Pituitary adenomas sometimes show rapid growth and recurrence, and about one third invade the structures surrounding the sella turcica. In an attempt to determine aggressive behavior at an early stage, we used the MIB-1 antibody to identify the Ki-67 antigen. The present study was designed to evaluate pituitary adenomatous tissue in terms of secretion and proliferation and to correlate the Ki-67 index with hormone phenotype and invasive behavior. Material from 159 patients submitted to one or more resections of pituitary adenomas was evaluated. Forty-two non-secretory adenomas and 43 adenomas immunoreactive for growth hormone, 19 for prolactin, 18 for growth hormone and prolactin, 16 for adrenocorticotropic hormone (ACTH), and 21 cases of plurihormonal/gonadotropin adenomas were detected by immunohistochemistry. The MIB-1 antibody was positive in 139 samples and the Ki-67 index ranged from 0.16 to 15.48% (mean = 1.22 ± 2.09%), with no significant difference between genders, age groups, or secretory and non-secretory status. The Ki-67 index was higher in ACTH-secreting adenomas. Invasive pituitary adenomas had a significantly higher Ki-67 index (2.01 ± 3.15%) than macroadenomas with or without supra-sellar extension (1.12 ± 1.87%; P = 0.02). The index was not significantly different in the subgroup of adenomas with invasion of the cavernous sinus compared to groups with other types of invasion. We conclude that tumoral proliferative activity evaluated by the detection of the Ki-67 antigen is significantly higher in invasive than noninvasive adenomas, information which can be useful in therapeutic postoperative management since index cut-off values associated with aggressive behavior can be established.

Inactivating mutations of TP53, a tumor suppressor gene, are associated with abnormal cell proliferation. Although p53 expression is common in many human malignancies, p53 protein has seldom been evaluated in pituitary tumors. When detected, the percentage of p53-positive cells is low, and, in general, it is exclusive for invasive lesions. The aim of the present study was to use immunohistochemistry to determine the presence of p53 protein in pituitary adenomas from tumor samples of 163 surgeries performed in 148 patients (40% male, 60% female). In 35% of the cases the adenoma was nonfunctional, while in the others it was associated with PRL, GH and/or ACTH endocrine hypersecretion syndrome. Macroadenomas were observed in 83.2% of the cases with available neuroimage evaluation, of which 28% invaded the cavernous, sphenoid and/or ethmoidal sinus, bone, third ventricle or subfrontal lobe. p53 protein was detected in 2/148 patients (1.3%). Immunohistochemistry was positive for PRL and GH in these cases. Due to the high percentage of invasive pituitary adenomas found in our study, the low frequency of p53 detection suggests that it is inadequate as a routine marker for aggressiveness and as a predictive factor of tumor behavior.

With the aim of evaluating the relationship between pituitary tumorigenesis and the presence of estrogen receptor-α (ERα) by immunohistochemistry (IH) and their relevance to patients’ clinical presentation, hormonal phenotypes of adenomas, preoperative neuroimaging findings, and the index of cellular replication MIB-1, a study was conducted with material from 91 women and 67 men with pituitary adenomas. The patients had acromegaly (29.7%), Cushing’s disease (14.6%), hyperprolactinemic syndrome (20.9%), and clinically nonfunctioning tumors (34.8%). Of the patients, 14.6% had microadenomas, 52.5% had macroadenomas with or without suprasellar growth, 28.5% had invasive macroadenomas and in 4.4% the adenoma was not visualized. IH showed that 43 were positive for growth hormone (GH), 16 for corticotropin (ACTH), 18 for prolactin (PRL), 18 for PRL+GH, 6 for luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 15 had a plurihormonal reaction, and 42 had nonfunctioning adenomas. The presence of ERα was positive in 9/158 adenomas with a median value for the percentage of labeled cells of 42.89%, and in 6/16 controls (autopsy samples) with a median value for the percentage of labeled cells of 0.024%. ERα was significantly more prevalent in controls than in patients with adenomas (37.5 versus5.7%; p = 0.001); however, the mean ERα concentration in adenomas was significantly greater than in controls (42.89 versus 0.024%; p < 0.001). No significant difference in the concentration of ERα was found across the clinical presentations, hormonal phenotypes or findings of preoperative CT. Among the ERα-positive adenomas, ERα values were significantly greater in invasive macroadenomas (80%) than in microadenomas (3.33%). MIB-1 values did not differ significantly between ERα-positive and -negative adenomas, nor did the correlation between ERα values and the MIB-1 index attain significance in the total sample, even when only ERα-positive adenomas and positive MIB-1 indexes were considered. It was concluded that, when present in pituitary tumors, ERα exhibits a high concentration, and is more common in nonfunctioning and invasive adenomas, but absent in ACTH-secreting ones.

