Publications by authors named "Monalisa Azevedo"

31 Publications

Controversial issues in the management of hyperprolactinemia and prolactinomas - An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism.

Arch Endocrinol Metab 2018 Mar-Apr;62(2):236-263

Serviço de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil.

Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.
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http://dx.doi.org/10.20945/2359-3997000000032DOI Listing
July 2018

Peripheral Nerve Stimulation for Painful Mononeuropathy Secondary to Leprosy: A 12-Month Follow-Up Study.

Neuromodulation 2018 Apr 29;21(3):310-316. Epub 2017 Oct 29.

Department of Endocrinology, University Hospital of Brasília, Brasilia, Brazil.

Objective: Leprosy affects approximately 10-15 million patients worldwide and remains a relevant public health issue. Chronic pain secondary to leprosy is a primary cause of morbidity, and its treatment remains a challenge. We evaluated the feasibility and safety of peripheral nerve stimulation (PNS) for painful mononeuropathy secondary to leprosy that is refractory to pharmacological therapy and surgical intervention (decompression).

Methods: Between 2011 and 2013 twenty-three patients with painful mononeuropathy secondary to leprosy were recruited to this prospective case series. All patients were considered to be refractory to optimized conservative treatment and neurosurgical decompression. Pain was evaluated over the course of the study using the neuropathic pain scale and the visual analog scale for pain. In the first stage, patients were implanted with a temporary electrode that was connected to an external stimulator, and were treated with PNS for seven days. Patients with 50% or greater pain relief received a definitive implantation in the second stage. Follow-ups in the second stage were conducted at 1, 3, 6, and 12 months.

Results: After seven days of trial in the first stage, 10 patients showed a pain reduction of 50% or greater. At 12-month follow-up in the second stage, 6 of the 10 patients who underwent permanent device implantation showed a pain reduction of 50% or greater (75% reduction on average), and two patients showed a 30% reduction in pain. Two patients presented with electrode migration that required repositioning during the 12-month follow-up period.

Conclusions: Our data suggest that PNS might have significant long-term utility for the treatment of painful mononeuropathy secondary to leprosy. Future studies should be performed in order to corroborate our findings in a larger population and encourage the clinical implementation of this technique.
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http://dx.doi.org/10.1111/ner.12714DOI Listing
April 2018

Prevalence of the rs1801282 single nucleotide polymorphism of the PPARG gene in patients with metabolic syndrome.

Arch Endocrinol Metab 2015 Aug;59(4):297-302

Universidade de Brasília, Brasília, DF, BR.

Objective: This study aimed to get the genotypic and allelic frequencies of rs1801282 in 179 volunteer donors and 154 patients with Metabolic syndrome (MetS) in Brasilia, Brazil and also examine the association with anthropometric, biochemical and hemodynamic variables in the latter group. MetS comprises a group of diseases resulting from insulin resistance, in-creased risk of type 2 diabetes and atherosclerotic cardiovascular disease. MetS is defined by the presence of increased visceral fat, atherogenic dyslipidemia (elevated triglycerides (TGL)), with decreased high density lipoprotein (HDL) and increased low density lipoprotein (LDL) levels, hypertension (BPH) and disturbances in glucose homeostasis representing a significant burden across the world due to the alarming increase in the incidence over the last decades besides their significant morbidity and mortality. Peroxisome proliferator activated receptor-gamma (PPARg) has been mentioned as a candidate gene for determining the risk of MetS. It is a member of the nuclear receptors superfamily and a ligand-activated transcription factor, which regulates the expression of genes involved in the network lipogenesis and adipogenesis, insulin sensitivity, energy balance, inflammation, angiogenesis and atherosclerosis. Among the PPARG genetic variants, single nucleotide polymorphism rs1801282 has been the most extensively studied one since it was first described by Yen and cols. in 1997. This polymorphism is characterized by the replacement of a proline (CCC) to an alanine (GCA) at codon 12 of exon B, due to the exchange of a cytosine with a guanine. The Ala allele frequency varies in different ethnic groups.

Materials And Methods: DNA was extracted using Chelex-100 method and determinations of genotypes were performed by allele-specific chain reaction.

Results: The distribution of genotype frequency of the MetS group was not statistically different from the frequency in the donor population at large. In the first group, genotype frequency was CC to 0.869 and 0.103 for CG, while allelic frequencies were 0.948 for C and 0.052 for G allele. In the group of donors, the genotype and allele frequencies were 0.882 for CC, 0.117 to CG; and 0.941 to 0.059 for G and C, respectively. GG genotype was not found in any of the two groups. The genotype distribution and allele frequencies were in Hardy-Weinberg equilibrium. No marker could be detected from the analysis of anthropometric, biochemical and hemodynamic variables in the MetS group.

