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Journal of Clinical Endocrinology & Metabolism
Journal Prestige (SJR): 2.941
Citation Impact (citeScore): 5
Number of Followers: 184  
 
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ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
Published by Endocrine Society, The Homepage  [3 journals]
  • Mutations in MAGEL2 and L1CAM Are Associated With Congenital
           Hypopituitarism and Arthrogryposis
    • Authors: Gregory L; Shah P, Sanner J, et al.
      Pages: 5737 - 5750
      Abstract: ContextCongenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome, a group of X-linked disorders that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis.ObjectiveWe investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients.PatientsThe heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus.ResultsHuman embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch.ConclusionWe report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.
      PubDate: Wed, 24 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00631
      Issue No: Vol. 104, No. 12 (2019)
       
  • The Medical Therapy of Craniopharyngiomas: The Way Ahead
    • Authors: Alexandraki K; Kaltsas G, Karavitaki N, et al.
      Pages: 5751 - 5764
      Abstract: ContextCraniopharyngiomas, which are categorized as adamantinomatous (ACPs) or papillary (PCPs), have traditionally been treated with surgery and/or radiotherapy, although when the tumors progress or recur, therapeutic possibilities are very limited. Following recent advances in their molecular pathogenesis, new medical therapeutic options have emerged.Evidence AcquisitionThe search strategy that we selected to identify the appropriate evidence involved the following medical subject headings (MeSH) terms: (“Craniopharyngioma” [MeSH] AND “Craniopharyngioma/drug therapy” [MeSH]) NOT (“review” [Publication Type] OR “review literature as topic” [MeSH Terms] OR “review” [All Fields]) AND (“2009/05/01” [PDat]: “2019/04/28” [PDat]).Evidence SynthesisMutations of β-catenin causing Wnt activation with alterations of the MEK/ERK pathway are encountered in the great majority of patients with ACPs; specific alterations also stratify patients to a more aggressive behavior. In most PCPs there is primary activation of the Ras/Raf/MEK/ERK pathway secondary to BRAF-V600E mutations. BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCPs producing clinically useful and, in some cases, sustained responses. In contrast to PCPs, drugs targeting β-catenin and its downstream MAPK pathway in ACPs have so far only been used in in vitro studies, but there appear to be promising new targets clinically.ConclusionsThe identification of specific genetic alterations in patients with craniopharyngiomas has expanded the therapeutic options, providing evidence for a customized approach using newer molecular agents. More studies including a larger number of carefully selected patients are required to evaluate the response to currently available and evolving agents alone and in combination.
      PubDate: Thu, 01 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01299
      Issue No: Vol. 104, No. 12 (2019)
       
  • Neonatal Screening for Congenital Hypothyroidism: What Can We Learn From
           Discordant Twins'
    • Authors: Medda E; Vigone M, Cassio A, et al.
      Pages: 5765 - 5779
      Abstract: ContextNewborn screening program for congenital hypothyroidism (CH) adopting rescreening in at-risk neonates.ObjectivesTo estimate the concordance rate for CH in twin pairs discordant at the first screening; to verify whether long-term follow-up of healthy cotwins belonging to CH discordant pairs may be useful to diagnose thyroid hypofunction during development; to evaluate the importance of genetic and environmental influences on liability to permanent and transient CH.Design and PatientsForty-seven screening discordant twin pairs were investigated. Proband was defined as the twin in the pair with a positive test at the first screening and a confirmed diagnosis of CH.ResultsSeven screening discordant twin pairs became concordant for CH within the first month of life (pairwise concordance of 14.9%) because seven screening negative cotwins showed high TSH values when retested. During long-term follow-up (range, 3 to 21 years), hypothyroidism was diagnosed in two monozygotic screening negative cotwins at the age of 9 months and 12 years, respectively. Furthermore, the twin analysis showed that 95% of liability to transient CH was explained by genetic factors and 5% by environmental (unshared) factors, whereas 64% of phenotypic variance of permanent CH was explained by common environmental factors (shared during the fetal life) and 36% by unshared environmental factors.ConclusionsThis study showed that the introduction of rescreening permits the diagnosis of CH in a greater number of twins. It also showed the importance of long-term follow-up in both twins in the pair, and the role of nongenetic factors in the etiology of permanent CH.
      PubDate: Tue, 09 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00900
      Issue No: Vol. 104, No. 12 (2019)
       
  • Cardiorespiratory Fitness May Influence Metabolic Inflexibility During
           Exercise in Obese Persons
    • Authors: Amaro-Gahete F; Sanchez-Delgado G, Ara I, et al.
      Pages: 5780 - 5790
      Abstract: ContextWe examined whether obese individuals have a reduced maximal fat oxidation (MFO) and the intensity that elicit MFO (Fatmax) compared with normal weight and overweight persons, taking into account their level of cardiorespiratory fitness.MethodsThe study subjects were 138 sedentary adults (87 women) aged 30.1 ± 13.6 years. Based on their body mass index, subjects were categorized as being of normal weight (n = 66), overweight (n = 48), or obese (n = 24). MFO and Fatmax were determined for all subjects by indirect calorimetry, using a walking graded exercise test. MFO was expressed in absolute terms (g/min) and relative to whole-body lean mass (mg/kgleanmass/min). Cardiorespiratory fitness was assessed via a maximal treadmill test.ResultsNo differences in absolute MFO and Fatmax values were seen between the obese, normal weight, and overweight subjects (all P > 0.2), although after adjusting for cardiorespiratory fitness, the obese subjects returned significantly higher values than did their normal weight and overweight counterparts (all P < 0.03). However, when expressed with respect to lean mass, the MFO of the normal weight subjects was significantly greater than that of the overweight and obese subjects, independent of age, sex, or cardiorespiratory fitness.ConclusionsObese individuals have higher absolute MFO values when cardiorespiratory fitness is taken into account, but when expressed with respect to lean mass, normal weight individuals show a greater capacity to oxidize fat during exercise per unit of metabolically active tissue independent of age, sex, or cardiorespiratory fitness. These findings suggest that obese individuals may suffer from metabolic inflexibility during exercise.
      PubDate: Fri, 19 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01225
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Why We Should Still Treat by Neurosurgery
           Patients With Cushing Disease and a Normal or Inconclusive Pituitary
           MRI”
    • Authors: Castinetti F; Graillon T, Dufour H, et al.
      Pages: 5791 - 5792
      Abstract: We read with interest the study by Cristante et al. (1) on the outcome of transsphenoidal surgery in patients with Cushing disease (CD) with normal or inconclusive pituitary MRI. For years there has been a controversy on whether surgery should be performed in such cases (2). In this monocentric retrospective study based on 195 patients who underwent microscopic or endoscopic surgery in the last 25 years, no difference in remission rates was found between patients with positive (89 microadenomas, 18 macroadenomas) and negative pituitary MRI (44 inconclusive and 44 normal MRI). The authors thus suggest that patients with CD should undergo surgery regardless of MRI status. We would like to tone down these conclusions with the following points.
      PubDate: Fri, 05 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01183
      Issue No: Vol. 104, No. 12 (2019)
       
  • Response to Letter to the Editor: “Why We Should Still Treat by
           Neurosurgery Patients With Cushing Disease and a Normal or Inconclusive
           Pituitary MRI”
    • Authors: Chabre O; Cristante J, Lefournier V, et al.
      Pages: 5793 - 5794
      Abstract: We read with interest the letter by Castinetti et al., who wished to tone down our conclusion that a neurosurgical transsphenoidal (TSS) approach should be offered to patients with Cushing disease (CD), normal or doubtful MRI findings, and a pituitary ACTH gradient at bilateral inferior petrosal sinus sampling (BIPSS) (1).
      PubDate: Fri, 05 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01384
      Issue No: Vol. 104, No. 12 (2019)
       
