The Journal of clinical endocrinology and metabolism

Publications in this journal

• Article: Multiplicity of Hormone-Secreting Tumors: Common Themes About Cause, Expression, and Management.

  Stephen Marx
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  ABSTRACT: Context:Multiplicity of hormone-secreting tumors occurs in a substantial portion of hormone-excess states. Multiplicity increases the difficulty of management and drives the selection of special strategies.Evidence Acquisition:This is a synthesis from publications about tumor development and expression, and about types of clinical strategy for hormone-secreting tumors.Evidence Synthesis:Comparisons were made between patient groups with solitary tumors versus those with multiple tumors. Major themes with clinical relevance emerged. Usually tumor multiplicity develops from a genetic susceptibility in all cells of a tissue. This applies to hormone-secreting tumors that begin either as being polyclonal (such as in the parathyroids of familial hypocalciuric hypercalcemia) or as being monoclonal (such as in the parathyroids of multiple endocrine neoplasia type 1 (MEN1)). High penetrance of a hereditary tumor frequently results in bilaterality and in several other types of multiplicity. Managements are better for the hormone excess than for the associated cancers. Management strategies can be categorized broadly as ablation that is total, subtotal, or zero. Examples are discussed for each category and one example of each category is named here: (1) total ablation of the entire tissue with effort to replace ablated functions (for example in C-cell neoplasia of multiple endocrine neoplasia type 2); (2) subtotal ablation with increased likelihood of persistent disease or recurrent disease (for example in the parathyroid tumors of MEN1); or (3) no ablation of tissue with or without use of pharmacotherapy (for example, with blockers for secretion of stomach acid in gastrinomas of MEN1).Conclusions:Tumor multiplicity usually arises from defects in all cells of the precursor tissue. Even the optimized managements involve compromises. Still, an understanding of pathophysiology and of therapeutic options should guide optimized management.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Hypothalamic involvement predicts cognitive performance and psychosocial health in adults with childhood onset craniopharyngioma.

  Sigridur Fjälldal, Helene Holmer, Lars Rylander, Maria Elfving, Bertil Ekman, Kai Österberg, Eva Marie Erfurth
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  ABSTRACT: http://jcem.endojournals.org/content/early/2013/06/13/jc.2013-2000.abstract?sid=00e0bdd6-8430-4aba-b068-4dfe7fbbeae6
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: New Genes in Bone Development: What's New in Osteogenesis Imperfecta.

  Joan C Marini, Angela R Blissett
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  ABSTRACT: Osteogenesis Imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and deformity, and growth deficiency. Most cases of OI (Classical types) have autosomal dominant inheritance and are caused by mutations in the type I collagen genes. During the past several years, a number of noncollagenous genes whose protein products interact with OI have been identified as the cause(s) of rare forms of OI. This has led to a paradigm shift for OI as a collagen-related condition. The majority of the non-Classical OI types have autosomal recessive inheritance and null mutations in their respective genes. The exception is a unique dominant defect in IFITM5, which encodes Bril, and leads to hypertrophic callus and interosseus membrane ossification. Three recessive OI types arise from defects in any of the components of the collagen prolyl 3-hydroxylation complex (CRTAP, P3H1, CyPB), which modifies the collagen α1(I)Pro986 residue. Complex dysfunction leads to delayed folding of the procollagen triple helix and increased helical modification. Next, defects in collagen peptidly-prolyl isomerases, HSP47 and FKBP65, lead to improper procollagen folding, and deficient collagen crosslinking in matrix, respectively. A form of OI with a mineralization defect is caused by mutations in SERPINF1, whose protein product, PEDF, is a well-known anti-angiogenesis factor. Defects in the C-propeptide cleavage enzyme, BMP1, also cause recessive OI. Additional genes, including SP7 and TMEM38B, have been implicated in recessive OI, but are yet unclassified. Elucidating the mechanistic pathways common to dominant and recessive OI may lead to novel therapeutic approaches to improve clinical manifestations.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Fibroblast Growth Factor 23, Bone Mineral Density, and Risk of Hip Fracture among Older Adults: The Cardiovascular Health Study.

