Endocrine Abstracts

LHX3, a LIM-homeodomain transcription factor, plays a critical role in pituitary and nervous system development. Mutations in the LHX3 gene are associated with combined pituitary hormone deficiency disease (CPHD). Two female siblings with neonatal complications were diagnosed with CPHD resulting from a novel, recessive mutation in LHX3. The index patient presented with classical symptoms of CPHD, featuring deficiencies of GH, LH, FSH, prolactin, TSH and later onset ACTH defici...

The oxyntic mucosa of digestive tract secretes two peptide hormones, ghrelin and obestatin, which are derived from the same gene transcript and play an important role in food intake, metabolic responses and growth and reproduction. Ghrelin and obestatin bind GH secretagogue receptor GHSR1α and G-protein coupled receptor GPR39 respectively, in the pituitary. A limited data in the literature demonstrate that levels of ghrelin peak during first 2 years of life and thereafter...

Several studies demonstrated that the thyroid hormones (TH) downregulate the transcriptional rate of beta and alpha TSH subunits. Recent data showed that T3 also acts posttranscriptionally reducing the polyadenylation and translational rate of the beta TSH mRNA, when acutely administered to thyroidectomized (Tx) rats. This study aimed to investigate whether similar effects occur for the alpha subunit synthesis after acute administration of T3 or T4</...

Introduction: Mutations in AIP have been associated with the familial isolated pituitary adenoma (FIPA) syndrome, an autosomal dominant disease with incomplete penetrance characterised by pituitary adenomas in a familial setting. However, the mechanisms by which AIP inactivation promotes pituitary tumorigenesis are unknown. Studies of AIP in model organisms, such as the fruitfly, harbouring the AIP orthologue CG1847, as well as the zebrafish, are theoretically promising models...

LHX3 is a LIM homeodomain transcription factor necessary for proper development of the pituitary and central nervous system. Patients with mutations in coding regions of the LHX3 gene have complex syndromes including combined pituitary hormone deficiency and nervous system defects resulting in symptoms such as dwarfism, thyroid insufficiency, infertility, and developmental delay. Although previous studies from our group and others have identified promoter and intronic elements...

Introduction: We have recently described a preformed signalosome associated with the GnRH receptor (GnRHR), which undergoes dynamic rearrangement upon stimulation with GnRH. This signaling complex included c-Src, focal adhesion kinase (FAK), paxillin, vinculin, tubulin, caveolin-1, protein kinase C (PKC) δ, PKCε, PKCα, Ras, kinase suppressor of Ras-1 (KSR), MAPK kinase (MEK) 1/2, ERK1/2 and the GnRHR. To sort out the role of the signalosomes associated with the ...

Recent data have shown that, in parallel to its transcriptional action down-regulating TSH synthesis, triiodothyronine (T3) also acts on posttranscriptional steps of beta TSH synthesis, reducing the polyadenylation and translational rate of the beta TSH mRNA, when acutely administered to thyroidectomized rats. This study aimed to investigate whether these effects also occur in TalphaT1 cells, and if they are dependent on gene transcription, which would characterize ...

In the pituitary, estrogens regulate several cell functions via the activation of membrane-associated estrogen receptors (mERs). We have previously reported that both 17β-estradiol (E2) and membrane-impermeable E2-BSA induce rapid apoptotic actions in anterior pituitary (AP) cells, lactotropes and somatotropes through the activation of mERs.In the present study, we investigated the involvement of mERα in the apoptotic action of E2 in...

Introduction: Severe hypoglycemia induced by sulfonylurea overdose is a result of insulin hypersecretion. Pasireotide (SOM230) is a multireceptor-targeted somatostatin analogue with high affinity for somatostatin receptor subtypes sstr1,2,3 and especially sstr5, which are expressed on rat and human β cells; pasireotide has been shown to inhibit insulin secretion in both species. The aim of these studies was to investigate the ef...

As for many tumor types, it has been shown that the Akt pathway is overexpressed and activated in human pituitary tumors. Thus, pituitary tumors may be sensitive to the anti-proliferative effects of mTOR inhibitors. However, part of non-functioning pituitary tumors are rapamycin-resistant. Torin1, second-generation ATP-competitive mTOR kinase inhibitor, suppresses both mTORC1 and mTORC2 complexes. To evaluate the in vitro effects of the mTOR inhibitor Torin1 on pituitar...

