vasoactive-intestinal-peptide and Adenoma

Topics: Adenoma; Adenylyl Cyclases; Adrenocorticotropic Hormone; Animals; Cyclic AMP; Growth Hormone; Haplorhini; Humans; Hypothalamus; In Vitro Techniques; Neurosecretion; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Rats; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) was infused into normal volunteers and patients with hyperprolactinaemia. Heart rate increased from 62 +/- 3 to 75 +/- 3 beats min-1 (P = 0.001) in controls and from 70 +/- 2 to 78 +/- 3 beats min-1 (P = 0.001) in hyperprolactinaemics. Similarly, haematocrit increased from 38 +/- 2 to 44 +/- 1% (P = 0.001) and from 40 +/- 1 to 43 +/- 2% (P = 0.002) and plasma renin activity from 910 +/- 59 to a peak of 3344 +/- 282 pg ml-1 h-1 (P = 0.001) and from 1577 +/- 671 to a peak of 4954 +/- 1364 pg ml-1 h-1 (P = 0.001) in the two groups, respectively. Prolactin concentrations rose in the control group only, from 134 +/- 11 to a peak of 377 +/- 35 mU 1(-1) (P = 0.001), whilst in the hyperprolactinaemics little change occurred from the pre-infusion concentration of 3873 +/- 2179 reaching a peak of 3998 +/- 2347 mU 1(-1) (P greater than 0.07). In separate studies, the normal subjects were pretreated with either bromocriptine or dexamethazone. Dexamethazone did not alter any parameter of the response to VIP. Bromocriptine did not affect the heart rate, haematocrit or renin response to VIP but clearly inhibited the rise in prolactin which remained at unmeasurable concentrations throughout the infusion.

Topics: Adenoma; Adult; Bromocriptine; Dexamethasone; Female; Heart Rate; Hematocrit; Humans; Male; Pituitary Neoplasms; Prolactin; Renin; Vasoactive Intestinal Peptide

This study assesses the action of hypercortisolism on the hormone and peptide periadenoma region of removed ACTH-producing microadenoma. Our findings show that cortisol excess affects both ACTH and GH production, with no immunoreaction for these hormones. The remaining pituitary hormones (TSH, FSH and PRL) and POMC-derived peptides (betaEnd, alphaMSH and betaMSH) were not modified. Likewise, we observed pituitary immunoreactive cells for Neurotensin (NT), Intestinal vasoactive peptide (VIP), Substance P (SP) and Angiotensin-II (Ang-II). The colocalization demonstrated that NT was expressed in thyrotrope and gonadotrope cells, VIP in gonadotrope cells and SP in corticotrope cells. The results about Ang-II were inconclusive. On the other hand, immunoreaction for the NPY and Gal peptides were not present. In the adenomatous cells, the peptide NT is present in ACTH cells as well as SP. These results suggest a peptide regulation of pituitary cells in the pathological state that can differ between normal and tumoural cells of the same pituitary.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenocorticotropic Hormone; Adult; Angiotensin II; Corticotrophs; Cushing Syndrome; Female; Gonadotrophs; Human Growth Hormone; Humans; Immunohistochemistry; Neuropeptides; Neurotensin; Pituitary Hormones; Substance P; Thyrotrophs; Vasoactive Intestinal Peptide

Six GH adenomas and three prolactinomas were investigated by light- and electron-microscopic morphological and immunocytochemical methods and the effect of vasoactive intestinal polypeptide (VIP) on growth hormone (GH) and prolactin (PRL) secretion was tested in vitro. The tumour cells of the acromegalic patients revealed both GH and PRL immunoreactivity while prolactinomas showed only PRL activity. All the adenomas stained immunocytochemically also for VIP. By electron microscopy, the tumours included two densely and two sparsely granulated GH, two mixed GH/PRL, and three sparsely granulated PRL adenomas. The dissociated cells were explanted, and cultured in vitro. The cultures in micro test plates were treated with VIP at different concentrations between 10(-5)-10(-12) M. GH and PRL contents in the culture media were measured by radioimmunoassay. GH release was significantly stimulated by VIP in a dose-dependent manner over the whole concentration range, while VIP was effective on the PRL release only at 10(-6)-10(-7) M concentration. The cells of a mixed adenoma were grown in Petri dishes and used for ultrastructural and immunocytochemical studies. The cytoplasmic structure of the cells treated with VIP corresponded to that of active hormone-secreting cells with large ergastoplasmic fields and Golgi zones containing secretory granules. Massive exocytotic events were encountered mainly in the GH-type cells. GH and PRL double immunocytochemistry showed the predominance of GH cells, many of them containing low amounts of PRL as well. Cells predominantly containing PRL were spread among them, they also might contain GH as well. Some of the cells contained only a single immunoreactive hormone. The intensity of gold labelling of the secretory granules appeared higher in the VIP-treated cells than in the untreated control ones which showed a cytoplasmic structure characteristic of glandular cells with low secretory activity. As all the adenoma cells both contained and reacted to VIP, our results are in agreement with an autocrine or paracrine effect of this peptide. The fine structure of the cells in the cultures treated with VIP supply an additional argument to the assumption that VIP may serve as a growth factor for these cell types.

Topics: Acromegaly; Adenoma; Adult; Cytoplasm; Cytoplasmic Granules; Exocytosis; Female; Human Growth Hormone; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The innervation of the human adrenal gland and of cortical lesions was studied in sections of cortical tissue (n=10), hyperplastic cortical tissue (n=3), and tissue from cortical adenomas (n=5) and carcinomas (n=6). The presence and distribution of nerve structures containing neuronal markers indicating sympathetic and parasympathetic innervation were studied by immunohistochemistry and the co-existence and co-localization patterns of the different markers by immunofluorescence. The cortex and hyperplastic cortical tissue had a moderate to rich supply of nerve structures containing the typical neuronal markers: protein gene product 9.5 (PGP 9.5), neuron-specific enolase (NSE), small vesicle synaptic protein type 2 (SV2), and nerves showing immunoreactivity to the adrenergic marker tyrosine hydroxylase (TH). All these immunoreactive nerves were located predominantly adjacent to blood vessels, but also among parenchymal cells. The cortex showed numerous nerve structures containing the neuropeptide substance P (SP), neuropeptide Y (NPY) and vasoactive intestinal protein (VIP), but few nerves containing these peptides were seen in hyperplastic cortical tissue. Typical markers were occasionally observed in cortical adenomas but were not found in carcinomas, except in a few cases where PGP 9.5 and NSE were present, but only adjacent to necrotic areas. Nerves containing NPY and VIP occurred in varying numbers in both adenomas and carcinomas. NPY- and VIP-immunoreactive nerve structures were seen mostly alongside blood vessels. There were several types of co-existence. For instance, NSE/VIP-, TH/VIP- and TH/NPY-immunoreactive nerve structures were often seen in the same trunk, but were only partly co-localized.