Conclusion: Our data suggest that this polymorphism is not correlated with predisposition to MetS. The results obtained on a small sample of the population of Brasilia, corroborate the data reported in the literature on the prevalence of this polymorphism in PPAR in populations of different ethnic origins.
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http://dx.doi.org/10.1590/2359-3997000000086DOI Listing
August 2015

Is IGSF1 involved in human pituitary tumor formation?

Endocr Relat Cancer 2015 Feb 19;22(1):47-54. Epub 2014 Dec 19.

Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USAGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba 80215, BrazilDepartment of Pharmacology and TherapeuticsMcGill University, Montréal, Québec, Canada H3G 1Y6Pediatric Endocrinology Inter-institute Training ProgramEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USAThe Liggins InstituteUniversity of Auckland, Auckland 1023, New ZealandTaranaki Base HospitalNew Plymouth 4310, New ZealandAuckland City Hospital & Greenlane Clinical CentreAuckland 1142, New ZealandDepartment of NeurosurgeryUniversity of Virginia Health Sciences Center, University of Virginia, Charlottesville, Virginia 22904, USASurgical Neurology BranchNational Institute for Neurological Diseases and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland 20892, USA Departments ofEndocrinology and Metabolic DisordersPediatricsLeiden University Medical Center, Leiden 2333, The Netherlands Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USAGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba 80215, BrazilDepartment of Pharmacology and TherapeuticsMcGill University, Montréal, Québec, Canada H3G 1Y6Pediatric

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.
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http://dx.doi.org/10.1530/ERC-14-0465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272759PMC
February 2015

Clinical and molecular genetics of the phosphodiesterases (PDEs).

Endocr Rev 2014 Apr 5;35(2):195-233. Epub 2013 Dec 5.

Section on Endocrinology Genetics (M.F.A., F.R.F., E.B., A.H., I.L., R.B.d.A., C.A.S.), Program on Developmental Endocrinology Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892; Section of Endocrinology (M.F.A.), University Hospital of Brasilia, Faculty of Medicine, University of Brasilia, Brasilia 70840-901, Brazil; Group for Advanced Molecular Investigation (F.R.F., R.B.d.A.), Graduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba 80215-901, Brazil; Cardiovascular Pulmonary Branch (F.A., V.M.), National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892; and Pediatric Endocrinology Inter-Institute Training Program (C.A.S.), NICHD, NIH, Bethesda, Maryland 20892.

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.
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http://dx.doi.org/10.1210/er.2013-1053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963262PMC
April 2014

Cyclic AMP and c-KIT signaling in familial testicular germ cell tumor predisposition.

J Clin Endocrinol Metab 2013 Aug 14;98(8):E1393-400. Epub 2013 Jun 14.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

Background: Familial testicular germ cell tumors (FTGCTs) are hypothesized to result from the combined interaction of multiple low-penetrance genes. We reported inactivating germline mutations of the cAMP-binding phosphodiesterase 11A (PDE11A) as modifiers of FTGCT risk. Recent genome-wide association studies have identified single-nucleotide polymorphisms in the KITLG gene, the ligand for the cKIT tyrosine kinase receptor, as strong modifiers of susceptibility to both familial and sporadic testicular germ cell tumors.

Design: We studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds, in whom the PDE11A gene had been sequenced by investigating the association between KITLG genome-wide association study single-nucleotide polymorphisms rs3782179 and rs4474514 and FTGCT risk in these patients and in 692 controls. We also examined cAMP and c-KIT signaling in testicular tissues and cell lines and extended the studies to 2 sporadic cases, one with a PDE11A defect and one without, as a comparison.

Results: We found a higher frequency of the KITLG risk alleles in FTGCT patients who also had a PDE11A sequence variant, compared with those with a wild-type PDE11A sequence. In NTERA-2 and Tcam-2 cells transfected with the mutated forms of PDE11A (R52T, F258Y, Y727C, R804H, V820M, R867G, and M878V), cAMP levels were significantly higher, and the relative phosphodiesterase activity was lower than in the wild-type cells. KITLG expression was consistently increased in the presence of PDE11A-inactivating defects, both at the RNA and protein levels, in familial testicular germ cell tumors. The 2 sporadic cases that were studied, one with a PDE11A defect and another without, agreed with the data in FTGTCT and in the cell lines.

Conclusions: Patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently. There may be an interaction between cAMP and c-KIT signaling in predisposition to testicular germ cell tumors.
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http://dx.doi.org/10.1210/jc.2012-2838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733859PMC
August 2013

Association of the rs7903146 single nucleotide polymorphism at the Transcription Factor 7-like 2 (TCF7L2) locus with type 2 diabetes in Brazilian subjects.

Arq Bras Endocrinol Metabol 2012 Nov;56(8):479-84

Instituto e Laboratório Sabin de Análises Clínicas, Unidade de Biologia Molecular, Brasília, DF, Brazil.