Estradiol (E2) may directly interact with growth factors stimulating cell proliferation and differentiation. Previously, we have demonstrated that E2 through membrane estrogen receptor α (mERα) modulates the lactotroph cell population which exhibit noticeable changes in the pituitary gland. The aim of this study was to analyze the mERα contribution on lactotroph cell proliferation in response to E2 and FGF-2 interaction evaluatin...

Introduction: During clinical observation the behaviour of pituitary tumours is frequently unpredictable. The work was aimed at evaluating Ki-67 and topoisomerase II alpha indices as markers of tumour invasiveness and prognostic factors for postoperative course of disease.Material and methods: The Ki-67 and topoisomerase IIα (Topo IIα) indices were determined by immunochemistry in specimens excised from neurosurgically removed pituitary tumours...

The aryl hydrocarbon receptor interacting protein (AIP) gene is abundantly expressed in normal somatotrophs. Somatotropinomas in patients with germline AIP mutations (AIPmut) are typically more aggressive than non-AIPmut adenomas and associated with higher GH/IGF1 secretion. AIP downregulation may also occur in sporadic somatotropinomas, especially in invasive tumours. We wished to evaluate the impact of somatostatin analogues (SSA) pre-treatment on AIP expression in sporadic ...

Our previous results demonstrate that estrogens increase the expression of death receptors TNFRI and Fas in the anterior pituitary and sensitize anterior pituitary cells to pro-apoptotic factors. c-FLIP is a protein that interacts with procaspases 8 and 10 modulating death receptor activity. In normal tissues, two isoforms of c-FLIP have been identified, the short isoform (c-FLIPs) and the long one (c-FLIPL). c-FLIPs has an anti-apoptotic action whereas c-FLIPL has either anti...

Introduction: Cytokines have been suggested to be involved in modulating anti-tumor responses and promoting tumor growth. Some studies have indicated that cytokines could also be involved in the pathogenesis of pituitary tumors. Th17 cells, characterized by expression of several cytokines as interleukin 22 (IL 22), might have a role in tumor immune-surveillance. IL-22 is a cytokine involved in the modulation of tissue responses during inflammation and, through activation of St...

Rab proteins (Rab GTPase) have been implicated in the trafficking and exocytosis of secretary vesicle and play a central role in the secretion of hormones or neurotransmitters. However, the involvement of Rabs and Rab effectors in the regulation of AVP secretion is still unknown. Embryonic stem (ES) cells are pluripotent cells that differentiate into all cell types. Recently, it has been reported that when dissociated ES cells are quickly reaggregeted in low cell-adhesion cult...

DNA methylation has recently been shown to play a role in postnatal as well as developmental gene regulation. Transfer and removal of methyl groups from CpG islands in the promoter region of specific genes has been associated with gene silencing or activation, respectively. POMC is known to present several methylation sites and demethylation of these sites has been shown to be linked to POMC expression by neuroendocrine tumors outside the pituitary.<p class="...

Introduction: VPA, antiepileptic drug, may cause a number of side effects including reproductive deficits in humans. Previously we found that VPA (1 μM) may suppress GnRH-stimulated release of LH from rat anterior pituitary cells in vitro without affecting its basal secretion (Neuroendocrinol Lett 2011 32 101–106). However mechanism of VPA suppressive activity is still unknown. Since pharmacological effects of VPA require GnRH-R activation, the m...

Background: Heterozygote mutations in AIP predispose carriers to young-onset pituitary adenomas, most often somatotroph or lactotroph adenomas. No other tumour type has been consistently detected in AIP mutation positive families, despite the fact that AIP is ubiquitously expressed. Current clinical and experimental data suggest that AIP is a tumour suppressor gene.Aims: To investigate the tumour suppressor role of AIP in a non-pituitary malignant cell l...

Objective: Macroprolactinaemia is the phenomenon of forming immunoglobulins (Igs) against prolactin (PRL). The Ig–PRL complex has an increased half-life resulting in elevated levels of immunoreactivity in most PRL immunoassays without having any significance. Identifying macroprolactinaemia-induced hyperprolactinaemia is essential in order to prevent unnecessary testing and treatment. This study is to establish the combined intra- and inter-individual variability in macro...