Topics: Adenoma; Adrenal Cortex; Adrenal Cortex Neoplasms; Carcinoma; Fluorescent Antibody Technique, Indirect; Humans; Hyperplasia; Immunoenzyme Techniques; Membrane Glycoproteins; Nerve Tissue Proteins; Neuropeptide Y; Parasympathetic Nervous System; Phosphopyruvate Hydratase; Sympathetic Nervous System; Thiolester Hydrolases; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

The endocrine cells in intraductal papillary-mucinous neoplasms (IPN) of the pancreas have rarely been investigated. In the normal pancreatic ducts of normal pancreases (n = 5) there were a few endocrine cells: argyrophil in 5 (100%), chromogranin A in (100%), pancreatic polypeptide (PP) in 3 (60%), and insulin in 7 (20%). These endocrine cells were scattered, and located in the basal portions of pancreatic ducts. In IPN of the pancreas (n = 9), there were many endocrine cells: argyrophil in 7 (78%), argentaffin in 8 (89%), chromogranin A in 8 (89%), PP in 7 (78%), serotonin in 7 (78%), insulin in 4 (44%), and gastrin in 5 (56%). In invasive ductal adenocarcinoma of the pancreas (n = 6), many endocrine cells were also detected: argyrophil cells in (67%), chromogranin A in 3 (50%), insulin in 3 (50%), glucagon in 4 (67%), and somatostatin in 3 (50%). In positive cases, endocrine cells were situated under or among the neoplastic cells and the proportion of endocrine cells in IPN was less than 5% of the total neoplastic cell population. These data show that normal pancreatic ducts contain endocrine cells and that IPN frequently contain argyrophil, argentaffin, chromogranin A, and hormone-containing endocrine cells. These data also suggest that endocrine differentiation occurs during neoplastic transformation and progression of IPN of the pancreas.

Topics: Adenocarcinoma, Mucinous; Adenoma; Aged; Aged, 80 and over; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Glucagon; Histocytochemistry; Humans; Immunohistochemistry; Insulin; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Serotonin; Vasoactive Intestinal Peptide

Topics: ACTH Syndrome, Ectopic; Adenoma; Adrenocorticotropic Hormone; Adult; Aged; Cushing Syndrome; Female; Humans; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary Neoplasms; Prolactin; Vasoactive Intestinal Peptide

We have investigated the prevalence of MEN 1 in patients with recognized pituitary adenomas. Since hyperparathyroidism is present in nearly 95-100% of patients with MEN 1 and frequently is the first condition to be identified, the study was limited to the identification of patients with hyperparathyroidism while the screening for gastroenteropancreatic (GEP) lesions was carried out in patients with both pituitary and parathyroid lesions.. Serum total and ionized calcium, phosphate and intact PTH 1-84 (EASIA) were measured in 166 patients (68 with non-functioning pituitary adenoma, 42 with prolactinoma, 35 with GH-secreting adenoma, 17-with ACTH-screening adenoma, 1 with TSH-secreting adenoma, 1 with FSH-secreting adenoma and 2 with an only alpha-subunit secreting adenoma) referred to our clinic from 1990 to 1996. Plasma gastrin, somatostatin, pancreatic polypeptide and vasoactive intestinal peptide were measured by RIA in patients with hyperparathyroidism.. Eight of 166 patients (4.8%) were found to have primary hyperparathyroidism and among these 2 also had a gastrinoma while there was no evidence of other GEP tumours. Considering the tumour type, 6 had prolactinoma (14.3%), 1 GH-secreting adenoma (2.8%) and 1 non-functioning adenoma (1.5%). In most patients the diagnosis of pituitary tumour was made several years before that of hyperparathyroidism (from 1 to 15 years) although 6 patients had previously suffered from urolithiasis and one had undergone gastric resections for recurrent peptic ulcers. One patient was identified as a MEN 1 gene carrier and 2 had relatives with signs and symptoms referable to parathyroid or GEP lesions.. The study shows a prevalence of 4.8% of primary hyperparathyroidism in unselected patients with known pituitary tumours similar to that reported in a previous study. By contrast, the prevalence of MEN 1 in patients with prolactinoma was definitely high (14.3%). In most patients the diagnosis of pituitary tumours was made several years before that of hyperparathyroidism. Although the patients were believed to harbour a sporadic pituitary tumour, most of them had had signs and/or symptoms referable to one or both of the other organs involved in MEN 1, often concomitantly with those of pituitary tumours. These data indicate that the diagnosis of MEN 1 syndrome is missed in a substantial proportion of patients with prolactinomas and therefore the screening of these patients for the syndrome is strongly recommended.

Topics: Adenoma; Adolescent; Adult; Aged; Biomarkers; Calcium; Female; Gastrinoma; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Polypeptide; Parathyroid Hormone; Phosphates; Pituitary Neoplasms; Prevalence; Prolactinoma; Somatostatin; Vasoactive Intestinal Peptide

The presence of the pertussis toxin (PTX) insensitive GTP-binding proteins (C-proteins) G(q) alpha and/or G(11) alpha has been demonstrated in three different prolactin (PRL) and growth hormone (GH) producing pituitary adenoma cell lines. Immunoblocking of their coupling to hormone receptors indicates that G(q) and/or G(11) confer throliberin (TRH) responsive phospholipase C (PL-C) activity in these cells. The contention was substantiated by immunoprecipitation analyses showing that anti G(q)/11 alpha-sera coprecipitated PL-C activity. In essence, only G(q)/11 (but neither G(12) G(13) nor G(o)) seems to mediate the TRH-sensitive PL-C activity, while G(o) may be coupled to a basal or constitutive PL-C activity. Immunoblocking studies imply that the B gamma-complex also, to some extent, may stimulate GH(3) pituitary cell line PL-C activity. Finally, the steady state levels of G(q)/(11) alpha mRNA and protein were down regulated upon long term exposure of the GH(3) cells to TRH (but not to vasoactive intestinal peptide = VIP).

