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K Kovacs

Publications and source records attributed to K Kovacs.

At least 19 recordsLinked to original sources
PubMed1999

Pituitary estrogen receptor alpha and dopamine subtype 2 receptor gene expression in transgenic mice with overproduction of heterologous growth hormones.

Pituitary somatotrophs are suppressed in mice transgenic for human (h) or bovine (b) growth hormone (GH) genes fused with metallothionein (MT) or phosphoenolpyruvate carboxykinase (PEPCK) promoters. Previous morphologic studies revealed that lactotrophs are inhibited in hGH transgenic lines probably due to prolactin-like effects of hGH whereas in female bGH transgenics, the lactotrophs are stimulated. In the present study, estrogen receptor (ERalpha) mRNA was studied by autoradiographic in situ hybridization (ISH), ERalpha protein by immunocytochemistry, and dopamine subtype 2 receptor (D2R) mRNA by ISH. In MT/ and PEPCK/hGH transgenic mice, silver grains signaling ERalpha mRNA were significantly decreased compared to controls; the reduction was stronger in males (8.6 and 37%) than in females (4.6 and 11%). The decrease in the number of ERalpha-immunoreactive nuclei followed the same pattern (13.3 and 6% in males vs 3.2 and 5.2% in females). In MT/hGH mice the D2R mRNA signal was significantly increased in males (6 and 15.4%) and females (16%). In MT/bGH transgenics, ERalpha mRNA and ERalpha-immunoreactive nuclei were significantly increased (25 and 6%) only in males; D2R mRNA was more decreased in females (23%) than in males (15%). In conclusion, the opposite changes in ERalpha and D2R gene expressions are correlated with lactotroph inhibition in hGH transgenic mice and their stimulation in bGH transgenic mice. The changes in ERalpha expression were stronger in males, whereas those of D2R were more pronounced in females.

Animals↗
PubMed1999

Apoptosis in nontumorous and neoplastic human pituitaries: expression of the Bcl-2 family of proteins.

Analyses of apoptosis and of the apoptosis regulatory proteins Bcl-2, Bax, Bcl-X, and Bad were done in 95 nontumorous and neoplastic pituitary tissues by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL), immunohistochemistry, and Western blotting. The apoptotic index was relatively low in all groups but was at least fourfold higher in pituitary carcinomas compared with any other groups. Pituitaries from pregnant and postpartum women had a fivefold higher apoptotic index compared with matched controls from nonpregnant females. Preoperative treatment of adenomas with octreotide or dopamine agonists did not change the apoptotic index significantly. The lowest levels of Bcl-2, Bax, and Bcl-X expression were in pituitary carcinomas as detected by immunostaining. An immortalized human pituitary adenoma cell line, HP75, developed in our laboratory using a replication-defective recombinant human adenovirus with an early large T-antigen, had a much higher level of apoptosis than nontumorous and neoplastic pituitaries. Treatment with transforming growth factor (TGF)-beta1 and protein kinase C (PKC) inhibitors increased apoptosis in this cell line. Analysis of the Bcl-2 family of proteins after treatment with TGF-beta1 and PKC inhibitors showed a 20% to 30% decrease in Bcl-X in the treated groups compared with controls. These results, which represent the first study of apoptosis in pituitaries from pregnant and postpartum cases and in pituitary carcinomas, indicate that 1) the apoptotic rate is low in nontumorous and neoplastic pituitary tissues but is relatively higher in pituitary carcinomas, 2) there are alterations in the expression of the Bcl-2 family of proteins in pituitary neoplasms with a decrease in Bcl-2 expression in pituitary carcinomas that may contribute to pituitary tumor pathogenesis and/or proliferation, and 3) cultured pituitary tumor cells respond to TGF-beta1 and PKC inhibitors by undergoing apoptotic cell death.

Adult↗
PubMed1999

Intrasellar paraganglioma presenting as nonfunctioning pituitary adenoma.