Angiogenesis, a fundamental process for the development and growth of a tumor, is less expressive in adenomas than in the normal pituitary tissue. There is controversy about the behavior of angiogenesis as a function of hormonal secretion or other characteristics of pituitary tumors. Endoglin (CD105) is a proliferation-associated antigen on endothelial cells, as well as an endothelial progenitor cell marker. We used the anti-endoglin antibody, a glycoprotein expressed in endothelial cells and conjunctive tissue, as a new marker particularly associated with neovascularization, in order to determine microvascular density (MVD) in pituitary adenomas. There were 77 samples, 31 males and 46 females, carriers of micro- (n = 24) or macroadenomas (n = 53). No significant difference was found in MVD concerning the variables of age, clinical presentation, and immunohistochemical phenotype or tumor size. MVD in males (median 5.4) was significantly higher (P = 0.001) than in females (median 3.0). Cell proliferation, as evaluated by the MIB-1 antibody (a cellular proliferation index [Ki-67 antigen], which is present in all stages of the cellular cycle except for the resting cells), ranged from 0% to 19.58%. No correlation was found between MIB-1 and MVD. It is possible to infer that the lower MVD found in pituitary adenomas in females reflects an inhibitory estrogen action on TGF-beta1, a protein involved in vascular remodeling. Because of its role as a TGF receptor ligand, endoglin proved to be sensitive in detecting this gender difference in pituitary tumor angiogenesis.

RESUMO -Sintomas psicológicos, especialmente ansiedade e depressão, têm sido associados à hiperprolactinemia. Para avaliar a presença desses sintomas, foram submetidos à entrevista através do Composed International Diagnostic Interview, seguido pela escala de Hamilton para depressão, 32 pacientes (5 homens e 27 mulheres) com hiperprolactinemia de várias etiologias e 16 normoprolactinêmicos. A prolactina sérica na época da avaliação variou de 28 a 180 ng/mL, sendo que 11 dos pacientes usavam bromocriptina. Detectou-se presença atual de distúrbios de ansiedade em 18 pacientes (56,2%) e 5 controles (31,2%), depressão em 10 pacientes (31,2%) e 2 controles (12,5%), distmia em duas pacientes e outros diagnósticos psiquiátricos em 6 pacientes (18,7%). Os escores da depressão variaram entre 16 e 31 nos pacientes e foram 12 e 16 nos controles. A frequência de sintomas psiquiátricos como um todo, foi significativamente maior nos hiperprolactinêmicos (teste do quiquadrado), mas a diferença não foi significativa na análise isolada de ansiedade ou depressão. A hiperprolactinemia representa um fator de risco de 3,57 para depressão, 3,32 para ansiedade e 3,84 para outros sintomas psiquiátricos. Não houve diferença significativa na frequência de sintomas psiquiátricos entre portadores ou não de adenomas hipofisários e usuários ou não de bromocriptina. Não houve correlação (r= 0,07) entre a prolactina e a frequência de sintomas psiquiátricos. Conclui-se pela necessidade de atentar para a concomitância de hiperprolactinemia e distúrbios psiquiátricos, cujo reconhecimento permitirá abordagem terapêutica específica. PALAVRAS-CHAVE: hiperprolactinemia, prolactinoma, ansiedade, depressão, bromocriptina. Hyperprolactinemia and psychological disturbanceABSTRACT -Psychological symptoms, specially anxiety and depression, have been associated to hyperprolactinemia. To evaluate the presence of these symptoms, 32 patients (5 men and 27 women) with hyperprolactinemia of several etiologies and 15 individuals with normal prolactin levels were submitted to the Composed International Diagnostic Interview, followed by the Hamilton rating scale for depression. The serum prolactin, at the time of evaluation, ranged between 28 and 180 ng/mL. Eleven patients were receiving bromocriptine. The presence of anxiety was detected in 18 patients (56.2%) and 5 controls (32.2%), depression was detected in 10 patients (31.2%) and 2 controls (12.5%), dysthymia in 2 patients and other psychiatric diagnosis in 6 patients (18.7%). The scores of depression ranged between 16 and 31 for the patients, and were 12 and 16 for the controls. The frequency of psychiatric symptoms, as a whole, was significantly higher in the hyperprolactinemic patients (chi-square test), but the difference was not significant in isolated analysis of anxiety and depression. The hyperprolactinemia represents a risk of 3.52 for depression, 3.32 for anxiety and 3.84 for other psychiatric symptoms. There was no significant difference in the frequency of psychiatric symptoms among patients with o...