Topics: Adenoma; Animals; Enzyme Activation; Female; GTP-Binding Proteins; Liver; Pertussis Toxin; Pituitary Gland; Pituitary Neoplasms; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyrotropin-Releasing Hormone; Tumor Cells, Cultured; Type C Phospholipases; Vasoactive Intestinal Peptide; Virulence Factors, Bordetella

Topics: Adenoma; Animals; Cats; Chickens; Humans; Nerve Fibers; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Parathyroid Glands; Parathyroid Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Reference Values; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

There are only a few studies on the innervation of the human parathyroid glands and the content of neurotransmitters. We therefore studied the occurrence and distribution of peptide-containing and adrenergic nerve fibres and the coexistence pattern of neuromessengers by immunocytochemistry in normal (unaffected) and adenomatous parathyroid glands from patients undergoing surgery for parathyroid adenoma. The unaffected parathyroid glands had a moderate-to-rich supply of nerve fibres and terminals containing two general neuronal markers, protein gene product 9.5 (PGP 9.5) and synaptophysin, neuropeptide Y (NPY) and tyrosine hydroxylase (TH). They were seen close to blood vessels and, occasionally, among the endocrine cells. Only a few nerves contained calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P (SP) and pituitary adenylate cyclase-activating peptide (PACAP). The general density of innervation, using PGP 9.5 and synaptophysin as markers, varied greatly among the different adenomas examined. This applied also to the density of fibres and terminals containing specific types of messengers. Some of the tumours had a rich supply of TH- and NPY-containing nerve fibres, while others contained only few scattered fibres. The CGRP-containing fibres varied from moderate in number to no detectable fibres. The PACAP-, SP- and VIP-containing fibres were always very few or not detectable. It is not inconceivable that the wide variation in general density of the innervation and frequency of peptide-containing nerves among individual parathyroid adenomas is of significance for their hormone secretory behaviour.

Topics: Adenoma; Calcitonin Gene-Related Peptide; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Fibers; Neuropeptides; Parathyroid Glands; Parathyroid Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Substance P; Synaptophysin; Thiolester Hydrolases; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

The effects of combined administration of vasoactive intestinal peptide (VIP) and the ornithine decarboxylase (ODC) inhibitor, 1,3-diaminopropane (DAP), on development of colon tumors induced by azoxymethane (AOM), on ODC activity of the colon wall, and on the labelling index of colon epithelial cells were investigated in inbred Wistar rats. Rats received weekly subcutaneous injections of AOM for 10 weeks and subcutaneous injections of VIP every other day and drinking water containing DAP (2.5 milligrams) ad libitum until the end of the experiment at week 45. Administration of VIP significantly increased the incidence of colon tumors at week 45. It also resulted in significant increases in colon ODC activity and in the labelling index during administration of AOM, but not after its cessation. Administration of both DAP and VIP significantly reduced the enhanced colon carcinogenesis by VIP. The DAP significantly attenuated the VIP enhancement of colon ODC activity and of the labelling index during AOM administration. These findings indicate that ODC inhibition attenuated enhancement of colon carcinogenesis, and suggest that enhancement of colon carcinogenesis by VIP may be mediated through its polyamine biosynthesis.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenoma; Animals; Azoxymethane; Colonic Neoplasms; Diamines; Male; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Random Allocation; Rats; Rats, Wistar; Vasoactive Intestinal Peptide

This study, carried out on 9 nonfunctioning pituitary adenomas, was undertaken in order to evaluate the ability of these tumors to synthesize and release gonadotropins and/or free alpha-subunit (alpha-SU) of glycoproteins. The morphological study included electron microscopy and immunofluorescence analysis while hormone release was evaluated by the reverse hemolytic plaque assay (RHPA) and measurements in culture media. By electron microscopy in all tumors (6 null cell adenomas and 3 oncocytomas), it was possible to identify rough endoplasmic reticulum, Golgi apparatus and secretory granules. By immunofluorescence, 5 of 6 tumors were immunoreactive for one or more gonadotropin subunits; in particular, 5 adenomas were positive for alpha-SU and LH-beta, and 3 for FSH-beta. By the RHPA, about 1% of cells obtained from one single tumor formed plaques for LH-beta and alpha-SU while the remaining tumors were negative. Similarly, the study of media concentrations of LH, FSH and alpha-SU in 2 h culture revealed very low amounts of released hormones. In these experimental conditions no modification was observed after the addition of stimulatory agents such as TRH, GnRH and VIP. The present study clearly indicates that although the large majority of nonfunctioning tumors are positive for gonadotropins their secretory capacity is very low in both basal and stimulated conditions.

Topics: Adenoma; Cytoplasmic Granules; Endoplasmic Reticulum; Fluorescent Antibody Technique; Follicle Stimulating Hormone; Glycoprotein Hormones, alpha Subunit; Golgi Apparatus; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Growth Hormone; Hemolytic Plaque Technique; Humans; Luteinizing Hormone; Microscopy, Electron; Pituitary Neoplasms; Prolactin; Thyrotropin-Releasing Hormone; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The presence of pituitary adenylate cyclase activating polypeptide (PACAP) receptors coupled to adenylate cyclase was investigated in four types of human pituitary adenomas: three null adenomas and five gonadotropin-, three ACTH-, four GH-, and four PRL-producing adenomas. In all samples, except in prolactinomas, PACAP(1-27) and PACAP(1-38) stimulated adenylate cyclase activity equally well and potently (K(act) around 3 nmol). Vasoactive intestinal polypeptide (VIP) was systematically 100- to 300-fold less potent than both PACAPs. In prolactinomas, PACAP(1-27), PACAP(1-38), and VIP were inactive despite a response of the enzyme to guanosine 5'-triphosphate, Gpp(NH)p, forskolin, and fluoride. [125I-AcHis1]PACAP(1-27) binding was detected in all samples except in prolactinomas. In addition, a detailed analysis of receptors was feasible in all five gonadotropin- and in two ACTH-producing adenomas, confirming the existence of selective PACAP receptors that recognized PACAP(1-27) and PACAP(1-38) with similar high affinity (IC50 0.8-1.5 nmol) and VIP with a low affinity (IC50 100 nmol/L).

Topics: Adenoma; Adenylyl Cyclases; Binding Sites; Humans; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Pituitary Neoplasms; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Hormone; Vasoactive Intestinal Peptide

The effects of hypothalamic peptides (TRH, GnRH, arginine vasopressin, vasoactive intestinal peptide, GHRH, CRH, and SRIH) on cytosolic free calcium concentrations ([Ca2+]i) and adenylyl cyclase (AC) activity were evaluated in 12 nonfunctioning pituitary adenomas. TRH, GnRH, and arginine vasopressin induced a marked [Ca2+]i rise in 10/12, 4/12, and 2/5 tumors, respectively. The transients induced by these peptides were due to both Ca2+ mobilization from the intracellular stores and Ca2+ influx from the extracellular medium. AC activity was evaluated in 10 adenomas; 1 microM vasoactive intestinal peptide induced a 2- to 6-fold stimulation of the enzyme activity in all tumors, while neither GHRH nor CRH were effective. Moreover, in 5/10 tumors 1 microM SRIH reduced both AC activity and [Ca2+]i, while in 2/10 the peptide caused a significant rise in [Ca2+]i despite the AC inhibition and in 3/10 SRIH did not modify either AC activity or [Ca2+]i. This study indicates that in nonfunctioning pituitary adenomas a wide spectrum of hypothalamic peptides modulate [Ca2+]i and AC activity. Moreover, the presence of biologically active receptors may offer a possible target for therapeutic intervention.

