Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophin. However, its role in human Alzheimer's disease (AD) is largely unknown. We examined PACAP expression in postmortem human AD and triple transgenic mouse (3xTG, Psen1/APPSwe/TauP301L) brains. We established an in vitro model of primary neuronal cell culture to study the protective effects of PACAP against β-amyloid (Aβ) toxicity. We further studied the PACAP-Sirtuin 3 (Sirt3) pathway on mitochondrial function. PACAP expression was reduced in AD and 3xTG mouse brains. This reduction was inversely correlated with Aβ and tau protein levels. Treatment with PACAP effectively protected neurons against Aβ toxicity. PACAP stimulated mitochondrial Sirt3 production. Similar to PACAP, Sirt3 was reduced in AD and 3xTG brains. Knocking down Sirt3 compromised the neuroprotective effects of PACAP, and this was reversed by over-expressing Sirt3. PACAP is reduced in AD and may represent a novel therapeutic strategy.     

Oncogene-Induced Senescence in Pituitary Adenomas—an Immunohistochemical Study

Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.     

Clonality of Pituitary Tumours: More Complicated than Initially Envisaged?

The application of allelotype microsatellite polymorphisms and X chromosome inactivation analysis in samples from women allow assessment of clonality. Early studies showed that sporadic human pituitary tumors are benign adenomas of monoclonal origin. This implies that they arise from de novo somatic mutation(s) within a single pituitary cell. However, the evidence obtained from a number of studies indicate that morphology cannot predict clonality, clonality within a given tumour may be multiple or single, multiple tumours arising on the background of hyperplasia may be of identical or differing clonality, and multiple "sporadic" tumours within a gland may be of differing clonal origin. Thus, while the early available evidence indicated that pituitary tumours appear largely monoclonal, it is simplistic to assume that this is inevitable and that these cannot be multiclonal in origin. These observations would be entirely compatible with an initiating stimulus resulting in hyperplasia of specific cell types in the pituitary, which itself gives rise to several distinct clones with variable potential to develop into tumours. Such stimuli might include hypothalamic trophic factors, intrapituitary growth factors, or pituitary specific oncogenes.     

Pituitary–adrenal responses to arm versus leg exercise in untrained man

The purpose of this study was to examine pituitary–adrenal (PA) hormone responses [beta-endorphin (β-END), adrenocorticotropic hormone (ACTH) and cortisol] to arm exercise (AE) and leg exercise (LE) at 60 and 80% of the muscle-group specific VO₂ peak. Eight healthy untrained men (AE VO₂ peak=32.4±3.0 ml kg⁻¹ min⁻¹, LE VO₂ peak=46.9±5.3 ml kg⁻¹ min⁻¹) performed two sub-maximal AE and LE tests in random order. Plasma β-END, ACTH and cortisol were not different (P>0.05) between AE and LE at either exercise intensity; the 60% testing elicited no changes from pre-exercise (PRE) values. For 80% testing, plasma β-END, ACTH and cortisol were consistently, but not significantly, greater during LE than AE. In general, plasma β-END and ACTH were higher (P<0.05) during 80% exercise, than PRE, for both AE and LE. Plasma cortisol was elevated (P<0.05) above PRE during 80% LE, and following 80% for both AE and LE. Plasma ACTH was higher (P<0.05) during 80% LE and AE versus 60% LE and AE, respectively. Plasma β-END and cortisol were significantly higher during and immediately after 80% LE than 60% LE. Thus, plasma β-END, ACTH and cortisol responses were similar for AE and LE at the two relative exercise intensities, with the intensity threshold occurring somewhere between 60 and 80% of VO₂ peak. It appears that the smaller muscle mass associated with AE was sufficient to stimulate these PA axis hormones in a manner similar to LE, despite the higher metabolic stress (i.e., plasma La^-) associated with LE.     

Primary Lymphoma of Pituitary Gland: A Neoplasm of Acquired Malt?

