pancreastatin and Adenoma

Pancreastatin, a C-terminally amidated peptide derived from chromogranin A, is known to inhibit insulin secretion, pancreatic enzyme release, and gastric acid secretion. It also inhibits parathyroid hormone (PTH) secretion in animals. The physiologic and clinical relevance of pancreastatin in humans, however, is not known. Because pancreastatin has been found in parathyroid adenomas, we investigated the plasma levels in patients with primary hyperparathyroidism (pHPT). Thirteen patients operated on for solitary parathyroid adenoma were investigated. Plasma levels of pancreastatin and serum levels of ionized calcium and intact PTH were measured before and 6 weeks after operation. In 10 patients the levels were also monitored before and 60 minutes after adenoma excision. The adenomas were investigated for pancreastatin immunoreactivity by immunocytochemistry. The median weight of the excised parathyroid adenoma was 0.64 g (range 0.07-2.00 g). Cells displaying pancreastatin immunoreactivity were present in all adenomas examined and varied in number and immunostaining intensity among and within the adenomas. Intraoperatively, after adenoma excision the levels of PTH and pancreastatin declined (p < 0.01), whereas the levels of ionized calcium did not change (p = 0.96). At the 6-week follow-up the levels of ionized calcium and PTH had decreased compared to the preoperative levels (p < 0.01), and all patients were normocalcemic. In contrast, the pancreastatin levels were not changed (14.5 +/- 6.1 pmol/L preoperatively vs. 12.8 +/- 11.2 pmol/L 6 weeks postoperatively; p = 0.12). In patients with pHPT, pancreastatin is likely to be produced by the parathyroid adenoma. The changes in pancreastatin levels immediately after surgery warrant further investigation.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Chromogranin A; Female; Humans; Hyperparathyroidism; Immunohistochemistry; Male; Middle Aged; Pancreatic Hormones; Parathyroid Neoplasms; Regression Analysis; Statistics, Nonparametric

Pituitary adenomas are members of the family of neuroendocrine cells and tumors which have secretory granules containing chromogranins/secretogranins and other proteins. Pituitary adenomas express the neuroendocrine specific proconvertases PC1 (also known as PC3) and PC2, which are important for the proteolytic processing of chromogranins/secretogranins molecules. We examined the distribution of PC1 and PC2 in primary cultures of 20 pituitary adenomas and analyzed the regulation of the proconvertase mRNAs and proteins by various secretagogues including hypothalamic hormones and phorbol ester to determine the role of PC1 and PC2 in CgA processing in pituitary adenomas. Although PC2 was present in all adenomas, there was a differential distribution of PC1 with PRL adenomas expressing lower levels of PC1 compared to other adenoma types by RT-PCR analysis, in situ hybridization and immunostaining. Treatment of primary cultures of pituitary adenomas with phorbol 12-myristrate 13-acetate (PMA) resulted in an increase in pancreastatin (PST) secretion in most pituitary adenomas and increased PC1 mRNA and protein expression in gonadotroph adenomas, but not in other types of adenomas. Analysis of a human pituitary adenoma cell line, immortalized by recombinant defective adenovirus (HP75), which expressed chromogranin A, FSH, PC1 and PC2 showed that PST was secreted by these immortalized cells. Treatment with TGF beta 1 resulted in an increase in PST secretion and in PC1 mRNA and protein. These results indicate that a) there is a differential distribution of PC1 in human pituitary adenomas with PRL adenomas expressing very little PC1 mRNA and protein and b) that PC1 expression in gonadotropin hormone-producing adenomas is regulated by PMA and TGF beta 1. These findings support the observation that chromogranin A is a substrate for the endoproteinase PC1 in human pituitary adenoma cells.

Topics: Adenoma; Aspartic Acid Endopeptidases; Base Sequence; Chromogranin A; Chromogranins; DNA Primers; Humans; Immunohistochemistry; In Situ Hybridization; Pancreatic Hormones; Pituitary Hormones; Pituitary Neoplasms; Proprotein Convertase 2; Proprotein Convertases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Subtilisins; Tumor Cells, Cultured

Pancreastatin, a carboxyl-terminal amidated peptide derived from chromogranin (Cg)A, inhibits secretion of insulin and parathyroid hormone. Our recent studies found significant amounts of immunoreactive pancreastatin in all pituitary adenomas except prolactin adenomas. To analyze the effects of pancreastatin on pituitary cell function, 17 cultured pituitary adenomas were examined for immunoreactive pancreastatin and pancreastatin secretion by the tumors. The effects of pancreastatin on pituitary hormone secretion and on pituitary hormone (follicle-stimulating hormone and prolactin), CgA, and CgB mRNA levels were also examined. Immunoreactive pancreastatin and CgA were present diffusely in gonadotroph and null cell adenomas, but only a few prolactin adenoma cells expressed pancreastatin or CgA. When cells were treated with hypothalamic peptides, gonadotroph adenomas were the only group that released increased amounts of pancreastatin in response to gonadotropin-releasing hormone (10(-7) mol/L). Pancreastatin (10(-7) mol/L) treatment did not stimulate pituitary hormone secretion significantly. In situ hybridization analyses showed that gonadotropin-releasing hormone and pancreastatin treatment led to significant increases in CgB and follicle-stimulating hormone mRNAs in gonadotroph adenomas, whereas CgA mRNA levels did not change significantly. These results show that there is a differential distribution of pancreastatin secretion in pituitary adenomas and that the hypothalamic hormone gonadotropin-releasing hormone and the CgA-derived peptide pancreastatin can regulate CgB mRNA in gonadotroph adenomas, suggesting an autocrine effect of pancreastatin on pituitary tumor function.

Topics: Adenoma; Adult; Aged; Child; Chromogranin A; Chromogranin B; Chromogranins; Female; Humans; Hypothalamic Hormones; Immunohistochemistry; In Situ Hybridization; Male; Middle Aged; Pancreatic Hormones; Pituitary Hormones; Pituitary Neoplasms; Prolactinoma; RNA, Messenger; Tumor Cells, Cultured