Topics: Adenoma; Adenylyl Cyclases; Adult; Aged; Arginine Vasopressin; Calcium; Corticotropin-Releasing Hormone; Cytosol; Female; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Humans; Hypothalamic Hormones; Male; Middle Aged; Pituitary Neoplasms; Second Messenger Systems; Somatostatin; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

We have investigated the regulation of mRNA levels of alpha- and beta-subunits of guanine nucleotide-binding regulatory proteins (G proteins) by peptide hormones in prolactin producing rat pituitary adenoma cells (GH3 cells) in culture. The cells were treated with thyroliberin (1 microM), vasoactive intestinal peptide (1 microM) or somatostatin (10 microM) for 6 to 48 hours. Thyroliberin and vasoactive intestinal peptide increased the levels of Gs alpha Go alpha, Gi-2 alpha, Gi-3 alpha, Gx alpha, G beta 36 and mRNAs. The effect of vasoactive intestinal peptide was however earlier and more pronounced. Gi-2 alpha mRNA levels showed the quantitatively largest alterations. Somatostatin upregulated Gs alpha and downregulated Go alpha and Gi-2 mRNAs. G protein mRNAs for Gi-2 alpha and Go alpha were increased by exposure of the cells to a medium devoid of serum. We conclude that G protein mRNA levels are subjected to alterations by hormones that act through the corresponding G proteins in the regulation of prolactin synthesis and secretion.

Topics: Adenoma; Animals; Blotting, Northern; GTP-Binding Proteins; Peptides; Pituitary Gland; Prolactin; Rats; RNA, Messenger; Somatostatin; Thyrotropin-Releasing Hormone; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

We have found vasoactive intestinal polypeptide (VIP)-, neurotensin-, substance P-, gastrin-releasing peptide-, calcitonin-, calcitonin gene related peptide (CGRP-2)-, and somatostatin-like immunoreactivities in extracts of sporadic human parathyroid adenomas (n = 18). The content of CGRP-2, substance P, and somatostatin in adenomas correlated directly with that of parathyroid hormone. In addition, concentrations of VIP versus substance P and somatostatin versus CGRP-2 in adenomas were directly correlated. Neuropeptide content of parathyroid hyperplasias differed from that of adenomas. VIP was detected in only one of seven parathyroid hyperplasias, and neurotensin was undetectable (0/7), whereas substance P was present in six of seven cases and GRP in five of seven hyperplasias. In hyperplasias, content of substance P correlated directly with that of gastrin-releasing peptide. Peroxidase immunohistochemistry localized VIP-like immunoreactivity to 20% to 50% of both chief and oxyphilic cells and rare clear cells and capillary endothelium in 11 of 12 adenomas studied. Focal staining was present in glandular epithelium of the rim of adjacent normal parathyroid tissue and in two of three normal parathyroid glands removed with thyroid goiters. This staining was both cytoplasmic and apical membrane. By contrast, in adenomas, neurotensin- and substance P-like positivities were confined to scattered (5% to 10%) oxyphilic cells. Cytoplasmic positivity for parathyroid hormone, noted in 30% to 70% of cells in serial sections, confirmed that these tissues were indeed parathyroid glands.

Topics: Adenoma; Calcitonin; Calcitonin Gene-Related Peptide; Gastrin-Releasing Peptide; Humans; Hyperplasia; Immunoenzyme Techniques; Neuropeptides; Neurotensin; Parathyroid Glands; Parathyroid Neoplasms; Peptides; Radioimmunoassay; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenoma; Adenylyl Cyclases; Animals; Colforsin; Cyclic AMP; Enzyme Activation; Norepinephrine; Phosphatidylinositols; Phosphodiesterase Inhibitors; Pituitary Neoplasms; Prolactin; Pyrrolidinones; Rats; Receptors, Adrenergic, beta; Rolipram; Thyrotropin-Releasing Hormone; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Recent evidence indicates that vasoactive intestinal peptide (VIP) may be involved in normal pituitary function. Immunocytochemistry was used to localize VIP in human biopsied pituitary adenomas and postmortem anterior pituitary glands. Paraffin sections were immunostained for VIP with the avidin-biotin-peroxidase technique. Strong VIP-like immunoreactivity (VIP-LI) was observed in 16 of 17 prolactinomas, 12 of 14 growth hormone-secreting tumors associated with acromegaly, four of 12 ACTH-secreting tumors, and 14 of 18 nonfunctioning pituitary adenomas. In most cases, VIP was colocalized with the classical pituitary hormones. Six of the 18 nonfunctioning tumors had no demonstrable hormone immunoreactivity; five of these stained strongly for VIP, whereas one was negative. Of 18 normal anterior pituitaries, 12 showed strong diffuse staining for VIP throughout the gland. One pituitary with VIP-LI came from an individual who had undergone pituitary stalk transection. Double-immunoenzyme labeling and immunoelectron microscopy demonstrated VIP-LI in many lactotrophs, scattered thyrotrophs, corticotrophs, and in an occasional gonadotroph. These results suggest the following: 1) VIP is present in more than one cell type in normal and adenomatous human pituitaries; and 2) VIP may be involved in the function and development of pituitary tumors.

Topics: Adenoma; Adult; Aged; Female; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Pituitary Gland; Pituitary Neoplasms; Vasoactive Intestinal Peptide

Middle ear adenoma (MEA) is a distinctive, rare entity that appears to be derived from the lining epithelium of the middle ear mucosa. We report four cases of MEA displaying the typical histologic growth pattern. Two distinct tumor cell immunophenotypes were identified in all cases; the first type exhibited positivity with anti-epithelial membrane antigen and anti-keratin antibodies, and the second type showed immunoreactivity with anti-keratin, anti-vimentin, and anti-neuron-specific enolase antibodies. Ultrastructural studies revealed bidirectional mucinous and neuroendocrine differentiation, demonstrated by the presence of two distinct cell types containing apically located mucous granules and basally concentrated neuroendocrine granules, respectively. The presence of neuroendocrine differentiation was supported by the immunohistochemical detection of vasoactive intestinal polypeptide in the tumor cells in one case and neuron-specific enolase in three cases. These findings suggest that the potential for mixed mucinous/neuroendocrine differentiation described in other endodermally derived tumors also exists in middle ear mucosa. We also believe that the rare lesions diagnosed as primary carcinoid tumors of the middle ear might in fact be MEA with predominant or only neuroendocrine differentiation. The clinical course of our four cases and our review of the pertinent literature confirm the benign nature of MEA and indicate that these tumors should be treated by complete local excision without additional therapy.

