VEGF, VEGF165b and EG-VEGF expression is specifically related with hormone profile in pituitary adenomas.

Vascular endothelial growth factor (VEGF), its inhibitory splice variant, VEGF165b and Endocrine Gland derived VEGF (EG-VEGF) have a controversial role in pituitary gland. We aim to study VEGF, VEGF165b and EG-VEGF expression in pituitary adenomas. A significant correlation was found between growth hormone (GH) and VEGF secretion (P=0.024). For prolactinomas, VEGF and prolactin expression, had a P-value of 0.02 for Kendall coefficient and a P-value of 0.043 for the Spearman coefficient. VEGF-mRNA amplification was detected in both tumor cells and folliculostellate cells. VEGF165b was positive in 16.66% of pituitary adenomas. EG-VEGF was significantly correlated with prolactin (P=0.025) and luteinizing hormone (P=0.028). Our data strongly support VEGF, VEGF165b and EG-VEGF as important players of pituitary adenomas tumorigenesis. Particular hormonal milieu heterogeneity, special vascular network with an unusual reactivity to tumor growth correlated with variability of VEGF, VEGF165b and EG-VEGF secretion may stratify pituitary adenomas in several molecular groups with a direct impact on therapy and prognosis.

Spontaneous resolution of pituitary apoplexy in a giant boy under 10 years old.

AIM: Pituitary gigantism is a very rare condition; the occurrence of pituitary apoplexy in children younger than 10 years old is even rarer. The aim of our study is to report this exceptional association. OBSERVATION: A boy aged 9 years and 6 months was hospitalized for the first time in November 2011 for symptoms suggesting pituitary apoplexy. The onset of his disease was difficult to determine as his health record has been poorly maintained. On October 10, 2011, he presented to an emergency department with a sudden drop of visual acuity with diplopia and retro-orbital headaches. An ophthalmological exam found very low visual acuity (1/20) with papillary edema. An MRI of the patient's brain revealed a hemorrhagic pituitary process reaching the chiasma, which was compressed, especially on the right side. Thereafter, the patient's vision improved spontaneously. Clinical examination was normal except for gigantism (+5 SD compared to the target stature). Hormonal assessment argued for mixed secretion [growth hormone (GH) = 39 ng/mL, n ≤ 5, prolactin ( PRL) = 470 ng/mL, n < 15]. Other pituitary functions were normal. Visual acuity normalized after 2 months, and an MRI showed a spontaneous reduction of the pituitary tumor. CONCLUSION: This unusual observation is a model of symptomatic pituitary apoplexy with spontaneous resolution in a boy with pituitary gigantism: phenomenon quite exceptional and worth to be reported.

Pituitary acidophil macroadenoma in a pygmy goat (Capra hircus hircus).

This report describes a pituitary acidophil macroadenoma in a goat. Antemortem clinical findings included hypothermia and rumen stasis. Clinicopathologic findings included refractory hypoglycemia, low total thyroxin and insulin concentrations, elevated bile acid concentration, and hyposthenuria. In addition to the pituitary macroadenoma, bilateral atrophy of the zona reticularis of the adrenal glands was observed histologically.

Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient.

