Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression

We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6

Pituitary tumors in patients with MEN1 syndrome

We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.

"Leiomyomatoid angiomatous neuroendocrine tumor" (LANT) of the pituitary reflects idiosyncratic angiogenesis in adenomas of the gonadotroph cell lineage.

Based on a single-case observation, the descriptive label "leiomyomatoid angiomatous neuroendocrine tumor" (LANT) has been tentatively applied to what was perceived as a possible novel type of dual-lineage pituitary neoplasm with biphasic architecture. We report on two additional examples of an analogous phenomenon encountered in male patients, aged 59 years (Case 1) and 91 years (Case 2). Both tumors were intra- and suprasellar masses, measuring 5.6 cm × 4.4 cm × 3.4 cm, and 2.7 cm × 2 cm × 1.7 cm, respectively. Histologically, Case 1 was an FSH-cell adenoma interwoven by vascularized connective tissue septa that tended to exhibit incremental stages of adventitial overgrowth. The epithelial component of Case 2 corresponded to an LH-cell adenoma, and lay partitioned by a maze of paucicellular to hyalinized vascular axes. Irrespective of architectural variations, perivascular spindle cells exhibited immunopositivity for vimentin, muscular actin, and smooth muscle actin. Conversely, negative results were obtained for CD34, EMA, S100 protein, GFAP, and TTF-1. Ultrastructural study failed to reveal metaplastic cell forms involving transitional features between adenohypophyseal-epithelial and mesenchymal-contractile phenotype. We propose that LANT be regarded as a peculiar reflection of maladaptive angiogenesis in some pituitary adenomas, rather than a genuine hybrid neoplasm. While no mechanistic clue is forthcoming to account for this distinctive pattern, hemodynamic strain through direct arterial - rather than portal - supply of the adenoma's capillary bed may be one such explanatory factor. The apparent predilection of the LANT pattern for macroadenomas of the gonadotroph cell lineage remains unexplained.

Predictive factors for the development of visual loss in patients with pituitary macroadenomas and for visual recovery after optic pathway decompression

Objective: To investigate clinical and MRI findings that are predictive of both visual loss in patients with pituitary adenomas and visual recovery after treatment. Design: Cohort study. Participants: Thirty patients (60 eyes) with pituitary adenoma. Methods: Patients underwent neuro-ophthalmic examination and MRI before and after optic chiasm decompression. Visual field (VF) was assessed using the mean deviation in standard automated perimetry (SAP) and temporal mean defect, the average of 22 temporal values of the total deviation plot. Tumour size was measured on sagittal and coronal cuts. Results: Visual loss was found in 47 eyes; 35 had optic atrophy (subtle in 9, moderate in 14, and severe in 12). Before treatment, the average SAP mean deviation and temporal mean defect were -11.78 (SD 8.56) dB and -18.66 (SD 11.20) dB, respectively. The chiasm was 17.3 (SD 6.2, range 10-34) mm above the reference line on the sagittal and 21.8 (SD 8.3, range 12-39) mm on the coronal images. Tumour size correlated with the severity of VF defect. VF improvement occurred in 80% of eyes after treatment. The degree of optic atrophy, visual loss, and tumour size were significantly associated with improvement after treatment. Conclusions: The best predictive factor for visual loss was tumour size, and factors related to visual recovery were the degree of optic atrophy, the severity of VF defect, and the tumour size. Diagnosing pituitary adenomas before optic atrophy becomes severe may be related to a better prognosis in such patients.

Immunolocalization of neuropeptide Y in human pituitary tumours.

Neuropeptide Y (NPY) gene is expressed in human pituitary gland where its function is partially elucidated. NPY could act as a neuroendocrine modulator within this gland. This study was undertaken to assess whether NPY expression is correlated to various pathological situations. Using a highly specific anti-NPY monoclonal antibody, immunohistochemistry analysis was performed in surgically removed pituitary glands. The study included biopsies from 112 human pituitary adenomas, 12 hyperplastic glands and normal anterior pituitary tissues in 34 cases. NPY is immunodetected in 33% of all adenomas, 25% hyperplastic glands and 12% of non-tumoral pituitary gland. NPY expression was significantly higher in adenomas compared to the normal gland. However, no correlation was observed between NPY content and the type of hormonal secretion, sex, age and the status of tumour proliferating potential.