  Anna Jovanovich, Petra Bùzková, Michel Chonchol, John Robbins, Howard A Fink, Ian H de Boer, Bryan Kestenbaum, Ronit Katz, Laura Carbone, Jennifer Lee, Gail A Laughlin, Kenneth J Mukamal, Linda F Fried, Michael G Shlipak, Joachim H Ix
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  ABSTRACT: ContextFibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.Objective Evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.Design and SettingLinear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease (CKD).Participants2008 women and 1329 men ≥65 years from the 1996-97 Cardiovascular Health Study visit.Main Outcome MeasuresDual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.ResultsWomen had higher plasma FGF23 concentrations than men (75 [56-107] vs. 66 [IQR 52-92] RU/mL; p<0.001). After adjustment, higher FGF23 concentrations were associated with greater TH and LS BMD in men only (ß per doubling of FGF23: 0.02 [95% CI 0.001, 0.04] g/cm(2) and 0.03 [95% CI 0.01, 0.06] g/cm(2)). During 8.2±3.7 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted HR: 0.95 [95% CI 0.78, 1.15] and 1.09 [95% CI 0.82, 1.46] per doubling of FGF23). Results did not differ by CKD status (p>0.4 for interactions).Conclusions In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater LS and TH BMD, but not with hip fracture risk.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: VERTEBRAL FRACTURES IN PATIENTS WITH ACROMEGALY: A 3-YEAR PROSPECTIVE STUDY.

  G Mazziotti, A Bianchi, T Porcelli, M Mormando, F Maffezzoni, A Cristiano, A Giampietro, L De Marinis, A Giustina
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  ABSTRACT: Context.Cross-sectional studies showed an elevated prevalence of vertebral fractures in acromegaly. However, no data are available on incident vertebral fractures in this clinical setting.Objective.To investigate the incidence and risk factors of vertebral fractures in patients with acromegaly.Design.Three-year prospective study.Setting.Referral centers.Subjects.88 patients with acromegaly (33 females, 55 males; mean age 50, range 21-88) and 106 control subjects, matched for sex and age (43 females and 63 males, mean age 55 years, range: 33-79), attending out-patient bone clinics.Main Measures.Patients and control subjects were evaluated for incidence of vertebral fractures using a quantitative morphometric approach on spine X-ray, which was performed at baseline and after 3 years of follow-up. At the same time-points, patients with acromegaly were also evaluated for bone mineral density (BMD) with DXA at lumbar spine and femoral neck.Results.After 3-year follow-up, 37 patients with acromegaly (42.0%) and 4 control subjects (3.8%) experienced incident vertebral fractures (p<0.001). The incidence of vertebral fractures was significantly higher in patients with active disease as compared to those who had controlled/cured acromegaly at the study entry (62.5% vs. 25.0%; p<0.001). Risk of incident vertebral fractures was significantly associated with hypogonadism, change in femoral neck BMD and prevalent vertebral fractures at the study entry only in patients with controlled/cured acromegaly, whereas in patients with active disease the fracture risk was not influenced by the above clinical factors but it was significantly associated with duration of active acromegaly.Conclusions.This prospective study demonstrates an high rate of incident vertebral fractures both in patients with active and controlled acromegaly.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Cyclic AMP and c-KIT signaling in familial testicular germ cell tumor predisposition.

  Monalisa F Azevedo, Anelia Horvath, Ethan R Bornstein, Madson Q Almeida, Paraskevi Xekouki, Fabio R Faucz, Evgenia Gourgari, Kiran Nadella, Elaine F Remmers, Martha Quezado, Rodrigo Bertollo de Alexandre, Christian P Kratz, Maria Nesterova, Mark H Greene, Constantine A Stratakis
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  ABSTRACT: 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 cyclic AMP (cAMP)-binding phosphodiesterase 11A (PDE11A) as modifiers of FTGCT risk. Recent genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) in the KITLG gene, the ligand for the cKIT tyrosine kinase receptor, as strong modifiers of susceptibility to both familial and sporadic TGCT.Design:We studied 94 patients with FTGCT and 50 at-risk male relatives from 63 unrelated kindreds, in whom the PDE11A gene had been sequenced by investigating the association between KITLG GWAS SNPs 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 two 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 relative PDE 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 TGCT. The two 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 TGCT.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status.