CONTEXT: Criteria to define the response to somatostatin (SS) analogs (SSA) in acromegaly are based on biochemical control of the disease. However, the mechanisms of action of SSAs in inhibiting tumor growth and hormonal secretion are only partially understood, and the two effects may occur independently. OBJECTIVE: The objective of the study was to investigate the dissociation between antiproliferative and antisecretive effects of SSA in an octreotide-resistant patient displaying dramatic tumor shrinkage during primary therapy with octreotide LAR. DESIGN AND SETTING: We characterized somatostatin and dopamine D(2) receptor expression by immunohistochemistry and real-time RT-PCR. The effects of different receptor-selective, bispecific analogs, and chimeric somatostatin/dopamine compounds on GH secretion and cell proliferation in primary cell cultures of the tumor were assessed. RESULTS: The expression of SS receptor subtypes (sst)(5) and D(2) receptor was higher, compared with the other receptor subtypes. GH inhibition by SS-14 and the two chimeric somatostatin/dopamine compounds was scant but greater than subtype-selective and sst(2)/sst(5) bispecific agonists. Conversely, cell growth was potently inhibited by all test substances. However, SS-14, sst(2)/sst(5) bispecific agonist, and chimeric molecules were more potent than the other compounds. CONCLUSIONS: The significant antiproliferative effect of octreotide seems to be related to the higher expression of sst(5) and the negligible antihormonal effect to the lower expression of sst(2). However, activation of multiple receptors by new analogs may produce better control of tumor cell activities. The dissociation between antisecretive and antiproliferative effects observed in vivo and in vitro confirms that SSAs may induce tumor shrinkage despite the lack of effect on GH secretion.

Characterization of human pituitary adenomas in cell cultures by light and electron microscopic morphology and immunolabeling.

The morphology and hormone production of pituitary adenoma cell cultures were compared in order to highlight their characteristic in vitro features. Cell suspensions were prepared from 494 surgical specimens. The 319 viable monolayer cultures were analyzed in detail by light microscopy and immunocytochemistry within two weeks of cultivation. Some cultures were further characterized by scanning, transmission and immunogold electron microscopy. The viability and detailed in vitro morphology of adenoma cells were found to be characteristic for the various types of pituitary tumors. The sparsely granulated growth hormone, the corticotroph and the acidophil stem cell adenomas provided the highest ratio of viable cultures. Occasionally, prolonged maintenance of cells resulted in long-term cultures. Furthermore, a variety of particular distributions of different hormone-containing granules were found in several cases. Both light microscopic and ultrastructural analyses proved that the primary cultures of adenoma cells retain their physiological features during in vitro cultivations. Our in vitro findings correlated with the routine histopathological examination. These results prove that monolayer cultures of pituitary adenoma cells can contribute to the correct diagnosis and are valid model systems for various oncological and neuroendocrinological studies.

Unmodified prolactin (PRL) promotes PRL secretion and acidophil hypertrophy and is associated with pituitary hyperplasia in female rats.

In this study, we have tested the hypothesis that unmodified prolactin (U-PRL) and phosphorylated prolactin (P-PRL) have differential roles in the autoregulation of PRL secretion in vivo. Recombinant human U-PRL and a molecular mimic of P-PRL (S179D PRL) were administered to male rats and to female rats in different physiological states and the effect on rat PRL release was measured. Administration of U-PRL elevated rat PRL in all female animals, but was without effect in males. By contrast, S179D PRL was inactive in females, but inhibited PRL release in males. Morphometric and immunohistochemical analyses demonstrated acidophil hypertrophy and evidence of increased PRL secretion in the pituitaries of U-PRL-treated females. Analysis of the two forms of PRL during prolactinoma induction in two differentially susceptible strains of rats found a strong temporal correlation among increased ratios of U-PRL: P-PRL, increased circulating PRL, and increased cell proliferation. We conclude (1). that the autoregulatory mechanism(s) can distinguish between the two major forms of PRL and that higher proportions of U-PRL not only allow for higher circulating levels of PRL, but are also autostimulatory, (2). that the autoregulatory mechanism( s) are set differently in males and females such that females are more sensitive to autostimulation by U-PRL and less sensitive to inhibition by P-PRL, and (3). that U-PRL and P-PRL may also have differential roles in the regulation of pituitary cell proliferation.

[DNA ploidy analysis and Ki-67 examination on renal neoplasms: investigation of degree of malignancy and biological behavior of small renal tumors].