Objective: To investigate the association of the T allele of the single nucleotide polymorphism (SNP) rs7903146 of TCF7L2 with the occurrence of T2D in a sample of subjects followed up at the Brasilia University Hospital.

Subjects And Methods: The SNP rs7903146 of TCF7L2 was genotyped by allele-specific PCR in 113 patients with known T2D and in 139 non-diabetic controls in Brasilia, Brazil.

Results: We found that the T allele of the SNP rs7903146 of TCF7L2 was significantly associated with T2D risk (odds ratio of 3.92 for genotype TT in the recessive genetic model, p = 0.004 and 1.5 for T allele, p = 0.032).

Conclusion: These results reinforce previous findings on the consistent association of this genetic factor and the risk of T2D in populations of diverse ethnic backgrounds.
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http://dx.doi.org/10.1590/s0004-27302012000800003DOI Listing
November 2012

Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas.

Pituitary 2013 Jun;16(2):189-94

Serviço de Endocrinologia, Faculdade de Medicina, Universidade de Brasília, SGAN Quadra 605, Asa Norte. Prédio Novo de Ambulatórios, Brasília, DF 70840-901, Brazil.

This study was carried out to evaluate the effectiveness of cabergoline in the treatment of nonfunctioning pituitary adenomas (NFPA), in a short-term follow-up period. Nineteen patients (10 men and 9 women) followed at the University Hospital of Brasilia and harboring nonfunctioning pituitary macroadenomas were enrolled in the study. Eleven patients were previously submitted to transsphenoidal surgery, and in 8 patients no previous treatment had been instituted. Their response to the use of cabergoline (2 mg/week) by 6 months was evaluated. Significant tumor shrinkage (above 25 % from baseline tumor volume) was observed in 6 (31.6 %) of the 19 patients, and no adverse effects were observed during treatment. In 9 patients (47.4 %), a reduction in tumor volume of at least 10 % was noted, whereas tumor growth was observed in four patients (increase above 25 % was only observed in one patient). Cabergoline (2 mg/week) can lead to significant tumor shrinkage in NFPA in a considerable number of patients, and this effect can be observed early (6 months after starting medication). Thus, this therapeutic strategy may be a low cost and safe alternative for treatment of NFPA in patients with remnant or recurrent tumor after transsphenoidal surgery or in those not operated by contraindications or refusal to surgical procedure.
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http://dx.doi.org/10.1007/s11102-012-0403-yDOI Listing
June 2013

Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours.

Clin Endocrinol (Oxf) 2012 Aug;77(2):195-9

Section on Endocrinology and Genetics and Pediatric Endocrinology Training Program, both at Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1103, USA.

Background: Genetic aberrations in various components of cAMP signalling pathway predispose to endocrine tumours. Mutations in the phosphodiesterases (PDEs) are involved in the predisposition to adrenocortical neoplastic conditions.

Objective: To screen for genetic variations in PDE8B among patients with different types of adrenocortical tumours.

Design And Subjects: This is a case-control study followed by functional analyses. Two hundred and sixteen unrelated patients with different types of adrenocortical tumours and 192 healthy control individuals participated in the study.

Methods: Bidirectional Sanger sequencing, in vitro cell line transfection and in silico modelling are used in this study.

Results: Nine different PDE8B sequence changes, six novel and three previously reported, were identified in our patients and controls. Two of the variations, seen only in the patient group, showed significant potential to impair protein function, both in vitro and in silico.

Conclusion: PDE8B is another PDE gene in which variations may contribute to predisposition of adrenocortical tumours.
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http://dx.doi.org/10.1111/j.1365-2265.2012.04366.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360985PMC
August 2012

KCNJ5 mutations in the National Institutes of Health cohort of patients with primary hyperaldosteronism: an infrequent genetic cause of Conn's syndrome.

Endocr Relat Cancer 2012 Jun 3;19(3):255-60. Epub 2012 May 3.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, NIH, Bethesda, Maryland 20892, USA.

KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.
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http://dx.doi.org/10.1530/ERC-12-0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041522PMC
June 2012

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations.

J Clin Endocrinol Metab 2012 Apr 18;97(4):E687-93. Epub 2012 Jan 18.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USA.

Context: The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas.

Objective And Design: The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings.

Results: MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions.

Conclusion: WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.
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http://dx.doi.org/10.1210/jc.2011-3000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319183PMC
April 2012

Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH?

J Clin Endocrinol Metab 2012 Mar 14;97(3):E357-66. Epub 2011 Dec 14.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USA.

Background: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD).

Aim: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma.

Patients And Methods: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors.

Conclusion: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.
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http://dx.doi.org/10.1210/jc.2011-1179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319210PMC
March 2012

Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment.

Curr Opin Pharmacol 2011 Dec 31;11(6):689-97. Epub 2011 Oct 31.

