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Neuroendocrinology Group, Department of Neurosurgery, Department of Neurosurgery, Department of Neurosurgery, Laboratorio de Fisiología y Biología Molecular, IBioBA–CONICET, Max Planck Institute of Psychiatry, Kraepelinstraße 10, D-80804 Munich, Germany
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Neuroendocrinology Group, Department of Neurosurgery, Department of Neurosurgery, Department of Neurosurgery, Laboratorio de Fisiología y Biología Molecular, IBioBA–CONICET, Max Planck Institute of Psychiatry, Kraepelinstraße 10, D-80804 Munich, Germany
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applied in recent studies ( Thomas et al . 2008 , Shahani et al . 2010 ), may overcome this problem in the future. Tumours of the anterior pituitary represent the second most frequent type of intracranial neoplasms and are mostly benign adenomas derived
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Introduction Pituitary adenomas account for 10–15% of all intracranial tumors. Ninety percent are represented by somatotroph adenomas (growth hormone (GH) secretors), clinically non-functioning adenomas (mainly gonadotroph) and
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The reported frequencies of Gs alpha mutations (gsp mutations) in growth hormone (GH)-secreting pituitary adenomas are variable (ranging from 4.4 to 43%), and the presence of these mutations in the other pituitary adenomas is still a matter of controversy. Previous clinical and biochemical analyses of patients with GH-secreting pituitary adenomas and gsp mutations produced conflicting results and did not demonstrate obvious characteristics. Therefore, we investigated the prevalence of gsp mutations in Korean patients with pituitary adenomas and elucidated the characteristics of these patients. Forty-four GH-secreting adenomas, 7 prolactin (PRL)-secreting adenomas and 32 clinically non-functioning adenomas were examined for the presence of point mutations in codon 201 and 227 of the Gs alpha gene using a nested PCR and direct sequencing of DNA extracted from fresh tissue or paraffin-embedded pituitary adenoma samples. Seven of the 44 GH-secreting pituitary adenomas had point mutations at codon 201 or 227; of these, five mutations were in codon 201 and two were in codon 227. In patients with gsp mutations, mean tumor size was significantly smaller than in patients without gsp mutations (15.9+/-8.7 mm vs. 24.9+/-14.9 mm, P<0.05). Age, sex, basal GH levels, GH response to oral glucose loading, GH response to octreotide and surgical outcome were not different in the two groups. One of the 32 clinically non-functioning pituitary adenomas had a point mutation at codon 201; none of the seven prolactinomas had these mutations. These results show that gsp mutations are not rare in Korean acromegalic patients and mean tumor size is significantly smaller in acromegalic patients with gsp mutations. Our results also confirm the low frequency of gsp mutations in clinically non-functioning pituitary adenomas and the absence of gsp mutations in prolactinoma.
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Abstract
Cellular receptors for sex steroids (SSRs) were studied in an unselected series of 55 human pituitary tumors. Cytosolic receptors for estrogen (ERcs) and progesterone (PgRcs) were determined in all cases and cytosolic androgen receptors (ARcs) in 47 cases. Nuclear receptors (ERns, PgRns, ARns) were also studied in 33 cases. ERs and PgRs were determined by an ELISA and ARs by [3H]methyltrienolone binding. Where both cytosolic and nuclear receptors were studied (n=33), ERs, PgRs and ARs were found in at least one subcellular fraction in 66·7, 60·6 and 81·8% of cases respectively, ERs and ARs being mainly recovered from the cytosol and PgRs from the nucleus. No linear correlation was found between preoperative plasma steroid hormones and their specific cellular receptors. Nonetheless, the differential expression of SSRs according to sex and gonadal status at the time of surgery strongly supports their regulation by the steroid environment in vivo: PgRcs were more frequent in tumors found in women (41·4 vs 15·4%, P<0·05), whereas a high expression of ERcs and ARcs (>15 fmol/mg protein) was more common in tumors found in men (34·5 vs 10·3%, P<0·05 and 54·5 vs 24·0% respectively). PgRs were positively correlated with ERns, indicating the possibility of estrogen priming of their expression, and negatively correlated with ARs in nuclear fractions. SSRs appeared to be widely distributed among pituitary tumors, although, compared with other hormone-secreting groups, prolactinomas displayed a higher ERc expression (34·8 ± 11·3 vs 4·8 ± 5·1 fmol/mg protein, P=0·007) and gonadotroph cell adenomas lower ARc values (1·3 ± 0·8 vs 38·2 ± 10·6 fmol/mg protein, P=0·048). Microadenomas were characterized by a higher PgR expression than macroadenomas, whereas hemorrhagic (macro)adenomas were characterized by a high ER expression (>90%). The present results indicate that most pituitary tumors are targets for sex steroids, SSR expression being partially triggered by the steroid environment itself. Possible physiopathological and therapeutic implications of these findings are discussed.