A 66-yr-old man presented with presyncopal episodes, dizziness, anorexia, nausea, and weight loss and was noted to have low blood pressure with a postural drop and sparse eyebrows. Laboratory investigations revealed evidence of hypopituitarism. Magnetic resonance imaging (MRI) revealed a non-enhancing mass arising from the adenohypophysis. The neurohypophysis was displaced laterally but appeared otherwise normal. The lesion was thought to be a nonfunctioning pituitary adenoma and a trans-sphenoidal hypophysectomy was performed. Histologically, this lesion was a diffuse large B-cell lymphoma that had features of a high grade mucosa associated lymphoid tissue (MALT)-type lymphoma arising in association with low-grade B-cell lymphoma of MALT type. There was no clinical or radiological evidence of lymphoma in other sites and there was no evidence of an immunocompromised state. Only one previous case of primary malignant lymphoma of the pituitary has been reported and this patient presented with compression of the optic chiasm. We describe the clinical and pathological features of a patient who presented with hypopituitarism and was found to have a pituitary lymphoma. This is the first reported case of a pituitary lymphoma presenting with pituitary failure and the first case characterized by lymphocyte-marker studies that confirmed it to be a B-cell lymphoma.     

Pituitary Adenoma with Neuronal Choristoma (PANCH): Composite Lesion or Lineage Infidelity?

Fifteen cases of the rare association of pituitary adenoma and neuronal choristoma (PANCH) were investigated by histology, immunohistochemistry, and electron microscopy. Acromegaly was apparent clinically in 11 patients and was equivocal in 1, and 3 lesions appeared to be nonfunctioning. Histology revealed various proportions of chromophobic PA and nervous tissue consisting of neuronlike cells and neuropil. Immunohistochemistry documented growth hormone (GH) in every PA, including those unassociated with clinical acromegaly. In contrast, the NCH component showed no consistent immunohis-tochemical profile. Most frequent reactivities were for the pituitary hormone a subunit, thyroid-stimulating hormone, and GH, whereas only a few cases displayed scattered positivity for GH-releasing hormone. Low-molecular weight keratin tested positive in PAs and in a few cells and processes of an NCH. A few fibrous bodies were immunoreactive for neurofilament protein. Electron microscopy revealed sparsely granulated GH cell adenoma, neurons, and neuropil. Cells intermediate between PA and neurons were numerous in 1 lesion. The present morphologic findings as well as lack of GH cell hyperplasia and the consistent association of NCH with but one type of PA do not support the causative role of NCH in the initiation of PA, as proposed previously. It appears that NCH is the result of neuronal differentiation within sparsely granulated GH cell adenomas.     

Response of Pituitary—Thyroid Axis to a Short-Term Shift in Deuterium Content in the Body

Bulletin of Experimental Biology and Medicine - We studied functional changes in rat pituitary—thyroid axis after a short-term shift in deuterium body content. Male Wistar rats consumed...     

Effect of Constant Illumination on the Function of the Hypothalamic—Pituitary—Adrenal Axis in Nonhuman Primates

Bulletin of Experimental Biology and Medicine - We studied the effect of constant illumination on the effects of administration of arginine vasopressin (AVP), one of the most important regulators...     

Silent Adenoma Subtype 3 of the Pituitary—Immunohistochemical and Ultrastructural Classification: A Review of 29 Cases