Section of Endocrinology and Genetics, Program on Developmental Endocrinology Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implicated in predisposition to tumor formation. This review focuses on the possible function of PDEs in a variety of tumors, primarily in endocrine glands, both in tumor predisposition and as potential therapeutic targets.
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http://dx.doi.org/10.1016/j.coph.2011.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727450PMC
December 2011

Unique gene expression profile associated with an early-onset multiple endocrine neoplasia (MEN1)-associated pituitary adenoma.

J Clin Endocrinol Metab 2011 Nov 14;96(11):E1905-14. Epub 2011 Sep 14.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USA.

Context: Multiple endocrine neoplasia type 1 (MEN1) is caused by mutations in the menin (MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown.

Objective: The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome.

Patients And Methods: A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes.

Results: In the MEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up- and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed.

Conclusions: We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cells after the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways.
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http://dx.doi.org/10.1210/jc.2011-1127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205896PMC
November 2011

A comparison of cabergoline and bromocriptine on the risk of valvular heart disease in patients with prolactinomas.

Pituitary 2012 Mar;15(1):44-9

Department of Internal Medicine, Federal University of Parana, Avenida Agostinho Leao Junior, 285, Curitiba, PR, 80030-110, Brazil.

Therapy with dopamine agonists has been associated with valvular heart disease (VHD) in Parkinson's disease, raising concern about the safety of these drugs. In hyperprolactinemic patients, the studies have mainly focused on the cardiac effects of cabergoline (CBG), with little information on bromocriptine (BRC). The aim of the present study was to evaluate the prevalence of VHD in patients with prolactinomas treated with CBG and BRC. The CBG group consisted of 51 patients (37 female; age 42.3 ± 13.5 years) who had been taking CBG for at least 1 year (mean 37.8 ± 21.3 months; cumulative doses 16-1,286.8 mg). The BRC group consisted of 19 patients (14 female; age 41.8 ± 11.5 years) who were on BRC for at least 1 year (mean 54.8 ± 30.2 months; cumulative doses 4,687.5-23,478.8 mg). The controls (CTR) were 59 healthy subjects matched for age, sex, and prevalence of arterial hypertension. Participants were subjected to transthoracic echocardiography and the valvular regurgitation was graduated as absent (grade 0), trace (1), mild (2), moderate (3) or severe (4). Compared to CTR, trace mitral (Mi) regurgitation (49% vs. 27.1%; P = 0.02), trace tricuspid (Tri) regurgitation (45.1% vs. 20.3%; P = 0.0003) and mild Tri regurgitation (7.8% vs. 0%; P = 0.0003) were more prevalent with CBG, while trace Tri regurgitation (73.7% vs. 20.3%; P = 0.0004) were more prevalent with BRC. Mitral tenting area was significantly higher in CBG than in BRC and CTR. None of the valvar abnormalities was associated with symptoms. In conclusion, patients with prolactinomas treated with either CBG or BRC showed higher prevalence of trace and mild Tri or Mi regurgitation, but these findings were not clinically significant.
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http://dx.doi.org/10.1007/s11102-011-0339-7DOI Listing
March 2012

The transcriptome that mediates increased cyclic adenosine monophosphate signaling in PRKAR1A defects and other settings.

Endocr Pract 2011 Jul-Aug;17 Suppl 3:2-7

Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

Objective: To review current knowledge on the involvement of cyclic adenosine monophosphate (cAMP) and interacting signaling pathways in predisposition to tumor formation in primary pigmented nodular adrenocortical disease (PPNAD), a type of bilateral adrenal hyperplasia (BAH) related to the multiple endocrine neoplasia Carney complex, and also in isolated PPNAD and other BAHs.

Methods: We review the pertinent literature and discuss genetic defects associated with various endocrine and nonendocrine tumors.

Results: A decade ago, we discovered that PPNAD and the Carney complex are caused by PRKAR1A mutations. PRKAR1A encodes the protein kinase A (PKA) regulatory subunit type IA, an important regulator of cAMP signaling in most cells. Recently, we described PKA or PRKAR1A abnormalities in a variety of other BAHs; in some of these cases, mutations in additional genes of the cAMP signaling pathway, the phosphodiesterases, were identified. Transcriptomic analyses of human lesions or animal models showed that abnormal cAMP/PKA signaling in the adrenal glands, and also in other tissues such as bone, leads to proliferation of tissue-specific pluripotential cells through activation of Wnt signaling.

Conclusion: Recent findings indicate the relevance of cAMP signaling in the pathogenesis of adrenocortical disease and point to the Wnt signaling pathway as a potential important mediator of tumorigenesis related to increased cAMP or PKA signaling (or both).
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http://dx.doi.org/10.4158/EP10412.RADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652399PMC
January 2012

Snapin mediates incretin action and augments glucose-dependent insulin secretion.

