neuropeptide-y and Pituitary-Neoplasms

The purpose of this study was to explore the role of neuropeptide Y (NPY) on molecular and histological changes in human pituitary adenomas. The localization of NPY and its expression at the protein, messenger RNA (mRNA), and receptor levels were investigated here in different subcategories of pituitary adenomas. Immunohistochemical staining was performed in all cases to assess expression of NPY. Reverse transcription-polymerase chain reaction (RT-PCR) was used to study the mRNA expression of NPY. NPY subcellular localization was observed using immunoelectron microscopy in cytoplasm, rough endoplasmic reticulum, and cell matrix in four of the six cases of pituitary adenoma. NPY protein expression was observed in 59.6% of 57 cases of pituitary adenoma and in 2 cases of pituitary hyperplasia. mRNA expression of NPY was observed in all 57 cases of pituitary adenoma and in 2 cases of pituitary hyperplasia. Significantly different levels of expression were observed across different subcategories of pituitary adenoma. mRNA expression of Y1R and Y2R was observed across all subcategories of pituitary adenomas, and a positive correlation was observed between NPY and Y2R. In conclusion, evidence is provided here for the expression of NPY and its receptors, Y1R and Y2R, in human pituitary adenoma, and the levels of expression were found to differ across different subcategories. Differences in expression of Y2R in human pituitary adenomas were found to have remarkable statistical significance.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adolescent; Adult; Aged; Cytoplasm; Endoplasmic Reticulum, Rough; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Hyperplasia; Immunohistochemistry; Male; Microscopy, Immunoelectron; Middle Aged; Neuropeptide Y; Pituitary Gland; Pituitary Neoplasms; Prolactinoma; Receptors, Neuropeptide Y; RNA, Messenger; Young Adult

At 2 years of age, 100% (23/23) of ERbeta(-/-) female mice have developed large pituitary and ovarian tumors. The pituitary tumors are gonadotropin-positive and the ovarian tumors are sex cord (less differentiated) and granulosa cell tumors (differentiated and estrogen secreting). No male mice had pituitary tumors and no pituitary or ovarian tumors developed in ERalpha(-/-) mice or in ERalphabeta(-/-) double knockout mice. The tumors have high proliferation indices, are ERalpha-positive, ERbeta-negative, and express high levels of nuclear phospho-SMAD3. Mice with granulosa cell tumors also had hyperproliferative endometria. The cause of the pituitary tumors appeared to be excessive secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus resulting from high expression of NPY. The ovarian phenotype is similar to that seen in mice where inhibin is ablated. The data indicate that ERbeta plays an important role in regulating GnRH secretion. We suggest that in the absence of ERbeta, the proliferative action of FSH/SMAD3 is unopposed and the high proliferation leads to the development of ovarian tumors. The absence of tumors in the ERalphabeta(-/-) mice suggests that tumor development requires the presence of ERalpha.

Topics: Aging; Animals; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Ki-67 Antigen; Male; Mice; Mice, Knockout; Neoplasms, Second Primary; Neuropeptide Y; Ovarian Neoplasms; Pituitary Neoplasms; Sex Characteristics

Patients with pituitary tumours often present with disabling headache but there is no clear relationship between tumour size and headache. Neuropeptide Y (NPY) has been identified in pituitary tumours and may serve as a biochemical marker of the propensity for headache. Using immunohistochemical techniques we examined 27 consecutive pituitary adenoma specimens for NPY (including one normal postmortem control anterior pituitary specimen). A separate observer divided the patients into two groups: headache and non-headache. The association between the presence of NPY and headache was tested. NPY positive immunoreactivity was seen in 13 tumour specimens (50%, 13 of 26 pituitary tumour specimens), characterized by cytoplasmic and nuclear staining patterns. There was no significant association between the presence of NPY and headache (chi(2) = 0.9, P = 0.34). We did not observe NPY in the normal anterior pituitary control specimen. NPY was present in four of five (80%) growth hormone-secreting tumours and two of two (100%) prolactinomas, compared with four of 11 (36%) non-functioning adenomas. The mechanism of many pituitary tumour-associated headaches remains undetermined. The significance of NPY positivity in pituitary tumours is unknown, although the results of this study may implicate this peptide in the control of somatotroph and lactotroph activity. Our data do not support a clear role for NPY pituitary tumour-associated headache.

Topics: Chi-Square Distribution; Female; Gene Expression; Headache; Humans; Immunohistochemistry; Male; Middle Aged; Neuropeptide Y; Pituitary Neoplasms

The aim of this study was to assess human intracranial tumours for their gene expression pattern of the vasoactive peptide adrenomedullin (AM), its receptor (AM-R) and leptin, which exerts multiple biological effects including proliferation and angiogenesis via the leptin receptor (OB-Rb). Gene activity of neuropeptide Y (NPY) was monitored additionally. We investigated whether there was a characteristic gene expression pattern of AM and leptin in different intracranial tumours, depending on their proliferation activity and biological behaviour. We investigated 35 non-functioning pituitary adenomas (including eight null cell, four silent plurihormonal, 23 silent gonadotroph adenomas), seven somatotropinomas, seven prolactinomas, eight meningiomas, five astrocytomas, two glioblastoma multiformes and unaffected temporal lobe (n = 8). Quantitative reverse transcriptase-polymerase chain reaction (TaqMan RT-PCR) was performed. AM mRNA was detectable in all tumour specimens. AM/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) ratio was significantly higher in somatotropinomas, as was AM/CD31 ratio in prolactinomas, compared with inactive adenomas (P < 0.05). AM-R mRNA was found in all tumour subgroups in small quantities but, in general, higher in tumours than in temporal lobe tissue, respectively. AM-R/CD31 ratio was significantly higher in prolactinomas than in inactive adenomas (P < 0.05). Leptin was detectable in very low quantities in each subgroup. OB-Rb gene expression was found in all tumour subgroups, OB-Rb/GAPDH ratio was highest for meningiomas (P < 0.0001, compared with temporal lobe). NPY mRNA was detectable in temporal lobe in higher quantities than in tumours (P < 0.0001), and almost undetectable in prolactinomas and astrocytomas. Our data demonstrate that AM and AM-R, NPY, as well as leptin and OB-Rb, are expressed in various intracranial tumours in humans but their particular function has to be elucidated further. At present, there is no evidence for a cross-talk on transcriptional level between the peptidergic vasodilative system AM and the putative angiogenic and proliferation affecting factor leptin.