Topics: Adenoma; Adult; Cell Nucleus; Cytoplasm; Cytoplasmic Granules; Ear Neoplasms; Ear, Middle; Female; Hearing Loss; Humans; Male; Microscopy, Electron; Middle Aged; Organelles; Phosphopyruvate Hydratase; Vasoactive Intestinal Peptide

Recent investigations suggest that although thyroid-stimulating hormone (TSH) is the major regulator of thyroid gland function, it is not the only hormone that regulates the thyroid gland. Another factor regulating thyroid gland function is vasoactive intestinal polypeptide (VIP), which is present in nerves that innervate thyroid blood vessels and follicles. Previous studies have documented that VIP stimulates adenylate cyclase (AC) activity in cultured normal and hyperplastic (Graves) thyroid tissue, thus increasing intracellular cyclic AMP concentration. To our knowledge, however, there is no information concerning the effect of VIP on neoplastic thyroid tissue. Therefore we studied the effect of VIP on normal and neoplastic human thyroid tissue from 10 patients (follicular adenomas, 4; follicular carcinomas, 3; and papillary carcinomas, 3). Adenylate cyclase activity was measured in a 8000 g membrane preparation in the basal state and when incubated with VIP, TSH, and both. VIP increased AC activity in normal tissue and tumor in a dose-dependent manner, with maximal stimulation at 10(-6) mol/L (p less than 0.05). In normal tissue, 10(-6) mol/L VIP and a maximally stimulating concentration of TSH (300 mU/ml) stimulated AC to the same degree. In tumors, although both TSH and VIP increased AC activity, the response to TSH was greater (p less than 0.01). VIP and TSH had an additive effect in normal tissue (p less than 0.05), whereas in tumors the AC response to VIP and TSH was the same as with TSH alone (p = 0.66). This study documents that VIP is a potent stimulator of adenylate cyclase in both normal and neoplastic human thyroid tissues. The magnitude of this effect is similar to that produced by TSH, which implies that VIP plays a physiologically important role in the regulation of the secretion and growth of normal and neoplastic thyroid tissues.

Topics: Adenocarcinoma; Adenoma; Adenylyl Cyclases; Carcinoma, Papillary; Cyclic AMP; Humans; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Vasoactive Intestinal Peptide

The effect of human atrial natriuretic peptide (hANP) on aldosterone, 18-OH-cortisterone, corticosterone, deoxycorticosterone, and cortisol secretion was examined in isolated human aldosteronoma cells from five patients with primary aldosteronism. hANP exerted a nearly identical inhibitory action on basal secretion of each of these steroids and antagonized also the stimulating effects of ACTH, serotonin, metoclopramide and vasoactive intestinal polypeptide. The results suggest that in human aldosteronoma cells hANP may be a non-selective inhibitor of corticosteroid biosynthesis and that the site of inhibition of steroidogenesis may be localized to the early pathway of steroid biosynthesis.

Topics: Adenoma; Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Aldosterone; Atrial Natriuretic Factor; Cosyntropin; Humans; In Vitro Techniques; Kinetics; Metoclopramide; Vasoactive Intestinal Peptide

1H- and 31P-NMR spectroscopy has been applied to rats carrying implanted tumours in vivo, and used to observe simultaneous changes in intracellular pH (pHi) and lactate concentration during the stimulatory action of vasoactive intestinal polypeptide (VIP). A maximal decrease in pHi to a mean of 0.29 units below basal values was recorded. At the same time, 11 min after VIP, a maximal increase in tumour lactate was found, with a mean value of 150% of the basal concentration. The magnitude of these changes was compatible with in vitro measurements of basal lactate concentration and buffering capacity made on the same tumour line. It is concluded that VIP stimulates glycolysis by the tumour cells, resulting in an accumulation of lactate and a consequent fall in pHi.

Topics: Adenoma; Animals; Glycolysis; Hydrogen; Kinetics; Lactates; Magnetic Resonance Spectroscopy; Phosphorus; Pituitary Neoplasms; Rats; Rats, Inbred WF; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) was administered (75 micrograms iv over 12 min) to 14 patients with Cushing's disease, 1 patient with Nelson's syndrome, and 8 normal subjects. VIP induced a significant rise of plasma ACTH levels in 6 patients with Cushing's disease, from a baseline of 13.2 pmol/l (9.9-18.5 pmol/l) to a peak of 24.5 pmol/l (7.7-18.9 pmol/l), median and range (P less than 0.05), and in the patient with Nelson's syndrome, from a baseline of 260.9 to 461.3 pmol/l. A significant elevation of cortisol levels was also observed, from a baseline of 567 nmol/l (185-842 nmol/l) to a peak of 727 nmol/l (364-1029 nmol/l); P less than 0.05. No modifications in plasma ACTH and cortisol levels were noticed in the other 8 patients with Cushing's disease, or in the normal subjects. In the responsive patients, the median plasma ACTH level reached after VIP was found to be less than that induced by CRH administration. In 2 of the responsive patients, VIP was injected again after successful microadenomectomy and did not then cause changes in ACTH and cortisol concentration. These data demonstrate that VIP specifically stimulates ACTH release in some patients with corticotropinomas but not in normal subjects; the disappearance of such abnormal ACTH responses after successful adenomectomy suggests the presence of specific VIP receptors only on the adenomatous corticotropes.

Topics: Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Humans; Hydrocortisone; Male; Middle Aged; Nelson Syndrome; Pituitary Neoplasms; Radioimmunoassay; Vasoactive Intestinal Peptide

Our patient had a left suprarenal mass. His blood pressure was normal, but his urinary catecholamines (CA), vanillylmandelic acid (VMA), total metanephrines (TMn) and 5-hydroxyindolacetic acid (5HIAA) were elevated. In addition, he had elevated, nonsuppressible urinary 17-ketosteroids (17KS) and androsterone, but his urinary 17-hydroxycorticoids (17OHCS) and free cortisol were normal, as were his plasma cortisol and ACTH. After resection of the suprarenal mass, the patient's urinary hormone values reverted to normal. The mass contained a pheochromocytoma and an adrenocortical adenoma. The pheochromocytoma was unusual in that it contained very little norepinephrine (NE) and dopamine (DA) and an abundance of epinephrine (E) despite normal enzyme concentrations. Electron micrographs showed primarily E granules with few of the NE-type. The immunoperoxidase histochemical stains for vasoactive intestinal peptide (VIP) and serotonin (S) were strongly positive. The patient's blood pressure may have been normal because his pheochromocytoma secreted E, VIP, or S. The associated adrenocortical adenoma produced no symptoms and was probably coincidental.