Cell Metab 2011 Mar;13(3):308-19

Department of Pediatrics, Metabolism Division, Johns Hopkins University, Baltimore, MD 21287, USA.

Impaired insulin secretion contributes to the pathogenesis of type 2 diabetes mellitus (T2DM). Treatment with the incretin hormone glucagon-like peptide-1 (GLP-1) potentiates insulin secretion and improves metabolic control in humans with T2DM. GLP-1 receptor-mediated signaling leading to insulin secretion occurs via cyclic AMP stimulated protein kinase A (PKA)- as well as guanine nucleotide exchange factor-mediated pathways. However, how these two pathways integrate and coordinate insulin secretion remains poorly understood. Here we show that these incretin-stimulated pathways converge at the level of snapin, and that PKA-dependent phosphorylation of snapin increases interaction among insulin secretory vesicle-associated proteins, thereby potentiating glucose-stimulated insulin secretion (GSIS). In diabetic islets with impaired GSIS, snapin phosphorylation is reduced, and expression of a snapin mutant, which mimics site-specific phosphorylation, restores GSIS. Thus, snapin is a critical node in GSIS regulation and provides a potential therapeutic target to improve β cell function in T2DM.
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http://dx.doi.org/10.1016/j.cmet.2011.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053597PMC
March 2011

The brazilian version of the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA): Four-stage translation and validation.

Arq Bras Endocrinol Metabol 2010 Dec;54(9):833-41

Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Objective: This study reports on the Brazilian Portuguese adaptation of the QoL-AGHDA (Quality of Life Assessment of Growth Hormone Deficiency in Adults) for use in adult growth hormone deficient (GHD) patients.

Materials And Methods: The translation process adopted the dual panel methodology. The questionnaire was tested through field-test interviews (16 GHD patients). In the final stage, data from 120 GHD patients (81 included in a test-retest analysis) were analyzed for internal consistency, test-retest reliability, convergent validity and validity among known groups.

Results: The translation panels were successful and the draft version was amended to improve the wording as a result of the field-test interviews. Cronbach's alpha was 0.90 and test-retest reliability 0.88. QoL-AGHDA scores had the expected pattern of association with NHP scale scores and QoL-AGHDA was able to differentiate significantly between patients based on patient-reported general health (p < 0.01) and QoL (p < 0.01).

Conclusions: The adaptation of the QoL-AGHDA for a Brazilian population was successful and the adapted questionnaire was shown to be reliable and valid.
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http://dx.doi.org/10.1590/s0004-27302010000900010DOI Listing
December 2010

Treatment of severe trigeminal headache in patients with pituitary adenomas.

Neurosurgery 2011 May;68(5):1300-8; discussion 1308

Department of Neurosurgery, University Hospital of Brasília, Brasilia, Brazil.

Background: The incidence of headache in patients with pituitary adenomas is high, and the underlying pathological mechanisms are not completely understood.

Objective: We tested the efficacy of percutaneous ganglion block and trigeminal rhizotomy in the treatment of severe trigeminal/autonomic headache associated with pituitary tumors.

Methods: Eleven patients treated surgically for pituitary adenomas in whom intractable trigeminal headaches developed were enrolled in the study and underwent ictal cerebral single-photon emission computed tomography before starting treatment. Initially, all patients underwent a 6-month medical treatment trial. Patients who did not experience improvement in headache severity, addressed by the Headache Impact Test-6 scale, underwent trigeminal percutaneous ganglion blockade. Two patients subsequently underwent trigeminal balloon rhizotomy.

Results: Among the 11 patients, 6 did not have improved Headache Impact Test-6 scale scores after 6 months of treatment with medications and underwent trigeminal ganglion blockade. Significant improvement in headache severity was noted in 3 of them. Long-term response was obtained in 1 patient, and the other 2, in whom the response was transient, were then successfully treated with trigeminal rhizotomy. Cerebral single-photon emission computed tomography showed increased uptake in the thalamus/hypothalamus region in patients who responded well to manipulation of the trigeminal-hypothalamic system.

Conclusion: Percutaneous ganglion blockade and trigeminal rhizotomy may be promising alternative options for the treatment of severe headache in selected patients with pituitary adenomas.
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http://dx.doi.org/10.1227/NEU.0b013e31820c6c9eDOI Listing
May 2011

Anterior pituitary adenomas: inherited syndromes, novel genes and molecular pathways.

Expert Rev Endocrinol Metab 2010 Sep;5(5):697-709

SEGEN, PDEGEN & Pediatric Endocrinology Program, NICHD, NIH, Building 10, CRC (East Laboratories), Room 1-3330, 10 Center Drive, MSC1103, Bethesda, MD 20892, USA.