Regulating Mechanisms of Gonadal and Pituitary Tumorigenesis in Mice Producing Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) are structurally and functionally similar glycoprotein hormones acting through the same luteinizing hormone chorionic gonadotropin receptor (LHCGR). The functions of LH in reproduction and hCG in pregnancy are well known. Recently, the expression of LHCGR has been found in many nongonadal tissues and cancers, and this has raised the question of whether LH/hCG could affect the function or tumorigenesis of these nongonadal tissues. We have also previously generated an hCG expressing mouse model presenting nongonadal phenotypes. Using this model it is possible to improve our understanding of nongonadal action of highly elevated LH/hCG. In the current study, we analyzed the effect of moderately and highly elevated hCG levels on male reproductive development and function. The main finding was the appearance of fetal Leydig cell (FLC) adenomas in prepubertal males. However, the development and differentiation of FLCs were not significantly affected. We also show that the function of hCG is different in FLCs and in adult Leydig cells (ALC), because in the latter cells hCG was not able to induce tumorigenesis. In FLCs, LHCGR is not desensitized or downregulated upon ligand binding. In this study, we found that the testicular expression of two G protein-coupled receptor kinases responsible for receptor desensitization or downregulation is increased in adult testis. Results suggest that the lack of LHCGR desensitization or downregulation in FLCs protect testosterone (Te) synthesis, but also predispose FLCs for LH/hCG induced adenomas. However, all the hCG induced nongonadal changes observed in male mice were possible to explain by the elevated Te level found in these males. Our findings indicate that the direct nongonadal effects of elevated LH/hCG in males are not pathophysiologically significant. In female mice, we showed that an elevated hCG level was able to induce gonadal tumorigenesis. hCG also induced the formation of pituitary adenomas (PA), but the mechanism was indirect. Furthermore, we found two new potential risk factors and a novel hormonally induced mechanism for PAs. Increased progesterone (P) levels in the presence of physiological estradiol (E2) levels induced the formation of PAs in female mice. E2 and P induced the expression and nuclear localization of a known cell-cycle regulator, cyclin D1. A calorie restricted diet was also able to prevent the formation of PAs, suggesting that obesity is able to promote the formation of PAs. Hormone replacement therapy after gonadectomy and hormone antagonist therapy showed that the nongonadal phenotypes observed in hCG expressing female mice were due to ovarian hyperstimulation. A slight adrenal phenotype was evident even after gonadectomy in hCG expressing females, but E2 and P replacement was able to induce a similar phenotype in WT females without elevated LH/hCG action. In conclusion, we showed that the direct effects of elevated hCG/LH action are limited only to the gonads of both sexes. The nongonadal phenotypes observed in hCG expressing mice were due to the indirect, gonadal hormone mediated effects of elevated hCG. Therefore, the gonads are the only physiologically significant direct targets of LHCGR signalling.

Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.

Endoscopic endonasal approach for pituitary adenoma: surgical complications in 301 patients

The authors investigate the complications of transnasal transsphenoidal endoscopic surgery in the treatment of 301 patients with pituitary adenomas. A retrospective analysis of complications in 301 patients submitted to transsphenoidal transnasal endoscopic surgery at the General Hospital of Fortaleza, Brazil between January 1998 and December 2009. The complications were divided in two groups: anatomical (oronasofacial, sphenoid sinus, intrasellar, suprasellar and parasellar) and endocrinological complications (anterior and posterior pituitary dysfunctions). We observed a total of 81 complications (26.9%) in our series. Anatomical complications occurred in 8.97% (27 cases): 8 CSF postoperative leaks (2.6%), 6 cases (1.9%) of delayed nasal bleeding, 5 cases (1.6%) of sphenoidal sinusitis, 3 cases (0.9%) of carotid artery lesion, 2 cases of meningitis (0.6%) and one case (0.3%) of each of the uncommon following complications: intrasella-suprasella hematoma, pontine hematoma and chiasmaplexy. Endocrinological complications occurred in 17.9% (54 cases): additional postoperative anterior lobe insufficiency in 35 cases (11.6%), and postoperative diabetes insipidus in 19 cases (6.3%). In our series, 3 cases of deaths (not directly related to the procedure) were also observed. Endoscopic transsphenoidal surgery represents an effective option for the treatment of patients with pituitary tumor. Complications still occur and must be reduced as much as possible. Successful endoscopic pituitary surgery requires extensive training in the use of an endoscope and careful planning of the surgery. Additional improvement can be expected with greater experience and new technical developments.