Topics: Adenoma; Adrenal Cortex Neoplasms; Androgens; Catecholamines; Gas Chromatography-Mass Spectrometry; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Microscopy, Electron; Middle Aged; Multiple Endocrine Neoplasia; Pheochromocytoma; Serotonin; Vasoactive Intestinal Peptide

Long-acting somatostatin analogues such as SMS 201-995 (Sandoz) are being evaluated in a wide range of clinical indications, including gut neuroendocrine tumours and acrogemaly. Long-term continuous SMS 201-995 treatment has achieved useful symptomatic improvement in diarrhoea in 4 patients with metastatic VIPomas who had relapsed following previous treatment. Clinical improvement has outlasted suppression of VIP secretion (suggesting an additional direct antisecretory action of SMS 201-995) and has occurred despite expansion of hepatic metastases. In 6 patients with tumours secreting gastrin and/or glucagon, secretion of these peptides was acutely inhibited by SMS 201-995. However, endocrine and clinical responses to chronic treatment have been less consistent. SMS 201-995 is active orally at doses of 4-8 mg and when given thrice-daily to 6 patients with active acromegaly, suppressed mean 24-h growth hormone levels by 51-88%. Despite significantly reduced plasma insulin concentrations, glucose tolerance did not deteriorate. SMS 201-995 was also effective in suppressing thyroid-stimulating hormone (TSH) and thyroid hormone secretion in a patient with mild thyrotoxicosis due to non-tumoural inappropriate TSH hypersecretion. In all cases SMS 201-995 treatment has been well tolerated and has few side-effects.

Topics: Acromegaly; Adenoma; Adult; Aged; Diarrhea; Female; Gastrointestinal Neoplasms; Glucagonoma; Growth Hormone; Humans; Hyperthyroidism; Liver Neoplasms; Male; Middle Aged; Neoplasms, Glandular and Epithelial; Octreotide; Pancreatic Neoplasms; Pituitary Neoplasms; Somatostatin; Streptozocin; Thyrotropin; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

It is now well known that dopamine (DA) plays a major role in the inhibitory control of prolactin (PRL); however, the mechanisms that are physiologically involved in the stimulation of PRL release are still under investigation. Indeed, although suppression of DA inhibitory tonus, administration of thyrotropin-releasing hormone (TRH) or vasoactive intestinal peptide (VIP) are all known PRL releasers, it is not clear whether they interact during physiological periods of PRL release such as suckling and estrus. No clear indications exist, furthermore, on whether they all act upon a same pituitary pool that may become depleted following repeated exposure to stimuli. Refractoriness to a single or a repeated stimulus has been reported to occur in prolactinoma-bearing or normal humans, respectively, the mechanism of which is still matter for discussion. Our present studies performed by perifusing normal or adenomatous rat lactotrophs attached to Cytodex I microcarrier beads was undertaken to try and answer some of these questions. The experimental period consisted in perifusing the cells for 1 h with Dulbecco's modified Eagle's medium (DMEM) containing DA 10(-5) M, then for 2 h with either DMEM, DMEM and TRH 10(-8) M, DMEM and VIP 10(-7) M, then again with DA in DMEM for 1 h, and finally with DMEM, DMEM and TRH, or DMEM and VIP. Three experiments of various combinations were performed. Lower PRL levels were observed under DA, while two periods (first and second) of PRL release followed the suppression of DA infusion with or without the addition of either one of the two peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenoma; Animals; Dopamine; Female; Pituitary Gland; Pituitary Neoplasms; Prolactin; Rats; Rats, Inbred F344; Rats, Inbred Strains; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

In an attempt to characterize GH and PRL secretion in acromegaly, the effects of various stimuli on GH and PRL release by cultured pituitary adenoma cells derived from acromegalic patients were studied. In addition, the PRL responses of somatotroph adenoma cells were compared to those of prolactinoma cells. GH-releasing hormone-(1-44) (GHRH) consistently stimulated GH secretion in all 14 somatotroph adenomas studied in a dose-dependent manner. The sensitivity as well as the magnitude of the GH responses to GHRH were highly variable in individual tissues. Somatotroph adenomas that did not respond to dopamine were more sensitive and had greater GH responses to GHRH. In 8 of 9 somatotroph adenomas that concomitantly secreted PRL, the addition of GHRH likewise increased PRL release. Omission of extracellular Ca2+ blocked the stimulatory effect of GHRH on GH and PRL secretion. When cells were coincubated with 0.1 nM somatostatin, GH and PRL secretion induced by 10 nM GHRH were completely blocked in most adenomas. Similarly, coincubation of dopamine resulted in inhibition of GHRH-induced hormone secretion in some adenomas. Addition of TRH to the incubation medium, on the other hand, significantly stimulated GH secretion in 8 of 14 adenomas, while TRH stimulated PRL release in all of the adenomas. Vasoactive intestinal peptide (VIP) and corticotropin-releasing hormone (CRH) produced an increase in GH and PRL secretion in other adenomas. In prolactinoma cells, somatostatin and dopamine unequivocally suppressed PRL secretion; however, other stimuli including GHRH, VIP, and CRF were ineffective. TRH induced a significant increase in PRL secretion in only one prolactinoma. These results suggest that responsiveness to GHRH and somatostatin is preserved in somatotroph adenomas; the responsiveness to GHRH is inversely correlated to that to dopamine; and PRL cells associated with somatotroph adenomas possess characteristics similar to those of GH cells. Further, the GH stimulatory actions of TRH and VIP are different.

Topics: Acromegaly; Adenoma; Adult; Cells, Cultured; Corticotropin-Releasing Hormone; Dopamine; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Radioimmunoassay; Somatostatin; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

To characterize the functional aspect of prolactin (Prl) cells coexisting with corticotroph adenomas, pituitary adenoma cells obtained from a patient with Cushing's disease and a patient with Nelson's syndrome, who were associated with hyperprolactinaemia, were cultured in monolayer and their Prl responses to various secretagogues were compared with those of prolactinoma cells in culture. Immunohistochemistry performed in one of these two adenomas demonstrated the presence of Prl-containing cells in addition to ACTH cells. When ACTH-Prl adenoma cells were exposed to ovine corticotrophin-releasing factor (CRF), a dose-dependent increase in both ACTH and Prl secretion was observed, which was blocked by coincubation with hydrocortisone. In contrast, no stimulatory effect of CRF on Prl release was observed in all of the experiments using prolactinoma cells. Thyrotrophin-releasing hormone, which consistently stimulated Prl secretion in ACTH-Prl adenomas, was effective in triggering Prl release in only 25% of the prolactinomas. Exposure of the cultured cells to lysine vasopressin, growth hormone-releasing factor and vasoactive intestinal peptide resulted in an increase in ACTH and Prl secretion in one ACTH-Prl adenoma, however, none of the prolactinomas responded to these stimuli to secrete Prl. Dopamine and somatostatin, on the other hand, uniformly suppressed Prl secretion from ACTH-Prl adenomas as well as from prolactinoma cells. These results suggest that the mode of Prl secretion by mixed ACTH-Prl pituitary adenomas is not identical to that by pure prolactinomas and is, at least in part, common to that of ACTh secretion.