Journal of Endocrinology (1996) 151, 175–184
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Macrophage migration inhibitory factor (MIF) is an essential regulator of the macrophage responses to endotoxin. MIF also has the ability to override the anti-inflammatory actions of glucocorticoids during an immune response, and is thus an important pro-inflammatory factor. The presence of MIF in cells of the anterior pituitary has been described, and high levels of MIF in other rapidly proliferating tIssues have also been demonstrated. It has been hypothesised that MIF release from these cells is influenced by the hypothalamo-pituitary-adrenal axis, and that ACTH and MIF are released simultaneously to exert counter-regulatory effects on cortisol. However, another intracellular role for MIF has also been suggested as it has been shown that MIF exerts an effect on the inhibitory cell cycle control protein p27 through an interaction with Jab1, a protein implicated in p27 degradation. We studied MIF expression in different normal and adenomatous human pituitary samples using immunohistochemistry and RT-PCR. There was evidence of co-immunoprecipitation of MIF with Jab1, suggesting an interaction of the two proteins. Our results showed that there is increased expression of MIF protein in the nuclei of all pituitary adenomas compared with normal tIssue (P=0.0067), but there was no statistically significant difference in nuclear MIF expression between the different adenoma types. Nuclear MIF expression correlated positively with p27 and its phosphorylated form in normal tIssue (P=0.0028 and P<0.0001); however, this relationship was not seen in the adenoma samples. Cytoplasmic expression of MIF was found to be variable both in normal and adenomatous samples, with no consistent pattern. MIF mRNA was demonstrated to be present in all tumour and normal samples studied. Somatotroph tumours showed higher MIF mRNA expression compared with normal pituitary or other types of adenomas. In conclusion, MIF is expressed in cell nuclei in pituitary adenomas to a greater extent than in normal pituitary tIssue. We speculate that it may play a role in the control of the cell cycle, but whether its higher level in adenomas is a cause or a consequence of the tumorigenic process remains to be clarified.
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Angiogenesis has been shown to be related to tumour behaviour, prognosis and response to treatment in many different tumour types. The aim of this study was to examine the relationship between angiogenesis and tumour behaviour and response to treatment in pituitary adenomas. The microvessel density (MVD) of pituitary tumours was assessed by counting blood vessels labelled with 3 different endothelial markers using antibodies to CD31, factor eight-related antigen and biotinylated Ulex europaeus (agglutinin I UEAI). One hundred and forty-two surgically removed pituitary adenomas (46 GH secreting, 6 microprolactinomas, 19 macroprolactinomas, 18 ACTH secreting and 53 functionless tumours) were carefully characterized and assessed. There was a significant negative correlation between age and MVD of GH secreting tumours (R(2)=33.8, P=0.005). Age was not related to MVD in other tumour types. Pre-treatment hormone production by the adenomas was related to MVD in prolactinomas (P<0.05), but not in GH secreting tumours. Invasive prolactinomas were significantly more vascular than non-invasive tumours (P<0.05). Drug treatment with metyrapone or bromocriptine did not appear to influence tumour angiogenesis. Surgical cure was more likely in macroprolactinomas and in ACTH secreting tumours with lower MVD. These results show that factors related to angiogenesis are very important in determining a number of clinical features of pituitary tumours, in particular the invasiveness of macroprolactinomas, the effect of age in tumours secreting GH and the outcome of surgical treatment in macroprolactinomas and ACTH secreting tumours.
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ABSTRACT
The presence of immunoreactive (ir)-α-MSH has been investigated by immunocytochemistry in 24 pituitary adenomas and one case of corticotroph hyperplasia causing Cushing's disease, in four adenomas causing Nelson's syndrome, and in ten 'silent' corticotroph adenomas. It was found that a high proportion of these adenomas have a population of cells containing ir-α-MSH in addition to ir-ACTH. In some instances, these adenomas were clearly not associated with the residual intermediate lobe of the pituitary. Radioimmunoassay of plasma from patients with Cushing's disease or Nelson's syndrome showed elevated levels of ir-α-MSH in the majority of cases. Characterization of the ir-α-MSH in adenoma cells by immunocytochemistry, using an antiserum selective for acetylated forms of α-MSH, suggested that only the desacetyl form was present in each case examined. High-performance liquid chromatography of adenoma tissue extracts revealed material co-eluting with acetylated forms of α-MSH in only one of six cases. These results have been compared with corticotroph adenomas in animal pituitary glands, and it is concluded that the presence of α-MSH peptides cannot be used as a marker for intermediate lobe tumours, and that desacetyl α-MSH is commonly produced by corticotroph adenomas.