  • Predictors of Poor Bone Microarchitecture Assessed by Trabecular Bone
           Score in Postsurgical Hypoparathyroidism
    • Authors: Sakane E; Vieira M, Lazaretti-Castro M, et al.
      Pages: 5795 - 5803
      Abstract: ContextThe effects of PTH deprivation on bone are still unclear. Our objective was to report the characteristics of patients with postsurgical hypoparathyroidism (PsH) at a specialized outpatient service and correlate their trabecular bone score (TBS) values to clinical, densitometric, and laboratory findings. A secondary objective was to evaluate the fracture rates and look for associations between these events and the collected data.ResultsEighty-two patients were enrolled, of whom 70 (85.4%) were female and 17 (20.7%) had type 2 diabetes mellitus (T2DM). The median body mass index (BMI) was 27.7 kg/m2 and the median age was 59 years. Of 68 dual-energy x-ray absorptiometry (DXA) scans obtained, osteopenia and osteoporosis were present in 32.4% and 2.9%, respectively. In all, 62 lumbar scans were analyzed by using TBS. The mean TBS value (±SD) was 1.386 ± 0.140, and 32.2% of the results were <1.310. TBS values correlated negatively with BMI (mainly > 30 kg/m2), age (mainly > 60 years), and glycemia, whereas abnormal TBS correlated with osteopenia, T2DM, low-impact fracture, and menopause. Six female patients had low-impact fractures, which were associated with a lower TBS (1.178 ± 0.065 vs. 1.404 ± 0.130 in the group without fractures; P < 0.001), older age, higher BMI, impaired renal function, abnormal glycemia, and osteopenia.ConclusionThe findings suggests that known risk factors for bone loss compromise the bone microarchitecture of individuals with PsH, regardless of DXA results. Menopausal women with PsH and older patients with PsH who have osteopenia, a higher BMI, or T2DM may be candidates for a more detailed assessment by using, for example, TBS.
      PubDate: Mon, 15 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00698
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Further Nonvertebral Fracture Reduction Beyond 3
           Years for Up to 10 Years of Denosumab Treatment”
    • Authors: Sugiyama T.
      Pages: 5804 - 5805
      Abstract: In their timely and highly important analyses of Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) and its Extension trials, Ferrari et al. (1) found that nonvertebral fracture rates during the latter 7-year FREEDOM Extension were lower than those during the former 3-year FREEDOM and confirmed that similar results had not been obtained in the case of bisphosphonates (1). In addition to several reasonable mechanistic insights discussed by the authors, physical activity could play a substantial role because participants were older women (mean age, ∼75 years of age at the FREEDOM EXTENSION baseline) and nonvertebral fractures would be generally caused by a minor trauma such as falls.
      PubDate: Wed, 10 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01241
      Issue No: Vol. 104, No. 12 (2019)
       
  • Response to Letter to the Editor: “Further Nonvertebral Fracture
           Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment”
    • Authors: Ferrari S.
      Pages: 5806 - 5806
      Abstract: We thank Dr. Sugiyama for his interesting comments regarding the potential mechanisms that could contribute to decreased fracture rates with long-term denosumab treatment observed in our study (1), beyond a continuous increase in bone mass, by preventing falls in part through an improvement of muscle function, as we recently reported in postmenopausal women and mice (2). Unfortunately, neither fall rates nor muscle function was assessed during the FREEDOM Extension, and hence this hypothesis remains to be further substantiated in prospective trials.
      PubDate: Wed, 10 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01388
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Central Precocious Puberty as a Presenting Sign
           of Nonclassical Congenital Adrenal Hyperplasia: Clinical
           Characteristics”
    • Authors: Anik A.
      Pages: 5807 - 5807
      Abstract: I read with great interest the article by Neeman et al. (1) on central precocious puberty as a presenting sign of nonclassic congenital adrenal hyperplasia (NCCAH) (1). The researchers found a 4.7% frequency of NCCAH among 147 patients with central precocious puberty (CPP) (7 cases) (1).
      PubDate: Fri, 19 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01352
      Issue No: Vol. 104, No. 12 (2019)
       
  • Response to Letter to the Editor: “Central Precocious Puberty as a
           Presenting Sign of Nonclassical Congenital Adrenal Hyperplasia: Clinical
           Characteristics”
    • Authors: Neeman B; Bello R, Lazar L, et al.
      Pages: 5808 - 5809
      Abstract: We thank Professor Anik for his comment regarding our article (1), reporting a prevalence of 4.8% girls with nonclassical congenital adrenal hyperplasia (NCCAH) among 147 girls with a clinical presentation of central precocious puberty (1).
      PubDate: Fri, 19 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01511
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Clinical but Not Histological Outcomes in Males
           With 45,X/46,XY Mosaicism Vary Depending on Reason for Diagnosis”
    • Authors: Dumeige L; Martinerie L.
      Pages: 5810 - 5811
      Abstract: We read with great interest the article recently published by Ljubicic et al. (1) concerning the outcomes of males with 45,X/46,XY mosaicism based on the reason for diagnosis. The originality of this article relies on a number of histological assessments in adulthood and direct comparison between patients diagnosed because of genital anomalies and patients diagnosed for other reasons. This multicenter retrospective study corroborates previous studies that underlined the possibility of growth failure, testicular impairment, risk of tumor development, and infertility in these patients even in the absence of variations in genital development (2–4).
      PubDate: Fri, 05 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01282
      Issue No: Vol. 104, No. 12 (2019)
       
  • Response to Letter to the Editor: “Clinical but Not Histological
           Outcomes in Males With 45,X/46,XY Mosaicism Vary Depending on Reason for
           Diagnosis”
    • Authors: Ljubicic M; Jørgensen A, Ribeiro de Andrade J, et al.
      Pages: 5812 - 5813
      Abstract: We are thankful for the opportunity to respond to the letter by Dumeige and Martinerie commenting on our study (1) on the clinical and histological outcomes in males with 45,X/46,XY mosaicism. We appreciate their interest in our report.
      PubDate: Fri, 05 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01413
      Issue No: Vol. 104, No. 12 (2019)
       
  • Glucocorticoid Replacement Affects Serum Adiponectin Levels and HDL-C in
           Patients With Secondary Adrenal Insufficiency
    • Authors: Hayashi R; Tamada D, Murata M, et al.
      Pages: 5814 - 5822
      Abstract: ContextLow serum adiponectin and high-density lipoprotein–cholesterol (HDL-C) levels are risk factors for cardiovascular disease. Patients with primary adrenal insufficiency are at higher risk of cardiovascular complications compared with healthy subjects. However, there is no information on the relationship between adiponectin and glucocorticoid replacement therapy in patients with secondary adrenal insufficiency (SAI).ObjectiveTo determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI.DesignPart 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study.SettingOsaka University Hospital, Osaka, Japan.PatientsPart 1: 58 patients diagnosed with nonfunctioning pituitary adenoma who underwent insulin tolerance test (ITT) for assessment of adrenal function. Part 2: 12 SAI patients randomly received hydrocortisone replacement therapy at a dose of 10, 20, or 30 mg/d for 4 weeks per term for three terms.Outcome MeasurementsPart 1: we analyzed the relationship between serum cortisol levels during ITT and serum adiponectin levels and the lipid profile. Part 2: serum adiponectin levels and lipid profile were measured every 4 weeks.ResultsSerum levels of adiponectin and HDL-C correlated significantly with peak cortisol levels after ITT. Serum adiponectin and HDL-C levels were significantly lower in patients with SAI than non-SAI. Serum levels of adiponectin and HDL-C increased in a hydrocortisone dose-dependent manner.ConclusionsGlucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI.
      PubDate: Wed, 10 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00420
      Issue No: Vol. 104, No. 12 (2019)
       
  • Risk Prediction Scores for Mortality, Cerebrovascular, and Heart Disease
           Among Chinese People With Type 2 Diabetes
    • Authors: Quan J; Pang D, Li T, et al.
      Pages: 5823 - 5830
      Abstract: ContextRisk scores for cardiovascular and mortality outcomes have not been commonly applied in Chinese populations.ObjectiveTo develop and externally validate a set of parsimonious risk scores [University of Hong Kong-Singapore (HKU-SG)] to predict the risk of mortality, cerebrovascular disease, and ischemic heart disease among Chinese people with type 2 diabetes and compare HKU-SG risk scores to other existing ones.DesignRetrospective population-based cohorts drawn from Hong Kong Hospital Authority health records from 2006 to 2014 for development and Singapore Ministry of Health records from 2008 to 2016 for validation. Separate five-year risk scores were derived using Cox proportional hazards models for each outcome.SettingStudy participants were adults with type 2 diabetes aged 20 years or over, consisting of 678,750 participants from Hong Kong and 386,425 participants from Singapore.Main Outcome MeasuresPerformance was evaluated by discrimination (Harrell C-index), and calibration plots comparing predicted against observed risks.ResultsAll models had fair external discrimination. Among the risk scores for the diabetes population, ethnic-specific risk scores (HKU-SG and Joint Asia Diabetes Evaluation) performed better than UK Prospective Diabetes Study and Risk Equations for Complications Of type 2 Diabetes models. External validation of the HKU-SG risk scores for mortality, cerebrovascular disease, and ischemic heart disease had corresponding C-indices of 0.778, 0.695, and 0.644. The HKU-SG models appeared well calibrated on visual plots, with predicted risks closely matching observed risks.ConclusionsThe HKU-SG risk scores were developed and externally validated in two large Chinese population-based cohorts. The parsimonious use of clinical predictors compared with previous risk scores could allow wider implementation of risk estimation in diverse Chinese settings.
      PubDate: Tue, 09 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00731
      Issue No: Vol. 104, No. 12 (2019)
       
  • Differential Effects of Oral Boluses of Vitamin D2 vs Vitamin D3 on
           Vitamin D Metabolism: A Randomized Controlled Trial
    • Authors: Martineau A; Thummel K, Wang Z, et al.
      Pages: 5831 - 5839
      Abstract: ContextVitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism.ObjectiveTo compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3.MethodsWe measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups.ResultsVitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4β,25(OH)2D3 to 25(OH)D3 did not differ between groups.ConclusionsBolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3.
      PubDate: Fri, 14 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00207
      Issue No: Vol. 104, No. 12 (2019)
       
