Case Report: Composite pheochromocytoma with ganglioneuroma component: A report of three cases.

Composite pheochromocytoma (CP) is a very rare tumor originating from neural crest cells, predominantly composed of pheochromocytoma (PCC), a chromaffin cell tumor arising in adrenal medulla, and ganglioneuroma, a tumor derived from autonomic ganglion cells of the nervous system. Moreover, CP may be present in the hereditary syndromes of which pheochromocytoma is part. Literature offers scarce data on this subject, and particularly about its biological behavior, clinical evolution, and molecular profile. We report the phenotype and outcome of three cases of CP (PCC and ganglioneuroma components), followed up at the Endocrine Service of the Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil. Two nonsyndromic patients (cases 1 and 2) were negative to germline mutations in genes VHL, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX, while the third case (case 3) had clinical diagnosis of neurofibromatosis syndrome. Cases 1, 2, and 3 were diagnosed at 29, 39, and 47 years old, respectively, and were followed up for 3, 17, and 9 years without no CP recurrence. All cases had apparent symptoms of catecholaminergic excess secreted by PCC. Ganglioneuroma, the neurogenic component present in all three cases, had a percentage representation ranging from 5% to 15%. Tumors were unilateral and large, measuring 7.0 cm × 6.0 cm × 6.0 cm, 6.0 cm × 4.0 cm × 3.2 cm, and 7.5 cm × 6.0 cm × 4.5 cm, respectively. All cases underwent adrenalectomy with no recurrence, metastasis, or development of contralateral tumor during follow-up. Genetic testing has been scarcely offered to CP cases. However, a similar frequency of genetic background is found when compared with classic PCC, mainly by the overrepresentation of NF1 cases in the CP subset. By literature review, we identified a notorious increase in cases reported with CP in the last decade, especially in the last 3 years, indicating a recent improvement in the diagnosis of this rare disorder in clinical practice.

Establishment of reference interval for thyroid-stimulating hormone using electrochemiluminescence assay in a healthy adult population from Fortaleza, Brazil

ABSTRACT Objective This study aimed to determine the thyroid-stimulating hormone (TSH) reference interval (RI) and to assess the influence of the use of thyroid ultrasonography (TUS) on reference individual selection from a healthy adult population in Fortaleza, Brazil. Subjects and methods This cross-sectional study recruited patients (N = 272; age = 18-50 years) with normal thyroid function (NTF) and placed them in three groups according to their test results: NTF (n = 272; all participants), TUS (n = 170; participants who underwent thyroid US), RI (n = 124; reference individuals with normal TSH levels). TSH, FT4, TT3, TgAb, and TPOAb concentrations were determined by electrochemiluminescence assay. TUS was performed using a 7-12 MHz multifrequency linear transducer by two radiologists. The 2.5th and 97.5th percentiles of the distribution curve corresponded to lower and upper TSH RI levels, respectively. Results The mean TSH level was 1.74 ± 0.96 mIU/L, and TSH range was 0.56-4.45 mIU/L. There was no difference in the TSH concentrations between men and women nor between the groups. TUS did not appear to be an essential tool for the reference group selection. Conclusion The upper limit of TSH was comparable to the reference interval provided by the assay manufacturer (4.45 vs. 4.20 mIU/L) but the lower limit was not (0.56 vs. 0.27 mIU/L). This finding may have a clinical impact since these values may lead to the misdiagnosis of euthyroid patients with subclinical hyperthyroidism.

Establishment of reference interval for thyroid-stimulating hormone using electrochemiluminescence assay in a healthy adult population from Fortaleza, Brazil.

Objective This study aimed to determine the thyroid-stimulating hormone (TSH) reference interval (RI) and to assess the influence of the use of thyroid ultrasonography (TUS) on reference individual selection from a healthy adult population in Fortaleza, Brazil. Subjects and methods This cross-sectional study recruited patients (N = 272; age = 18-50 years) with normal thyroid function (NTF) and placed them in three groups according to their test results: NTF (n = 272; all participants), TUS (n = 170; participants who underwent thyroid US), RI (n = 124; reference individuals with normal TSH levels). TSH, FT4, TT3, TgAb, and TPOAb concentrations were determined by electrochemiluminescence assay. TUS was performed using a 7-12 MHz multifrequency linear transducer by two radiologists. The 2.5th and 97.5th percentiles of the distribution curve corresponded to lower and upper TSH RI levels, respectively. Results The mean TSH level was 1.74 ± 0.96 mIU/L, and TSH range was 0.56-4.45 mIU/L. There was no difference in the TSH concentrations between men and women nor between the groups. TUS did not appear to be an essential tool for the reference group selection. Conclusion The upper limit of TSH was comparable to the reference interval provided by the assay manufacturer (4.45 vs. 4.20 mIU/L) but the lower limit was not (0.56 vs. 0.27 mIU/L). This finding may have a clinical impact since these values may lead to the misdiagnosis of euthyroid patients with subclinical hyperthyroidism.