Pituitary adenomas are common tumors. Although rarely malignant, pituitary adenomas cause significant morbidity due to mass effects and/or hormonal hypo- and/or hyper-secretion. Molecular understanding of pituitary adenoma formation is essential for the development of medical therapies and the treatment of post-operative recurrences. In general, mutations in genes involved in genetic syndromes associated with pituitary tumors are not a common finding in sporadic lesions. By contrast, multiple endocrine neoplasia type 1 (MEN-1) and aryl hydrocarbon receptor-interacting protein (AIP) mutations may be more frequent among specific subgroups of patients, such as children and young adults, with growth hormone-producing adenomas. In this article, we present the most recent data on the molecular pathogenesis of pituitary adenomas and discuss some of the most recent findings from our laboratory. Guidelines for genetic screening and clinical counseling of patients with pituitary tumors are provided.
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http://dx.doi.org/10.1586/eem.10.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024595PMC
September 2010

Role of the addition of cabergoline to the management of acromegalic patients resistant to longterm treatment with octreotide LAR.

Pituitary 2011 Jun;14(2):148-56

Division of Endocrinology, Hospital das Clinicas, Federal University of Pernambuco, Recife, Brazil.

The aim of this prospective open trial was to evaluate the efficacy in normalizing IGF-I levels of the addition of cabergoline to the treatment of acromegalic patients partially responsive to Octreotide-LAR (OCT-LAR), a long acting somatotastin analog (SSA). Fifty-two patients who did not achieve hormonal control after longterm therapy (at least, 12 months) with OCT-LAR (30 mg every 28 days intramuscularly) were given cabergoline in addition to the SSA treatment. Normalization of IGF-I levels was achieved in 40.4% of patients by 6 months after the addition of cabergoline (1.0-3.0 mg/week; mean, 2.19 ± 0.64), and these patients were considered responsive. Compared to non-responsive subjects, responsive patients had significantly lower mean %ULNR-IGF-I and GH levels. However, the rate of hyperprolactinemia and positive immunohistochemical staining for PRL was similar in both groups, before the addition of cabergoline. Responsive patients were followed for at least 12 months on combination treatment and persisted with normal IGF-I levels. Patients with baseline %ULNR IGF-I up to 220% and/or GH up to 5 ng/ml were those who benefited the most from combination treatment. No patients with %ULNR-IGF-I>250% reached normalization of IGF-I levels. Our findings demonstrated that the addition of cabergoline, even at relatively low doses, is effective in both short- and long-term control of IGF-I levels in acromegalic patients partially responsive to octreotide LAR, particularly in those with mild/moderately elevated GH/IGF-levels, irrespective of prolactin status.
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http://dx.doi.org/10.1007/s11102-010-0272-1DOI Listing
June 2011

An unusual presentation of pediatric Cushing disease: recurrent corticotropinoma of the posterior pituitary lobe.

J Pediatr Endocrinol Metab 2010 Jun;23(6):607-12

Section on Endocrinology and Genetics, Program on Developmental Endocrinology Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Cushing's syndrome (CS) is rare in childhood and adolescence and its diagnosis and work up are often challenging. We report the case of a 15-year-old girl with a recurrent corticotrophin (ACTH)-secreting adenoma, located in the posterior lobe of the pituitary gland. At the age of 11, she presented with classic CS symptoms; biochemical investigation was compatible with ACTH-dependent Cushing disease, although pituitary gland imaging did not show any tumor. Following transsphenoidal surgery (TSS), histopathological analysis identified an ACTH-secreting pituitary microadenoma arising from the posterior gland. The patient went into remission but 4 years later she presented with recurrent CS; this time, pituitary gland imaging showed a microadenoma located in the posterior lobe, which was resected after TSS. Posterior lobe pituitary adenomas are very rare and often hard to diagnose and treat; this is the first case of such a tumor causing recurrent Cushing's disease in a child.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727444PMC
http://dx.doi.org/10.1515/jpem.2010.100DOI Listing
June 2010

Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene.

J Clin Endocrinol Metab 2010 Aug 25;95(8):4066-71. Epub 2010 May 25.

Department of Pediatrics, Faculty of Medicine, University Hospital of Brasília, Faculty of Health Sciences, University of Brasília, SGAN Quadra 605, Asa Norte, Prédio Novo de Ambulatórios, 70840-901, Brasília-DF, Brazil.

Context: Selenoproteins are essential for life, and their biosynthesis requires the incorporation of the rare amino acid selenocysteine (Sec) in a process mediated by the Sec insertion sequence-binding protein 2 (SBP2). Although SBP2 is considered a rate-limiting factor mediating Sec incorporation, there has been little evidence so far linking SBP2 dysfunction to widespread selenoprotein-related disease.

Objective: The objective of the study was to report the discovery of novel truncation mutations in the SBP2 gene (R120X/R770X) in a female adolescent and the clinical consequences of the combined deficiency of selenoproteins.

Subjects And Methods: A 12-yr-old girl who presented with a syndrome of abnormal thyroid hormone metabolism, delayed bone maturation, congenital myopathy, and impaired mental and motor coordination development and her family were studied. The coding region of the SBP2 gene was analyzed by sequencing, and gel shift assays were performed to address the in vitro binding properties of the mutant SBP2 protein.

Results: Serum levels of selenium and glutathione peroxidase in the proband were reduced, and selenoprotein P levels were undetectable. DNA sequencing of the SBP2 gene revealed a compound heterozygous mutation (R120X/R770X). The R120X mutation disrupted all functional motifs and the R770X inhibited the binding of SBP2 to Sec insertion sequence elements. Interestingly, selenium supplementation normalized serum selenium and glutathione peroxidase but not selenoprotein P levels and did not restore thyroid hormone metabolism dysfunction.

Conclusions: This distinctive phenotype can only be explained by the combined deficiency of functionally important selenoproteins and pinpoints the clinical relevance of selenoproteins and selenium economy in human development.
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http://dx.doi.org/10.1210/jc.2009-2611DOI Listing
August 2010

Hyperfunctioning thyroid cancer: a five-year follow-up.

Arq Bras Endocrinol Metabol 2010 Feb;54(1):78-80

Serviço de Endocrinologia, Hospital Universitário, Universidade de Brasília, Brasília, DF, Brasil.

Differentiated thyroid cancer rarely occurs in association with hyperfunctioning nodules. We describe a case of a 47-year-old woman who developed symptoms of hyperthyroidism associated with a palpable thyroid nodule. Thyroid scintigraphy showed an autonomous nodule, and fine-needle aspiration biopsy was suggestive of papillary carcinoma. Laboratorial findings were consistent with the diagnosis of hyperthyroidism. The patient underwent thyroidectomy and a papillary carcinoma of 3.0 x 3.0 x 2.0 cm, follicular variant, was described by histological examination. The surrounding thyroid tissue was normal. Postoperatively, the patient received 100 mCi of (131)I, and whole body scans detected only residual uptake. No evidence of metastasis was detected during five years of follow-up. Hot thyroid nodules rarely harbor malignancies, and this case illustrated that, when a carcinoma occurs the prognosis seems to be very good with no evidence of metastatic dissemination during a long-term follow-up.
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http://dx.doi.org/10.1590/s0004-27302010000100013DOI Listing
February 2010

Management of prolactinomas in Brazil: an electronic survey.

Pituitary 2010 Sep;13(3):199-206

Division of Endocrinology, Hospital das Clinicas, Pernambuco Federal University, Rua Clovis Silveira Barros, 84/1202, Boa Vista, Recife, PE, CEP 50.050-270, Brazil.

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.
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http://dx.doi.org/10.1007/s11102-010-0217-8DOI Listing
September 2010

Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease.

Pituitary 2010 Jun;13(2):123-9

Division of Endocrinology, Hospital das Clínicas, Federal University of Pernambuco, Recife, Brazil.

The expression of dopamine receptor subtypes has been reported in corticotroph adenomas, and this finding support the possibility for medical treatment of Cushing's disease (CD) with dopamine agonists when conventional treatment has failed. The aim of this study was to evaluate the effectiveness of cabergoline (at doses of up 3 mg/week), alone or combined with relatively low doses of ketoconazole (up to 400 mg/day), in 12 patients with CD unsuccessfully treated by transsphenoidal surgery. After 6 months of cabergoline therapy, normalization of 24 h urinary free cortisol (UFC) levels occurred in three patients (25%) at doses ranging from 2-3 mg/week, whereas reductions ranging from 15.0 to 48.4% were found in the remaining. The addition of ketonocazole to the nine patients without an adequate response to cabergoline was able to normalize UFC excretion in six patients (66.7%) at doses of 200 mg/day (three patients), 300 mg/day (two patients) and 400 mg/day (one patient). In the remaining patients UFC levels did not normalize but a significant reduction ranging from to 44.4 to 51.7% was achieved. In two of the six responsive patients to combination therapy, the weekly dose of cabergoline could be later reduced from 3 to 2 mg. Our findings demonstrated that cabergoline monotherapy was able to reverse hypercortisolism in 25% of patients with CD unsuccessfully treated by surgery. Moreover, the addition of relatively low doses of ketoconazole led to normalization of UFC in about two-thirds of patients not achieving a full response to cabergoline.
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http://dx.doi.org/10.1007/s11102-009-0209-8DOI Listing
June 2010

Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene.

Eur J Endocrinol 2007 Oct;157(4):383-91

Department of Endocrinology, Internal Medicine, University of Brasília, Brasília DF, Brazil.

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of such mutations in large international cohorts. Detailed genetic and clinical studies within AIP mutation-positive families have been limited.

Aim: To undertake a comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers.