Paragangliomas arising in the sellar region are rare. We report a case of intrasellar paraganglioma of a 54-year-old man who presented with gradually decreasing visual acuity. Physical examination revealed bitemporal hemianopsia with no apparent signs of endocrinologic dysfunction. Magnetic resonance imaging revealed a large sellar mass believed to be a nonfunctioning pituitary adenoma. The tumor was removed transsphenoidally and submitted for histologic examination. The morphologic features, based on histologic, immunocytochemical, and electron microscopic analyses, were consistent with the diagnosis of paraganglioma. The diagnostic morphologic features and the immunocytochemical profile of the tumor are reported.

Adenoma↗
PubMed1998

Kenny-Caffey syndrome and microorchidism.

We report on two adolescent boys with Kenny-Caffey syndrome and microorchidism. The first patient had elevated levels of serum follicle-stimulating hormone, but normal levels of luteinizing hormone and testosterone. There was no evidence of a microdeletion of the Y chromosome. The second patient had Leydig cell hyperplasia with normal seminiferous tubules and spermatogenesis, and normal pituitary histologic findings at autopsy. The presence of microorchidism in these patients confirms the previous observations and suggests subfertility, but does not fully clarify the pathogenesis.

Abnormalities, Multiple↗
PubMed1998

Localization of insulin-like growth factor-II mRNA in human pituitary adenomas.

Insulin-like growth factors (IGFs) have been reported to promote cell proliferation in many tumours, but their contribution to pituitary adenoma development and growth has not been characterized. We report the presence of insulin-like growth factor II (IGF-II) mRNA in pituitary adenomas using in situ hybridization (ISH). The intensity of IGF-II hybridization signal was correlated with adenoma type, and the presence of Ki-67. Among the 109 adenomas examined, 55 (50.4%) were positive for IGF-II mRNA. All acidophil stem cell, functioning corticotrophic and plurihormonal adenomas contained the message; a high incidence of signal was found among sparsely (7/8) and densely (4/6) granulated growth hormone (GH) cell adenomas, mixed GH cell-prolactin (PRL) cell adenomas (6/7), thyrotrophic (4/6) and null-cell (6/7) adenomas. Less frequently, IGF-II mRNA was localized in mammosomatotrophic, silent subtype 3, gonadotrophic, and oncocytic adenomas, whereas all sparsely granulated PRL cell adenomas and silent corticotrophic adenomas of subtypes 1 and 2 were negative. The MIB-I labelling index was significantly higher in adenomas with a moderate to intense IGF-II signal than in adenomas with weak or no signal. The results suggest that IGF-II, when highly expressed, may have a role in pituitary adenoma proliferation.

Adenoma↗
PubMed1998

A composite silent corticotroph pituitary adenoma with interspersed adrenocortical cells: case report.

OBJECTIVE AND IMPORTANCE: A case report of an extraordinary sellar pituitary tumor composed of corticotrophs and adrenocortical cells is presented. To our knowledge, this is only the second one reported in the literature. CLINICAL PRESENTATION: An 18-year-old female patient presented with amenorrhea. INTERVENTION: Investigations revealed a sellar mass, which was excised transsphenoidally. Histologically, two cell types could be readily distinguished, i.e., small basophilic cells that were positive for periodic acid Schiff and adrenocorticotropic hormone and large cells with abundant, slightly vacuolated, eosinophilic cytoplasm that were negative for periodic acid Schiff and adrenocorticotropic hormone. The nature of the tumor was revealed by ultrastructural examination, thus highlighting the importance of this technique in the investigation of pituitary adenomas. Immunohistochemistry with a panel of steroidogenic dehydrogenases and hydroxylases was positive in the large cells, confirming these as adrenocortical cells. CONCLUSION: We suggest that the designation "composite silent corticotroph pituitary adenoma with adrenocortical cells" is an appropriate name for this tumor. The explanation for the presence of the two cell types is obscure. Two theories are considered, as were proposed by the authors of the previous case report regarding the same entity, i.e., 1) the possibility of misplaced embryonic adrenocortical cells and 2) the presence of uncommitted stem cells that differentiate into adrenocortical cells.

Adenoma↗
PubMed1998

Improved diagnostic accuracy of inferior petrosal sinus sampling over imaging for localizing pituitary pathology in patients with Cushing's disease.