  Tae Hyuk Kim, Kyung Won Kim, Hwa Young Ahn, Hoon Sung Choi, Hojeong Won, Yunhee Choi, Sun Wook Cho, Jae Hoon Moon, Ka Hee Yi, Do Joon Park, Kyong Soo Park, Hak C Jang, Seong Yeon Kim, Young Joo Park
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  ABSTRACT: Context:The widespread use of thyroid tests in asymptomatic individuals identifies many patients with transient subclinical hypothyroidism.Objective:To determine the effect of seasonal change on serum TSH levels and the transition between subclinical hypothyroid and euthyroid status.Design, Setting, and Subjects:This was a retrospective longitudinal study of 1751 subclinical hypothyroid and 28096 euthyroid subjects aged over 18 years who underwent serial thyroid function tests at a health screening center between October 2003 and May 2011. Main Outcome Measures:Age-adjusted geometric mean values of the TSH level by month were calculated using linear mixed models. Adjusted odds ratios of test season and multiple baseline clinical factors were determined using generalized estimating equations.Results:During median 36 months of follow-up, 57.9% of subclinical hypothyroid subjects reverted to euthyroidism, and 4.3% of euthyroid subjects developed subclinical hypothyroidism. The monthly distribution of follow-up TSH levels indicated a biphasic pattern, i.e., an increase during the winter-spring season and a decrease during the summer-fall season, with a maximal TSH difference of 0.69 mIU/L in subclinical hypothyroid and 0.30 mIU/L in euthyroid subjects. Normalization of subclinical hypothyroidism was increased 1.4-fold in follow-up tests during the summer-fall follow-up, whereas subclinical hypothyroidism increased 1.4-fold in euthyroid subjects during the winter-spring follow-up.Conclusions:The season in which thyroid testing was performed was independently related to the transition between subclinical hypothyroid and euthyroid status. Seasonal variations in TSH concentration should be considered before deciding on treatment of subclinical hypothyroidism, particularly in the areas with a wide annual temperature range.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Hypothalamic involvement predicts cognitive performance and psychosocial health in long term survivors of childhood craniopharyngioma.

  Sigridur Fjalldal, Helene Holmer, Lars Rylander, Maria Elfving, Bertil Ekman, Kai Osterberg, Eva Marie Erfurth
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  ABSTRACT: Context:Hypothalamic damage caused by craniopharyngioma (CP) is associated with poor functional outcome.Objective:To assess cognitive function and quality of life (QoL) in childhood onset CP on hormonal replacement, including GH treatment.Design:A cross sectional study with a median follow-up time of 20 years (1-40).Setting:Patients were recruited from the South Medical Region of Sweden.Participants:The study included 42 patients (20 women), surgically treated for a childhood onset CP between 1958 and 2000. Patients were aged ≥17 years. Equally many controls, matched for age, sex, residence and smoking habits, were included. Tumor growth into the third ventricle (TGTV) was found in 25 patients.Main Outcome Measures:All subjects were examined with a battery of cognitive tests and the questionnaires: Symptom Checklist-90 (SCL-90), the Interview Schedule for Social Interaction and the Social Network concept.Results:The CP patients had lower cognitive performance, reaching statistical significance in 12 of 20 test variables, including executive function and memory. Comparison of patients with TGTV to controls revealed, a significant lower mean total score (P = 0.006). A significant negative correlation was recorded between mean z-score of cognitive performance and years since operation (r= -0.407; P = 0.014). No statistically significant group differences were observed across any of the nine SCL-90 subscales.Conclusions:Adults with childhood onset CP, on hormone replacement, including GH treatment, have memory defects, disturbed attention and impaired processing speed. Patients with hypothalamic involvement are more affected. Patients rated their QoL as good as their matched controls.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Large Scale Pooled Next-Generation Sequencing of 1077 Genes To Identify Genetic Causes of Short Stature.