Journal of Endocrinology (1989) 120, 531–536
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Galanin is a biologically active 29 amino acid peptide, widely distributed in the central and peripheral nervous system, and most abundantly in the hypothalamus where it may serve in the regulation of anterior pituitary hormones. We herein report that mice carrying the rat preprogalanin cDNA specifically targeted to the somatomammotroph cell lineage, under the control of the rat GH promoter, over-express and over-secrete galanin. Galanin peptide is localised within the GH and prolactin secretory granules. GH and prolactin release is increased as well, predominantly in males, while older transgenic animals develop pituitary hyperplasia and adenoma. In both male and female transgenic mice there is a significant increase in serum galanin (P<0.00003 and P<0.001 respectively) and prolactin (P<0.002 and P<0.05 respectively) levels, while only in male transgenic mice is there a significant increase in the serum levels of GH. Furthermore, in male transgenic mice serum prolactin levels are significantly correlated with the serum galanin levels (P<0.03). We conclude that galanin plays a key role in the process of pituitary hyperplasia, acting as a growth factor to promote pituitary cell proliferation, and participates in pituitary adenoma formation not necessarily dependent on oestrogens. Targeted over-expression and over-secretion of galanin in the somatomammotroph cell lineage stimulates predominantly hyperprolactinaemia in an oestrogen-independent manner.
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Cell cycle dysregulation is one of the defining features of cancer. Cyclin-dependent kinase 4 (CDK4), together with its regulatory subunit cyclin D, governs cell cycle progression through the G1 phase. Cyclin-dependent kinase inhibitors, including p16(INK4A) (encoded by CDKN2A), in turn regulate CDK4. In particular, dysregulation of the p16/CDK4/cyclin D complex has been established in a variety of types of human tumours. Dominant activating mutations affecting codon 24 of the CDK4 gene (replacement of Arg24 by Cys or His) render CDK4 insensitive to p16(INK4) inhibition and are responsible for melanoma susceptibility in some kindreds. However, 'knock-in' mice homozygous for the CDK4(R24C) mutation were noted to develop multiple neoplasia, most commonly including endocrine tumours: pituitary adenomas, insulinomas and Leydig cell testicular tumours. We therefore speculated that sporadic human endocrine tumours might also harbour such mutations. The aim of the current study was to analyze the CDK4 gene for the two characterized activating mutations, R24C and R24H, in sporadic human pituitary adenomas, insulinomas and Leydig cell tumours. We used DNA extracted from 61 pituitary adenomas, and paired tumorous and neighboring normal genomic DNA extracted from 14 insulinoma and 6 Leydig cell tumour samples. Genomic DNA from patients with familial melanoma harbouring the R24C or the R24H mutations served as positive controls. All samples were subjected to PCR, mutation-specific restriction digests and/or sequencing. Both methodologies failed to detect mutations at these two sites in any of the sporadic endocrine tumours including pituitary adenomas, benign or malignant insulinomas or Leydig cell tumours, while the positive controls showed the expected heterozygote patterns. Protein expression of CDK4 was demonstrated by immunohistochemistry and Western blotting in pituitary and pancreatic samples. These data suggest that the changes in the regulatory 'hot-spot' on the CDK4 gene, causing various endocrine tumours in CDK4(R24C/R24C )mice, are not a major factor in sporadic pituitary, insulin beta-cell or Leydig cell tumorigenesis.
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ABSTRACT
Growth hormone-secreting human pituitary adenoma cells in long-term culture show a decline in GH secretion. We investigated the effects of dexamethasone on GH production and on the responsiveness of the adenoma cells to various drugs. Twenty-four-hour GH secretion by cultures from seven acromegalics was consistently stimulated by 100 nM-dexamethasone. In four out of seven cultures the effect of dexamethasone occurred within 24 h. After 3 weeks in culture the decline in GH secretion by control cultures was over 90%, while in dexamethasone-treated cultures this was limited to less than 50%. The effect of dexamethasone was dose-dependent over a range of 1 nmol/l to 10 μmol/l. Dexamethasone stimulated not only GH secretion (fivefold), but also GH content (twofold). Cycloheximide and actinomycin D blocked the stimulatory effect of dexamethasone on GH secretion, the latter irreversibly. After 4 days of treatment with 100 nm-dexamethasone, the relative effects of somatostatin, prostaglandin E1, bromocriptine and thyrotrophin releasing hormone were the same in treated and untreated cultures. However, the response to synthetic GH releasing factor (GRF) was greatly enhanced by pretreatment of adenoma cells with dexamethasone (100 and 5 nmol/l). Cells unresponsive to small concentrations of GRF could be stimulated effectively by GRF after pretreatment with dexamethasone.
In conclusion, dexamethasone prevents the decline in GH production as seen in control cultures, possibly by stimulation of DNA transcription. Furthermore, the response to GRF is greatly enhanced in the presence of dexamethasone, while the relative effects of other direct GH stimulatory and inhibitory compounds seem to be unchanged.
J. Endocr. (1984) 100, 353–360