The majority of patients with Cushing's disease can be cured by transsphenoidal microsurgery; however, precise localization of the pituitary source of ACTH is not always possible by standard imaging techniques. Bilateral venous sampling from the inferior petrosal sinuses (IPSS) is also useful for diagnosing Cushing's disease, but the interpretation of discordant findings between IPSS and imaging remains problematic. We tested the ability of imaging and IPSS to localize an ACTH-secreting pituitary lesion in comparison to definitive histopathological examination of the pituitary in patients with Cushing's disease (n = 37). Bilateral IPS catheterization was technically feasible in 32 patients and provided evidence of lateralization in 31 patients. Histological examination confirmed a corticotropic adenoma in 28 patients and corticotropic hyperplasia in 2 patients; Crooke's hyaline change was found in 7 patients, among whom 1 subsequently was found to have an ectopic sphenoid corticotropic adenoma, and the remainder had suspected microadenomas that were not identified microscopically. Accurate localization of the pituitary lesion was more frequent when based on IPSS results than on imaging studies (70% vs. 49%, P < 0.06). The 2 tests provided directly discrepant results for 8 patients; among these, IPSS was more likely than imaging to agree with final pathology (63% vs. 13%, P < 0.10). Imaging was entirely normal for another 9 patients, in whom IPSS accurately localized the lesion for the majority (89%; 95% confidence interval: 50-99%). We suggest that IPSS is an effective tool for localizing pituitary pathology and planning surgery for patients with Cushing's disease.

Adrenocorticotropic Hormone↗
PubMed1998

Telomeres and telomerase in endocrine pathology.

Telomeres representing repetitive DNA sequences of chromosome ends are necessary for maintaining chromosomal integrity. The enzyme telomerase synthesizes de novo telomeric repeats and incorporates them onto the DNA 3'-ends of chromosomes. Stability of chromosome ends and activation of telomerase are elementary requirements for cell immortalization and tumor progression. The telomeric length and telomerase activity have been recently studied in several human neoplasms, including those of endocrine tissues. Assessment of telomerase activity may help to distinguish normal or hyperplastic from neoplastic tissues. Inhibition or inactivation of telomerase activity may provide novel strategies for cancer therapy.

Animals↗
PubMed1998

Pituitary adenoma producing growth hormone and adrenocorticotropin: a histological, immunocytochemical, electron microscopic, and in situ hybridization study. Case report.

The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH. The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells--one somatotroph and one corticotroph--transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.

Acromegaly↗
PubMed1998

Transferrin and transferrin receptor in human hypophysis and pituitary adenomas.

Transferrin (Tf), a major transport protein for iron in the blood and an essential growth factor in some tissues, acts via specific transferrin receptor (TfR). We studied the cellular distribution of Tf and TfR gene expression in 50 human nontumorous autopsy pituitaries and 42 surgically removed pituitary adenomas. Tf and TfR mRNA accumulation was correlated with Ki-67 proliferation marker. In nontumorous pituitaries without iron deposits Tf immunoreactivity was localized in some growth hormone, prolactin, adrenocorticotropin, thyrotropin, and luteinizing hormone cells. Most adenohypophysial cells were immunopositive for TfR. In pituitaries with iron deposits, Tf and TfR were localized only in iron-free cells. Tf mRNA and protein were present in 27 and 32 adenomas, respectively; Ki-67 labeling index of tumors positive for Tf mRNA was significantly higher than in those without transcript (0.94% versus 0.51%; P < 0.025). A positive linear correlation between tumor growth fraction and Tf mRNA signal intensity was evident (r = 0.32; P = 0.04). TfR mRNA and encoded protein were demonstrated in 26 and 31 adenomas, respectively; Ki-67 immunoreactivities were not correlated with the presence of TfR transcripts and signal intensities. These data suggest that Tf may act as a growth-promoting factor for pituitary tumors.

Adenoma↗
PubMed1997

Transgenic models of pituitary diseases.