  Sophie R Wang, Heather Carmichael, Shayne F Andrew, Timothy C Miller, Jennifer E Moon, Michael A Derr, Vivian Hwa, Joel N Hirschhorn, Andrew Dauber
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  ABSTRACT: Context:The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes potentially leading to genetic diagnoses.Objectives:To discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology.Design:Prospective cohort study of subjects with short statureSetting:Pediatric endocrinology and genetics clinics at an academic centerPatients:192 children with short stature with no defined genetic etiology as well as 192 individuals of normal stature from the Framingham Heart StudyIntervention:Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genesMain Outcome Measures:Number of rare nonsynonymous genetic variants found in cases but not controls, known pathogenic variants in cases, and potentially pathogenic variants in IGF1RResults:We identified 4928 genetic variants in 1077 genes that were present in cases but not in controls. Of those, 1349 variants were novel (898 nonsynonymous). False positive rates from pooled sequencing were 4-5% and false negative rate was 0.1% in regions covered well by sequencing. We identified three individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, likely pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject.Conclusions:Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature but data interpretation is complex. Noonan Syndrome may be an underdiagnosed cause of short stature.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Long-Term Bioavailability After a Single Oral or Intramuscular Administration of 600,000 IU of Ergocalciferol or Cholecalciferol: Implications for Treatment and Prophylaxis.

  Cristiana Cipriani, Elisabetta Romagnoli, Jessica Pepe, Stefania Russo, Luciano Carlucci, Sara Piemonte, Luciano Nieddu, Donald J McMahon, Ravinder Singh, Salvatore Minisola
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  ABSTRACT: Context:We previously showed that a single high dose of oral (po) cholecalciferol (D3) sharply increases serum 25-hydroxyvitamin D [25(OH)D].Objective:We evaluated the long-term bioavailability and metabolism of a single po or intramuscular (im) high dose of ergocalciferol (D2) or D3.Design:This was a prospective intervention study.Setting:The study was conducted in an ambulatory care setting.Patients:Participants were 24 subjects with hypovitaminosis D.Interventions:A single dose of 600,000 IU of po or im D2 or D3 was administered.Main Outcome Measures:Serum 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were measured at baseline and at days 30, 60, 90, and 120 by RIA. Serum 1,25(OH)2D2, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 24,25-hydroxyvitamin D2 [24,25(OH)D2], and 24,25-hydroxyvitamin D3 [24,25(OH)D3] were measured by liquid chromatography-tandem mass spectrometry in a subgroup of patients receiving the po formulations.Results:The areas under the curve of 25(OH)D after D3 were significantly higher than those after D2 (P < .0001). Serum 25(OH)D basal difference significantly increased at day 30 with po D2 and D3 (P < .01 and P < .0001) and up to day 90 with po D3 (P < .01). The im formulations produced a slow increased, and values peaked at day 120 relative to the other time points (P < .0001). We found a decrease in 1,25(OH)2D at day 30 (P < .05) and up to day 120 (P < .001) and an increase in 1,25(OH)2D2 at day 30 (P < .01) and up to day 120 (P < .01) after po D2. Oral D2 and D3 produced increases in 24,25(OH)D2 and 24,25(OH)D3, respectively, at day 30 (P < .001).Conclusions:A po dose of 600,000 IU of D2 or D3 is initially more effective in increasing serum 25(OH)D than the equivalent im dose and is rapidly metabolized. Our RIA assay for 1,25(OH)2D may not recognize 1,25(OH)2D2.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Nrf2 is commonly activated in papillary thyroid carcinoma, and it controls antioxidant transcriptional responses and viability of cancer cells.