Alkaline phosphatase: reference interval transference from CALIPER to a pediatric Brazilian population / Fosfatase alcalina: transferência de intervalos de referência do CALIPER para uma população pediátrica brasileira

ABSTRACT Introduction: Interpreting laboratory tests requires reference intervals (RI) that may vary between different populations. For the diagnosis of hypophosphatasia (HPP), lower limits of alkaline phosphatase (ALP) levels must be determined. Objective: To transfer the RI findings for ALP obtained by the Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER) in children and adolescents, adjusted for the Brazilian population. Methods: The ALP measures from 1690 subjects (aging from 1-18 years) were analyzed. The CALIPER subgroups and the Clinical and Laboratory Standards Institute (CLSI) guideline were used for validation. Inclusion criteria were patients with normal range of hepatic and renal function, bone metabolism, and blood counts. Exclusion criteria were hospitalization, low weight, and use of drugs that could interfere in the ALP measurement and patients in with more than three orders for ALP measuring test. The RI obtained were considered valid if more than 90% of patients were whitin of the CALIPER RI. Results: The ALP RI results (IU/l) obtained were: 149-301 for both sexes aged 1-9 years; 127-326 for both sexes aged 10-12 years; 62-212 for girls and 129-437 for boys aged 13-14 years; 52-120 for girls and 78-268 for boys aged 15-16 years; 45-97 for girls and 40-129 for boys aged 17-18 years. In 92.4% of the patients, the results were comparable with those of the CALIPER study. Conclusion: The results demonstrated that the ALP RI for Brazilian children and adolescents are comparable to the CALIPER study in 92.4% of the patients and can be used for this population.

RESUMO Introdução: A interpretação de exames laboratoriais necessita de intervalos de referência (IR) que podem variar entre diferentes populações. Para o diagnóstico de hipofosfatasia, deve-se determinar limites inferiores do IR da fosfatase alcalina (FA). Objetivo: Transferir os resultados de IR da FA obtidos pela Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER) em crianças e adolescentes, ajustados para a população brasileira. Métodos: Analisaram-se as dosagens de FA de 1690 indivíduos (1 a 18 anos). Subgrupos do CALIPER e diretrizes do Clinical and Laboratory Standards Institute (CLSI) foram utilizados. Os critérios de inclusão foram pacientes com função hepática, renal, exames do metabolismo ósseo e hemograma normais; já os de exclusão, hospitalização, baixo peso, uso de drogas interferentes na dosagem de FA e pacientes com mais de três solicitações de FA. Os IR seriam considerados válidos se mais de 90% dos pacientes se encontrassem dentro dos IR do CALIPER. Resultado: Os resultados dos IR de FA (UI/l) obtidos foram: 149-301 para ambos os sexos entre 1-9 anos; 127-326 para ambos os sexos entre 10-12 anos; 62-212 para meninas e 129-437 para meninos entre 13-14 anos; 52-120 para meninas e 78-268 para meninos entre 15-16 anos; 45-97 para meninas e 40-129 para meninos entre 17-18 anos de idade. Em 92,4% dos pacientes os resultados eram comparáveis com os do CALIPER. Conclusão: Os resultados demonstraram que os IR de FA para crianças e adolescentes brasileiras são comparáveis com o estudo CALIPER em 92,4% dos pacientes e podem ser utilizados para essa população.

Screening of Undiagnosed Hypothyroidism in Elderly Persons with Diabetes according to Age-Specific Reference Intervals for Serum Thyroid Stimulating Hormone and the Impact of Antidiabetes Drugs.

Background. Studies have suggested that hypothyroidism is more frequent in the elderly with diabetes mellitus. However, an adaptation of TSH levels to age should be considered in this assessment. Some antidiabetes drugs reportedly interfere with TSH levels. The objectives of this study were to evaluate the prevalence of undiagnosed hypothyroidism in patients with diabetes and the influence of antidiabetes drugs. Material and Methods. 1160 subjects, 60 years and older (751 with diabetes), were studied; results were compared according to diabetes treatment and with persons without diabetes. TSH, FT4, antithyroperoxidase, fasting glucose, and HbA1c were measured. Results and Discussion. 6.4% of patients with diabetes had hypothyroidism, a higher prevalence compared with persons without diabetes (5.1%), but lower than observed in many studies. The use of age-specific TSH reference interval (RI) could explain this difference. Patients taking metformin (MTF) had TSH (showed in medians) slightly lower (2.8 mU/L) than those not on MTF (3.3 mU/L), p < 0.05. MTF doses influenced TSH levels. Conclusions. The use of specific TSH RI could avoid the misdiagnosis of hypothyroidism in elderly with diabetes. Patients in use of MTF as single drug had lower TSH than those using other medications and persons without diabetes.

Prevalence of obstructive sleep apnea in patients with prolactinoma before and after treatment with dopamine agonists.

OBJECTIVES: Obesity is the main risk factor for the development of obstructive sleep apnea (OSA). Hyperprolactinemia has also been related to obesity. To determine the OSA prevalence in patients with prolactinoma before and after dopamine agonist (DA) and to evaluate the correlation between the apnea-hypopnea index (AHI) and prolactin levels, body mass index (BMI), waist circumference (WC), visceral fat volume (VFV), subcutaneous fat volume, and other metabolic parameters. METHODS: Thirty-five patients with prolactinoma at baseline and twenty-one who completed the 6-month DA treatment were submitted to clinical/laboratorial evaluations, polysomnography and abdominal imaging. RESULTS: Before treatment, the prevalence of obesity/overweight and OSA were, respectively, 68.5 and 34.2 %. We found a positive correlation between AHI and weight (r = 0.57; p < 0.001), BMI (r = 0.56; p < 0.001), WC (r = 0.61; p < 0.001), VFV (r = 0.55; p = 0.002), insulin levels (r = 0.57; p < 0.001), and HOMA-IR index (r = 0.57; p < 0.001); and a negative correlation between AHI and HDL-cholesterol (r = -0.47; p = 0.005). After multivariate analysis, VFV and insulin levels were the most important predictors for AHI (p = 0.001 and p = 0.02, respectively). After DA, the obesity/overweight and OSA prevalence did not change. CONCLUSIONS: The OSA prevalence in patients with prolactinoma is similar to the obese subjects and did not change after treatment. Higher BMI and visceral obesity, but not prolactin levels, seem to be the major factor involved in the occurrence of OSA in these patients.

Reference interval of thyroid stimulating hormone and free thyroxine in a reference population over 60 years old and in very old subjects (over 80 years): comparison to young subjects.

BACKGROUND: Studies based on laboratory data about thyroid stimulating hormone (TSH) and free thyroxine (FT4) reference interval (RI) show conflicting results regarding the importance of using specific values by age groups with advancing age. Retrospective laboratory data or non-specific criteria in the selection of subjects to be studied may be factors leading to no clear conclusions. The aim of this study is to test the hypothesis that TSH and FT4 have specific RI for subjects over 60 to 80 years. METHODS: We evaluated prospectively 1200 subjects of both sexes stratified by age groups, initially submitted to a questionnaire to do the first selection to exclude those with factors that could interfere in TSH or FT4 levels. Then, we excluded those subjects with goiter or other abnormalities on physical examination, positive thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), and other laboratory abnormalities. RESULTS: TSH increased with age in the whole group. There was no statistical difference in the analysis of these independent subgroups: 20-49 versus 50-59 years old (p > 0.05), and 60-69 versus 70-79 years old (p > 0.05). Consequently, we achieved different TSH RI for the three major age groups, 20 to 59 years old: 0.4 - 4.3 mU/L, 60 to 79 years old: 0.4 - 5.8 mU/L and 80 years or more: 0.4 - 6.7 mU/L. Conversely, FT4 progressively decreases = significantly with age, but the independent comparison test between the sub-groups showed that after age 60 the same RI was obtained (0.7 - 1.7 ng/dL) although the minimum value was smaller than that defined by manufacturer. In the comparison between TSH data obtained by this study and those defined by the manufacturer (without segmentation by age) 6.5% of subjects between 60 and 79 years and 12.5% with 80 years or more would have a misdiagnosis of elevated TSH. CONCLUSIONS: TSH normal reference range increases with age, justifying the use of different RI in subjects 60 years old and over, while FT4 decreases with age. Using specific-age RI, a significant percentage of elderly will not be misdiagnosed as having subclinical hipothyroidism.

Hipertireoidismo: abordagem das principais causas e conduta diagnóstica / Hyperthyroidism: approach the main causes and conduct diagnostic

A tireotoxicose é um estado hipermetabólico decorrente dos efeitos de níveis teciduais elevados de hormônios tireoideanos (HTs). O hipertireoidismo é a causa mais comum, e decorre do excesso de hormônios produzidos pela tireoide. Outras causas de tireotoxicose ocorrem por produção extratireoideana ou administração exógena de hormônios tireoideanos. A principal causa de tireotoxicose, o bócio difuso tóxico (BDT) de causa autoimune, responsável por até 80% dos casos, é aqui abordado, assim como as demais causas. O tratamento é realizado com drogas antitireoideanas, iodo radioativo ou cirurgia e exige acompanhamento de longo prazo, tanto pela possibilidade de recidivas como do desenvolvimento de hipotireoidismo.

Thyrotoxicosis is a hypermetabolic state due to the effects of high tissue levels of thyroid hormones (TH). Hyperthyroidism is the most common cause and results from excess hormones produced by the thyroid. Other causes of thyrotoxicosis occur extra thyroid production or exogenous administration of thyroid hormones. The main cause of thyrotoxicosis, the diffuse toxic goiter (DTG) of autoimmune cause, accounting for up to 80% of cases, is discussed here, as well as other causes. The treatment is performed with antithyroid drugs, radioactive iodine or surgery and requires long-term follow-up, due to both the possibility of recurrence and the development of hypothyroidism.

Aortic root ectasia in patients with acromegaly: experience at a single center.

BACKGROUND: Acromegaly is associated with increased cardiovascular mortality, and increased aortic root diameter has been recently described in the literature as a possible feature of acromegalic cardiomyopathy. OBJECTIVE: To assess the aortic root diameter and the prevalence of aortic ectasia in acromegalic patients. PATIENTS AND METHODS: This paper presents a transversal analysis of 42 acromegalic patients by Doppler echocardiogram and comparison with 42 age, sex, body surface area and hypertension matched controls. RESULTS: The mean aortic root diameter at the level of the aortic leaflets was increased in acromegalic patients when compared to controls (3·4 ± 0·5 vs 2·9 ± 0·4 cm, respectively, P < 0·0001). The aortic root diameter was significantly greater in men than in women (3·6 ± 0·6 cm vs 3·2 ± 0·4 cm, respectively, P = 0·004), and the left ventricular mass index was positively correlated with the diameter of the aorta (r = 0·37, P = 0·01). Using a cut-off point ≥ 3·8 cm, an aortic ectasia prevalence of 26·1 vs 2·3% was found in acromegalic patients and controls, respectively (P = 0·002). Only acromegaly was associated with aortic ectasia (P = 0·01). CONCLUSION: The aortic root diameter was higher, and the prevalence of aortic ectasia was more common in acromegalic patients than in controls. In addition, only acromegalic disease was associated with aortic ectasia, suggesting the direct effects of GH and insulin-like growth factor-I excess on the cardiovascular system.

BMI and metabolic profile in patients with prolactinoma before and after treatment with dopamine agonists.

Hyperprolactinemia might be related to weight gain, metabolic syndrome (MS), and insulin resistance (IR). Treatment with dopamine agonist (DA) has been shown to reduce body weight and improve metabolic parameters. The objectives of this study were to determine the prevalence of obesity, overweight, MS, and IR in patients with prolactinoma before and after therapy with DA and to evaluate the relation between prolactin (PRL), body weight, fat distribution, leptin levels, IR, and lipid profile before treatment. In addition, we investigated the correlation of the reduction in PRL levels with weight loss and metabolic profile improvement. Twenty-two patients with prolactinoma completed 6 months of treatment with DA. These patients were submitted to clinical (BMI, waist circumference, blood pressure (BP)), laboratory evaluation (leptin, glucose, low-density lipoprotein (LDL)-cholesterol, and triglyceride (TG) levels) and abdominal computed tomography (CT) before and after treatment. The statistical analyses were done by nonparametric tests. At the beginning of the study, the prevalence of obesity, overweight, MS, and IR was 45, 27, 27, and 18%, respectively. After 6 months of treatment with DA, PRL levels normalized, but no significant difference in BMI was observed. However, there was a significant decrease on homeostasis model assessment of insulin resistance (HOMA(IR)) index, glucose, LDL-cholesterol, and TG levels. This study suggests a possible involvement of prolactinoma on the prevalence of obesity. We should consider that DA may be effective on improving metabolic parameters, and we speculate that a period longer than 6 months of treatment is necessary to conclude whether this drug can interfere in the body weight of patients with prolactinoma.

Diagnóstico da Síndrome de Turner: a experiência do Instituto Estadual de Diabetes e Endocrinologia - Rio de Janeiro, de 1970 a 2008 / Diagnosis of Turner's Syndrome: the experience of the Rio de Janeiro State Institute of Diabetes and Endocrinology between 1970 and 2008

OBJETIVOS: descrever a experiência no diagnóstico da Síndrome de Turner (ST), focalizando a distribuição dos cromossomos, a idade, os sinais e sintomas característicos, conforme as fases da vida (lactância, infância, adolescência e adulta). MÉTODOS: estudo descritivo com 178 pacientes, atendidos de 1970 até 2008. Para análise estatística das diferenças percentuais usou-se o Epi-Info-2000 e para as diferenças entre as médias de idades o teste t de Student e o ANOVA. RESULTADOS: os cariótipos encontrados foram: 79 com 45,X (35,4 por cento), 36 com isocromossomo Xq (20,2 por cento) e 63 com outros mosaicos (35,4 por cento). A média de idade do diagnóstico foi de 12,6 anos, sendo menor naquelas com 45,X. Tiveram o diagnóstico feito na lactância 11,3 por cento das pacientes, 25,3 por cento na infância, 51,1 por cento na adolescência e 12,4 por cento na fase adulta. Daquelas diagnosticadas antes dos cinco anos de idade, 70,6 por cento apresentaram 45,X. Os sinais que levaram à suspeita diagnóstica na lactância foram o pescoço alado e o linfedema congênito de pés/mãos associados às dismorfias típicas; na infância e adolescência foi a baixa estatura. Cubitus valgus foi encontrado em 72,5 por cento das pacientes e orelhas anômalas em 65 por cento das pacientes diagnosticadas com menos de um ano de idade. CONCLUSÃO: o diagnóstico da ST é desnecessariamente atrasado, levando-se em consideração que algumas características típicas podem já estar presentes desde o nascimento.

OBJECTIVES: to describe the Rio de Janeiro State Institute of Diabetes and Endocrinology's experience in diagnosing Turner Syndrome (TS), focusing on the distribution of chromosomes, age, and typical signs and symptoms, according to life stage (breast feeding, childhood, adolescence and adulthood). METHODS: a descriptive study was conducted of 178 patients, attending the Institute between 1970 and 2008 for the purposes of statistical analysis of the percentage differences using Epi-Info-2000 and of the differences between the mean ages using Student's t test and ANOVA Results: the caryotypes found were: 79 with 45,X (35.4 percent), 36 with isochromosome Xq (20.2 percent) and 63 with other mosaics (35.4 percent). The mean age on diagnosis was 12.6 years, this figure being lower in patients with 45,X. The syndrome was diagnosed during breast feeding in 11.3 percent of patients, during childhood in 25.3 percent, during adolescence in 51.1 percent, and in 12.4 percent in adulthood. In those diagnosed before the age of five years, 70,6 percent had 45,X, signs that led to a suspected diagnosis during breast feeding were a webbed neck and congenital lymphedema in the hands and feet associated with typical dysmorphias. In childhood and adolescence the sign was short stature. Cubitus valgus was found in 72.5 percent of patients and abnormal ears in 65 percent of those diagnosed at an age of less than one year. CONCLUSION: diagnosis of TS does not necessarily have to be late, as some typical characteristics may already be present at birth.

[Evaluation of glucose metabolism in acromegalic patients before and after treatment with octreotide LAR]. / Avaliação do metabolismo da glicose em pacientes acromegálicos antes e após tratamento com octreotide LAR.

AIM OF THE STUDY: To evaluate the glucose metabolism in acromegalic patients before and after treatment with octreotide LAR. PATIENTS AND METHODS: This was a prospective and longitudinal study involving 30 patients from the acromegaly research outpatient clinic of the Endocrinology unit of the HUCFF/UFRJ. They underwent clinical and laboratorial evaluations, with measurements of growth hormone (GH), insulin-like growth factor type I (IGF-I), insulin, proinsulin, C peptide, glycosylated hemoglobin (HbA1c), IGF binding protein type 1 (IGFBP-1) and glucose, during oral glucose tolerance test (OGTT), before and after six months of treatment with octreotide LAR. The Wilcoxon signed-rank test was used and values of 5% were considered statistically significant. RESULTS: We found 16 (54%) patients with normal glucose tolerance, 7 (23%) with impaired glucose tolerance and 7 (23%) diabetics. Twelve patients completed the six-month treatment, out of which three showed worsening of glucose tolerance and two (diabetics) had worse blood glucose control. Whereas there was an increase in waist circumference (p=0.03), there was a decrease in GH (p=0.04), with %IGF-I above the upper limit of reference values (% ULRV) [p=0.001], insulin (p=0.019), C peptide levels (p=0.002) and homeostatic model assessment (HOMA-IR) [p=0.039]. CONCLUSIONS: In this series, treatment with octreotide LAR led to a worsening of glucose tolerance in three non-diabetic patients and worsened glycemic control in two diabetics, in spite of reducing insulin resistance.

Prevalence of sleep apnea and metabolic abnormalities in patients with acromegaly and analysis of cephalometric parameters by magnetic resonance imaging.

OBJECTIVES: To determine the prevalence of sleep apnea (SA) and SA syndrome (SAS) in patients with acromegaly and correlate SA with clinical, laboratory, and cephalometric parameters. DESIGN AND METHODS: Prospective and cross-sectional study of 24 patients with active acromegaly evaluated by clinical and laboratory (GH, IGF-I) parameters, polysomnography and magnetic resonance imaging (MRI) of the pharynx. RESULTS: Out of 24 patients, 21 had SA (87.5%), of which 20 (95.3%) had the predominant obstructive type. Median age of these 21 patients was 54 years (range 23-75) and median estimated disease duration was 60 months (range 24-300). The frequency in SA patients of impaired glucose tolerance, diabetes mellitus (DM), and hypertension was 19, 33.3, and 71.4% respectively. Goiter was found in 10 patients (47.6%) and obesity in 18 (90%). Median GH level was 14 mug/l (1.4-198) and median %IGF-I (percentage above the upper limit of normal range of IGF-I) was 181% (-31.6 to 571.2). The prevalence of SAS was 52.4%. Apnea-hypopnea index (AHI) correlated significantly with age, waist circumference, body mass index, and hypopharynx area. The AHI was significantly higher in patients with hypertension and DM. CONCLUSIONS: The prevalence of SA and SAS in acromegaly was similar to the one previously described in other series. Age was a significant risk factor, and hypertension and DM were significantly associated complications of SA. Obesity was also significantly related to SA, as a risk factor, a complication or both. Overall, cephalometric parameters by MRI did not correlate with SA.

Quality of life in women with microprolactinoma treated with dopamine agonists.

OBJECTIVES: To evaluate QOL in women with microprolactinomas treated with dopamine agonists, comparing the patients with normal versus those with elevated prolactin levels, and to identify clinical and biochemical influences on patients' QOL. MATERIAL AND METHODS: A cross-sectional evaluation was performed in two University referral centers. Fifty women with microprolactinoma answered the SF-36 questionnaire by the time of their clinical evaluation. Their biochemical analysis included PRL, estradiol, testosterone, and SHBG. Fifty women of similar age distribution served as controls. RESULTS: Patients had lower scores than controls in all SF-36 categories: physical functioning, physical role, pain, general health, vitality, social functioning, emotional aspect, and mental health. Within the patients' group, the ones with normal PRL levels had higher scores than those with high PRL levels in all categories but the physical role. The physical functioning score correlated with the free androgen index, while the pain, vitality, social functioning, emotional aspect, and mental health scores were associated with the prolactin levels obtained at study entry. CONCLUSIONS: QOL is impaired in women with microprolactinoma treated with dopamine agonists, and was inversely associated with the PRL levels. This latter finding reinforces the importance of providing adequate disease control for these patients in order to avoid the adverse consequences of hyperprolactinemia on QOL.

Quantitative analysis of somatostatin receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR.

OBJECTIVE: To determine whether the somatostatin receptor subtype (SSTR) expression profile correlates with hormonal and tumor volume responses to postsurgical octreotide long acting repeatable (OCT LAR) treatment. DESIGN AND METHODS: Quantitative real-time RT-PCR was used to evaluate the absolute mRNA copy numbers for all five SSTR subtypes in 22 somatotropinomas. Response to OCT LAR was studied by hormone levels (GH and IGF-I) and tumor volume (sella turcica magnetic resonance imaging). RESULTS: SSTR5 was present at the highest level followed by SSTR2, SSTR3, SSTR1, and SSTR4 (2327 (1046-5555), 2098 (194-23 954), 97 (0-460), 14 (0-29 480), and 0 (0-652) copies respectively). Positive correlations were found between SSTR2 levels and the percentage decrease of GH and IGF-I after 3 (r=0.49, P<0.027 and r=0.49, P<0.029 respectively) and 6 (r=0.59, P<0.006 and r=0.58, P<0.008 respectively) months of OCT LAR. A negative correlation was found between SSTR5 mRNA levels and the percentage decrease of GH after 3 months of OCT LAR (r=-0.52, P=0.016, n=21). A higher SSTR2/SSTR5 ratio was observed among patients who obtained hormonal control with OCT LAR, when compared with those uncontrolled (2.4 (0.7-10) vs 0.3 (0.1-7.7), P=0.001). A ROC curve analysis showed a SSTR2/SSTR5 ratio of 1.3 as the best predictor of disease control, with a sensitivity of 88% and a specificity of 92% - area under curve, 0.9. A positive correlation was also found between SSTR2 mRNA levels and the percentage decrease in tumor volume after 6 months of OCT LAR (r=0.79, P=0.002, n=12). CONCLUSIONS: Somatostatin receptor subtype 2 mRNA expression levels in somatotropinomas correlate positively with in vivo hormonal and tumor volume responses to OCT LAR.

