Citations

Previous studies showed that in pregnancy the pituitary enlarges and increases in weight due to lactotroph hyperplasia. We demonstrated that in pituitaries of pregnant women, microvessel density is significantly increased compared to those of age– matched non pregnant women. Vascular endothelial growth factor (VEGF) stimulates new vessel formation in several tissues and neoplasms. The aim of the present study was to reveal whether VEGF is involved in the causation of increased vascularity in the pituitaries of pregnant women. We assessed VEGF immunoexpression in 20 autopsy obtained pituitaries of pregnant women and compared the results with 20 controls. Slides were immunostained for VEGF and pituitary hormones using the streptavidin‐biotin‐peroxidase complex method. VEGF immunoexpression was evaluated in 10 random high‐power fields using an image analyzer and the results compared by chi‐square or Fisher exact tests. Immunoexpression of VEGF was not increased in the adenohypophyses of pregnant women compared with the controls indicating that VEGF plays no major role in the causation of increased vascularity. The cause remains to be investigated.

Pituitary enlargement, development of pregnancy cells and prolactin cell hyperplasia are known to occur in pregnancy. In the present work, we assessed microvessel densities in the 20 pituitaries of pregnant women who passed away. Twenty pituitaries of age matched non‐pregnant women who died from non‐endocrine diseases were used as controls. The autopsy obtained pituitaries were formalin fixed and paraffin embedded. Slides were immunostained for adenohypophysial hormones and for CD‐34, an endothelial cell biomarker using the streptavidin‐biotin‐ peroxidase complex method. Microvessel densities were evaluated quantitatively in 10 random high‐ power fields. For statistical analysis, the chi‐square and Fisher exact tests were applied. The results confirmed that the pituitaries of pregnant women increased in weight and contained more PRL immunopositive cells compared to the controls. The formation of pregnancy cells was also evident. In the pituitaries of pregnant women compared to the control, microvessel densities were significantly higher. The cause of increased vascularity remains to be evaluated. This work was supported by the Jarislowsky and Lloyd Carr‐Harris Foundations.

Angiogenesis is a crucial event in tumor growth, invasion and development of metastasis. Endoglin (CD‐105), a disulfide‐linked homodimeric cell membrane glycoprotein of 180 kDa, located on chromosome 9q and binds to several components of the TGF beta family. In contrast to other endothelial cell markers, endoglin can be demonstrated only in proliferating endothelial cells. We investigated endoglin immunoexpression in various surgically removed human pituitary tumor types and compared the results with CD‐34 immunoexpression. For immunohistochemistry, the streptavidin‐biotin‐peroxidase complex method was used and the number of vessels were counted in 10 low power fields. Results show that endoglin immunostains fewer vessels than CD‐34 in every pituitary adenoma type. The number of endoglin immunopositive vessels is highest in untreated prolactinomas and subtype 3 silent pituitary adenomas and lowest in subtype 1 silent corticotroph adenomas and GH adenomas exposed to somatostatin analogs and prolactinomas exposed to dopamine agonists. Our findings are consistent with the view that endoglin is upregulated in proliferating endothelial cells and its expression can be used as an indicator of vascular neoformation in pituitary tumors. The low levels of endoglin expression in pituitary tumors exposed to somatostatin or dopamine agonists suggests that these therapeutic drugs can inhibit angiogenesis.

Objective MGMT expression in brain and pituitary tumors has been correlated with temozolomide treatment. Few medical therapies are available in patients with Nelson Syndrome. The aim of the present study was to assess immunohistochemical expression of MGMT in ACTH‐secreting pituitary adenomas in patients with Nelson Syndrome. Methods Our material consisted of specimens from ACTH‐secreting pituitary adenomas from patients with Nelson Syndrome. Immunohistochemical staining for MGMT was performed using the streptavidin‐biotin‐peroxidase complex method. MGMT immunoreactivity was assessed microscopically and recorded as an estimated percentage of nuclear MGMT immunopositivity. (0=none, 1=<10%, 3=<50%, 4=>50%) Results Male:Female ratio was 3:5, with average patient age being 62 (range 57–66). Five of the eight specimens (65%) exhibited no MGMT immunoreactivity, with two out of eight cases (25%) showing slight MGMT immunopositivity and one out of eight cases (12%) demonstrating moderate MGMT immunopositivity (<25%). Conclusions Temozolomide therapy may be useful in patients with Nelson Syndrome. Absent or low MGMT staining in brain and other neoplasms has been shown to correlate with successful treatment with temozolomide, and recent reports assessing aggressive pituitary adenomas suggest similar outcome.

Following traumatic brain injury (TBI) approximately 25% of patients develop partial or complete hypopituitarism (HP). In our previous histologic study we found no changes in the pituitaries of patients who died instantly after TBI (Group I). In 43% of patients who survived 1‐7 days acute pituitary infarcts were apparent (Group II). In the present work, 3 group I and 7 group II pituitaries with infarcts were selected for histological and immunohistochemistry (IH) evaluation. IH was performed for adenohypophyseal hormones by the streptavidin‐biotin‐peroxidase method. In group I pituitaries, no histological changes were found and IH showed normal distribution and intensity for GH, PRL, ACTH, TSH, FSH, LH and α‐subunit (α‐SU). In group II pituitaries acute infarct (size range: 10% to 80%) was evident. IH in the non‐necrotic areas revealed no significant change. In the area of early necrosis the dying cells were still immunopositive (IP) for GH, PRL, ACTH, TSH, FSH, LS, and α‐SU. Even in the necrotic cells with loss of cell membrane, nuclear pyknosis, rhexis and lysis IP cytoplasms were still apparent indicating that hormone release is affected by ischemia. Subsequently the intensity of IP cells gradually decreased and IP granules leaked out from the necrotic cells and were seen extracellularly. In conclusion infarction and loss of adenohypophyseal cells may contribute to HP but other factors should also be considered.

SNAP‐25, a synaptosome associated exocytosis protein of 25 kDa plays an important role in the secretory activity of several endocrine cells. In the present study, we investigated 15 PRL, 10 GH, 5 ACTH, 5 TSH, 15 FSH/LH/ alpha subunit producing, and 5 null cell adenomas. Surgically removed, formalin‐fixed and paraffin embedded human pituitary tumors were used. Sections were immunostained by the streptavidin‐biotin‐peroxidase complex method. The results showed that 10 PRL producing adenomas were strongly immunoreactive for SNAP‐25. The immunopositive material was located mainly on the plasmalemma. The nuclei were immunonegative, the cytoplasm was mildly immunopositive in several cells. Treatment of patients with dopamine agonists before surgery decreased markedly SNAP‐25 immunopositivity in 5/10 cases. In GH producing adenomas SNAP‐25 was seen in 5 cases. Immunopositivity was mild‐ moderate, membrane bound and cytoplasmic. Somatostatin analogs caused no marked reduction in immunopositivity (5 cases). Other adenoma types were practically immunonegative. Among human pituitary adenomas only PRL producing tumors release their secretory granules via exocytosis as was demonstrated by electron microscopy. This observation is concordant with our results. In dopamine agonist treated patients, decreased SNAP‐25 expression in PRL producing adenoma cells is consistent with reduction of blood PRL levels.

Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.