  • PTH Immunoassay Interference Due to Human Anti-Mouse Antibodies in a
           Subject With Obesity With Normal Parathyroid Function
    • Authors: Laudes M; Frohnert J, Ivanova K, et al.
      Pages: 5840 - 5842
      Abstract: ContextImmunoassay interference has been most often found with prolactin measurement. However, only few data exist on immunoassay interference for other hormones.Case DescriptionA 36-year-old woman with obesity (body mass index, 31 kg/m2) had regularly attended our endocrine unit for type 2 diabetes therapy. When she was included as a control subject in a study for obesity management, detailed laboratory testing was performed, including PTH. In the absence of clinical symptoms, she presented with normal calcium, phosphate, and vitamin D levels. However, the PTH levels were >5000 ng/L. These results were obtained using the Roche Elecsys electrochemiluminescence assay. Repeated measurements with this assay (mouse antibody) led to the same findings. However, using an Euroimmun assay (goat antibody), the exact PTH values were measured at 18.0 ng/L. After pretreatment with a heterophilic antibody blocking reagent, the results of the Roche assay had decreased to a normal level. This phenomenon was explained by the detection of human anti-mouse antibodies in the proband’s serum.ConclusionsIn cases of prolactin immunoassay interference, endogenous antibodies will bind to the hormone in vivo, resulting in complexes of a high molecular weight that are less efficiently cleared by the kidneys and, thus, accumulate in the blood. In contrast, the PTH values >5000 ng/L detected in our subject most likely had resulted from the specific interference of the human anti-mouse antibodies present in the proband’s serum with the assay antibody, resulting in artificial stimulation of the Roche assay detection system ex vivo.
      PubDate: Wed, 14 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01321
      Issue No: Vol. 104, No. 12 (2019)
       
  • 68Ga-Exendin-4 PET/CT Detects Insulinomas in Patients With Endogenous
           Hyperinsulinemic Hypoglycemia in MEN-1
    • Authors: Antwi K; Nicolas G, Fani M, et al.
      Pages: 5843 - 5852
      Abstract: ContextSurgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size ≥20 mm. Functioning PanNETs, such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery.ObjectiveTo evaluate the feasibility and sensitivity of 68Ga-DOTA-exendin-4 positron emission tomography (PET)/CT in the detection of clinically relevant lesions in patients with MEN-1 and EHH in combination with MRI.DesignPost hoc subgroup analysis of a larger prospective imaging study with 52 patients with EHH.PatientsSix of 52 consecutive patients with EHH and genetically proven MEN-1 mutation were included.InterventionsAll patients received one 68Ga-DOTA-exendin-4 PET/CT and one MRI scan within 3 to 4 days. Thereafter, surgery was performed based on all imaging results.Main Outcome MeasuresLesion-based sensitivity of PET/CT and MRI for detection of clinically relevant lesions was calculated. Readers were unaware of other results. The reference standard was surgery with histology and treatment outcome. True positive (i.e., clinically relevant lesions) was defined as PanNETs ≥20 mm or insulinoma.ResultsIn six patients, 37 PanNETs were confirmed by histopathology. Sensitivity (95% CI) in the detection of clinically relevant lesions for combined PET/CT plus MRI, MRI, and PET/CT was 92.3% (64% to 99.8%), 38.5% (13.9% to 68.4%), and 84.6% (54.6% to 98.1%), respectively (P = 0.014 for the comparison of PET/CT plus MRI vs MRI). Postsurgery, EHH resolved in all patients.Conclusion68Ga-DOTA-exendin-4 PET/CT is feasible in patients with MEN-1 and EHH. The combination with MRI is superior to MRI alone in the detection of insulinomas and may guide the surgical strategy.
      PubDate: Fri, 12 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02754
      Issue No: Vol. 104, No. 12 (2019)
       
  • Association Between Maternal Thyroid Hormones and Birth Weight at Early
           and Late Pregnancy
    • Authors: Zhang C; Yang X, Zhang Y, et al.
      Pages: 5853 - 5863
      Abstract: ContextPrevious studies suggest that maternal thyroid function affects fetal growth, but the association between combined thyroid hormones from early to late pregnancy and newborn birth weight remains unknown.ObjectiveTo explore the association of maternal thyroid function during early and late pregnancy with birth weight.DesignA large prospective cohort study of a Chinese population.SettingThis study recruited pregnant women who underwent first-trimester prenatal screenings at the International Peace Maternity and Child Health Hospital between January 2013 and December 2016.ParticipantsThis study enrolled 46,186 mothers in whom TSH, free thyroxine (FT4), T3, and thyroid peroxidase antibody concentrations were measured in the first and third trimesters and in whom data on birth weight were available.Main Outcome MeasuresBirth weight, small for gestational age, large for gestational age (LGA).ResultsA higher TSH or FT4 concentration, or a lower T3 concentration, during the first or third trimester was associated with a lower birth weight. The lowest percentiles of maternal FT4 (FT4 < 2.5th percentile) in both trimesters were associated with a 0.34-SD higher birth weight. The effect estimates were greater in those in the first trimester (0.23 SD) or in the third trimester (0.17 SD). The association of maternal TSH and FT4 with birth weight differed according to fetal sex.ConclusionsPersistently low FT4 concentrations throughout pregnancy were associated with higher birth weight and an increased risk of LGA. Based on these findings, we recommend monitoring mildly altered concentrations of thyroid hormone throughout pregnancy.
      PubDate: Wed, 19 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00390
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Two-Thirds of All Fractures Are Not Attributable
           to Osteoporosis and Advancing Age: Implications for Fracture Prevention”
           
    • Authors: Wen Z; Chen R, Liu H.
      Pages: 5864 - 5865
      Abstract: We thank Mai et al. (1) for sharing their interesting study. In the study, 3700 participants aged 50 years and older underwent lumbar spine and femoral neck bone mineral density (BMD) measurements, with fragility fractures assessed by X-ray reports and postfracture mortality as the primary outcomes. Mai et al. (1) thought that the treatment of individuals with osteoporosis was unlikely to reduce a large number of fractures in the general population. However, there are some concerns with this study.
      PubDate: Fri, 12 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01326
      Issue No: Vol. 104, No. 12 (2019)
       
  • Response to Letter to the Editor: “Two-Thirds of All Fractures Are Not
           Attributable to Osteoporosis and Advancing Age: Implications for Fracture
           Prevention”
    • Authors: Mai H; Tran T, Ho-Le T, et al.
      Pages: 5866 - 5866
      Abstract: We thank Wen et al. for their interest in our article (1). All of their comments are facts that have been well documented in textbooks; they contribute absolutely nothing to the literature. We would like to comment on their comments as follows.
      PubDate: Fri, 12 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01457
      Issue No: Vol. 104, No. 12 (2019)
       
  • Three Discrete Patterns of Primary Aldosteronism Lateralization in
           Response to Cosyntropin During Adrenal Vein Sampling
    • Authors: Wannachalee T; Zhao L, Nanba K, et al.
      Pages: 5867 - 5876
      Abstract: ContextCosyntropin [ACTH (1–24)] stimulation during adrenal vein (AV) sampling (AVS) enhances the confidence in the success of AV cannulation and circumvents intraprocedure hormonal fluctuations. Cosyntropin’s effect on primary aldosteronism (PA) lateralization, however, is controversial.ObjectivesTo define the major patterns of time-dependent lateralization, and their determinants, after cosyntropin stimulation during AVS.MethodsWe retrospectively studied patients with PA who underwent AVS before, 10, and 20 minutes after cosyntropin stimulation between 2009 and 2018. Unilateral (U) or bilateral (B) PA was determined on the basis of a lateralization index (LI) value ≥4 or <4, respectively. Available adrenal tissue underwent aldosterone synthase–guided next-generation sequencing.ResultsPA lateralization was concordant between basal and cosyntropin-stimulated AVS in 169 of 222 patients (76%; U/U, n = 110; B/B, n = 59) and discordant in 53 patients (24%; U/B, n = 32; B/U, n = 21). Peripheral and dominant AV aldosterone concentrations and LI were highest in U/U patients and progressively lower across intermediate and B/B groups. LI response to cosyntropin increased in 27% of patients, decreased in 33%, and remained stable in 40%. Baseline aldosterone concentrations predicted the LI pattern across time (P < 0.001). Mutation status was defined in 61 patients. Most patients with KCNJ5 mutations had descending LI, whereas those with ATP1A1 and ATP2B3 mutations had ascending LI after cosyntropin stimulation.ConclusionPatients with severe PA lateralized robustly regardless of cosyntropin use. Cosyntropin stimulation reveals intermediate PA subtypes; its impact on LI varies with baseline aldosterone concentrations and aldosterone-driver mutations.
      PubDate: Tue, 13 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01182
      Issue No: Vol. 104, No. 12 (2019)
       