  Panos G Ziros, Stavroula D Manolakou, Ioannis G Habeos, Ioannis Lilis, Dionysios V Chartoumpekis, Vasiliki Koika, Paula Soares, Venetsana E Kyriazopoulou, Chrisoula D Scopa, Dionysios J Papachristou, Gerasimos P Sykiotis
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  ABSTRACT: Context:The antioxidant transcription factor NFE2-related factor 2 (Nrf2), encoded by NFE2L2, has been implicated as mediator of thyroid cancer cell lines' resistance to proteasome inhibitors. However, the activity status of the Nrf2 pathway in human thyroid cancer remains unknown.Objective:Assessment of the Nrf2 pathway's activity status in papillary thyroid carcinoma (PTC); investigation of its role(s) in antioxidant transcriptional responses and viability of cancer cells.Design:Retrospective immunohistochemical analyses of PTC specimens, adjacent normal tissue, and benign lesions. Assays of viability and gene expression in the PTC cell lines K1 and TPC-1 after genetic/pharmacological manipulation of Nrf2. DNA sequencing.Setting:Academic medical center.Patients:42 PTC; 42 benign lesions (24 adenomas, 18 nodular hyperplasias).Main Outcome Measures:Abundance of Nrf2, Nqo1, Keap1, and 4HNE. Cell line viability and mRNA expression of Nrf2, Nqo1, and Trdx1. Sequence of NFE2L2, KEAP1, and BRAF.Results:Nrf2 and its target Nqo1 were undetectable in normal tissue; their levels were significantly higher in PTC than in benign lesions (p<0.0001 and p=0.024, respectively). The Nrf2 inhibitor Keap1 was variably abundant in PTC and its levels did not correlate with Nrf2 (p=0.37), arguing against decreased levels as mechanism for Nrf2 activation. The oxidized lipid 4HNE was more abundant in PTC than normal tissue (p<0.001), indicating oxidative stress. Nrf2 mediated transcriptional antioxidant responses in both the PTC cell lines K1 and TPC-1 and in the non-transformed cell line TAD2, but it conferred a viability advantage specifically in the PTC cells lines.Conclusions:The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Change in beta cell mass in Japanese non-diabetic obese individuals.

  Kinsei Kou, Yoshifumi Saisho, Seiji Satoh, Taketo Yamada, Hiroshi Itoh
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  ABSTRACT: Aim:To clarify change in beta cell mass in Japanese obese individuals.Methods:We obtained the pancreas at autopsy from 39 lean and 33 obese Japanese non-diabetic individuals (age 47 ± 13 vs. 47 ± 12 years, p = 0.83, BMI 20.4 ± 1.6 vs. 28.5 ± 3.9 kg/m(2), p <0.01). Pancreatic sections were stained for insulin, and beta cell area (%BCA) was measured as the fraction of beta cell area to total pancreas area. Beta cell mass (BCM) was then calculated as the product of %BCA and estimated pancreas weight. Beta cell replication and apoptosis were assessed by double-staining for insulin and Ki67, and insulin and single-stranded DNA, respectively. The frequencies of insulin-positive duct cells and scattered beta cells were assessed as surrogate markers of beta cell neogenesis. Alpha cell area (%ACA) was also measured, and %ACA to %BCA ratio was determined.Results:There was no increase in BCM in obese individuals compared with lean individuals (0.6 ± 0.4 vs. 0.7 ± 0.4 g, p = 0.12). Neither beta cell replication, beta cell neogenesis nor beta cell apoptosis was significantly increased in the presence of obesity. There was no significant difference in %ACA to %BCA ratio between obese and lean individuals (0.91 ± 1.09 vs. 0.75 ± 0.51, p = 0.47).Conclusion:There was no increase in beta cell mass and no detectable change in beta cell turnover in Japanese obese individuals.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study.

  K Sacre, M Dehoux, Mp Chauveheid, M Chauchard, O Lidove, R Roussel, T Papo
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  ABSTRACT: ContextGlucocorticoid therapy is being used in a wide variety of systemic disorders. Reference papers, published more than 20 years ago, showed no correlation between adrenal insufficiency risk and dose or duration of glucocorticoid therapy.Objective To evaluate the extent to which long-term glucocorticoid therapy damages the pituitary-adrenal axis in patients with systemic inflammatory disordersDesignRetrospective observational study from January 2011 to August 2012SettingMonocentric study, Department of Internal Medicine, Bichat Hospital, Paris-Diderot University, Paris, FranceParticipantsSixty consecutive patients who were receiving long-term prednisone therapy for systemic inflammatory disorders and in whom discontinuation of glucocorticoid treatment was planned.InterventionA short synacthen test (SST) was performed. A bolus of 0.25mg of 1-24-ACTH was injected in the morning, 24 hours after the most recent dose of prednisone. Cortisol was measured at baseline and 60 minutes after synacthen injectionMain outcome measuresFrequency and risk estimate of pituitary-adrenal dysfunctionResultsTwenty-nine patients (48.3%) had adrenal insufficiency defined by a plasmatic cortisol <100 nmol/l (n=13) at baseline (T0) or <550 nmol/l (n=16) 60 minutes (T60) after synacthen injection. Cumulative dose (area under the ROC curve, AUC 0.77 [95% CI: 0.62-0.91], p=0.007) and exposure (AUC 0.80 [95% CI: 0.67-0.93], p=0.002) to prednisone were predictive for adrenal insufficiency based on a T0 <100 nmol/l. Prednisone was stopped in 29/31 (93.5 %) patients showing a normal response to SST; none of these patients required hydrocortisone replacement with a mean follow-up of 10 (± 6) months.Conclusion Adrenal insufficiency is frequent in patients treated with long-term glucocorticoids for systemic inflammatory disorders and is related to duration and cumulative dose of steroids.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Serum sTWEAK concentrations and risk of developing type 2 diabetes in a high cardiovascular risk population: a nested case-control study.

