNA was extracted from tissue samples and, after RT, a duplex PCR reaction with primers for the GHS-R gene and for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was performed, allowing semiquantitation of GHS-R expression.
The expression of ghrelin in somatotroph and other types of pituitary adenomas
Neuro endocrinology letters, 2008
It has been suggested that ghrelin synthesized locally in pituitary regulates the function and growth of pituitary cells in autocrine/paracrine way and might be an important factor of pituitary tumorogenesis. The expression of ghrelin receptor in neoplastic cells of pituitary adenomas has also been demonstrated. In vitro studies confirmed that ghrelin stimulates the proliferation of somatotroph cells in GH3 cell line. The presence of both ghrelin mRNA and protein was detected in a number of benign and malignant neoplasms as well as in neoplastic cells of the tissues which do not express ghrelin in physiological conditions. This study showed the presence of ghrelin mRNA and its protein in different types of pituitary adenomas. The samples of 37 pituitary adenomas were obtained during standard neurosurgical tumor removal. The study tissues included 20 somatotroph tumors (15 patients treated and 5 patients untreated with octreotide LAR before the surgery), 12 nonfunctioning adenomas, 4...
2003
OBJECTIVE Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. METHODS We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. RESULTS No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two non-functioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary ( P < 0·05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue ( P < 0·0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary ( P = 0·005), and trended lower in corticotroph tumours ( P = 0·07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue ( P < 0·01). CONCLUSIONS Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.
Production of alpha-subunit of glycoprotein hormones by pituitary somatotroph adenomas in vitro
European Journal of Endocrinology, 1993
Somatotroph adenomas of the pituitary secrete growth hormone in excess and are associated with acromegaly. Morphologically, they can be separated into two entities, densely and sparsely granulated variants. It has been shown that a number of somatotroph adenomas produce α-subunit of glycoprotein hormones; however, it is not clear whether α-subunit production correlates with tumor cell morphology. We studied 32 surgically removed pituitary somatotroph adenomas in tissue culture to determine structure-function correlations of growth hormone and α-subunit production. All tumors were classified on the basis of detailed histological, immunocytochemical and electron-microscopic studies. Fifteen tumors were densely granulated and 1 7 were sparsely granulated. In addition to growth hormone, all 15 densely granulated tumors released α-subunit in vitro, whereas of the 1 7 sparsely granulated tumors only 4 released α-subunit moreover, the mean baseline levels of α-subunit were significantly hi...
Clinical Endocrinology, 2003
OBJECTIVE Ghrelin and its receptor, growth hormone secretagogue (GHS) receptor (GHSR), are expressed in the normal pituitary gland and various types of pituitary adenoma. Somatic mutations in the subunit of Gs α α α α protein (gsp), which led to a constitutive activation of adenylyl cyclase, are reported in GH-producing pituitary adenomas. We analysed the relationship between ghrelin mRNA and GHSR mRNA expression levels in gsp mutation-positive and-negative GH-producing pituitary adenomas. PATIENTS Pituitary adenoma tissue was obtained at surgery from 20 patients with acromegaly. METHODS The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT-PCR method. To detect the gsp mutations, amplified Gs α α α α subunit cDNA fragments were sequenced directly using RT-PCR method. RESULTS There was no significant difference in the expression of ghrelin mRNA between mutation-positive and-negative adenomas. The expression of GHSR mRNA was significantly lower in gsp mutation-positive than-negative adenomas. There was a significant negative correlation between the levels of ghrelin mRNA and GHSR mRNA expression in mutation-negative adenomas; no such correlation was found in mutation-positive adenomas. CONCLUSION These results suggest that GHSR mRNA expression is downregulated by ghrelin in gsp mutationnegative GH-producing pituitary adenomas, and that changes in intracellular signalling pathways in gsp mutation-positive GH-producing pituitary adenomas affect the expression of G protein-coupled receptors such as GHSR. The absence of negative correlation between ghrelin and GHSR expression might be induced by lowered GHSR expression in gsp mutation-positive GH-producing adenomas.
New Insights in the Pathogenesis of Pituitary Tumours
InTech eBooks, 2013
Additional tumour types deriving from non-endocrine cells of the anterior pituitary and the neurophypohysis can be found [3], which pathogenesis is poorly known and will not be considered in this review. 2.1. Classification PA may be classified according to their macroscopic characteristics into micro-(< 1 cm) or macro-adenomas (≥ 1 cm), and enclosed or invasive adenomas. Invasion of the surrounding structures (cavernous sinuses, bone, sphenoidal sinus) is generally defined according to neuroradiological imaging-especially magnetic resonance imaging-, although intraoperative findings may introduce some correction to the pre-operative radiological classification or reveal macroscopic dural invasion. Of note, microscopic evidence of dural invasion is rarely present on surgical samples. The functional classification of PA is based on their hormone-secreting potential, which may be associated with bio-clinical evidence of hormone hypersecretion or recognized by immunohistochemistry (IHC) for pituitary hormones and/or by specific ultrastructural features. From an epidemiological point of view, prolactinomas are by far the most frequent (50-60%), followed by clinically nonfunctioning PA (NFPA) (20-30%), somatotrophinomas (10-15%), corticotrophinomas (5-10%) and thyreotrophinomas (1-2%) [1,2,4]. Recruitment bias are frequently encountered in pathological series, since most prolactinomas are treated by DA only. Clinicopathological correlations in PA have been recently reviewed [4]. In the large majority of PA associated with bio-clinical evidence of hormone secretion, except functional hyperprolactinemia, pathological examination will confirm the diagnosis of PRL, GH, ACTH or TSHsecreting tumours and potentially identify bi-or multi-hormonal secretion. This is especially true for GH-secreting PA, which may also secrete PRL, less frequently glycoprotein hormones, or both (multihormonal). TSH-secreting adenomas are rare and frequently multihormonal. Ultrastructural studies of secreting PA may disclose a "densely granulated" (DG) or "sparsely granulated" (SG) pattern, which may reflect significant differences in hormone secretion and tumour behaviour. This has been well studied in somatotrophinomas, where IHC for cytokeratin can be used to disclose the typical "dot-like" staining pattern of SG adenomas. Although a continuum exists between the SG and DG types, pure SG are typically more aggressive than DG somatotrophinomas [5]. Pathological examination of NFPA may show negative immunostaining for all pituitary hormones (the "null cell" or endocrine inactive histotype), positive immunostaining for FSH and/or LH (gonadotrophinomas) or reveal silent secretion of other pituitary hormones, in particular ACTH and GH ("silent" secreting PA). Cell lineage may also be identified by the expression of specific transcription factors (see "pituitary ontogenesis") [4]. It is generally accepted that most NFPA derive from the gonadotroph lineage, since data obtained from primary cultures or molecular analysis of these tumours frequently reveal a silent expression of gonadotropins or their subunits, including α−subunit only. Also, transgenic mice overexpressing SV40 under the control of the βFSH promoter develop gonadotroph hyperplasia Hot Topics in Endocrine and Endocrine-Related Diseases 28 Hot Topics in Endocrine and Endocrine-Related Diseases