  • Pregnancy and Live Birth In Women With Pathogenic LHCGR Variants Using
           Their Own Oocytes
    • Authors: Lu X; Yan Z, Cai R, et al.
      Pages: 5877 - 5892
      Abstract: ContextThe LH/chorionic gonadotropin receptor (LHCGR) is mainly expressed in gonads and plays important roles in estradiol production, ovulation, and luteal formation. Women with pathogenic LHCGR variants suffer from infertility, and successful fertility treatments for such women have never been reported.ObjectiveThe purpose of this study was to determine whether women with pathogenic LHCGR variants can achieve successful pregnancies through in vitro fertilization.DesignThree women with LH resistance and infertility and their parents underwent exome sequencing. The biochemical characteristics and functional effects of LHCGR mutation were assessed in transfected human embryonic kidney -293T cells and primary granulosa cells.ResultsAll affected women harbored pathogenic LHCGR variants. The LHCGR variants lacked cell surface localization and signal transduction abilities in vitro and in vivo. After dual triggering and prolonging the interval between triggering and oocyte pick-up, all three patients achieved oocytes and high-quality embryos. After frozen embryo transfer, one woman successfully birthed twins, and one woman successfully birthed a live boy. Apart from difficulties in oocyte retrieval, no obvious abnormalities in fertilization or during embryo development and pregnancy were identified in these patients.ConclusionsThis study is, to our knowledge, the first to report successful assisted reproductive treatment of women with pathogenic LHCGR variants using their own oocytes. Our results supported that defects in LHCGR disrupted ovulation but had no effect on fertilization and embryo development.
      PubDate: Thu, 08 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01276
      Issue No: Vol. 104, No. 12 (2019)
       
  • Treatment of Menopausal Vasomotor Symptoms With Fezolinetant, a Neurokinin
           3 Receptor Antagonist: A Phase 2a Trial
    • Authors: Depypere H; Timmerman D, Donders G, et al.
      Pages: 5893 - 5905
      Abstract: ContextThe thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs).ObjectiveTo evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs.DesignTwelve-week, double-blind, randomized, placebo-controlled study.SettingEight Belgian centers from September 2015 to October 2016.ParticipantsGenerally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs.InterventionsSubjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks.Main Outcome MeasuresSubjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were safety and tolerability.ResultsOf 122 subjects screened, 87 were randomized and 80 (92%) completed the study. At week 12, fezolinetant significantly reduced total VMS score vs placebo (−26.5 vs −12.2, P < 0.001) and decreased mean frequency of moderate/severe VMSs by five episodes per day vs placebo. Severity and frequency of moderate/severe VMSs were reduced from the first day of treatment. Improvements were achieved in all quality-of-life measures. Fezolinetant was well tolerated. The most common fezolinetant-related adverse event was gastrointestinal disorder (n = 6).ConclusionsFezolinetant rapidly and significantly reduced moderate/severe VMSs, supporting its potential as an effective nonhormonal treatment option for menopausal women.
      PubDate: Thu, 15 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00677
      Issue No: Vol. 104, No. 12 (2019)
       
  • Clinical Course of Nonfunctional Pituitary Microadenoma in Children: A
           Single-Center Experience
    • Authors: Thaker V; Lage A, Kumari G, et al.
      Pages: 5906 - 5912
      Abstract: ContextPituitary lesions consistent with microadenomas are increasingly discovered by MRI. Sparse data are available on the long-term clinical and imaging course of such lesions in children.ObjectiveThe aim of this study was to define the clinical and imaging course of pituitary lesions representing or possibly representing nonfunctioning microadenomas in children to guide clinical management.DesignRetrospective observational study.MethodsThe clinical data warehouse at a tertiary care academic children’s hospital was queried with the terms “pituitary” AND “microadenoma” and “pituitary” AND “incidentaloma.” The electronic health records of the identified subjects were reviewed to extract data on the clinical and imaging course.ResultsA total of 78 children had nonfunctioning pituitary lesions incidentally discovered during clinical care, of which 44 (56%) were reported as presumed or possible microadenomas. In the children with microadenoma (median age 15 years, interquartile range 2), a majority (70%) underwent imaging for nonendocrine symptoms, the most common being headache (n = 16, 36%). No significant increase in the size of the microadenoma or cysts or worsening of pituitary function was seen over the average clinical follow-up of 4.5 ± 2.6 years. Four cases of drug-induced hyperprolactinemia resolved with discontinuation of the offending medication.ConclusionsAsymptomatic pituitary lesions representing cysts, microadenomas, or possible microadenomas follow a benign course in children. In the absence of new endocrine or visual symptoms, repeat MRI may not be needed, and if performed, should be done in no less than a year. When possible, it is prudent to discontinue hyperprolactinemia-inducing medications before imaging.
      PubDate: Wed, 07 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01252
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Comparison of Teriparatide and Denosumab in
           Patients Switching from Long-Term Bisphosphonate Use”
    • Authors: Sugiyama T.
      Pages: 5913 - 5914
      Abstract: In their clinically crucial observational study that compared changes in areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry after switching to treatment with teriparatide vs denosumab among older adults treated with long-term bisphosphonates, Lyu et al. (1) highlighted the limited effect of teriparatide in the hip when used after bisphosphonates. I fully agree with the authors’ reasonable mechanistic explanation and their recommendation of using teriparatide before bisphosphonates to maximize the effect of teriparatide. Consequently, when we consider switching from long-term treatment with bisphosphonates, for example in patients at high fracture risk who are sustaining fractures as described in the Endocrine Society’s clinical practice guideline for the pharmacological management of osteoporosis in postmenopausal women (2), modeling-based rather than remodeling-based bone formation therapy seems to be theoretically appropriate.
      PubDate: Tue, 13 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01650
      Issue No: Vol. 104, No. 12 (2019)
       
  • The Role of Serum Procalcitonin in Predicting Bacterial Sepsis in Patients
           With Hypothyroidism
    • Authors: Shirali A; Wu J, Zhu C, et al.
      Pages: 5915 - 5922
      Abstract: ContextSerum levels of procalcitonin (PCT), a protein produced by the thyroid C cells under physiologic conditions, are high during sepsis.ObjectiveTo assess the test performance of serum PCT in predicting bacterial sepsis and septic shock in patients with hypothyroidism compared with those who have euthyroidism.Design and MethodsThis retrospective study evaluated patients with no history of thyroid dysfunction (euthyroid), primary hypothyroidism [medical hypothyroidism (MH)], and postsurgical hypothyroidism from total thyroidectomy (TT) identified from a prospectively maintained database who had PCT testing from 2005 to 2018. Quick Sequential Organ Failure Assessment score ≥ 2 or positive bacterial cultures identified bacterial sepsis, and a mean arterial pressure less than 65 mm Hg or a vasopressor requirement defined septic shock. Sensitivity and specificity of PCT for evaluation of bacterial sepsis and septic shock were measured.ResultsWe identified 217 euthyroid patients, 197 patients with MH, and 84 patients with TT. Bacterial sepsis was found in 98 (45.2%), 92 (46.7%), and 36 (42.9%) of these patients, respectively (P > 0.05). Septic shock was identified in 13 (6.0%), 13 (6.6%), and 5 (6.0%) patients (P > 0.05), respectively. With use of a PCT cutoff of 0.5 µg/L for bacterial sepsis, the sensitivity was 59%, 61%, and 53% (P > 0.05) and specificity was 81%, 77%, and 81% (P > 0.05) for the diagnosis of bacterial sepsis in euthyroid, MH, and TT patients, respectively. With use of a PCT cutoff of 2.0 µg/L for septic shock, the sensitivity was 46%, 62%, and 63% (P > 0.05) and specificity was 86%, 82%, and 91% (P > 0.05) for the diagnosis of septic shock in these patients, respectively.ConclusionsDespite the thyroidal origin of PCT, hypothyroidism did not affect the diagnostic performance of serum PCT levels in predicting bacterial sepsis or septic shock.
      PubDate: Tue, 30 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01082
      Issue No: Vol. 104, No. 12 (2019)
       
  • Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With
           46,XY Gonadal Dysgenesis Spectrum
    • Authors: da Silva T; Gomes N, Lerário A, et al.
      Pages: 5923 - 5934
      Abstract: Context46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS).ObjectiveTo report a gene for 46,XY GD etiology, especially for ETRS.DesignScreening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing.SettingTertiary Referral Center for differences/disorders of sex development (DSD).Patients and InterventionsWe selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology.ResultsWe identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells.ConclusionThis strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.
      PubDate: Tue, 09 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00984
      Issue No: Vol. 104, No. 12 (2019)
       