  Andrés Díaz-López, Elsa Maymó-Masip, Mònica Bulló, Matilde R Chacón, Miguel A Martínez-González, Ramón Estruch, Joan Vendrell, Josep Basora, Javier Díez-Espino, María-Isabel Covas, Jordi Salas-Salvadó
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  ABSTRACT: Context and Objective:Because serum concentrations of soluble forms of TNF-like weak inducer of apoptosis (sTWEAK) and scavenger receptor-CD163 (sCD163) have been associated with insulin resistance and type 2 diabetes (T2D), we tested the associations of sTWEAK and sCD163 with the future development of T2DM in elderly subjects at high cardiovascular risk.Design, Setting, and Participants:A prospective, matched case-control study of 153 cases of newly diagnosed diabetic subjects and 306 individually matched-controls who did not develop diabetes during a mean 5-year follow-up was conducted using data from the PREDIMED study. Conditional logistic regression was used to estimate matched odds ratio (OR) for incident T2D according to categories of baseline sTWEAK and sCD163 concentrations measured by ELISA.Results:Baseline sTWEAK concentrations were lower in cases than controls. There were no case-control differences in sCD163 concentrations. In the conditional logistic model that took into account the matching factors, the ORs for T2D incidence in the highest vs the lowest quartile of sTWEAK and the sCD163/sTWEAK ratio were 0.49 (95%CI, 0.31-0.76); P for trend <0.01 and 1.67 (1.06-2.63); P for trend =0.05, respectively. Further adjustment for potential lifestyle confounding factors had little impact on these estimates, while adjustment for metabolic syndrome components and fasting insulin levels attenuated the magnitude of associations and only the sTWEAK remained statistically significant [0.63 (0.40-0.98); P for trend=0.05].Conclusion:These findings indicate that in a population at high cardiovascular risk, reduced circulating levels of sTWEAK are associated with an increased risk of diabetes incidence.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: One day of mixed meal overfeeding reduces hepatic insulin sensitivity and increases VLDL particle but not VLDL-triglyceride secretion in overweight and obese men.

  Gordon I Smith, Faidon Magkos, Dominic N Reeds, Adewole L Okunade, Bruce W Patterson, Bettina Mittendorfer
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  ABSTRACT: Context:The exact mechanisms responsible for increased plasma triglyceride (TG) concentration in obese people are unclear and it is not known whether excess energy intake per se is involved in the pathophysiology of this abnormality.Objective:The purpose of our study was to examine how excess energy intake from a balanced diet for one day affects VLDL-TG kinetics and its putative regulators hepatic insulin sensitivity and plasma free fatty acid (FFA) availability.Subjects and Design:We used stable isotope labeled tracer methods to evaluate glucose and lipid kinetics in eight overweight and obese men (age: 38 ± 3 years; body mass index: 33.7 ± 1.7 kg/m(2); means ± SEM) on two occasions (randomized cross-over design): once, the day after they consumed a balanced diet that provided an amount of energy that matched their energy expenditure and another time, the day after they consumed a balanced diet that provided 30% excess calories. Eight healthy, lean men (34 ± 1 years; 22.5 ± 0.6 kg/m(2)) were studied under isocaloric conditions only to provide a reference for "normal" lipid kinetics.Results:VLDL-TG and VLDL-apoB-100 concentrations and secretion rates were significantly greater (P< 0.01) in overweight/obese compared to lean men. Hypercaloric, compared with isocaloric feeding in overweight/obese men, increased glucose rate of appearance in plasma (904 ± 21 vs. 873 ± 26 μ mol·min(-1)), the hepatic insulin resistance index (10.9 ± 2.2 vs. 8.3 ± 1.8), and VLDL-apoB-100 concentration and secretion rate (1.91 ± 0.24 vs. 1.53 ± 0.13 nmol·min(-1)) whereas VLDL-apoB-100 plasma clearance rate, VLDL-TG secretion and plasma clearance rates, and FFA rate of appearance in plasma were not affected by overfeeding.Conclusion:One day of moderate overfeeding (30% excess energy intake) stimulates hepatic glucose and VLDL-apo-B-100 secretion rates but has no effect on hepatic and adipose tissue fatty acid metabolism in overweight/obese men.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Concurrence of primary hyperparathyroidism and metastatic breast carcinoma affected a parathyroid gland.