Topics: Adenoma; Adrenocorticotropic Hormone; Adult; Cells, Cultured; Corticotropin-Releasing Hormone; Cushing Syndrome; Dopamine; Female; Haloperidol; Humans; Lypressin; Nelson Syndrome; Pituitary Neoplasms; Prolactin; Radioimmunoassay; Somatostatin; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

The effect of an iv bolus injection of 1 microgram/kg body weight of vasoactive intestinal polypeptide (VIP) on plasma prolactin (Prl) levels was tested in 13 normal volunteers and 15 patients with hyperprolactinaemia of various aetiology: 9 with Prl-producing pituitary tumours (6 prolactinoma, 3 mixed pituitary adenoma, secreting Prl and growth hormone (GH)), 6 with hyperprolactinaemia secondary to a hypothalamic lesion (4 craniopharyngioma, 1 hypothalamic germinoma, 1 meningoencephalitis). In the normal subjects, an iv injection of VIP caused a prompt increase in plasma Prl with peaks 2- to 3-fold greater than the basal values. On the other hand, none of the 9 patients with a Prl producing pituitary tumour showed any obvious Prl rise after VIP irrespective of a marked difference in their basal Prl levels. Lack of a Prl response to VIP was also found in the 2 patients with hypothalamic lesions (1 craniopharyngioma, 1 hypothalamic germinoma) whose basal Prl concentration was higher than 100 ng/ml. However, in the remaining 4 patients with hypothalamic lesions whose basal Prl concentration was less than 100 ng/ml, VIP injection resulted in a stimulation of the Prl secretion with a maximal net increment of 11.3 +/- 3.8 ng/ml, which is not different statistically form that (16.3 +/- 3.3 ng/ml) in the normal subjects, but significantly higher than that (-2.3 +/- 2.7 ng/ml) in the 4 patients with Prl-secreting adenoma and a basal Prl concentration of less than 100 ng/ml. These results indicate that the VIP test may be a useful diagnostic tool for discriminating a Prl-producing tumour from a hypothalamic lesion in patients with mild hyperprolactinaemia.

Topics: Adenoma; Adolescent; Adult; Child; Diagnosis, Differential; Female; Humans; Hyperprolactinemia; Hypothalamic Diseases; Injections, Intravenous; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Vasoactive Intestinal Peptide

Topics: Adenoma; Adenylyl Cyclases; Bucladesine; Culture Techniques; Dopamine; Dose-Response Relationship, Drug; Female; Gastrointestinal Hormones; Humans; Male; Pituitary Neoplasms; Prolactin; Sodium Fluoride; Vasoactive Intestinal Peptide

The effects of vasoactive intestinal polypeptide (VIP), dopamine, and somatostatin (SRIF) on GH secretion were examined in vitro in perifused pituitary adenoma tissues obtained at surgery from seven patients with acromegaly. The perifusion of VIP at 5 x 10(-8) M resulted in a significant increase in effluent GH levels in five of the seven adenomas. A dose-related GH response was observed from 5 x 10(-9) to 5 x 10(-7) M VIP in two adenomas examined. SRIF at 5 x 10(-8) to 10(-7) M suppressed not only baseline secretion of GH but also inhibited GH rises elicited by VIP in six of the seven adenomas. Dopamine at 5 x 10(-7) to 5 x 10(-6) M decreased the baseline secretion of GH in six of the seven adenomas. In four of the six adenomas responsive to dopamine, dopamine suppressed VIP-induced GH release when perifused simultaneously. In the remaining two dopamine-sensitive adenomas in which VIP alone failed to affect GH release, the inhibition by dopamine of GH release was blocked by VIP perifused concomitantly with dopamine. Synthetic TRH or theophylline perifused at the end of the experiment stimulated GH release in all of the adenomas, indicating the viability of tumor cells throughout the study. These results suggest that VIP stimulates GH release by its direct action on pituitary adenoma cells of acromegalic patients and that VIP, SRIF, and dopamine interact at the pituitary level in modulating GH secretion from these adenomas.

Topics: Acromegaly; Adenoma; Adult; Dopamine; Female; Gastrointestinal Hormones; Growth Hormone; Humans; Male; Middle Aged; Pituitary Neoplasms; Somatostatin; Theophylline; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

In three families with the multiple endocrine adenomatosis type I (MEA I) trait, 51 members were investigated by measurement of circulating peptide hormones as tumor markers. Twenty-five of 51 members (49 percent) were considered to be affected by MEA I disorders. The incidence rose with age (75 percent in generation II). Both sexes were affected equally. Hyperparathyroidism was present in 20 of 25 affected members (80 percent), and pituitary tumors (prolactinomas) were found in four of 25 (16 percent). Endocrine pancreatic tumors were found in nine of 25 affected members (36 percent), but when "probable" tumors (seven) are included the frequency rises to 72 percent. Hyperparathyroidism was found in all except one member with proved lesions in other organs. Among patients with proved and possible endocrine pancreatic tumors, elevated serum levels of gastrin and pancreatic polypeptide were frequently found, 78 percent and 67 percent, respectively, and we suggest that serum gastrin and pancreatic polypeptide levels are the most useful screening markers at present for pancreatic lesions in MEA I.

Topics: Adenoma; Adolescent; Adult; Age Factors; Aged; Female; Gastrins; Humans; Hyperparathyroidism; Insulinoma; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Parathyroid Neoplasms; Pedigree; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The effect of vasoactive intestinal peptide (VIP), cholecystokinin octapeptide (CCK), bombesin, arginine vasopressin (AVP), and hydrocortisone (HC) on ACTH release from human corticotropinoma cells in culture has been studied. Tumor tissue was obtained from 6 patients with pituitary corticotropinomas. Eleven to 21 cultures yielding 0.7-2.0 X 10(6) cells/culture, were obtained from each tumor and maintained for periods of 4 weeks to longer than 6 months. VIP (500 ng/ml) significantly (P less than 0.005) stimulated ACTH release from all tumors studied, and a dose (5-500 ng/ml)-response effect was observed in 3 of 5 tumors. Stimulation by VIP was seen at 2,4, and 24 h and was maximal at 4 h. CCK and bombesin were without effect on ACTH release from 4 tumors studies at 4 h. AVP (1-10 mU/ml) stimulated ACTH from 4 tumors studied at 60 min or 4 h. Coincubation of cultures with VIP (50-500 ng/ml) and AVP (1-10 mU/ml) resulted in at least an additive effect. HC (100 ng/ml) significantly (P less than 0.025) inhibited basal ACTH secretion from 2 of 4 tumors at 4 h and from 3 of 4 (P less than 0.005) at 24 h. Simultaneous coincubation of cultures with VIP (50 ng/ml) and HC (100 ng/ml) resulted in an attenuation or blockade of the VIP-stimulated ACTH release, whereas prior incubation of cultures with HC for 28 h before exposure to VIP did not. The results demonstrate that VIP is a potent ACTH secretagogue from human corticotropinoma cells in culture; its effects are additive to those of AVP and modulated by HC.