  • Continuous Free Cortisol Profiles—Circadian Rhythms in Healthy Men
    • Authors: Bhake R; Kluckner V, Stassen H, et al.
      Pages: 5935 - 5947
      Abstract: ContextThe pituitary–adrenal axis had historically been considered a representative model for circadian rhythms. A recently developed portable collection device has provided the opportunity to evaluate free cortisol profiles using the microdialysis approach in individuals free to conduct their day-to-day activities in their own surroundings.MethodsTwo separate experiments were conducted in healthy male volunteers. The total and subcutaneous (SC) free cortisol levels were measured at 10-minute intervals for a 24-hour period in one experiment, and the SC free cortisol levels were measured at 20-minute interval for 72 consecutive hours in free-living individuals in the second experiment.ResultsThe characteristic circadian rhythm was evident in both serum total and SC free cortisol, with the lowest levels achieved and maintained in the hours surrounding sleep onset and the peak levels occurring in every individual around waking. In all free-living individuals, the circadian rhythm was consistent across the 72-hour period, despite a wide range of activities. All the participants also showed increased cortisol after the consumption of lunch. The lowest levels during all 24-hour periods were observed during the hours after lights off, at the onset of sleep.ConclusionsTo the best of our knowledge, the present study is the first to report up to three consecutive 24-hour measurements of SC free cortisol in healthy individuals. We believe our study is a landmark study that paves the way for ambulatory monitoring of free cortisol profiles continuously for a period of 72 hours in free-living individuals performing their day-to-day activities whether healthy or with diseases involving the hypothalamic–pituitary–adrenal axis.
      PubDate: Mon, 29 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00449
      Issue No: Vol. 104, No. 12 (2019)
       
  • National Treatment Practice for Adrenocortical Carcinoma: Have They
           Changed and Have We Made Any Progress'
    • Authors: Tierney J; Chivukula S, Poirier J, et al.
      Pages: 5948 - 5956
      Abstract: BackgroundAdrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials.MethodsThe National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created.ResultsFrom 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03).ConclusionsSince 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.
      PubDate: Tue, 30 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00915
      Issue No: Vol. 104, No. 12 (2019)
       
  • Association of Maternal Iodine Status With Child IQ: A Meta-Analysis of
           Individual Participant Data
    • Authors: Levie D; Korevaar T, Bath S, et al.
      Pages: 5957 - 5967
      Abstract: ContextAlthough the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established.ObjectiveTo study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability.DesignMeta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively.SettingGeneral community.Participants6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease.Main Outcome MeasureChild nonverbal and verbal IQ assessed at 1.5 to 8 years of age.ResultsThere was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (−0.6 point; 95% CI: −1.7 to 0.4 points; P = 0.246) or lower verbal IQ (−0.6 point; 95% CI: −1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation.ConclusionsFetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.
      PubDate: Thu, 28 Mar 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02559
      Issue No: Vol. 104, No. 12 (2019)
       
  • Hydroxylated Long-Chain Acylcarnitines are Biomarkers of Mitochondrial
           Myopathy
    • Authors: Vissing C; Dunø M, Wibrand F, et al.
      Pages: 5968 - 5976
      Abstract: ContextPlasma acylcarnitines are biomarkers of β-oxidation and are useful in diagnosing several inborn errors of metabolism but have never been investigated systematically in patients with mitochondrial myopathy.ObjectiveWe hypothesized that acylcarnitines can also be biomarkers of mitochondrial myopathy and sought to investigate the prevalence and pattern of elevated acylcarnitines.DesignThis was a prospective cohort study of patients with confirmed mitochondrial myopathy followed at Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark.PatientsWe included 35 patients (44 ± 15 years, 15 women) with mitochondrial myopathy caused by single, large-scale deletions of mitochondrial DNA (n = 17), pathogenic variants in mitochondrial transfer RNA (n = 13), or in proteins of the respiratory chain complexes (n = 5).Concentrations of 35 acylcarnitines were measured using ultra-HPLC and tandem mass-spectrometry. Findings were compared with muscle mutation load in all patients and to respiratory chain activity in 26 patients.Main Outcome MeasuresPrevalence of elevated concentrations of acylcarnitines related to acyl-coenzyme A (CoA) dehydrogenases in patients with mitochondrial myopathy and relation to genotypes/phenotypes.ResultsIn total, 27 (77%) patients had elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases. Elevated concentrations of seven acylcarnitine species were more common in patients compared with a control cohort of >900 individuals, and a specific pattern involving hydroxylated long-chain acylcarnitines occurred in 22 (63%) patients. Severity of derangements was correlated with muscle mutation load and genotypes/phenotypes.ConclusionIn conclusion, elevated concentrations of acylcarnitines is common in patients with mitochondrial myopathy and shows a specific pattern affecting hydroxylated long-chain acylcarnitines, which can have implications for future diagnostic workup of patients.
      PubDate: Thu, 11 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00721
      Issue No: Vol. 104, No. 12 (2019)
       
  • Switching to Degludec From Other Basal Insulins Is Associated With Reduced
           Hypoglycemia Rates: A Prospective Study
    • Authors: Fadini G; Feher M, Hansen T, et al.
      Pages: 5977 - 5990
      Abstract: ContextObservational studies of insulin degludec (degludec) with hypoglycemia events prospectively recorded are lacking.ObjectiveTo evaluate the safety and effectiveness of degludec in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) switching from other basal insulins in routine care.DesignResults From Real-World Clinical Treatment With Tresiba® was a multinational, multicenter, prospective, observational, single-arm study comprising a 4-week baseline period (preswitch basal insulin) and 12-month follow-up (degludec).SettingRoutine clinical practice.Patients or Other ParticipantsInsulin-treated patients (≥18 years) with T1D (n = 556) or T2D (n = 611) with treatment plans to initiate degludec.InterventionsSwitching to degludec from other basal insulins.Main Outcome MeasureChange from baseline in number of overall hypoglycemic events recorded in patient diaries.ResultsIn T1D, the 12-month follow-up/baseline rate ratios (95% CI) of overall [0.80 (0.74 to 0.88)], nonsevere [0.83 (0.76 to 0.91)], severe [0.28 (0.14 to 0.56)], and nocturnal [0.61 (0.50 to 0.73)] hypoglycemia suggested significantly lower hypoglycemia rates with degludec (all Ps < 0.001). At 12 months, HbA1c, fasting plasma glucose (FPG), and basal insulin dosage decreased significantly. Body weight increased, and treatment satisfaction improved significantly. In T2D, the hypoglycemia rate ratios were overall [0.46 (0.38 to 0.56)], nonsevere [0.53 (0.44 to 0.64)], and nocturnal [0.35 (0.20 to 0.62)] (all Ps < 0.001; too few events for analysis of severe hypoglycemia). At 12 months, HbA1c and FPG decreased significantly. Body weight and insulin dosages remained unchanged, and treatment satisfaction was significantly improved.ConclusionsIn a routine clinical care setting, switching to degludec from other basal insulins was associated with significantly lower rates of hypoglycemia, improved glycemic control, and treatment satisfaction in patients with T1D or T2D.
      PubDate: Fri, 09 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01021
      Issue No: Vol. 104, No. 12 (2019)
       
  • Fatty Acid–Binding Protein 4 and Risk of Type 2 Diabetes, Myocardial
           Infarction, and Stroke: A Prospective Cohort Study
    • Authors: Aleksandrova K; Drogan D, Weikert C, et al.
      Pages: 5991 - 6002
      Abstract: ContextAdipocyte fatty acid-binding protein (FABP4) is expressed in adipose tissue and may impair glucose homeostasis and promote atherosclerotic processes.ObjectiveWe examined the association between serum FABP4 and risk of type 2 diabetes (T2D), myocardial infarction (MI), and stroke.DesignCase-cohort study embedded within a sample of 27,548 participants of the EPIC-Potsdam cohort.Participants and SettingA randomly selected subcohort (n = 2194) of participants who were free of cardiovascular disease and T2D at study baseline and 728 incident T2D cases, 206 incident stroke cases, and 185 incident MI cases with an average 8.2 (±1.7) years of follow-up.Main Outcome MeasuresIncident T2D, MI, and stroke.ResultsIn a multivariable-adjusted model, the hazard ratios (HRs) in the highest vs lowest quartile of FABP4 were 1.81 (95% CI, 1.21 to 2.70; Ptrend = 0.01) for T2D, 0.93 (95% CI, 0.55 to 1.55; Ptrend = 0.68) for MI, and 1.41 (95% CI, 0.80 to 2.49; Ptrend = 0.24) for stroke, respectively. In analyses stratified by sex, no statistically significant differences could be seen for associations between FABP4 and T2D and MI (Pinteraction by sex = 0.27 and 0.84, respectively), whereas a higher risk of stroke was observed in men (HR: 2.70, 95% CI 1.20 to 6.00; P = 0.04), but not in women (HR: 0.70, 95% CI 0.31 to 1.60; P = 0.53; Pinteraction = 0.02).ConclusionsThese data support the hypothesis that elevated FABP4 levels may contribute to T2D risk. In contrast, our data did not support the hypothesis that circulating FABP4 may be relevant for MI, whereas the observed association with stroke in men may need further evaluation.
      PubDate: Tue, 18 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00477
      Issue No: Vol. 104, No. 12 (2019)
       
