Naoko Sanno

Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas

OBJECTIVE The level of growth hormone (GH), growth hormone secretogogue (GHS) and GHS receptor (GHSR) messenger ribonucleic acid (mRNA) expression has been reported as being higher in GH‐producing pituitary adenomas than in other types of pituitary adenomas. Recently, ghrelin, an endogenous ligand specific for GHSR, was isolated. Therefore, we attempted to clarify whether ghrelin mRNA is expressed in various types of human pituitary adenoma by competitive reverse transcription‐polymerase chain reaction (RT‐PCR). We also examined the relationship between the levels of ghrelin or GHSR mRNA and hormonal and tumour characteristics in patients with pituitary adenomas.

Lymphocytic hypophysitis: case report.

We report a rare case of lymphocytic hypophysitis in a 52-year-old man who presented with a combination of hypopituitarism and diabetes insipidus. Magnetic resonance imaging with a contrast medium revealed an expanding sellar mass and thickening of the pituitary stalk with homogeneous enhancement. These findings may be useful in differentiating lymphocytic hypophysitis from pituitary adenoma. The unique clinical and radiological features of this case are discussed.

Proliferative potential in pituitary adenomas: Measurement by monoclonal antibody MIB-1

SummaryThe proliferative potential of 45 pituitary adenomas was compared with their biological behaviour as determined by immunohistochemical studies, radiological findings, and clinical manifestations. The PCI (proliferating cell index) as measured using antibody MIB-1 in this study ranged from 0.05 to 4.80%, with an average PCI of 1.49±0.19% (mean±standard error of the mean). There was no significant correlation between proliferation and hormonal state, maximum size, intra-adenomatous haemorrhage, or invasiveness. However, a PCI ≧ 1.5% appeared to correlate with the likelihood of tumour regrowth (regrowth rate: 50%); for PCIs < 1.5%, the rate was 16%. Regrowth adenomas had a higher mean MIB-1 PCI than non-regrowth adenomas [2.34±0.58% (SE) versus 1.14±0.16%, p ≦ 0.05]. MIB-1 PCIs may provide information that is useful for planning follow-up studies and treatment after surgical resection.

Thyrotropin-secreting pituitary adenomas. Clinical and biological heterogeneity and current treatment

Thyrotropin (TSH)-secreting pituitary adenomas represent about 1–2% of all pituitary adenomas and cause secondary or central hyperthyroidism. TSH-secreting adenomas are part of the syndrome of ‘inappropriate secretion of TSH’ (SITSH). The hormonal profile is characterized by nonsuppressed TSH in the presence of high levels of free thyroid hormones (FT3 and FT4). Previous reports have described the surgical cure of TSH adenoma to be more difficult than other functional adenomas because of large and invasive features. However, with the current introduction of ultrasensitive immunometric assays, TSH-secreting adenomas are more often recognized. Early diagnosis of TSH-secreting adenomas leads to a high rate of remission of hyperthyroidism after surgery. However, some of those type of adenomas have clinical heterogeneity, and subsequently cannot be cured by surgery alone. We present our experiences and review reported cases of TSH-secreting adenomas to direct current nobreak management.

Mutations of the MEN1 tumor suppressor gene in sporadic pituitary tumors

Pituitary adenoma is a common neoplasm accounting for 10% of all intracranial tumors. Although the molecular mechanisms underlying the formation of these tumors are largely unknown, a small portion of pituitary adenomas occur in patients with the multiple endocrine neoplasia syndrome type 1 (MEN 1). Although two groups in the United States and Canada have recently reported that sporadic pituitary adenomas very rarely harbor a somatic mutation in the MEN1, MEN1 gene mutation analysis in sporadic pituitary adenomas has not yet been carried out in the Japanese population. To elucidate the potential etiological role of the MEN1 gene in the formation of sporadic pituitary adenomas in Japan, we investigated 40 Japanese patients with sporadic pituitary adenomas (16 hormone-secreting and 24 nonsecreting tumors) for MEN1 gene mutation. Polymerase chain reaction-single-stranded DNA conformation polymorphism analysis and sequencing demonstrated a somatic mutation in the MEN1 gene in only one of the 40 tumors, a prolactinoma, which had a 1-bp deletion in the coding sequence of exon 2. The data suggest that somatic mutations in the MEN1 gene do not play a prominent role in the pathogenesis of sporadic pituitary adenomas.

Expression of Ptx1 in the adult rat pituitary glands and pituitary cell lines: hormone-secreting cells and folliculo-stellate cells.

Abstract The pituitary homeobox1 gene (Ptx1) was initially identified as encoding a pituitary-restricted transcription factor for the proopiomelanocortin (POMC) gene. In order to elucidate the expression pattern of the Ptx1 protein, we investigated the localization of the protein in adult rat pituitary gland and in various pituitary cell lines. We produced an antibody specific for Ptx1 protein, and confirmed its specificity by Western blot analysis. Immunohistochemically, many nuclei in the anterior pituitary cells as well as in the intermediate cells were positive for Ptx1 staining with this specific antibody. Immunohistochemical double staining revealed the presence of Ptx1 not only in all types of hormone-secreting cells but also in some folliculo-stellate (FS) cells. Furthermore, the expression of Ptx1 mRNA was confirmed in various pituitary cell lines and in the FS cell line by using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Our studies indicated that Ptx1 may not only play a role as a basic transcriptional factor for production of various hormones, but may also play some important role(s) in FS cells. Possible synergistic actions with other factors remain to be investigated. The novel finding of Ptx1 in FS cells is of particular interest, and may suggest that FS cells and hormone-secreting cells are derived from a common cellular ancestor.