Topics: Adenoma; Adrenomedullin; Adult; Aged; Brain Neoplasms; Carrier Proteins; Female; Gene Expression; Hormones; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Peptides; Pituitary Neoplasms; Receptors, Adrenomedullin; Receptors, Cell Surface; Receptors, Leptin; Receptors, Peptide

Neuropeptide Y (NPY) gene is expressed in human pituitary gland where its function is partially elucidated. NPY could act as a neuroendocrine modulator within this gland. This study was undertaken to assess whether NPY expression is correlated to various pathological situations. Using a highly specific anti-NPY monoclonal antibody, immunohistochemistry analysis was performed in surgically removed pituitary glands. The study included biopsies from 112 human pituitary adenomas, 12 hyperplastic glands and normal anterior pituitary tissues in 34 cases. NPY is immunodetected in 33% of all adenomas, 25% hyperplastic glands and 12% of non-tumoral pituitary gland. NPY expression was significantly higher in adenomas compared to the normal gland. However, no correlation was observed between NPY content and the type of hormonal secretion, sex, age and the status of tumour proliferating potential.

Topics: Adenoma; Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Child; Child, Preschool; Female; Gonadotropins, Pituitary; Human Growth Hormone; Humans; Hyperplasia; Immunohistochemistry; Infant; Male; Middle Aged; Neuropeptide Y; Pituitary Gland, Anterior; Pituitary Neoplasms

To investigate factors governing proteolytic processing and routing of biologically active peptides in the secretory pathway, cDNAs for preproneuropeptide Y (preproNPY) and preproneuropeptide Y fused to a membrane anchor were transfected into pituitary cells. The anchor was the transmembrane and COOH-terminal cytoplasmic domain of peptidylglycine alpha-amidating monooxygenase (PAM); these domains are essential for correct routing of integral membrane forms of PAM. Like proneuropeptide Y (proNPY), the integral membrane form of proNPY was a good substrate for the endogenous prohormone convertases, yielding soluble NPY stored in regulated secretory granules. Tethering of proNPY to the membrane resulted in only a small delay in the rate of cleavage to produce mature NPY and in the arrival of NPY in regulated secretory granules. In contrast, the COOH-terminal region of proNPY remained attached to the transmembrane/COOH-terminal domain of PAM and was rerouted to the vicinity of the trans-Golgi network, where integral membrane forms of PAM are concentrated. Thus, the COOH-terminal of proNPY cannot override the signals in the PAM membrane anchor.

Topics: Animals; Binding Sites; Cell Membrane; Immunohistochemistry; Mice; Mixed Function Oxygenases; Multienzyme Complexes; Neuropeptide Y; Peptide Fragments; Pituitary Neoplasms; Precipitin Tests; Protein Precursors; Rabbits; Subcellular Fractions; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

We examined the effects of intravenous bolus injection of human neuropeptide Y (NPY, 100 micrograms) on the plasma growth hormone (GH) and prolactin (PRL) responses in 15 patients with prolactinoma (PRLoma). The GH and PRL responses to NPY were considered positive (a paradoxical increase) when an increase over baseline of at least 100% occurred. Although NPY did not affect PRL secretion in any of the patients examined, 60% (9 of 15) of the patients showed a significant rise in GH secretion after NPY. The presence or absence of the positive paradoxical increase in GH after NPY was not related to the age of the patients, basal PRL levels, the size of the pituitary adenoma (macro- or microadenoma), or the presence or absence of suprasellar extension of the adenoma. Although the underlying mechanism of the NPY stimulation of GH secretion and also its pathophysiological significance in PRLoma are open to question, the present observation may represent another example of paradoxical hormone responses which are occasionally found in functioning pituitary adenomas.

Topics: Adolescent; Adult; Female; Human Growth Hormone; Humans; Injections, Intravenous; Neuropeptide Y; Pituitary Neoplasms; Prolactinoma; Secretory Rate

Neuropeptide Y (NPY) is a 36 amino acid peptide, widely distributed throughout the brain and is found in hypothalamic neurones. This latter finding suggests that NPY may possess a hypophysiotropic function. A number of studies have demonstrated effects of NPY on LH and GH secretion by rat pituitary cells. We report here the results of experiments investigating the effects of NPY on GH secretion by tumorous human somatotropic pituitary cells in culture. NPY (0.25-25 nmol/l) inhibited GH secretion by 20-53%, the maximal effect depending upon the tumour studied. The potency of NPY was less than that of somatostatin (SRIH). The stimulatory effects of growth hormone releasing factor (GHRH) and theophylline were reduced by NPY, but NPY did not modify the inhibitory effect of SRIH on GH secretion. It is concluded that NPY may be involved in the control of GH secretion, at least by tumorous human pituitary somatotropes.

Topics: Cells, Cultured; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Neuropeptide Y; Pituitary Neoplasms; Somatostatin; Theophylline