  • Longitudinal Phenotypes of Type 1 Diabetes in Youth Based on Weight and
           Glycemia and Their Association With Complications
    • Authors: Kahkoska A; Nguyen C, Adair L, et al.
      Pages: 6003 - 6016
      Abstract: ContextSubclinical and clinical complications emerge early in type 1 diabetes (T1D) and may be associated with obesity and hyperglycemia.ObjectiveTest how longitudinal “weight-glycemia” phenotypes increase susceptibility to different patterns of early/subclinical complications among youth with T1D.DesignSEARCH for Diabetes in Youth observational study.SettingPopulation-based cohort.ParticipantsYouth with T1D (n = 570) diagnosed 2002 to 2006 or 2008.Main Outcome MeasuresParticipants were clustered based on longitudinal body mass index z score and HbA1c from a baseline visit and 5+ year follow-up visit (mean diabetes duration: 1.4 ± 0.4 years and 8.2 ± 1.9 years, respectively). Logistic regression modeling tested cluster associations with seven early/subclinical diabetes complications at follow-up, adjusting for sex, race/ethnicity, age, and duration.ResultsFour longitudinal weight-glycemia clusters were identified: The Referent Cluster (n = 195, 34.3%), the Hyperglycemia Only Cluster (n = 53, 9.3%), the Elevated Weight Only Cluster (n = 206, 36.1%), and the Elevated Weight With Increasing Hyperglycemia (EWH) Cluster (n = 115, 20.2%). Compared with the Referent Cluster, the Hyperglycemia Only Cluster had elevated odds of dyslipidemia [adjusted odds ratio (aOR) 2.22, 95% CI: 1.15 to 4.29], retinopathy (aOR 9.98, 95% CI: 2.49 to 40.0), and diabetic kidney disease (DKD) (aOR 4.16, 95% CI: 1.37 to 12.62). The EWH Cluster had elevated odds of hypertension (aOR 2.18, 95% CI: 1.19 to 4.00), dyslipidemia (aOR 2.36, 95% CI: 1.41 to 3.95), arterial stiffness (aOR 2.46, 95% CI: 1.09 to 5.53), retinopathy (aOR 5.11, 95% CI: 1.34 to 19.46), and DKD (aOR 3.43, 95% CI: 1.29 to 9.11).ConclusionsWeight-glycemia phenotypes show different patterns of complications, particularly markers of subclinical macrovascular disease, even in the first decade of T1D.
      PubDate: Wed, 10 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00734
      Issue No: Vol. 104, No. 12 (2019)
       
  • Neither Hormonal Factors Nor AGEs Explain Lower Prostate Cancer Risk in
           Older Men With Diabetes Mellitus
    • Authors: Chan Y; Alfonso H, Fegan P, et al.
      Pages: 6017 - 6024
      Abstract: ContextDiabetes mellitus is conventionally associated with an increased risk of cancer; however, inverse associations of diabetes with prostate cancer are well described. Mechanisms are unclear, although hormonal factors, including alterations in sex hormone and IGF1 concentrations due to metabolic disturbances, have been hypothesized to play a role.ObjectiveTo assess sex hormones, IGF1, glucose, and advanced glycation end products (AGEs) as potential mediators of the association between diabetes mellitus and prostate cancer.Design and ParticipantsLongitudinal cohort study. The association of baseline diabetes with prostate cancer incidence was assessed using proportional hazards competing risks analysis in 3149 men followed for 12 years. Baseline hormone, glucose, and carboxymethyllysine (CML) levels were examined as potential mediators of this association.ResultsDiabetes was associated with a lower prostate cancer risk (fully adjusted subhazard ratio, 0.63; 95% CI, 0.43 to 0.92; P = 0.017). This association was unchanged after accounting for testosterone, DHT, estradiol, or SHBG. Similarly, the addition of IGF1 or its binding proteins 1 and 3, or glucose, did not alter this association. CML was not associated with the risk of prostate cancer, and additional correction for CML in the fully adjusted model did not alter the inverse association of diabetes and prostate cancer risk.ConclusionsIn this study, alterations in sex hormone, IGF1, glucose, and CML levels did not account for the inverse association of diabetes and prostate cancer risk. Further studies are required to provide more insight into underlying causes of this association.
      PubDate: Tue, 23 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01142
      Issue No: Vol. 104, No. 12 (2019)
       
  • Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy
    • Authors: Jéru I; Vantyghem M, Bismuth E, et al.
      Pages: 6025 - 6032
      Abstract: ContextHeterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population.ObjectivesTo reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4.MethodsWe performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants.ResultsWe identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration.ConclusionsThese data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.
      PubDate: Thu, 27 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00849
      Issue No: Vol. 104, No. 12 (2019)
       
  • A Simplified Approach to Reducing Cardiovascular Risk
    • Authors: Schade D; Eaton R.
      Pages: 6033 - 6039
      Abstract: ContextCardiovascular disease remains the number one cause of morbidity and mortality in the United States, despite major advances in our understanding of its pathogenesis and prevention. One reason for this continued epidemic is the poor adherence to treatment guidelines by caregivers and the lack of understanding by patients relative to its reversibility with treatment. Current guidelines are complex and often contradictory; there are at least 21 organizations publishing guidelines.ObjectiveThis article proposes a simplified approach that is based on the low-density lipoprotein (LDL) hypothesis stating that the lower the LDL cholesterol (LDL-C), the less the cardiovascular disease. This goal focuses on obtaining a plasma LDL-C <50 mg/dL.DesignA positive coronary artery calcium scan in conjunction with an intermediate online cardiovascular risk score will identify individuals with substantial cardiovascular disease risk. With lifestyle improvements (including a low cholesterol diet) and low-dose hypolipemic generic oral medications, this LDL-C concentration is readily achievable in the majority of asymptomatic patients at risk for atherosclerosis.ConclusionControlling the cardiovascular epidemic will require participation of both the patient and the physician caregiver. By simplifying the therapeutic regimen, patient compliance will increase, and an important reduction in cardiovascular morbidity and mortality will follow.
      PubDate: Wed, 20 Feb 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02509
      Issue No: Vol. 104, No. 12 (2019)
       
  • Maternal Thyroid Function, Use of Antithyroid Drugs in Early Pregnancy,
           and Birth Defects
    • Authors: Andersen S; Knøsgaard L, Olsen J, et al.
      Pages: 6040 - 6048
      Abstract: ContextAntithyroid drug (ATD) therapy in early pregnancy is associated with birth defects, but more data are needed to substantiate the risk associated with different types of ATD. Furthermore, the role of abnormal maternal thyroid function per se remains unclarified.ObjectiveTo evaluate the risk of birth defects associated with the use of ATD in an extended nationwide cohort and the role of abnormal maternal thyroid function in birth cohorts including stored maternal blood samples from early pregnancy.ParticipantsDanish pregnant women and their live-born children, including 1,243,353 children from a Nationwide Register-Based Cohort (NRBC), 1997 to 2016; 8830 children from the Danish National Birth Cohort (DNBC), 1997 to 2003; and 14,483 children from the North Denmark Region Pregnancy Cohort (NDRPC), 2011 to 2015.Main Outcome MeasuresBirth defects diagnosed before 2 years of age.ResultsIn the NRBC, altogether 2718 (0.2%) children had been exposed to ATD in early pregnancy. The overall frequency of birth defects was 6.7% (95% CI, 6.7% to 6.8%) in nonexposed children and higher after exposure to methimazole/carbimazole (9.6%; 95% CI, 8.2% to 11.2%) and propylthiouracil (8.3%; 95% CI, 6.7% to 10.3%). On the other hand, the frequency of maternal thyroid dysfunction in early pregnancy was similar in the random cohort and in cases of birth defect in the DNBC (12.4 vs 12.6%, P = 0.8) and the NDRPC (15.1 vs 15.4%, P = 0.8).ConclusionsResults corroborate an increased risk of birth defects associated with the use of ATD in early pregnancy and suggest that abnormal maternal thyroid function is not a major risk factor for birth defects.
      PubDate: Tue, 13 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01343
      Issue No: Vol. 104, No. 12 (2019)
       
  • Endogenous Circadian Regulation of Female Reproductive Hormones
    • Authors: Rahman S; Grant L, Gooley J, et al.
      Pages: 6049 - 6059
      Abstract: ContextStudies suggest that female reproductive hormones are under circadian regulation, although methodological differences have led to inconsistent findings.ObjectiveTo determine whether circulating levels of reproductive hormones exhibit circadian rhythms.DesignBlood samples were collected across ∼90 consecutive hours, including 2 baseline days under a standard sleep-wake schedule and ∼50 hours of extended wake under constant routine (CR) conditions.SettingIntensive Physiological Monitoring Unit, Brigham and Women’s Hospital.ParticipantsSeventeen healthy premenopausal women (22.8 ± 2.6 years; nine follicular; eight luteal).InterventionsFifty-hour CR.Main Outcome MeasuresPlasma estradiol (E2), progesterone (P4), LH, FSH, SHBG, melatonin, and core body temperature.ResultsAll hormones exhibited significant 24-hour rhythms under both standard sleep-wake and CR conditions during the follicular phase (P < 0.05). In contrast, only FSH and SHBG were significantly rhythmic during the luteal phase. Rhythm acrophases and amplitudes were similar between standard sleep-wake and CR conditions. The acrophase occurred in the morning for P4; in the afternoon for FSH, LH, and SHBG; and during the night for E2.ConclusionsOur results confirm previous reports of ∼24-hour rhythms in many female reproductive hormones in humans under ambulatory conditions but demonstrate that these hormones are under endogenous circadian regulation, defined as persisting in the absence of external time cues. These results may have important implications for the effects of circadian disruption on reproductive function.
      PubDate: Thu, 15 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00803
      Issue No: Vol. 104, No. 12 (2019)
       