The silent adenoma subtype 3 (SAS-3) of undetermined cellular derivation is a seemingly nonfunctioning aggressive pituitary tumor with a high recurrence rate. At the time of diagnosis SAS-3s are macro- or giant adenomas particularly aggressive in young individuals, especially women. They are usually associated with mild hyperprolactinemia and are unremarkable by histology. Immunohistochemistry, demonstrating scattered immunoreactivity mostly for GH, PRL, TSH, and α-subunit, is not diagnostic. Presently, only TEM permits conclusive diagnosis. Ultrastructurally, the large polar adenoma cells contain abundant RER, masses of SER, extensive multipolar Golgi apparatus, and unevenly clustered mitochondria, displaced by RER and SER, which may show close spatial relationship to RER. Cell membranes often form plexiform interdigitations. Nuclear pleomorphism and nuclear inclusions are common. The 100- to 200-nm secretory granules accumulate heavily in cell processes, which is a hallmark of glycoprotein hormone cell differentiation. The endothelial cells may contain tubuloreticular inclusions. Complete surgical removal of the large often invasive tumors is difficult necessitating postoperative treatment. SAS-3 is sensitive to conventional radiation. Some tumors express somatostatin receptors and respond well to somatostatin analogues, offering long-term control in patients with residual tumor. Possible derivation of SAS-3 from rostral thyrotrophs, a cell type presently known in rodents is comtemplated.     

Decreased TAp63 and ΔNp63 mRNA Levels in Most Human Pituitary Adenomas Are Correlated with Notch3/Jagged1 Relative Expression

Despite recent advances in molecular genetics, the pituitary adenoma initiation, development, progress, and the molecular basis of their unique features are still poorly understood. In this sense, it is proposed that stem cell could be involved in pituitary adenoma tumorigenesis. It is suggested that TP63 has important functions in stem cells, and it may have interplay of TP63 and Notch and its ligand Jagged in this process. This study aimed to evaluate the distinct expression of TP63 isoforms (TAp63 and ΔNp63), as well as its correlation with Notch3 receptor and its ligand Jagged1 in human pituitary adenomas at the messenger RNA (mRNA) level. We included 77 pituitary adenoma tumor samples from patients who underwent surgical resection. The expression levels of TP63 isoforms (TAp63 and ΔNp63) and Notch3 and its ligand Jagged1 were evaluated by qRT-PCR using isoform-specific primers. We also evaluated proliferation index immunohistochemically using KI-67 antibody. The expression levels were associated with clinical outcomes, as age, gender, tumor size, and tumor subtype. In summary, we found that mRNA expression of both TP63 isoforms decreased in pituitary adenomas compared with normal pituitary control. On the other hand, there was an increase of relative Notch3 and Jagged1 mRNA expression in the majority of examined samples. The mRNA expression of three genes evaluated was correlated and statistically significantly. There was no significant association between gene expression and the analyzed clinical data. The current study has provided the first time evidence that Tap63 and ΔNp63 isoforms are underexpressed in most pituitary adenomas. These results are correlated with Notch3 and its ligand Jagged1 overexpression, corroborating previous studies pointing its antagonistic interactions.     

Determination of Cell Proliferation Using Mcm2 Antigen and Evaluation of Apoptosis and TGF-β1 Expression in GH-secreting or Clinically Nonfunctioning Pituitary Adenomas

Pituitary adenomas (PA) occasionally show aggressive behavior, with invasion of the surrounding tissues. The identification of markers able to recognize aggressive PA in early stages remains a challenge. We aimed to determine the expression of a new cell proliferation marker, Mcm2, and the presence of apoptosis in PA, and to evaluate the association of clinicopathological features with the apoptotic and proliferative indices. Additionally, the TGF-β1 expression, an inducer of apoptosis, was determined. The proliferative index was determined in GH-secreting or clinically nonfunctioning PA using immunohistochemical (IH) methods for Mcm2 and Ki-67 antigens. The apoptosis was assessed by the TUNEL method and the TGF-β1 expression by IH. A significant positive correlation was found between log Mcm2 index and log Ki-67 index (p < 0.001). Mcm2 and Ki-67 detected a similar number of proliferating cells. Mcm2 index showed a significant association with tumor extension (p = 0.02), but not with tumor invasion. Apoptosis was detected in 17% of the adenomas, with a maximum apoptotic index of 0.77%. Immunoreactivity to TGF-β1 was observed in 77% of the adenomas, showing an association with tumor extension. We concluded that, in this sample, Mcm2 was similar to Ki-67 in the identification of the proliferating cells and that apoptosis was rare.