Cesar Luiz Boguszewski

Heterogeneous Genetic Background of the Association of Pheochromocytoma/Paraganglioma and Pituitary Adenoma: Results From a Large Patient Cohort

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: The study was conducted at university hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. Outcome: Outcomes included genetic screening and clinical characteristics. Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs

The aim of this cross sectional study was to evaluate bone mineral density (BMD) and serum levels of 25-hydroxy vitamin D (25OHD) in a group of patients taking antiepileptic drugs (AED) for a seizure disorder. Between May-2001 and January-2003, we evaluated 58 patients (40 women/18 men), 34.4+/-6 years old living in Curitiba or in its metropolitan area, on antiepileptic therapy for 2 to 38 years (10 on monotherapy /48 on multiple drugs regime). The group was matched by age, gender, and bone mass index to 29 healthy subjects (20 women/ 9 men); 34.2+/-5.9 years old. Medical history and physical exam were performed on all subjects with particular information sought about fractures and risks factors for osteoporosis. Blood samples were collected for total serum calcium, albumin, phosphorus, creatinine, total alkaline phosphatase, and liver function tests. BMD of the lumbar spine, femur and forearm was determined by dual energy X-ray absorptiometry (DXA, Hologic QDR 1000). Between February and April-2003, other blood samples were collected to measure 25OHD, intact paratohormone (PTH) and calcium. Unemployment and smoking history were more frequent among patients than among controls (p<0.05). Fifteen patients had a fracture history, all of which occurred during a seizure. The BMD of the lumbar spine (0.975+/-0. 13 g/cm2 vs. 1.058+/-0.1 g/cm2; p<0.03) and of the total femur (0.930+/-0.1 g/cm2 vs. 0.988+/-0.12 g/cm2; p<0.02) was lower in patients than in controls. In 63.5% of patients and in 24.1 % of controls a T-score < -1.0 in at least one site was seen. The AED users had higher total alkaline phosphatase and lower 25OHD (p<0.02). No correlations between BMD and 25OHD were found. The use of phenytoin was correlated with a greater incidence of fractures (RR: 2.38). We conclude that patients on chronic use of AED have alterations in bone metabolism characterized in this study by lower BMD of the lumbar spine and total femur and lower serum concentrations of 25OHD.

Cabergoline versus bromocriptine in the treatment of hyperprolactinemia: a systematic review of randomized controlled trials and meta-analysis

Cabergoline and bromocriptine are the most used drugs in the treatment of hyperprolactinemia, they are able to normalize the prolactin levels, restore gonadal function and promote tumor reduction in the majority of patients. We undertake a systematic review and meta-analysis of randomized controlled trials to compare cabergoline versus bromocriptine in the treatment of patients with idiopathic hyperprolactinemia and prolactinomas. The data sources were: Embase, Pubmed, Lilacs and Cochrane Central. The outcome measures were: normalization of prolactin secretion, restoration of gonadal function, reduction of tumoral volume, quality of life and adverse drug effects. Were identified 418 references and after screening by title and abstract, we obtained complete copies of 34 articles potentially eligible for inclusion in the review. From this total, 19 were selected to be included, but fifteen of them were excluded due to the following reasons: one randomized study compared cabergoline versus placebo and other randomized study compared different doses of cabergoline; five references were cases series; four were only controlled studies; three were retrospectives series and; one was a cohort study. Therefore, four publications were included in the review and in the final analysis. The meta-analysis of normalization of serum prolactin levels and menstruation with return of ovulatory cycle showed a significant difference in favor of cabergoline group (RR 0.67 [CI 95% 0.57, 0.80]) e (RR 0.74 [CI 95% 0.67, 0.83]), respectively. The number of adverse effects was significantly higher in the bromocriptine number than in cabergoline group (RR 1.43 [CI 95% 1.03, 1.98]). The meta-analysis showed new evidence favoring the use of cabergoline in comparison with bromocriptine for the treatment of prolactinomas and idiopathic hyperprolactinemia.

Skeletal microstructural abnormalities in postmenopausal women with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with osteoporosis and fragility fractures. The objectives of this study were to assess static and dynamic indices of cancellous and cortical bone structure in postmenopausal women with COPD. Twenty women with COPD who had not received chronic oral glucocorticoids underwent bone biopsies after double tetracycline labeling. Biopsies were analyzed by histomorphometry and µCT and compared with age‐matched controls. Distribution of the patients according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was: Type I (15%), Type II (40%), Type III (30%), and Type IV (15%). Mean (±SD) cancellous bone volume (15.20 ± 5.91 versus 21.34 ± 5.53%, p = .01), trabecular number (1.31  ±  0.26 versus 1.77 ± 0.51/mm, p = .003), and trabecular thickness (141 ± 23 versus 174 ± 36 µm, p = .006) were lower in patients than in controls. Connectivity density was lower in COPD (5.56 ± 2.78 versus 7.94 ± 3.08/mm, p = .04), and correlated negatively with smoking (r = −0.67; p = .0005). Trabecular separation (785 ± 183 versus 614 ± 136 µm, p = .01) and cortical porosity (4.11 ± 1.02 versus 2.32 ± 0.94 voids/mm2; p < .0001) were higher in COPD while cortical width (458 ± 214 versus 762 ± 240 µm; p < .0001) was lower. Dynamic parameters showed significantly lower mineral apposition rate in COPD (0.56 ± 0.16 versus 0.66 ± 0.12 µm/day; p = .01). Patients with more severe disease, GOLD III and IV, presented lower bone formation rate than GOLD I and II (0.028 ± 0.009 versus 0.016 + 0.011 µm3/µm2/day; p = 04). This is the first evaluation of bone microstructure and remodeling in COPD. The skeletal abnormalities seen in cancellous and cortical bone provide an explanation for the high prevalence of vertebral fractures in this disease.

Influence of the Exon 3-Deleted/Full-Length Growth Hormone (GH) Receptor Polymorphism on the Response to GH Replacement Therapy in Adults with Severe GH Deficiency

CONTEXT There is considerable individual variation in the clinical response to GH replacement therapy in GH deficient (GHD) adults. Useful predictors of treatment response are lacking. OBJECTIVE The aim of the study was to assess the influence of the exon 3-deleted (d3-GHR) and full-length (fl-GHR) GH receptor isoforms on the response to GH replacement therapy in adults with severe GHD. DESIGN AND PATIENTS A total of 124 adult GHD patients (79 men; median age, 50 yr) were studied before and after 12 months of GH therapy. GHD patients were divided into those bearing fl/fl alleles (group 1) and those bearing at least one d3-GHR allele (group 2), and the genotype was related to the effects of GH therapy on IGF-I levels and total body fat (BF). INTERVENTION GH dose was individually titrated to obtain normal serum IGF-I levels. MAIN OUTCOME MEASURES GHR genotype was determined by PCR amplification, IGF-I levels by immunoassay, and BF by a four-compartment model. RESULTS Seventy-two (58%) patients had fl/fl genotype and were classified as group 1, whereas 52 (42%) had at least one d3-GHR allele and were classified as group 2 (40 were heterozygous and 12 were homozygous). At baseline, there were no significant differences in the study groups. Changes in IGF-I and BF after 12 months of GH treatment did not differ significantly between the two genotype groups. CONCLUSION The presence of d3-GHR allele did not influence the response to GH replacement therapy in our cohort of adults with severe GHD.

Decrease in leptin production by the adipose tissue in obesity associated with severe metabolic syndrome.

OBJECTIVE To evaluate the associations between leptinemia and the components of metabolic syndrome (MetS). METHODS Fifty-one obese adults (9 men; 36.7 +/- 10.0 years; body mass index (BMI) 46.2 +/- 10.0 kg/m(2)) were submitted to clinical examination, determinations of body fat mass (BF, bioimpedance) and resting energy expenditure (REE, indirect calorimetry), and to hormonal and biochemical analysis. Patients were categorized into three groups, according to the number of criteria for MetS: Group I: none or 1; Group II: 2; and Group III: 3 or 4 criteria. RESULTS Absolute leptinemia (LepA; 37.5 +/- 16.9 ng/mL) was directly correlated with BMI (r = 0.48; p = 0.0004), waist circumference (r = 0.31; p = 0.028) and BF (r = 0.52; p = 0.0001). Leptinemia adjusted for BF (LepBF) was inversely correlated with weight (r = -0.41; p=0.027), REE (r = -0.34; p = 0.01) and number of MetS criteria (r = -0.32; p = 0.02). There was no difference in LepA among the groups. LepBF in Group III (0.58 +/- 0.27 ng/mL/kg) was significantly lower compared to Group I (0.81 +/- 0.22 ng/mL/kg; p = 0.03) and Group II (0.79 +/- 0.30 ng/mL/kg; p = 0.02). CONCLUSIONS Leptin production by the adipose tissue is decreased in obese subjects fulfilling three or more criteria of MetS, suggesting a state of relative leptin deficiency in obesity associated with advanced stages of MetS.

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

IntroductionAcromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.MethodsWe conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.Findings and conclusionsSuccessful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and cancer: an old debate revisited

Based on experimental and animal models, epidemiological data from non-acromegaly populations, and longitudinal and cross-sectional cohorts of patients with acromegaly, a potential association between acromegaly and cancer has long been hypothesized, in particular colorectal cancer, and, to a lesser extent, breast, thyroid and prostate cancers. The exact mechanisms underlying this potential association have not been fully elucidated. Results from studies examining cancer incidence and mortality in acromegaly have been inconsistent, with some demonstrating increased risk, whereas others show no increase. This article reviews the existing data relating to cancer risk and mortality in acromegaly, exploring the limitations of study designs and the impact of changes in disease control and patient outcomes over time.

Insulin-Like Growth Factor-1, Leptin, Body Composition, and Clinical Status Interactions in Children with Cystic Fibrosis

Background/Aims: Children with cystic fibrosis (CF) are of increased risk of reduced fat body mass (FBM) and lean body mass (LBM). Serum concentrations of insulin-like growth factor-1 (IGF-1)and leptin could be markers of LBM and/or FBM depletion. To evaluate the relationships between disease activity, body composition, IGF-1and leptin concentrations in CF children. Methods: A cross-sectional study with 26 CF children aged 5.0–15.5 years and 33 healthy controls, mean age 9.4 years. Body composition was evaluated by dual-energy X-ray absorptiometry. Fasting blood samples were analyzed for leptin, IGF-1and IGFBP-3. Results: FBM standard deviation score (SDS; CF boys –0.02 ± 0.88 vs. 0.78 ± 0.65, p < 0.01; CF girls –0.37 ± 1.15 vs. 0.70 ± 0.97, p < 0.05), leptin concentration (CF boys 2.07 ± 0.79 vs. 3.07 ± 1.28 ng/ml, p < 0.05; CF girls 2.71 ± 0.86 vs. 5.00 ± 2.95 ng/ml, p < 0.05) and IGF-1SDS (CF boys –1.43 ± 1.50 vs. –0.32 ± 0.88, p < 0.05; CF girls –0.66 ± 1.66 vs. 0.64 ± 0.57, p < 0.01) were lower in CF children compared to controls. Shwachman score was the strongest predictor of lean body mass (R = 0.63). Leptin levels explain 60% of the variability in FBM. Conclusion: Serum concentrations of IGF-1 and leptin are decreased in children with CF and are associated with clinical conditions and body composition.

Growth hormone (GH) replacement therapy in GH-deficient women during pregnancy

objective The present recommendation is to discontinue GH replacement therapy in hypopituitary women, as they become pregnant. We report our experience of managing GH deficiency with GH replacement therapy in pregnant hypopituitary women.