  • Factors Associated With Diagnosis and Treatment of Thyroid Microcarcinomas
    • Authors: Esfandiari N; Hughes D, Reyes-Gastelum D, et al.
      Pages: 6060 - 6068
      Abstract: ContextNearly one-third of all thyroid cancers are ≤1 cm.ObjectiveTo determine diagnostic pathways for microcarcinomas vs larger cancers.Design/Setting/ParticipantsPatients from Georgia and Los Angeles Surveillance, Epidemiology, and End Results (SEER) registries with differentiated thyroid cancer diagnosed in 2014 or 2015 were surveyed. Survey data were linked to SEER data on tumor and treatment characteristics. Multivariable logistic regression analysis was performed.Main Outcome MeasuresMethod of nodule discovery; reason for thyroid surgery.ResultsOf patients who underwent surgery, 975 (38.2%) had cancers ≤1 cm, and 1588 cancers (61.8%) were >1 cm. The reported method of nodule discovery differed significantly between patients with cancers ≤1 cm and those with cancers >1 cm (P < 0.001). Cancer ≤1 cm was associated with nodule discovery on thyroid ultrasound (compared with other imaging, OR, 1.59; 95% CI, 1.21 to 2.10), older patient age (45 to 54 years vs ≤44, OR, 1.45; 95% CI, 1.16 to 1.82), and female sex (OR, 1.51; 95% CI, 1.22 to 1.87). Hispanic ethnicity (OR, 0.71; 95% CI, 0.57 to 0.89) and Asian race (OR, 0.67; 95% CI, 0.49 to 0.92) were negative correlates. Cancers ≤1 cm were associated with lower likelihood of surgery for a nodule suspicious or consistent with cancer (OR, 0.48; 95% CI, 0.40 to 0.57).ConclusionThyroid microcarcinomas are more likely to be detected by ultrasound and less likely to be associated with surgery scheduled for known thyroid cancer. Understanding diagnostic pathways allows for targeted interventions to decrease overdiagnosis and overtreatment.
      PubDate: Thu, 15 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01219
      Issue No: Vol. 104, No. 12 (2019)
       
  • Denosumab in Patients With Fibrous Dysplasia Previously Treated With
           Bisphosphonates
    • Authors: Majoor B; Papapoulos S, Dijkstra P, et al.
      Pages: 6069 - 6078
      Abstract: ContextFibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete.ObjectiveTo evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy.DesignCase series.SettingAcademic center of expertise for rare bone diseases.PatientsData were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months.Main outcome(s)Sustained reduction of BTMs and bone pain.ResultsA 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated.ConclusionOur results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.
      PubDate: Wed, 07 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02543
      Issue No: Vol. 104, No. 12 (2019)
       
  • Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones
    • Authors: Fassler C; Gutmark-Little I, Xie C, et al.
      Pages: 6079 - 6089
      Abstract: ContextThe age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset.ObjectiveWe sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones.Design and SettingLongitudinal observational study.Participants and Main Outcome MeasuresIn 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling.ResultsMean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events.ConclusionsHormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease.
      PubDate: Tue, 13 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00889
      Issue No: Vol. 104, No. 12 (2019)
       
  • Intramyocardial Triglycerides Among Women With vs Without HIV: Hormonal
           Correlates and Functional Consequences
    • Authors: Toribio M; Neilan T, Awadalla M, et al.
      Pages: 6090 - 6100
      Abstract: ContextWomen with HIV (WHIV) on anti-retroviral therapy (ART) are living longer but facing heightened vulnerability to heart failure.ObjectiveWe investigated metabolic/hormonal/immune parameters relating to diastolic dysfunction—a precursor to heart failure—among WHIV without known cardiovascular disease (CVD).Design and Outcome MeasuresNineteen ART-treated WHIV and 11 non-HIV-infected women without known CVD enrolled and successfully completed relevant study procedures [cardiac magnetic resonance spectroscopy (MRS) and cardiac MRI]. Groups were matched on age and body mass index. Primary outcome measures included intramyocardial triglyceride content (cardiac MRS) and diastolic function (cardiac MRI). Relationships between intramyocardial triglyceride content and clinical parameters were also assessed.ResultsAmong WHIV (vs non-HIV-infected women), intramyocardial triglyceride content was threefold higher [1.2 (0.4, 3.1) vs 0.4 (0.1, 0.5)%, P = 0.01], and diastolic function was reduced (left atrial passive ejection fraction: 27.2 ± 9.6 vs 35.9 ± 6.4%, P = 0.007). There was a strong inverse relationship between intramyocardial triglyceride content and diastolic function (ρ = −0.62, P = 0.004). Among the whole group, intramyocardial triglyceride content did not relate to chronologic age but did increase across the reproductive aging spectrum (P = 0.02). HIV status and reproductive aging status remained independent predictors of intramyocardial triglyceride content after adjusting for relevant cardiometabolic parameters (overall model R2 = 0.56, P = 0.003; HIV status P = 0.01, reproductive aging status P = 0.02).ConclusionsFor asymptomatic WHIV, increased intramyocardial triglyceride content is associated with diastolic dysfunction. Moreover, relationships between intramyocardial triglyceride accumulation and women’s reproductive aging are noted.
      PubDate: Thu, 08 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01096
      Issue No: Vol. 104, No. 12 (2019)
       
  • Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors:
           Prevalence, Risk Factors and Long-Term Health Outcomes
    • Authors: van Iersel L; Li Z, Srivastava D, et al.
      Pages: 6101 - 6115
      Abstract: ContextData on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited.ObjectiveTo describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP).DesignRetrospective with cross-sectional health outcomes analysis.SettingEstablished cohort; tertiary care center.PatientsParticipants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years.Main Outcome MeasureMultivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes.ResultsThe estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD).ConclusionHP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.
      PubDate: Fri, 02 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00834
      Issue No: Vol. 104, No. 12 (2019)
       
  • Letter to the Editor: “Association of Maternal Iodine Status With Child
           IQ: A Meta-Analysis of Individual-Participant Data”
    • Authors: Sztal-Mazer S.
      Pages: 6116 - 6117
      Abstract: Poor awareness underpins inadequate adherence to maternal iodine supplementation guidelines. I read with interest how Levie et al. (1) described the association they found between maternal iodine status and offspring verbal IQ, along with the time-critical nature of this finding. They observed that the relationship was strongest in the first 12 weeks of pregnancy; the finding held true, but less so, between 12 and 14 weeks of pregnancy and was no longer present after 14 weeks of pregnancy. The implications, in keeping with existing World Health Organization and American Thyroid Association guidelines (2, 3), are that iodine supplementation (usually as part of a pregnancy multivitamin) should be commenced at least 3 months before conception. Despite these universal recommendations, adherence is generally poor (4) because of, in my opinion, inadequate knowledge of the recommendations.
      PubDate: Wed, 17 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01407
      Issue No: Vol. 104, No. 12 (2019)
       
  • Macronutrient-Mediated Inflammation and Oxidative Stress: Relevance to
           Insulin Resistance, Obesity, and Atherogenesis
    • Authors: Biobaku F; Ghanim H, Batra M, et al.
      Pages: 6118 - 6128
      Abstract: ContextThe intake of macronutrients as components of a Western dietary pattern leads to oxidative stress and inflammation.Evidence AcquisitionData were largely retrieved from our previous and most recent work. PubMed and Google Scholar were searched for recent articles on the effect of macronutrients/dietary intake on inflammation, insulin resistance, obesity, and atherogenesis. The most relevant, high-quality articles were included in our review.Evidence SynthesisOur previous work has demonstrated the molecular mechanisms of macronutrient-mediated oxidative stress and inflammation. With the induction of inflammation, proinflammatory molecules potentially interfere with insulin signal transduction, thus causing insulin resistance. In addition, other molecules promote atherogenic inflammation. More recently, our work has also shown that certain foods are noninflammatory or anti-inflammatory and thus, do not interfere with insulin signaling. Finally, as obesity is induced by chronic excessive caloric intake, it is characterized by an increase in the expression of proinflammatory molecules, which are induced acutely by a Western diet. Caloric restriction, including fasting, is associated with a reduction in oxidative and inflammatory stress.ConclusionsThis review summarizes and attempts to provide an up-to-date profile of the molecular mechanisms involved in macronutrient-mediated oxidative/inflammatory stress and its potential consequences. An understanding of these underlying mechanisms is crucial for making appropriate dietary choices.
      PubDate: Thu, 20 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-01833
      Issue No: Vol. 104, No. 12 (2019)
       