Transgenic mice are valuable experimental models of human endocrine diseases. Targeted ablation of specific cell lineages or insertion of genes coding for releasing factors, hormones, growth factors, and oncogenes fused with appropriate promoters, or mutated genes, can induce several pituitary disorders. Various hyposecretory and hypersecretory states have been induced, some of them due to functioning pituitary adenomas. Adenohypophysial changes in such disorders have been thoroughly investigated in many of the transgenic lines. Functioning and silent pituitary adenomas resemble those seen in human patients, and are invaluable models of tumorigenesis. The available models have not been sufficiently exploited and new models are expected in the near future. In this review, the morphologic changes of the pituitary are described in transgenic mice and, when available, the ultrastructural alterations are included.

Adenoma↗
PubMed1997

Pituitary-directed leukemia inhibitory factor transgene forms Rathke's cleft cysts and impairs adult pituitary function. A model for human pituitary Rathke's cysts.

Leukemia inhibitory factor (LIF) and LIF receptors are expressed in adenohypophyseal cells and LIF regulates pituitary hormone transcription and cell replication in vitro. Therefore, transgenic mice expressing pituitary-directed LIF driven by the rat growth hormone (GH) promoter were generated to evaluate the impact of LIF on pituitary development. Three founders were established with diminished linear growth and body weight (57-65% of wild type [WT]), and intense anterior pituitary LIF immunoreactivity. Cystic cavities observed in pituitary anterior lobes were lined by cuboidal, ciliated epithelial cells, focally immunopositive for cytokeratin and S-100 protein and immunonegative for adenohypophyseal hormones. Transgenic pituitaries showed decreased GH (40%) and prolactin (PRL) (26%) cells, and decreased GH and PRL mRNAs by in situ hybridization. ACTH cells increased 2.2-fold, whereas gonadotrophs and thyrotrophs were unchanged. Serum GH was undetectable (< 0.78 ng/ml), PRL levels were one third of WT (P < 0.05), IGF-I levels were 30% of WT (P < 0. 001), and T4 was normal. 10 human pituitary Rathke's cysts studied all showed conclusive LIF immunoreactivity in cyst-lining cells. Thus, intrapituitary murine LIF overexpression causes cystic invaginations from the anterior wall of Rathke's cleft, suggesting failed differentiation of Rathke's epithelium to hormone-secreting cells. Arrested murine pituitary maturation with formation of pituitary Rathke's cleft cysts, GH deficiency, and short stature provide a model to study human Rathke's cyst pathogenesis.

Adrenocorticotropic Hormone↗
PubMed1997

Stress-response proteins in human pituitary adenomas. Expression of heat-shock protein 72 (HSP-72).

The presence of heat-shock protein 72 (HSP-72) was investigated by immunohistochemistry (IHC) in a series of 28 surgically removed pituitary adenomas including six somatotroph, two mammosomatotroph, five lactotroph, six corticotroph, four null cell adenomas, and three oncocytomas. Overall, 25 tumors (90%) were positive for HSP-72. One somatotroph, one lactotroph, and one null cell adenomas each contained only sparse, small HSP-72 immunoreactive granules and were regarded as negative. The expression of HSP-72 was commonly uneven differing in degree from cell to cell and among various tumors. In most adenomas, the immunoreactivity was seen as fine granules of moderate density, distributed throughout the cytoplasm. In some cells, the immunoreactivity was strong and diffuse. In one somatotroph, two corticotroph, one null cell, and one oncocytic adenomas, nearly all tumor cells were strongly positive. Adenoma cells, located adjacent to capillaries and small vessels, commonly showed a selective and strong immunoreactivity for HSP-72. The fragments of nontumorous adenohypophysial parenchyma also contained fine immunoreactive cytoplasmic granules accumulating in scattered hormone-producing cells in stellate cells. These results show that HSP-72 is expressed in most pituitary adenomas with a mostly focal and less frequently diffuse pattern of overexpression.

Adenoma↗
PubMed1997

Characterization of spherical amyloid protein from a prolactin-producing pituitary adenoma.