Introduction: E-cadherins are found in epithelial tissue. Reduced expression in somatotroph pituitary adenomas has been demonstrated to correlate with dedifferentiated phenotype; reduced tumour size, increased invasiveness, and reduced somatostatin analog response. Recently, correlations between corticotroph tumour dedifferentiation and both E-cadherin immunostaining and reduced E-cadherin gene (CDH1) mRNA was demonstrated.Glucocorticoids induces ...

AMP-activated protein kinase (AMPK) activation decreased GH release and intracellular GH storage in rat pituitary cell cultures and reduced cell proliferation in rat pituitary adenomatous cells (GH3) cultures.We investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) as compared to somatostatin-14 on cell viability (MTT assay after 48-h) and GH secretion (over 24 h) in 16 human GH-secreting pituitary adenomas ...

Introduction: Evidence suggests a relationship between high tumoral Ki-67 LI with persistence of tumor after surgery and lower response rate to medical therapy. Therefore, we aimed to determine the relationship between Ki-67 LI and p53 with age, gender, number of surgeries, cure after surgery and cavernous sinus invasion in pituitary adenomas of patients with acromegaly.Methods: The paraffin-embedded tissue sections of 30 patiets with acromegaly, operate...

Introduction: About 30% of all familial isolated pituitary adenoma (FIPA) and 50% of acromegaly families have a mutation in the aryl hydrocarbon receptor-interacting protein gene (AIP; Chahal, TEM, 2010). The functional role of AIP in somatotroph cells is unknown. Recently, it has been proposed that wild type AIP (wtAIP) is a tumor suppressor gene, role that is lost in the different mutant AIPs (mAIP; Leontiou, JCEM, 2008). In the adenomas, mAIPs are usually foun...

Pituitary adenomas account for ~10–15% of intracranial tumors and result in morbidity due to both altered hormonal patterns as well as side effects of therapy. Currently, great attention has been given to natural coumpouds from functional foods. Among these substances, we highlight that the consumption of carotenoids is associated with reduced risk of chronic diseases including cancer and vascular diseases. In this study we evaluate the influence of β-carotene and ly...

Clinically non-functioning pituitary adenomas account for about one-third of pituitary tumors. The majority of them are pathologically classified as gonadotropinomas or null-cell adenomas without hormonal expression. The rest represent silent corticotroph adenomas and plurihormonal tumors. Conservative therapy with dopamine agonists and somatostatine analogues is effective in some cases only depending on the expression of somatostatine (SSTR) and dopamine 2 receptors (D2R).</p...

There are a limited number of studies investigating the immunological alterations accompanying the Sheehan Syndrome. The aim of this study was to evaluate lymphocyte subsets in these patients.Flow cytofluorometry was used for the immunophenotyping of peripheral blood leukocytes from 15 patients (mean age 61.6±11.3, range 34–75 years) and 25 healthy controls (mean age 56.7±10.6, range 34–80 years). The percentages of CD3+, C...

Corticotropin-releasing hormone (CRH) is known to be produced and secreted by normal rat corticotropes and to contribute in a paracrine manner to POMC synthesis and ACTH secretion in these cells. The regulation of intrapituitary CRH however still has to be clarified.Aim: This study was to establish whether CRH gene expression can be measured in rat pituitaries in vitro and whether CRH modulates its own gene expression within the pitu...

Objective: Resveratrol is a phytoestrogen with various antiproliferatic and proapoptotic effects. One of the underlying mechanisms is downregulation of apoptosis inhibitors, such as Survivin. In human pituitary adenoma cells, Survivin expression is increased as compared to healthy pituitary gland tissue. This in vitro study aims to analyze the effect of Resveratrol on GH3 pituitary adenoma cells of the rat.Methods: GH3 cells were cultivated in F-1...

Cushing Disease (CD) is a serious endocrine disorder that is primarily caused by an ACTH-secreting pituitary adenoma. Current treatments of CD present low efficiency in controlling the tumor mass growth and reducing the release of ACTH. This work investigates a possible new therapy for the treatment of pituitary tumors. Using a nanoparticle extract (nanoOse) of a typical Brazilian palm tree, we verify the in vitro effects of this extract on a ACTH-secreting mouse pituit...