Topics: Adenoma; Adrenocorticotropic Hormone; Arginine Vasopressin; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Female; Gastrointestinal Hormones; Humans; Hydrocortisone; Pituitary Neoplasms; Vasoactive Intestinal Peptide

The effect of vasoactive intestinal polypeptide (VIP) on in vitro ACTH release and adenylate cyclase activity was investigated in human ACTH-secreting pituitary adenomas from 4 patients with Cushing's disease and 2 patients with Nelson's syndrome. In all the tumors tested, VIP elicited a dose-dependent stimulation of hormone release from adenoma fragments (90-247% at 10-7 M VIP) and of cAMP formation in membrane preparations (75-140% at 3 X 10-6 M VIP). Therefore a role of VIP in the control of ACTH secretion in human ACTH-secreting adenomas is suggested; a cAMP-dependent mechanism of action can also be hypothesized.

Topics: Adenoma; Adenylyl Cyclases; Adrenocorticotropic Hormone; Animals; Gastrointestinal Hormones; Humans; Pituitary Neoplasms; Stimulation, Chemical; Swine; Vasoactive Intestinal Peptide

The mechanisms by which bacterial enterotoxins cause secretory diarrheas have been well defined, and the definitions of such mechanisms have been important in developing a consistently successful therapeutic approach. The less common secretory diarrheas, caused by the interaction of hormones of tumor origin with the gut small intestinal mucosa have also been clearly defined, and their pathogenetic mechanisms are similar to those by which the cholera and E. coli enterotoxins cause secretory diarrhea. The mechanisms by which histamine and gastrin of tumor origin cause gastric hypersecretion are less clearly delineated; secretory diarrhea caused by both of these agents can be stopped by total gastrectomy without removal of the responsible tumor. The secretory diarrhea caused by villous adenomas of the colon, which does not appear to be related to a distally produced humoral agent, results in the same picture of hypokalemic acidosis that is characteristic of the nonbacterial secretory diarrheas originating in the small intestine and is cured by resection of the responsible tumor.

Topics: Adenoma; Antigens, Bacterial; Bacterial Toxins; Cholera; Cholera Toxin; Colonic Neoplasms; Diarrhea; Enterotoxins; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Fimbriae Proteins; Hormones, Ectopic; Humans; Hydrogen-Ion Concentration; Intestinal Mucosa; Neoplasms, Hormone-Dependent; Prostaglandins; Vasoactive Intestinal Peptide; Water-Electrolyte Balance; Zollinger-Ellison Syndrome

The effects of vasoactive intestinal polypeptide (VIP), TRH, dopamine, and rat median eminence extract on GH release from GH-secreting pituitary adenomas were studied in vitro using a sensitive superfusion method. Dispersed pituitary tumor cells obtained from three patients with acromegaly were placed in a superfusion column, and the amounts of GH in the superfusate were determined. The addition of VIP (10(-6) M) to the perfusion system resulted in a marked increase in GH release in all three cases, and a dose-response relationship in VIP (10(-8) 10(-6) M) induced GH secretion was observed in one case studied. TRH (10(-7) M) and median eminence extract (1 equivalent/ml) also caused an abrupt and marked increase in GH release in all of the experiments. The infusion of either dopamine (10(-7) M) or bromocriptine (10(-7) M) inhibited GH secretion. These results suggest that VIP as well as TRH stimulate GH secretion by a direct action on GH-secreting pituitary tumor cells in at least some acromegalic patients.

Topics: Adenoma; Adult; Dopamine; Dose-Response Relationship, Drug; Female; Gastrointestinal Hormones; Growth Hormone; Humans; In Vitro Techniques; Male; Median Eminence; Perfusion; Pituitary Neoplasms; Thyrotropin-Releasing Hormone; Tissue Extracts; Vasoactive Intestinal Peptide

Topics: Adenoma; Adenylyl Cyclases; Egtazic Acid; Gastrointestinal Hormones; Guanosine Triphosphate; Humans; In Vitro Techniques; Pituitary Neoplasms; Prolactin; Vasoactive Intestinal Peptide

A case of vasoactive intestinal peptide-producing adenoma of the tail of the pancreas (VIP) successfully managed by surgical resection is presented. Peripheral venous VIP levels correlated with the severity of the diarrhea. Intraoperatively, the VIP levels in the splenic and portal veins were 485 and 100 pg./ml., respectively. These data suggest that preoperative selective transhepatic venous catheterization for VIP sampling might be used to establish the site of VIP production and, thereby, direct surgical management. This technic requires further evaluation regarding its role in this clinical setting.

Topics: Adenoma; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

A father and son each presented with severe watery diarrhea. The son was found to have a pancreatic islet-cell tumor associated with the pancreatic cholera syndrome, as well as a parathyroid adenoma. The father was found to have multiple islet-cell adenomas and the Zollinger-Ellison syndrome. Pancreatic tumor tissue from each patient contained detectable gastrin and vasoactive intestinal peptide; however, a much higher gastrin concentration was found in the tumor tissue from the father and a much higher vasoactive intestinal peptide content in the tumor tissue from the son. Thus, watery diarrhea may be mediated by different hormones in families having multiple endocrine neoplasia; the precise cause of the diarrheal syndrome should be defined to ensure the proper therapy.

Topics: Adenoma; Adenoma, Islet Cell; Adult; Diarrhea; Endocrine System Diseases; Gastrins; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Parathyroid Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Evidence that VIP is the principal humoral mediator of the watery diarrhea syndrome includes: (a) actions of VIP in experimental anaimals parallel the clinical manifestations of the syndrome; (b) infusions of VIP induce watery diarrhea in intestinal loops of dogs and a picture resembling the clinical syndrome in pigs, at circulating levels of the peptide similar to those observed in human disease; (c) most patients with the watery diarrhea syndrome and underlying tumors have elevated plasma levels of VIP; (d) in those patients in whom pre- and postoperative measurements were made, plasma VIP levels fell to the normal range with removal of the tumor and relief of the diarrhea; and (e) extracts of such tumors are rich in VIP-immunoreactivity and VIP-like biologic activity. A few patients with the syndrome have been reported to have normal plasma VIP levels, and it is possible that other humoral agents (such as pancreatic polypeptide, prostaglandins) may contribute to the production of the diarrhea.

Topics: Adenocarcinoma; Adenoma; Adenoma, Islet Cell; Animals; Diarrhea; Dogs; Gastrointestinal Hormones; Humans; Neoplasms; Pancreatic Neoplasms; Swine; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma; Adrenal Cortex Hormones; Carcinoma, Bronchogenic; Diarrhea; Gastrointestinal Hormones; Humans; Lung Neoplasms; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide