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.

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.

Ectopic growth hormone-releasing adenoma in the cavernous sinus--case report.

A 55-year-old woman presented a rare ectopic pituitary adenoma in the right cavernous sinus manifesting as acromegaly. The tumor was removed via transsphenoidal approach. Intraoperative observation showed the adenoma was located entirely within the right cavernous sinus, and separated from the normal pituitary gland by the medial wall of the cavernous sinus. There was no communication between the tumor and the pituitary. Histological examination showed a growth hormone-releasing adenoma. Including our case, only eight of 86 reported ectopic adenomas have occurred in the cavernous sinus. Such ectopic presentation may be responsible for failed transsphenoidal surgery for endocrinologically active tumors.

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.

Pituitary carcinoma: an ultrastructural study of eleven cases.

Pituitary carcinomas are very rare. Defined as adenohypophysial tumors that undergo craniospinal and/or systemic metastasis, most are PRL- or ACTH-producing. Their ultrastructural features, particularly relative to benign adenomas of similar functional type, have not been sufficiently explored. Eleven cases of immunohistochemically characterized pituitary carcinoma with documented cerebrospinal and/or systemic metastases were collected from various institutions and studied by transmission electron microscopy. The tumors were surgically removed from 7 women and 4 men ranging in age between 28 and 74 years (mean, 50 years). All were endocrinologically functioning. Six tumors secreted PRL; three were ACTH-producing; one each was GH/PRL- and TSH-producing. The patients with the ACTH-producing tumors had all presented with Cushing's disease and two of them had undergone adrenalectomy (Nelson syndrome). In most cases significant cellular atypia and mitotic activity were observed. In terms of morphologic features of functional differentiation, electron microscopy revealed that in 9 cases the tumor cells maintained at least some ultrastructural markers of their basic phenotype. A unique feature in 2 ACTH carcinomas was the variable admixture of smooth endoplasmic reticulum with intermediate (cytokeratin) filaments. In 2 cases, both PRL-producing carcinomas, the cell type comprising the tumor could not be identified on an ultrastructural basis alone. Ultrastructural investigation of pituitary carcinomas confirms their endocrine nature and, in most but not all cases, reveals their functional differentiation. Despite the diagnostic utility of electron microscopy in the assessment of these rare tumors, the distinction of pituitary carcinoma from pituitary adenoma cannot be firmly made on ultrastructural grounds alone.

[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.

Long-acting peptidomimergic control of gigantism caused by pituitary acidophilic stem cell adenoma.

Gigantism is caused by GH hypersecretion occurring before epiphyseal long bone closure and usually is associated with pituitary adenoma. A 15-yr-old female patient presented with accelerated growth due to a large pituitary tumor that was surgically resected to relieve pressure effects. Second surgery to remove residual tumor tissue was followed by administration of octreotide LAR, a long-acting depot somatostatin analog, together with long-acting cabergoline. Height was over the 95th percentile, with evidence of a recent growth spurt. Serum GH levels were more than 60 ng/mL (normal, <10 ng/mL) with no suppression to 75 g oral glucose, and serum PRL (>8,000 ng/mL; normal, <23 ng/mL) and insulin-like growth factor I levels (845 ng/mL; age-matched normal, 242-660 ng/mL) were elevated. Histology, immunostaining, and electron microscopy demonstrated a pituitary acidophil stem cell adenoma. Tumor tissue expressed both somatostatin receptor type 2 and dopamine receptor type 2. The Gs alpha subunit, GHRH receptor, and MEN1 genes were intact, and tumor tissue abundantly expressed pituitary tumor transforming gene (PTTG). Serum GH and PRL levels were controlled after two surgeries, and with continued cabergoline and octreotide LAR GH, PRL, and insulin-like growth factor I levels were normalized. In conclusion, administration of long-acting somatostatin analog every 4 weeks in combination with a long-acting dopamine agonist biweekly controlled biochemical parameters and accelerated growth in a patient with gigantism caused by a rare pituitary acidophil stem cell adenoma.

Gamma Knife radiosurgery as a primary surgical treatment for hypersecreting pituitary adenomas.

OBJECT: To estimate the efficacy of Gamma Knife radiosurgery (GKR) especially as a primary surgical treatment for hypersecreting pituitary adenomas. METHODS: 274 patients were treated with GKR. The mean tumor volume was 1.86 cm(3). The mean peripheral dose was 28.7 Gy. RESULTS: 223 patients were followed up for an average of 31.6 months. The dose related to the tumor growth control and endocrinological normalization was detailed and statistical analysis of the data was performed. CONCLUSION: GKR as a primary surgical treatment for hypersecreting pituitary adenomas may be safe and effective.

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.

The role of GRH mediated AC-cAMP system in the pathogenesis of human pituitary GH-secreting adenomas.

OBJECTIVE: To investigate the role of AC-cAMP system in the transmission of the action of the growth hormone releasing hormone (GRH) on growth hormone (GH) release in pituitary GH-secreting adenomas. METHODS: The effects of GRH (10(-7) mol/L) on intracellular cAMP levels and GH release and the effects of AC-cAMP stimulators, cholera toxin (Ct, 50 micrograms/L), forskolin (10(-5) ml/L) and db-cAMP (10(-3) mol/L) on GH secretion were studied in cultured cells of 21 GH-secreting adenomas obtained from operation for acromegalic patients. RESULTS: GRH and Ct failed to stimulate GH secretion in 61.9% (13/21 cases) and 57.1% (12/21 cases) pituitary GH adenoma cell cultures respectively. Forskolin stimulated GH release in 88.9% (8/9 cases), while db-cAMP induced GH secretion in all cases tested (5/5 cases). The intracellular cAMP levels were elevated by GRH in the 4 out of 9 cases of tumor cell cultures, but not in the other 5 cases. According to the GH secretory responses to GRH and Ct, the 21 GH tumors were divided into 4 groups. In group A and B, GRH can stimulate GH release, but Ct has stimulative role only in group A. In group C and D, GRH fails to stimulate GH secretion. However group A can respond to Ct, but group D has no response. CONCLUSIONS: The GH hypersecretion in most acromegalic patients is mainly due to the defects of pituitary adenoma cells, especially the abnormalities of GRH receptor and/or stimulative guanosine protein.

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.

[Transsphenoidal microsurgical removal of GH-secreting pituitary adenoma in: a report of 200 cases].

From July 1979 to April 1992, 212 cases of GH-secreting pituitary adenoma were treated transsphenoidally by microsurgical technique, of whom two hundred cases monitored with their GH levels at preoperative and postoperative periods. The majority of cases totally 132 cases were of macroadenoma, and 68 cases were of microadenoma. 138 cases were operated on after April 1986. The cure and remission rate averaged to 72.5%, rising from 44.4% (before 1986) to 80.5% for microadenoma and from 31.4% to 69.1% for macroadenoma due to improvement of technique and accumulation of experience. One patient died of angiocardiopathy suddenly during operation. Mortality rate was 0.5%. The follow-up observation of postoperative GH levels in 52 cases revealed that the GH levels within 2 weeks after operation were the same as in 3-6 months. It is thought that the early GH levels may represent the surgical results. The surgical technique is described and factors influencing the surgical results, prevention and treatment of operative complications are discussed in this paper.

[Bladder cancer associated with growth hormone-producing pituitary tumor: a case report].

A case of bladder cancer associated with a growth hormone (GH) producing pituitary tumor is reported. A 67-year-old male underwent hypophysectomy for a GH producing pituitary tumor, 31 months earlier. Although the serum GH decreased postoperatively, recurrence of pituitary tumor with increased serum GH was found and followed by a neurosurgeon. He was referred to our department for asymptomatic gross hematuria. Cystoscopy revealed a papillary pedunculated tumor. Under the diagnosis of superficial bladder tumor, transurethral resection (TUR) was performed. Pathological examination showed transitional cell carcinoma. As the bladder cancer recurred with a high level of serum GH seven months later, TUR was repeated. We reviewed and discussed the relationship between GH or GH producing tumor and bladder cancer.

[GH-secreting pituitary adenomas--correlation between clinical features, growth potential and histopathological studies].

We compared clinical features, including endocrinological and radiological findings, histological features and the proliferative parameters (PCNA, MIB-1 and AgNORs) with immunohistochemical features in growth hormone (GH) secreting pituitary adenomas. 18 cases were divided into two groups based on immunohistochemical intracytoplasmic stainings for cytokeratin: a prominent dot-like pattern (group I, 6 cases) and a diffuse perinuclear pattern (group II, 12 cases). Patients in group I (6 females, m = 37.6 years old) were younger, showed female predominance and had a shorter history of acromegaly compared with patients in group II (7 males, 5 females, m = 44.9 years old). Although the size of the adenomas tend to be larger in group I, no difference was recognized in plasma GH levels between the two groups. Increased serum prolactin (PRL) levels were accompanied more common in group I. Abnormal GH responses to TRH and LHRH injection and GH suppressions to bromocriptine administration were more frequently noted in group II than group I. Surgical approaches were transcranial in most cases of group I and transphenoidal in group II. There was no difference in surgical results as to the correction rate of GH levels between the two groups. Histopathologically, group I adenomas were mostly chromophobic, weakly positive for GH, and were generally negative for PRL and alpha-subunit. On the other hand, group II adenomas were mostly acidophilic, diffusely stained for GH, and were often positive for PRL and alpha-subunit. However, there was no significant difference in proliferating parameters between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

[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.

Actions of L-363,586, a cyclic hexapeptide analogue of somatostatin, on GH secretion by human somatotrophinoma cells in vitro.

L-363,586 is a cyclic, hexapeptide analogue of somatostatin-14 with potent inhibitory actions on rat growth hormone (GH) release in vitro. The studies reported here investigate the direct effects of L-363,586 on basal and growth hormone-releasing factor (GRF)-stimulated GH secretion from 3 human somatotrophinomas in dispersed cell culture. 1nM and 10nM L-363,586 inhibited both basal and GRF-stimulated GH release from cells of all 3 somatotrophinomas during a 2h treatment period, whilst 100nM L-363,586 had a prolonged inhibitory action on basal GH secretion from cells of 2 of the tumours throughout treatment and recovery periods. Rebound release of GH was observed with cells of 1 tumour following treatment with L-363,586 plus GRF. The actions of L-363,586 were similar to those of somatostatin-14. These data suggest that L-363,586 may have a role in the treatment of acromegaly.

[Effect of dopamine and bromocriptine on secretion of growth hormone by pituitary growth hormone secreting tumor in cell culture].

This article reports the effect of dopamine (DA) and its agonist bromocriptine (CB154) on the secretion of growth hormone (GH) by pure GH-secreting pituitary tumor in cell culture as well as a comparison of the effects of these dopaminergic drugs and SMS201-295 (SMS). DA of 10(-8) and 10(-7) mol/L reduced GH secretion to 50.6 and 44.4% of the control, respectively, in 1 out of 6 tumors. CB154 of 10(-7) and 10(-6) mol/L suppressed GH secretion to 59.0 +/- 8.9% of the control in 3 out of 4 tumors. CB154 was at least 10 times less potent than SMS vis a vis GH secretion. CB154 of 10(-6) mol/L inhibited GH secretion to 63.3 +/- 13. 8% (n = 4), but SMS of 10(-7) mol/L induced GH secretion to 45.5 +/- 13.1% (n = 4), the concentration difference between CB154 and SMS was 10 times. CB154 suppressed not only GH secretion, but also GH synthesis in two tumor cell cultures. The major role of SMS in GH secretion was inhibition. The results suggest that DA and CB154 have direct inhibitory effects on GH secretion, at least in some pure pituitary GH secreting tumors. The activities of DA and CB154 are not entirely the same as that of SMS.

[Endonasal removal of pituitary growth hormone-adenoma: report of 56 cases].

Fifty-six cases of pituitary GH-adenoma removed by endonasal method are reported. In 50 cases, plasma hGH decreased postoperatively. According to biological evaluation, 18 patients were cured, 21 were improved and 17 presented no change. Postoperative high hGH (greater than or equal to 5 ng/ml) indicated that there were some residual functioning tumor cells in the Sella. Such cases must be followed up regularly in order to assess when and what treatment should be given. Postoperative radiation usually raises the curability of acromegaly. Endonasal method is simple, effective and less injurious to the neighboring structure of the nose.