Methods: The kindred included 122 subjects across six generations; all underwent clinical examination. Genetic studies were performed to identify E174fs mutation carriers. E174fs-positive subjects underwent magnetic resonance imaging (MRI) and hormonal assessments.

Results: Of the ten germline AIP mutation carriers, three had pituitary tumors, while seven were asymptomatic carriers. Three patients with pituitary tumors showed variability in terms of tumor phenotype (two with acromegaly, one with prolactinoma, or mixed prolactin/GH-secreting tumor) and age at diagnosis; both patients with acromegaly had poor responses to octreotide. Tumor AIP immunohistochemistry from the operated patient showed decreased expression when compared with normal tissue. Two adult subjects with normal MRI had elevated IGF-I in the absence of other causes. A 2-year-old child with the E174fs mutation and a normal MRI had premature thelarche, ovarian development, and advanced bone age in the absence of other underlying causes.

Conclusions: The penetrance of pituitary tumors in AIP mutation-positive adult subjects was 33.3%, while clinical/hormonal features were variable. The features noted in AIP-mutation carriers in this kindred suggest that clinical characteristics of such carriers may extend beyond pituitary tumors.
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http://dx.doi.org/10.1530/EJE-07-0533DOI Listing
October 2007

[Endogenous Cushing's syndrome: clinical and laboratorial features in 73 cases].

Arq Bras Endocrinol Metabol 2007 Jun;51(4):566-74

Serviço de Endocrinologia, Hospital das Clínicas, UFPE.

We studied clinical and laboratorial features of 73 patients with endogenous Cushing's syndrome, subdivided as follows: 46 (63%) with Cushing's disease (CD), 21 (28.7%) with an adrenal tumor and 6 (8.2%) with ectopic ACTH secretion (EAS). The rate of typical manifestations of hypercortisolism was similar regardless its etiology. In 100% of cases of Cushing's syndrome we observed serum cortisol levels greater than 1.8 microg/dL in low-dose dexamethasone (DMS) suppression tests, as well as elevation of serum or salivary midnight cortisol. However, urinary free cortisol was normal in 11.5% of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and always high in EAS. In the 8-mg overnight DMS suppression test, serum cortisol suppression > 50% was observed in 78.2% of cases of CD and in 33.3% of subjects with EAS, while an 80% suppression was only seen in CD. After stimulation with CRH or DDAVP an ACTH increase > 35% occurred in 81% of individuals with CD and 16.6% of those with EAS, while an ACTH increase > 50 achieved 100% specificity. Moreover, the combination of serum cortisol suppression > 50% and an ACTH increase > 35% in both tests only occurred in Cushing's disease. Pituitary magnetic resonance imaging identified 100% of macroadenomas and 59.4% of microadenomas in patients with CD. Among 10 patients that underwent bilateral inferior petrosal sinus sampling, a central-to-peripheral ACTH gradient > 3 after CRH or DDAVP had 90% sensitivity and 100% specificity for Cushing's disease.
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http://dx.doi.org/10.1590/s0004-27302007000400010DOI Listing
June 2007

[Prevalence of macroprolactinemia among 115 patients with hyperprolactinemia].

Arq Bras Endocrinol Metabol 2007 Feb;51(1):86-91

Serviço de Endocrinologia, Hospital das Clínicas, Universidade Federal de Pernambuco.

Macroprolactinemia is characterized by the predominance in the serum of macroprolactin, a prolactin (PRL) with high molecular mass and low biological activity that does not need treatment. The prevalence of macroprolactinemia was evaluated in 115 consecutive patients with hyperprolactinemia. Among them, 19 (16.5%) had solely macroprolactinemia, 4 (3.5%) polycystic ovary syndrome, 7 (6.1%) acromegaly, 8 (6.9%) idiopathic hyperprolactinemia, 10 (8.6%) primary hypothyroidism, 14 (12.2%) clinically non-functioning pituitary adenomas, 20 (17.4%) drug-induced hyperprolactinemia and 33 (28.7%) prolactinomas. The diagnosis of macroprolactinemia was established by the demonstration of a PRL recovery < 30% after treatment of sera with polyethylene glycol. Among the 19 patients with isolated macroprolactinemia, 16 (84.2%) were female and 12 (63.2%) were asymptomatic, while 4 (21%) presented with oligomenorrhea and 3 (15.8%) with galactorrhea. In contrast, only 11.5% of individuals with other causes of hyperprolactinemia were asymptomatic (p< 0.001). Prolactin levels in cases of macroprolactin ranged from 45.1 to 404 ng/mL (mean 113.3 +/- 94.5) but in 15 (78.9%) were < 100 ng/mL. Our findings demonstrate that macroprolactinemia is a common condition and, therefore, we suggest that it should be routinely screened in patients with hyperprolactinemia.
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http://dx.doi.org/10.1590/s0004-27302007000100014DOI Listing
February 2007