  Sang Hee Lee, Bo Hyun Kim, Min Jung Bae, Yang Seon Yi, Won Jin Kim, Yun Kyung Jeon, Sang Soo Kim, Yong Ki Kim, In Joo Kim
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  ABSTRACT: Objective:Involvement of the parathyroid glands by metastatic tumor is rare. Breast is one of the primary sites in metastatic cancers. We introduce a rare case of metastatic breast carcinoma affected a parathyroid gland, which was clinically combined with parathyroid gland hyperplasia.Case Report:A 65-year-old woman was referred due to hypercalcemia and constipation. The patient had a history of left breast carcinoma. She was admitted to the hospital because of the recent discovery of hypercalcemia and elevation of parathyroid hormone. A Tc99m-sestamibi scan showed retained uptake in the right thyroid and in the lower pole of the left thyroid gland. Aspiration biopsy results revealed the nodule in the posterior portion of the right thyroid was metastatic breast cancer and the nodule in the left thyroid gland was the hyperplastic parathyroid gland.Conclusion:The case illustrates that hyperparathyroidism caused by parathyroid hyperplasia which was concurrent with metastatic breast cancer to a parathyroid gland without disseminated systemic metastasis. Although, this case is a very uncommon and it is not clear whether there is relationship between breast cancer and primary hyperparathyroidism, its possibility should always be considered as the cause of hypercalcemia in patients with breast cancer.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Role of insulin-like growth factors in initiation of follicle growth in normal and polycystic human ovaries.

  Sharron A Stubbs, Lisa J Webber, Jaroslav Stark, Suman Rice, Raul Margara, Stuart Lavery, Geoffrey H Trew, Kate Hardy, Stephen Franks
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  ABSTRACT: Context:Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by disordered follicle development including activation and accelerated growth of preantral follicles. Data from experimental animals and preliminary results from studies of human ovarian tissue suggest that insulin-like growth factors (IGFs) affect preantral follicle development.Objective:To investigate the expression of the Type-1 IGF receptor (IGFR-1) in the human ovary, and to determine whether IGFs are involved in stimulating the transition of follicles from primordial to primary stage in normal and polycystic ovaries.Design:Use of archived ovarian tissue for protein expression studies and small cortical biopsies for follicle isolation and for tissue culture.Setting:A laboratory-based study, using clinical tissue samples.Patients:54 women: 33 with normal ovaries and 21 with polycystic ovaries, classified by reference to menstrual cycle history and ultrasonography.Main outcome measures:Expression of IGFR-1 mRNA in isolated preantral follicles and of protein in archived ovarian tissue samples from normal and polycystic ovaries. Effects of exogenous IGF-I on preantral follicle development and survival in cultured fragments of normal and polycystic ovaries.Results:IGFR-1 mRNA and protein was expressed in preantral follicles at all stages of development and enhanced expression was noted in PCOS follicles during early preantral development. IGF-I stimulated initiation of follicle growth in normal tissue but had little effect on preantral follicle growth in polycystic ovaries in which, characteristically; there was a higher proportion of follicles that had entered the growing phase even before culture.Conclusions:IGFs are plausible candidates in regulation of initiation of human follicle growth and accelerated preantral follicle growth in PCOS may be due to increased activity of endogenous IGFs.Precis:Aberrant preantral follicle development in polycystic ovary syndrome is associated with enhanced expression of the type 1 IGF receptor and altered responsiveness to exogenous IGF-1.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Severe hyperemesis gravidarum is associated with reduced insulin sensitivity in the offspring in childhood.