Modulation of Protein Kinases and Microtubule-associated Proteins and Changes in Ultrastructure in Female Rat Pituitary Cells: Effects of Estrogen and Bromocriptine:

This study focused on the intracellular signal transduction system and microtubule-associated proteins (MAPs), such as MAP-2 and Tau protein. The modulation of these proteins and their correlation with ultrastructural changes were investigated in rat pituitary prolactin (PRL) cells. Adult female Wistar rats were treated with estrogen and bromocriptine and their pituitary glands were removed for analysis of the expression of tubulin, MAP-2, Tau protein, protein kinase C (PKC), and calcium calmodulin (CaM) kinase. Western blot analysis showed that estrogen increased and bromocriptine decreased the expression of PKCα, β1, β2, CaM kinase α, β, MAP-2, and Tau protein. MAP-2 and Tau protein, which are cytosolic proteins, being translated on free ribosomes, were associated with the membrane of whirling rough endoplasmic reticulum (RER) in estrogen-treated cells and dissociated with vesiculated RER induced by bromocriptine. These results suggested that the modulation of MAP-2 and Tau protein may reflect changes of PKC and CaM kinase, and that the quantitative changes and intracellular modulation of MAPs induced by estrogen and bromocriptine, i.e., estrogen-induced association and bromocriptine-induced dissociation of MAP-2 and Tau protein with membrane of RER, may reflect the dynamics of microtubules and are associated with structural changes in the RER and changes in the synthesis and intracellular transport of PRL.

Immunohistochemical Expression of Retinoid X Receptor Isoforms in Human Pituitaries and Pituitary Adenomas

Retinoid X receptors (RXRs) are transcriptional factors that belong to the steroid/thyroid hormone receptor superfamily. There are 3 RXR isoforms-alpha, beta, gamma-known to bind 9-cis-retinoic acid as their ligand. The expression of RXRs in human pituitary glands and pituitary adenomas has not been extensively investigated. To determine whether specific RXR isoforms may play roles in the state of differentiation of pituitary adenomas, we have investigated the immunohistochemical expression of RXR alpha and RXR gamma in 6 nontumorous pituitaries and in 60 different pituitary adenomas using isoform-specific antibodies. In the nontumorous pituitaries. RXR alpha was expressed in the nuclei of almost all cells, while RXR gamma was only expressed in thyrotropin (TSH) cells and in some cells positive for growth hormone (GH) and glycoprotein alpha-subunit (alpha SU) but not in luteinizing hormone (LH) beta-subunit, follicle-stimulating hormone (FSH) beta-subunit, prolactin (PRL) or adrenocorticotropin (ACTH) cells by double immunostaining. All 60 adenomas were RXR alpha positive, and 39 of 60 adenomas (65%) were positive for RXR gamma. The incidence of RXR gamma immunoreactivity in the different adenoma types was: 13 of 16 GH-producing adenomas (81.3%), 9 of 14 PRL-secreting adenomas (64.3%), 6 of 6 TSH-secreting adenomas (100%), 2 of 5 ACTH-secreting adenomas (40%) and 9 of 19 nonfunctioning adenomas (47.4%) including immunohistochemically gonadotropin-subunit-positive adenomas. The colocalization of RXR gamma with the TSH beta subunit, GH and alpha SU in the same adenoma cells was frequently observed, and sometimes RXR gamma was colocalized with PRL, ACTH, FSH beta or LH beta as shown by double immunostaining. We conclude that RXR alpha is expressed in both human pituitaries and pituitary adenomas. In contrast, RXR gamma is expressed more broadly in pituitary adenomas than in normal pituitaries and thus may play a role in the differentiation-specific cell types in the human pituitary both under physiological and pathological conditions.

PTTG overexpression is correlated with angiogenesis in human pituitary adenomas.

Human pituitary tumor transforming gene (hPTTG1) was recently identified as a proto-oncogene, which is a regulator of the cell cycle, as a homolog of yeast securin and a transcriptional activator of several angiogenic factors. Here we examined the relationships of hPTTG1 expression with cell proliferation, expression of the angiogenic factor, VEGF (vascular endothelial growth factor), and numbers of the blood vessels in the normal and/or adenomatous pituitary. With the exception of TSHoma, the expression of hPTTG1 was significantly higher in pituitary adenomas than in the normal pituitary gland. The cell proliferation activity was higher in pituitary adenomas than in the normal pituitary. Pituitary cell proliferation was significantly correlated with the level of hPTTG1 expression in the normal pituitary tissue, but there was no such correlation in the adenomas. The significant correlation of hPTTG1 with the VEGF expression and the numbers of the blood vessels was elucidated in pituitary adenomas. It is particularly noteworthy that immunohistochemical double staining indicated co-localization of VEGF in many hPTTG1-positive tumor cells. In conclusion, higher levels of hPTTG1 expression contribute to the pathobiology of pituitary adenomas by promoting angiogenesis rather than by activating cell proliferation, whereas hPTTG1 expression is related to mitotic activity in the normal pituitary gland.

Malignant carcinoid tumor of the anterior mediastinum metastasis to a prolactin-secreting pituitary adenoma: A case report

BACKGROUND Although the pituitary gland is known to harbor metastatic deposits, metastasis from a carcinoid tumor is extremely rare. Metastasis to a pituitary adenoma also is an infrequent occurrence. CASE REPORT A case of malignant carcinoid tumor of the anterior mediastinum with metastasis to a prolactin-secreting pituitary adenoma is presented in this 46-year-old woman. This metastatic pituitary tumor demonstrated a high proliferative potential. CONCLUSION To our knowledge, this case represents the first documentation of metastasis from a malignant carcinoid tumor to a pituitary adenoma.