Prolactin (PRL)-producing pituitary adenomas are in some cases associated with deposition of abundant spherical amyloid; however, the origin of the amyloid has not been established. In this report, a PRL-producing pituitary adenoma composed almost entirely of spherical amyloid was analyzed biochemically. The tumor was removed surgically from a 56-year-old man. Immunohistochemical analysis revealed that residual tumor cells were strongly positive for PRL, while the spherical amyloid was not. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a band of approximately 4 kDa associated with the amyloid, which was not present in a nonamyloid producing prolactinoma. The 4-kDa band is similar in size to other known amyloidogenic peptides. Immunoblot analysis of the tumor material using polyclonal anti-human PRL antibodies revealed a small amount of normal-sized PRL; however, the abundant 4-kDa band was nonimmunoreactive. Amino acid sequencing showed that this peptide represents the first 34 amino acids of the intact PRL protein with a predicted size of 4313 Da. The presence of a small amount of normal-sized PRL in this tumor, as well as elevated circulating levels of PRL implies that intact PRL is being abnormally processed in the formation of spherical amyloid.

Amino Acid Sequence↗
PubMed1997

Salivary gland-like tumors of the sellar region.

Herein we present a group of rare tumors of the sella region that have not been previously recognized. Although clinically and radiographically the tumors resemble nonfunctioning pituitary adenomas, their histologic, immunohistochemical, and ultrastructural features differ and indicate a salivary gland origin. The lesions cover a morphologic spectrum that includes cellular pleomorphic adenoma, monomorphic adenoma, oncocytoma, and low-grade adenocarcinoma of the salivary gland. All tumors except the oncocytoma were immunoreactive for cytokeratin and were negative for pituitary hormones and synaptophysin. Ultrastructural characteristics in the cases examined include hypodense stromal material, basal lamina, and tonofilament bundles. The single oncocytoma was packed with mitochondria and lacked membrane-bound secretory granules. DNA ploidy based on image analysis and MIB-1 labeling indices showed diversity within this group of tumors, with labeling indices ranging from 0.06% to 15%. The presumed origin of these rare neoplasms is from salivary gland rests related to the normal pituitary gland. Despite their varied morphology, such tumors are easily confused with pituitary adenoma. Although rare, tumors of salivary gland origin should be considered in the differential diagnosis of unusual adenohypophyseal tumors.

Adenocarcinoma↗
PubMed1997

Pituitary morphology in anencephalic human fetuses.

Anencephalic fetuses provide a model of pituitary development in the absence of the hypothalamus. We studied pituitaries of 10 anencephalic fetuses at various stages of gestation using formalin-fixed paraffin-embedded tissue with immunocytochemistry for known adenohypophysial hormones, the transcription factors Pit-1 and SF-1, cytokeratins and S-100 protein. Ten age- and sex-matched fetuses with no endocrine abnormality were controls. At 17-18 weeks of gestation, pituitaries of 4 anencephalics had no posterior lobe; the number and size of cells containing adenohypophysial hormones and the transcription factors were indistinguishable from controls, however, juxtanuclear cytokeratin-positive fibrous bodies were inconspicuous in anencephalics and were prominent in the adenohypophyses of controls. At 26-28 weeks of gestation, there was a marked reduction in number and staining intensity of cells containing SF-1, alpha-subunit of glycoprotein hormones and both gonadotropin beta-subunits in the adenohypophyses of 2 anencephalics. After 32 weeks, corticotropes were reduced in number and size, and gonadotropes were almost entirely absent; in contrast, somatotropes, lactotropes and thyrotropes were numerous. S-100 protein immunoreactivity was increased in anencephalic pituitaries after 32 weeks, when it was found in numerous cells that did not have the usual morphology of folliculo-stellate cells. These data indicate that adenohypophysial cells can differentiate in the absence of the hypothalamus, and that the transcription factors implicated in cytodifferentiation are expressed in anencephalic pituitaries, but that hypothalamic factors are essential for maintenance of gonadotropes and corticotropes. The functional role of fibrous bodies in somatotropes is unknown, but these structures are inconspicuous in the adenohypophyses of anencephalics. Finally, the appearance of S-100 protein-immunoreactive cells is abnormal in anencephalic fetuses.

Anencephaly↗