Avaliação do metabolismo da glicose em pacientes acromegálicos antes e após tratamento com octreotide LAR / Evaluation of glucose metabolism in acromegalic patients before and after treatment with octreotide LAR

OBJETIVO: Avaliar o metabolismo da glicose em pacientes acromegálicos antes e após o tratamento com octreotide LAR. PACIENTES E MÉTODOS: Este foi um estudo longitudinal e prospectivo com 30 pacientes do ambulatório de pesquisa em acromegalia do Serviço de Endocrinologia do Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro (HUCFF/UFRJ). Eles foram submetidos à avaliação clínica e laboratorial com dosagens de hormônio do crescimento (GH), fator de crescimento semelhante à insulina tipo I (IGF-I), insulina, pró-insulina, peptídeo C, hemoglobina glicosilada (HbA1c), proteína de ligação do IGF tipo 1 (IGFBP-1) e a um teste oral de tolerância à glicose (TOTG), antes e após seis meses de tratamento com octreotide LAR. Foi aplicado o teste dos postos sinalizados de Wilcoxon e o critério de determinação de significância adotado foi o nível de 5 por cento. RESULTADOS: Encontraram-se 16 pacientes (54 por cento) com tolerância normal à glicose, sete (23 por cento) com intolerância à glicose e sete (23 por cento) com diabetes melito (DM). Doze pacientes completaram os seis meses de tratamento, sendo que houve piora da tolerância à glicose em três e piora do controle glicêmico dos dois pacientes diabéticos. Houve aumento da circunferência abdominal (p = 0,03) e queda do GH (p = 0,04), por cento IGF-I acima do limite superior do valor de referência ( por centoLSVR) (p = 0,001), insulina (p = 0,019), peptídeo C (p = 0,002) e do modelo de avaliação homeostática (HOMA-IR) (p = 0,039). CONCLUSÕES: Nesta série, o tratamento com octreotide LAR acarretou piora da tolerância à glicose em três pacientes não-diabéticos e piora do controle glicêmico em dois diabéticos, apesar da diminuição da resistência insulínica (RI).

AIM OF THE STUDY: To evaluate the glucose metabolism in acromegalic patients before and after treatment with octreotide LAR. PATIENTS AND METHODS: This was a prospective and longitudinal study involving 30 patients from the acromegaly research outpatient clinic of the Endocrinology unit of the HUCFF/UFRJ. They underwent clinical and laboratorial evaluations, with measurements of growth hormone (GH), insulin-like growth factor type I (IGF-I), insulin, proinsulin, C peptide, glycosylated hemoglobin (HbA1c), IGF binding protein type 1 (IGFBP-1) and glucose, during oral glucose tolerance test (OGTT), before and after six months of treatment with octreotide LAR. The Wilcoxon signed-rank test was used and values of 5 percent were considered statistically significant. RESULTS: We found 16 (54 percent) patients with normal glucose tolerance, 7 (23 percent) with impaired glucose tolerance and 7 (23 percent) diabetics. Twelve patients completed the six-month treatment, out of which three showed worsening of glucose tolerance and two (diabetics) had worse blood glucose control. Whereas there was an increase in waist circumference (p=0.03), there was a decrease in GH (p=0.04), with percentIGF-I above the upper limit of reference values ( percent ULRV) [p=0.001], insulin (p=0.019), C peptide levels (p=0.002) and homeostatic model assessment (HOMA-IR) [p=0.039]. CONCLUSIONS: In this series, treatment with octreotide LAR led to a worsening of glucose tolerance in three non-diabetic patients and worsened glycemic control in two diabetics, in spite of reducing insulin resistance.

Bone density in women with prolactinoma treated with dopamine agonists.

OBJECTIVES: (1) to evaluate bone density in women with prolactinoma treated with dopamine agonists and healthy controls, using dual energy x-ray absorptiometry (DXA), (2) to classify the results according to the current International Society for Clinical Densitometry (ISCD) criteria, and (3) to correlate bone density with lean and fat masses, biochemical data and clinical aspects of prolactinomas. MATERIALS AND METHODS: A cross-sectional study was performed in two University referral centers. Forty-five premenopausal women with prolactinoma were submitted to DXA and blood analysis (prolactin, estradiol, testosterone, SHBG, calcium, phosphorus, PTH, C-telopeptides of type 1 collagen, and osteocalcin) by the time of their clinical evaluation. They were compared with 25 control women of similar age and body mass index distribution. RESULTS: Women with prolactinoma had lower lumbar spine Z-score than controls. Femoral neck, trochanter, and total proximal femur Z-scores were similar in patients and controls. Twenty-two percent of the patients had Z-scores below the expected age range vs. 4% in the control group. Lumbar spine, femoral neck, and total proximal femur Z-scores were mainly correlated with the amenorrhea duration. The trochanter Z-score was associated with the gynoid lean/fat mass ratio. CONCLUSIONS: Based on the current ISCD criteria, bone density evaluation in women with prolactinoma reveals bone loss, especially of trabecular type. Bone density in these patients was particularly associated with the duration of amenorrhea, which reinforces the importance of the adequate disease control in women with prolactinoma in order to avoid complications of this disease.

Body fat in nonobese women with prolactinoma treated with dopamine agonists.

OBJECTIVES: To evaluate body fat in nonobese women with prolactinoma treated with dopamine agonists, using whole body dual energy X-ray absorptiometry (DXA) and to correlate DXA results with biochemical data and clinical aspects of the prolactinoma. DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study was performed in two University referral centres. Thirty-one nonobese premenopausal women with prolactinoma were subjected to DXA and blood analysis at clinical evaluation. They were compared with 21 control women of similar age and body mass index (BMI). RESULTS: Women with prolactinoma treated with dopamine agonists and controls had similar body fat percentages in all sites evaluated with DXA (arms, legs, trunk, android, gynoid and total body). Patients with normal PRL levels at study entry had lower body fat percentages in all sites. In the patient group, arm, leg, truncal, android, gynoid and total body fat were positively associated with PRL levels. CONCLUSION: Body fat percentage is similar in nonobese women with prolactinoma and in controls. The lower body fat content in patients with normal PRL levels is likely to be due to the metabolic effects of adequate dopamine receptor type 2 (DR2) activation as a result of regular dopamine agonist treatment. This finding reinforces the importance of the appropriate treatment with dopamine agonists in women with prolactinoma, which, besides normalizing PRL levels, reduces body fat content and the consequent risk of developing Metabolic Syndrome and its complications.

Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas.

OBJECTIVE: It is believed that the variable effectiveness of somatostatin analogs in post-surgical management of somatotropinomas and non-functioning pituitary adenomas (NFPA) may be due in part to variable expression of somatostatin receptor isoforms (SSTR1-5), within and between pituitary tumor types. DESIGN AND METHODS: Quantitative real-time RT-PCR was used to compare absolute mRNA copy numbers for all five SSTR isoforms in 23 somatotropinomas and 19 NFPA. RESULTS: Somatostatin receptor subtype 5 mRNA was present at the highest level in somatotropinomas, followed by SSTR2>SSTR3>>SSTR1>>>SSTR4. In contrast, SSTR3 mRNA was present at the highest level in NFPA, followed by SSTR2, while SSTR1, SSTR4, and SSTR5 transcripts were only detectable in select tumors. Among somatotropinomas, a positive correlation was found between SSTR2 mRNA levels and the percent decrease of GH (%GH) after 3 and 6 months of therapy with octreotide long acting repeatable (LAR) (r=0.51 and r=0.66; P=0.05 and P=0.008). Also the percent decrease of IGF-I (%IGF-I) after 3 months of octreotide LAR was negatively correlated with SSTR5 and %IGF-I after 6 months of octreotide LAR was positively correlated with SSTR2. CONCLUSIONS: The present report is a large series examining SSTR mRNA levels in somatotropinomas and NFPA. These initial findings suggest that detailed knowledge of the SSTR mRNA expression profile in somatotropinomas can help to predict the hormonal response to therapy with LAR. Also, it appears that SSTR3 in NFPA may be a potential target for SSTR3 preferential or universal ligands such as pasireotide.

[Cardiac morphology and performance alterations and analysis of determinant factors of left ventricular hypertrophy in 40 patients with acromegaly]. / Alterações morfológicas e funcionais cardíacas e análise dos fatores determinantes de hipertrofia ventricular esquerda em 40 pacientes com acromegalia.

Acromegaly has a high mortality rate due mainly to cardiovascular complications. The aim was to evaluate the determinant factors of left ventricular hypertrophy (LVH) and cardiac alterations in 40 acromegalic patients submitted to clinical-laboratorial studies and echocardiogram. The variables analyzed were age, sex, disease duration, arterial hypertension (AH), impaired glucose tolerance/DM, previous treatment with octreotide, GH and %IGF-I. Univaried analysis showed that patients with LVH were older (p= 0.031), had higher prevalence of AH (p= 0.009) and higher %IGF-I (p= 0.002), than those without LVH. Multivaried analysis showed AH and %IGF-I as determinants of LVH (p= 0.035 and p= 0.016). After dichotomizing of %IGF-I, a score was created and the frequency of LVH was 9%, 65%, 92% x 0, 1, 2; p< 0.0001. Prevalence of aortic ectasia was higher and valvar disease was smaller than reported in the literature. We conclude that AH and %IGF-I were determinants of LVH.