OBJECTIVE: To investigate the degree of malignancy and the biological behavior of small renal tumors and provide a pathological basis for clinicians in determination of further treatment and prognosis. METHODS: Flow cytometry and immunohistochemical studies were performed on 48 small tumors with diameters less than 3 cm. and 39 renal cell carcinomas with diameters larger than 3 cm in comparison to assess their DNA ploidy status and Ki-67 PR (proliferation rate). RESULTS: Of the 48 small renal tumors, 6 adenoma were all diploid with low PR (< 1%). Aneuploid rate of 42 small renal tumors with clear and granular cell type was 16.7%, showing no statistical difference with the 33.3% aneuploid rate of 39 large renal cell carcinomas. 42 small renal tumors had a lower mean PR than large renal cell carcinoma. DNA ploidy correlated closely with nuclear grade, stage and histological type. There existed a close relation between PR and grade. CONCLUSION: Small renal tumors consist of both adenoma and carcinoma, therefore tumor size can not be used as a criterion in their differential diagnosis. DNA ploidy and Ki-67 PR are important indicators for predicting the biological behavior and prognosis of renal parenchymal tumors.

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.

Lactation associated with acidophilic pituitary adenoma, pheochromocytoma, and cystic endometrial hyperplasia in two goats.

Two unbred adult female goats were examined for persistent, inappropriate lactation. Prostaglandin F2 alpha treatment was ineffective in relieving the condition. Over 5 months, 1 goat developed evidence of CNS disease; this same goat had persistently high serum prolactin concentrations. At necropsy, both goats had an acidophilic adenoma of the pars distalis, a condition that, to our knowledge, has not previously been reported in goats. In addition, both goats had pheochromocytomas and cystic endometrial hyperplasia, conditions that are rarely reported in small ruminants. The inciting cause of inappropriate lactation in goats can be difficult to determine. Pituitary adenomas should be suspected when treatment with prostaglandins is unsuccessful, signs of CNS disease develop, or persistently high serum prolactin concentrations are detected.

Diabetes mellitus in a dog with a growth hormone-producing acidophilic adenoma of the adenohypophysis.

A 9-year-old male Doberman Pinscher was referred to the Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, for polyuria/polydipsia, anorexia, and vomiting. Laboratory examination of blood and urine revealed hyperglycemia, glucosuria, and acidosis. Diabetes mellitus was diagnosed but was very resistant to subsequent insulin treatment. At the owners' request, the dog was euthanatized and a postmortem examination was performed. In addition to hepatic, pancreatic, and renal changes compatible with diabetes mellitus, an acidophilic adenoma of the adenohypophysis was found. Immunohistochemical staining for growth hormone, adrenocorticotropic hormone, and prolactin showed a strong immunolabeling for growth hormone within the cytoplasm of the tumor cells. Although growth hormone level was not measured in the plasma, our findings suggest that the diabetes mellitus in this dog was caused by excess growth hormone secreted by the pituitary neoplasm.

Lymphocytic hypophysitis: unusual features of a rare disorder.

OBJECTIVE: Lymphocytic hypophysitis is a rare disorder which usually affects women and is often associated with pregnancy. We reviewed our experience of this disorder in order to see whether these features were universal amongst our patients. DESIGN: A retrospective review of case notes. PATIENTS: Four patients with histologically proven lymphocytic hypophysitis. MEASUREMENTS: Each patient had undergone full radiological and biochemical assessment of anterior and posterior pituitary function. RESULTS: Only one woman presented during pregnancy, one patient was a man with coexistent active acromegaly, and one progressed over 5 years to panhypopituitarism. In one further patient, histological analysis revealed normal anterior pituitary tissue adjacent to lymphocytic follicles. CONCLUSIONS: Lymphocytic hypophysitis should be considered in the differential diagnosis of any patient with a pituitary mass. We suggest that the entire removal of such a mass is warranted both for accurate diagnosis and definitive treatment.

Prolactin-secreting pituitary adenomas with mammary dysplasia in New Zealand white rabbits.

Nine aged (mean age = 3.2 years) nulliparous New Zealand white rabbit does were found to have markedly enlarged teats. The teats were frequently engorged with fluid but were not hot and did not cause signs of pain. The number of affected teats per animal ranged from 1 to 8 (mean = 4). The teats and associated glandular tissue were typically discolored grey, blue, or greenish black (n = 6). Prolactin concentrations were evaluated by radioimmunoassay. Serum prolactin concentrations ranged from 22.4 ng/ml to 2.21 micrograms/ml (mean = 397.3 ng/ml), which was 10- to 1000-fold greater than normal values in nonpregnant rabbits. Conventional radiography of the skull of six rabbits did not reveal pituitary enlargement. Necropsy revealed an enlarged pituitary gland and sella turcica in six of nine does. The diaphragma sellae had ruptured in two rabbits. All nine rabbits had pituitary acidophil adenomas. The neoplastic portions of the pituitaries were diffusely immunoreactive when stained immunohistochemically for prolactin. In contrast, only small clusters of five to seven cells stained positively in normal pituitaries selected as controls. Histologic examination of the mammary glands revealed numerous large dilated cystic spaces containing proteinaceous fluid. Many cysts had numerous papillary epithelial infoldings. The cystic dilations extended into and included the teat canal producing the gross appearance. Prolactin-secreting acidophil adenomas have not been previously reported in the rabbit, and the association with mammary dysplasia is unique.

Sudden blindness from pituitary apoplexy: a report of two cases.

Two cases of acidophil adenoma of the pituitary causing sudden blindness from pituitary apoplexy are presented. The tumours had been clinically silent, without producing any symptoms of endocrine dysfunction. Radiological evidence was very conclusive. Transfrontal craniotomy with decompression resulted in quick and dramatic visual improvement. The interesting syndrome of clinical manifestations is discussed.

Pathological and experimental investigations in a case of gigantism.

A pituitary adenoma was transsphenoidally removed from a 4.5-year-old girl suffering from gigantism. Prior to the operation both the growth hormone (GH) and the prolactin (PRL) levels in the serum were elevated. By light microscopy the tumor appeared to be an acidophilic adenoma. Two distinct cell types, the densely granulated and the sparsely granulated cells, could be distinguished by electron microscopy. Double immunolabeling revealed the presence of GH alone in some densely granulated cells and PRL alone in some sparsely granulated cells, as well as GH and PRL co-localized in both of the morphologically distinguished cell types. Both cell types were identified in the monolayer and the suspension cultures by electron microscopy. GH and PRL concentrations in the culture media were measured by radioimmunoassay. The basal secretion of growth hormone was almost uniform during the 3-week cell culture period. GH and PRL release was significantly inhibited by bromocriptine. Our studies revealed a bimorphous and bihormonal mixed adenoma in childhood.

Double adenomas of the pituitary: a clinicopathological study of 11 tumors.

Of more than 3000 cases of surgically removed pituitary adenomas, 11 were defined as "double adenomas," i.e., 2 morphologically or immunocytologically distinct tumors. In 8 cases, the lesions exhibited differing histological features and immunophenotypes; in 2 specimens, distinct ultrastructural features were noted as well. In another instance, despite histological and immunocytological uniformity, the two neoplastic components demonstrated distinct ultrastructure. In yet another case, the two adenomas were consecutively removed; despite similar histological features, they differed in immunocytological and ultrastructural characteristics. Last, in one case, the adenoma was histologically uniform, but a portion of the mass exhibited immunoreactivity by ultrastructural features distinct from those of the remainder of the lesion. Hormonal excess attributed to both tumors could be correlated with endocrine manifestations in two cases. Double adenomas of the pituitary occur infrequently. In routine histological sections of surgical material, they are often difficult if not impossible to identify. Presented herein are clinical and endocrinological data on 10 cases of double pituitary adenomas correlated with morphological and immunocytochemical results. The literature regarding multiple adenomas is reviewed as are the diagnostic and therapeutic difficulties associated with these rare lesions.