Glucocorticoid Replacement and Mortality in Patients with Nonfunctioning Pituitary Adenoma

Current treatment guidelines generally suggest using lower and weight-adjusted glucocorticoid replacement doses in patients with insufficiency of the hypothalamic-pituitary-adrenal (HPA) axis. Although data in patients with acromegaly revealed a positive association between glucocorticoid dose and mortality, no comparable results exist in patients with nonfunctioning pituitary adenomas (NFPA).

Characterization of MENX-associated pituitary tumours

Aims: The aim of this study is to evaluate the pathological features, serum hormone levels and ex-vivo cultures of pituitary adenomas that occur in rats affected by MENX syndrome. MENX is multiple endocrine neoplasia syndrome caused by a germline mutation in the cell cycle inhibitor p27. Characterisation of MENX adenomas is a prerequisite to exploit this animal model for molecular and translational studies of pituitary adenomas. Methods: We investigated MENX pituitary adenomas with immunohistochemistry, double immunofluorescence, electron microscopy, RT-PCR, measurement of serum hormone levels and ex-vivo cultures. Results: Adenomas in MENX rats belong to the gonadotroph lineage. They start from 4 months of age as multiple neoplastic nodules and progress to become large lesions that efface the gland. Adenomas are composed of chromophobic cells predominantly expressing the glycoprotein alpha-subunit (αGSU). They show mitotic activity and high Ki67 labelling. A few neoplastic cells co-express gonadotrophins and the transcription factor SF1, together with growth hormone or prolactin and Pit-1, suggesting that they are not fully committed to one cell lineage. Ex vivo cultures show features similar to the primary tumour. Conclusions: Our results suggest that p27 function is critical in regulating gonadotroph cells growth. The MENX syndrome represents a unique model to elucidate the physiological and molecular mechanisms mediating the pathogenesis of gonadotroph adenomas. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.

Pilocytic astrocytoma following radiotherapy for craniopharyngioma: case report

Administration of fractionated doses of irradiation is part of the adjutant therapy for CNS tumours such as craniopharyngiomas and pituitary adenomas. It can maximise cure rates or expand symptom-free period. Among the adverse effects of radiotherapy, the induction of a new tumour within the irradiated field has been frequently described. The precise clinical features that correlate irradiation and oncogenesis are not completely defined, but some authors have suggested that tumors are radiation induced when they are histologically different from the treated ones, arise in greater frequency in irradiated patients than among normal population and tend to occur in younger people with an unusual aggressiveness. In this article, we report a case of a papillary astrocytoma arising in a rather unusual latency period following radiotherapy for craniopharyngioma.

Association between tumoral GH-releasing peptide receptor type 1a mRNA expression and in vivo response to GH-releasing peptide-6 in ACTH-dependent Cushing`s syndrome patients

Objective: GH secretagogues (GHS) produce exaggerated ACTH and cortisol responses in Cushing`s disease (CD) patients, attributable to their direct action on GH-releasing peptide receptor type la (GHSR-1a). However, there are no studies correlating the ill vivo response to GHS and GHSR-1a mRNA expression in ACTH-dependent Cushing`s syndrome (CS) patients. The aim of this study is to correlate the patterns of ACTH and cortisol response to GH-releasing peptide-6 (GHRP-6) to GHSR-1a expression in ACTH-dependent CS patients Design: Prospective study in a tertiary referral hospital center. Fifteen CD patients and two ectopic ACTH syndrome (EAS) patients were studied. Methods: Tumor fragments were submitted to RNA extraction, and GHSR-1a expression was studied through real-time qPCR and compared with normal tissue samples. The patients were also submitted to desmopressin test and vasopressin receptor type 1B (AVPR1B) mRNA analysis by qPCR. Results: GHSR-1a expression was similar in normal pituitary samples and in corticotrophic tumor samples. GHSR-1a expression was higher in patients (CD and EAS) presenting ill vivo response to GHRP-6. Higher expression of AVPR1B was observed in the EAS patients responsive to desmopressin, as well as in corticotrophic tumors, as compared with normal pituitary samples, but no correlation between AVPR1B expression and response to desmopressin was observed in the CD patients. Conclusions: Our results revealed a higher expression of GHSR-1a in the ACTH-dependent CS patients responsive to GHRP-6, suggesting an association between receptor gene expression and ill vivo response to the secretagogue in both the CD and the EAS patients.

Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment

About one-third of acromegalics are resistant to the clinically available somatostatin analogs (SA). The resistance is related to density reduction or different expression of somatostatin receptor subtypes (SSTR). This study analyzes SSTR`s expression in somatotrophinomas, comparing to SA response, hormonal levels, and tumor volume. We analyzed 39 somatotrophinomas; 49% were treated with SA. The most expressed SSTR was SSTR5, SSTR3, SSTR2, SSTR1, and SSTR4, respectively. SSTR1 and SSTR2 had higher expression in patients that had normalized GH and IGF-I. SSTR3 was more expressed in patients with tumor reduction. There was a positive correlation between the percentage of tumor reduction and SSTR1, SSTR2 and SSTR3 expression. Also, a positive correlation between SSTR2 mRNA expression and the immunohistochemical reactivity of SSTR2 was found. Our study confirmed the association between the SA response to GH and IGF-I and the SSTR2. Additionally, this finding was also demonstrated in relation to SSTR1.

Influence of the Fibroblast Growth Factor Receptor 4 Expression and the G388R Functional Polymorphism on Cushing`s Disease Outcome

Context: Abnormal FGFR4 expression has been detected in pituitary tumors, especially in larger and invasive adenomas. In addition, the FGFR4 functional polymorphism G388R has been associated with poor outcome in several human malignancies. Then, we hypothesized that FGFR4 expression and genotype could be markers of adverse outcome of Cushing`s disease after transsphenoidal surgery. Objectives: The objective was to investigate whether there is an association between the postoperative outcome of Cushing`s disease (remission/recurrence) and the FGFR4 G388R genotype or the FGFR4 expression in corticotrophinomas. Design and Patients: Clinical, hormonal, and pathological data of 76 patients who underwent the first transsphenoidal surgery were retrospectively reviewed. All patients were genotyped for G388R polymorphism. FGFR4 expression was assessed by real-time PCR in 18 corticotrophinomas. Main Outcome Measures: The outcome measures included the FGFR4 G388R genotype and FGFR4 expression in postoperative remission and recurrence of Cushing`s disease. Results: Homozygosis for FGFR4 glycine (Gly(388)) allele was associated with reduced disease-free survival, in the univariate analysis (hazard ratio of 6.91; 95% confidence interval of 1.14-11.26; P = 0.028). Male gender (P = 0.036), lack of pathology confirmation (P = 0.009), and cortisol levels more than 2 mu g/dl in the early postoperative period (P < 0.001) were also significant predictors of Cushing`s disease recurrence in the univariate analysis. FGFR4 overexpression was found in 44% of the corticotrophinomas, and it was associated with lower postoperative remission rate (P = 0.009). Conclusions: Our data suggest that homozygosis for FGFR4 Gly(388) allele and FGFR4 overexpression are associated with higher frequency of postoperative recurrence and persistence of Cushing`s disease, respectively. (J Clin Endocrinol Metab 95: E271-E279, 2010)

Management of prolactinomas in Brazil: an electronic survey

Dopamine agonists are the treatment of choice for prolactinomas. However, there are still controversies concerning dose, treatment duration and criteria for drug withdrawal in different clinical situations. The aim of this study was to assess diagnostic and therapeutic approaches to prolactinomas among members of the Brazilian Society of Endocrinology and Metabolism (SBEM). SBEM members answered a questionnaire sent by e-mail that included 18 questions related to controversial issues about the management of prolactinomas. Among SBEM members, 721 (approximately 24% of total) answered the questionnaire. Concerning the diagnosis, 38% of the respondents stated that prolactin levels < 100 ng/ml would exclude the presence of a prolactinoma. Most of them favored the screening for macroprolactin in asymptomatic individuals instead of a routine screening (74% vs. 26%). Regarding the treatment, 70% of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas whereas similar proportions advised cabergoline or bromocriptine as the best treatment for microprolactinomas (52% vs. 48%). Only 20% and 34% of respondents favored treatment withdrawal 2-3 years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively. In case of pregnancy, only 58 and 70% of respondents advocated discontinuation of treatment with dopamine agonists in patients with macroprolactinomas and microprolactinomas, respectively. Finally, only 36% would allow breast-feeding without restriction, 44% would restrict it to patients with microprolactinomas and 20% would not recommend it for women with prolactinomas There are several points of disagreement among SBEM members regarding the management of prolactinomas.