  Ahila Ayyavoo, José G B Derraik, Paul L Hofman, Janene Biggs, Frank H Bloomfield, Barbara E Cormack, Peter Stone, Wayne S Cutfield
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  ABSTRACT: Background:Hyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum affects glucose homeostasis and body composition in the offspring in childhood.Methods:Healthy pre-pubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with severe hyperemesis gravidarum (SHG; n=36) and offspring of mothers from control pregnancies (Control; n=42). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman's minimal model. Other assessments included lipid and hormonal profiles, and body composition using whole-body dual-energy X-ray absorptiometry.Results:Insulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 x10(-4)·min(-1)·(mU/l); p=0.014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/l; p=0.024) and lower IGFBP-1 (11.8 vs 19.0 ng/ml; p=0.004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/l; p=0.021). Children in both groups were anthropometrically similar.Conclusion:Children born to mothers who experienced severe hyperemesis gravidarum have lower insulin sensitivity, which may increase their long-term risk of developing diabetes mellitus. Follow up of SHG offspring is essential to determine later risk of metabolic disease.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma.

  Jenny Welander, Stina Garvin, Rickard Bohnmark, Lars Isaksson, Roger W Wiseman, Peter Söderkvist, Oliver Gimm
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  ABSTRACT: Abstract Not Available.
  The Journal of clinical endocrinology and metabolism 06/2013;
• Article: Thyroid Diseases and Adverse Pregnancy Outcomes in a Contemporary US Cohort.

  Tuija Männistö, Pauline Mendola, Jagteshwar Grewal, Yunlong Xie, Zhen Chen, S Katherine Laughon
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  ABSTRACT: Context:Thyroid diseases are inconsistently reported to increase risk for pregnancy complications.Objective:The objective of this study was to study pregnancy complications associated with common and uncommon thyroid diseases.Design, Setting, and Participants:We analyzed singleton pregnancies (N = 223 512) from a retrospective US cohort, the Consortium on Safe Labor (2002-2008). Thyroid diseases and outcomes were derived from electronic medical records. Multivariable logistic regression with generalized estimating equations estimated adjusted odds ratios (ORs) with 99% confidence intervals (99% CI).Main Outcome Measures:Hypertensive diseases, diabetes, preterm birth, cesarean sections, inductions, and intensive care unit (ICU) admissions were analyzed.Results:Primary hypothyroidism was associated with increased odds of preeclampsia (OR = 1.47, 99% CI = 1.20-1.81), superimposed preeclampsia (OR = 2.25, 99% CI = 1.53-3.29), gestational diabetes (OR = 1.57, 99% CI = 1.33-1.86), preterm birth (OR = 1.34, 99% CI = 1.17-1.53), induction (OR = 1.15, 99% CI = 1.04-1.28), cesarean section (prelabor, OR = 1.31, 99% CI = 1.11-1.54; after spontaneous labor OR = 1.38, 99% CI = 1.14-1.66), and ICU admission (OR = 2.08, 99% CI = 1.04-4.15). Iatrogenic hypothyroidism was associated with increased odds of placental abruption (OR = 2.89, 99% CI = 1.14-7.36), breech presentation (OR = 2.09, 99% CI = 1.07-4.07), and cesarean section after spontaneous labor (OR = 2.05, 99% CI = 1.01-4.16). Hyperthyroidism was associated with increased odds of preeclampsia (OR = 1.78, 99% CI = 1.08-2.94), superimposed preeclampsia (OR = 3.64, 99% CI = 1.82-7.29), preterm birth (OR = 1.81, 99% CI = 1.32-2.49), induction (OR = 1.40, 99% CI = 1.06-1.86), and ICU admission (OR = 3.70, 99% CI = 1.16-11.80).Conclusions:Thyroid diseases were associated with obstetrical, labor, and delivery complications. Although we lacked information on treatment during pregnancy, these nationwide data suggest either that there is a need for better thyroid disease management during pregnancy or that there may be an intrinsic aspect of thyroid disease that causes poor pregnancy outcomes.
  The Journal of clinical endocrinology and metabolism 06/2013;