[Ocular findings in pituitary adenoma].

Of 315 cases (629 eyes) of surgically confirmed pituitary adenoma, 487 eyes (77.4%) suffered diminished visual acuity, 393 eyes (62.5%) primary optic atrophy and 500 eyes (79.5%) visual field defects. Ophthalmoplegia and papilledema were also observed. The ocular changes and visual prognosis were discussed.

Hormone secretion in vitro by plurihormonal pituitary adenomas of the acidophil cell line.

Pituitary tumors producing GH and PRL are morphologically classified as monomorphous bihormonal acidophil stem cell adenomas (ASCAs) which cause hyperprolactinemia and two tumor types which are usually associated with acromegaly, the monomorphous plurihormonal mammosomatotroph adenomas (MSAs) and bimorphous mixed somatotroph-lactotroph adenomas. We studied 12 MSAs, 2 ASCAs, and 10 mixed adenomas in vitro to assess the secretory behavior of these tumors diagnosed by immunohistochemistry and electron microscopy. GH release by MSAs and all but one mixed tumor was greater than that of PRL; the opposite was true of the ASCAs. One mixed tumor which caused impotence and hyperprolactinemia contained predominantly lactotrophs and released greater amounts of PRL than of GH in vitro. All 12 MSAs and 6 of 10 mixed tumors released alpha-subunit of glycoprotein hormones. Incubation with GHRH increased release of GH and PRL by all tumors and of alpha-subunit when present; the responses of all hormones were parallel among MSAs whereas among mixed adenomas, GH and alpha-subunit had greater responses than PRL. TRH stimulated GH, PRL, and alpha-subunit release by MSAs in parallel; among mixed adenomas, PRL response was generally greater than that of GH or alpha-subunit. SRIH markedly reduced GH release by all MSAs; it inhibited GH and alpha-subunit release by mixed tumors more than it affected PRL. Bromocriptine inhibited GH, PRL, and alpha-subunit release by most MSAs and mixed tumors but did not inhibit GH or PRL release by ASCAs. This study demonstrates release of GH, PRL, and alpha-subunit by these morphologically classified plurihormonal tumors in vitro. Variable quantities of GH and PRL released by the different tumor types correlate with immunohistochemical and clinical data. The dynamic studies indicate that regulation of GH, PRL, and alpha-subunit release can be affected by GHRH, TRH, SRIH, and bromocriptine in these adenomas and suggest differences in receptor status. Our data strengthen the view that these three plurihormonal adenomas of the acidophil cell line are not only morphologically but also functionally different and warrant separation.

[Effects of 1,25-(OH)2D3 on the secretion of growth hormone by human pituitary growth hormone-secreting tumors in vitro].

This work studied the effects of 1,25-(OH)2D3 on the secretion of growth hormone (GH) in 15 cases of human pituitary GH-secreting tumor cell cultures. At physiological doses (40-80 pg/ml) of 1,25-(OH)2D3, a GH secretion response was found in 14 cases of pituitary tumor: GH secretion was suppressed significantly in 9 of 14 cases and was markedly stimulated in only 2 of 14 cases of pituitary tumors. In the other 3 cases, the GH response was variable at different days of culture. The degree of suppression of GH secretion induced by 1,25-(OH)2D3 in all cases was 63.1 +/- 3.3% (means +/- sx of the control, and the average increase of GH secretion was 164.0 +/- 6.2% of control. There was no correlation between the type of GH reaction and the dose rang of 1,25-(OH)2D3 used in the experiment. The stimulatory effect on GH secretion did not appear after 2 weeks of culture. The results demonstrate that 1,25-(OH)2D3 at physiological doses has a direct regulatory effect (mainly suppressive) on GH secretion in most pituitary GH-secreting tumors in cell culture.