  • Surgical Management, Preoperative Tumor Localization, and Histopathology
           of 80 Patients Operated on for Insulinoma
    • Authors: Andreassen M; Ilett E, Wiese D, et al.
      Pages: 6129 - 6138
      Abstract: IntroductionDiagnosis and pathological classification of insulinomas are challenging.AimTo characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma.MethodsPatients with surgically resected sporadic insulinoma were included.ResultsEighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a.ConclusionLocalization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.
      PubDate: Thu, 01 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01204
      Issue No: Vol. 104, No. 12 (2019)
       
  • Association Between Vitamin D, Frailty, and Progression of Frailty in
           Community-Dwelling Older Women
    • Authors: Buchebner D; Bartosch P, Malmgren L, et al.
      Pages: 6139 - 6147
      Abstract: ContextVitamin D (25OHD) is involved in many physiological functions that decline with age, contributing to frailty and increased risk for negative health outcomes. Whether 25OHD is a long-term risk marker for frailty over a longer time and whether it is consistent with advancing age is unclear.ObjectiveTo investigate the association between 25OHD and frailty in older women followed for 10 years.Design and SettingProspective, population-based, cohort study in Malmö, Sweden.ParticipantsCommunity-dwelling women, age 75 years (N = 1044) with reassessments at ages 80 (n = 715) and 85 (n = 382) years.MethodsFrailty was quantified using a 10-variable frailty index. Women were categorized as 25OHD insufficient (<50 nmol/L) or sufficient (≥50 nmol/L).ResultsAt ages 75 and 80 years, women with insufficient 25OHD were frailer than women with sufficient 25OHD (0.23 vs 0.18, P < 0.001; and 0.32 vs 0.25, P = 0.001, respectively). At age 80 years, 25OHD insufficiency was associated with subsequent frailty 5 years later (0.41 vs 0.32; P = 0.011). Accelerated progression of frailty was not associated with lower 25OHD levels, and 25OHD level >75 nmol/L was not additionally beneficial with regard to frailty. No association between 25OHD and frailty was observed at age 85 years. Within the frailty index, variables associated with 25OHD were related to muscle strength and function.ConclusionIn this study, 25OHD insufficiency was associated with increased frailty in all but the oldest old. This study supports the value of maintaining sufficient 25OHD levels for healthy aging.
      PubDate: Tue, 09 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00573
      Issue No: Vol. 104, No. 12 (2019)
       
  • Carriers of a Classic CYP21A2 Mutation Have Reduced Mortality: A
           Population-Based National Cohort Study
    • Authors: Nordenström A; Svensson J, Lajic S, et al.
      Pages: 6148 - 6154
      Abstract: ContextCongenital adrenal hyperplasia (CAH) is a common monogenic recessive disorder. It has been suggested that CYP21A2 deficiency is common because carriers may have a survival advantage, 1 in 15,000 in most populations. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype with a more prompt cortisol response to ACTH.ObjectiveWe investigated whether the mortality was lower, and determined the cause of death in carriers and population controls.DesignA total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents. The mortality and cause of death were identified through the Swedish Cause of Death Registry. The hazard ratios (HRs) and 95% CIs were calculated. The results were compared with controls from the general population, matched for sex and age.ResultsThe overall mortality was lower in carriers of a CYP21A2 mutation compared with the controls (HR 0.79; 95% CI, 0.678 to 0.917; P = 0.002). The difference was more marked among carriers of a more severe mutation. Infection as the cause of death was significantly lower (HR 0.65; 95% CI, 0.48 to 0.87; P < 0.01), particularly for death in pneumonia (HR 0.22; 95% CI, 0.06 to 0.88; P = 0.03). The lower overall mortality among women compared with men in the general population was confirmed among both carriers and controls.ConclusionObligate CYP21A2 carriers of a classic mutation had a reduced mortality. Specifically, a possible reduced mortality due to pneumonia was seen.
      PubDate: Thu, 08 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01199
      Issue No: Vol. 104, No. 12 (2019)
       
  • Epigenetic Reprogramming of Immune Cells in Women With PCOS Impact Genes
           Controlling Reproductive Function
    • Authors: Hiam D; Simar D, Laker R, et al.
      Pages: 6155 - 6170
      Abstract: ContextPolycystic ovary syndrome (PCOS) is a chronic disease affecting reproductive function and whole-body metabolism. Although the etiology is unclear, emerging evidence indicates that the epigenetics may be a contributing factor.ObjectiveTo determine the role of global and genome-wide epigenetic modifications in specific immune cells in PCOS compared with controls and whether these could be related to clinical features of PCOS.DesignCross-sectional study.ParticipantsWomen with (n = 17) or without PCOS (n = 17).SettingRecruited from the general community.Main Outcome MeasuresIsolated peripheral blood mononuclear cells were analyzed using multicolor flow cytometry methods to determine global DNA methylation levels in a cell-specific fashion. Transcriptomic and genome-wide DNA methylation analyses were performed on T helper cells using RNA sequencing and reduced representation bisulfite sequencing.ResultsWomen with PCOS had lower global DNA methylation in monocytes (P = 0.006) and in T helper (P = 0.004), T cytotoxic (P = 0.004), and B cells (P = 0.03). Specific genome-wide DNA methylation analysis of T helper cells from women with PCOS identified 5581 differentially methylated CpG sites. Functional gene ontology enrichment analysis showed that genes located at the proximity of differentially methylated CpG sites belong to pathways related to reproductive function and immune cell function. However, these genes were not altered at the transcriptomic level.ConclusionsIt was shown that PCOS is associated with global and gene-specific DNA methylation remodeling in a cell type–specific manner. Further investigation is warranted to determine whether epigenetic reprogramming of immune cells is important in determining the different phenotypes of PCOS.
      PubDate: Wed, 07 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01015
      Issue No: Vol. 104, No. 12 (2019)
       
  • Hepatic Fatty Acid Balance and Hepatic Fat Content in Humans With Severe
           Obesity
    • Authors: Lytle K; Bush N, Triay J, et al.
      Pages: 6171 - 6181
      Abstract: ObjectiveNonalcoholic fatty liver disease can lead to hepatic inflammation/damage. Understanding the physiological mechanisms that contribute to excess hepatic lipid accumulation may help identify effective treatments.DesignWe recruited 25 nondiabetic patients with severe obesity scheduled for bariatric surgery. To evaluate liver export of triglyceride fatty acids, we measured very-low-density lipoprotein (VLDL)–triglyceride secretion rates the day prior to surgery using an infusion of autologous [1-14C]triolein-labeled VLDL particles. Ketone body response to fasting and intrahepatic long-chain acylcarnitine concentrations were used as indices of hepatic fatty acid oxidation. We measured intraoperative hepatic uptake rates of plasma free fatty acids using a continuous infusion of [U-13C]palmitate, combined with a bolus dose of [9,10-3H]palmitate and carefully timed liver biopsies. Total intrahepatic lipids were measured in liver biopsy samples to determine fatty liver status. The hepatic concentrations and enrichment from [U-13C]palmitate in diacylglycerols, sphingolipids, and acyl-carnitines were measured using liquid chromatography/tandem mass spectrometry.ResultsAmong study participants with fatty liver disease, intrahepatic lipid was negatively correlated with VLDL-triglyceride secretion rates (r = −0.92, P = 0.01) but unrelated to hepatic free fatty acid uptake or indices of hepatic fatty acid oxidation. VLDL-triglyceride secretion rates were positively correlated with hepatic concentrations of saturated diacylglycerol (r = 0.46, P = 0.02) and sphingosine-1-phosphate (r = 0.44, P = 0.03).ConclusionWe conclude that in nondiabetic humans with severe obesity, excess intrahepatic lipid is associated with limited export of triglyceride in VLDL particles rather than increased uptake of systemic free fatty acids.
      PubDate: Tue, 13 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00875
      Issue No: Vol. 104, No. 12 (2019)
       
  • Gene Expression in Granulosa Cells From Small Antral Follicles From Women
           With or Without Polycystic Ovaries
    • Authors: Owens L; Kristensen S, Lerner A, et al.
      Pages: 6182 - 6192
      Abstract: ContextPolycystic ovary syndrome (PCOS) is the most common cause of anovulation. A key feature of PCOS is arrest of follicles at the small- to medium-sized antral stage.Objective and DesignTo provide further insight into the mechanism of follicle arrest in PCOS, we profiled (i) gonadotropin receptors; (ii) characteristics of aberrant steroidogenesis; and (iii) expression of anti-Müllerian hormone (AMH) and its receptor in granulosa cells (GCs) from unstimulated, human small antral follicles (hSAFs) and from granulosa lutein cells (GLCs).SettingGCs from hSAFs were collected at the time of cryopreservation of ovarian tissue for fertility preservation and GLCs collected during oocyte aspiration before in vitro fertilization/intracytoplasmic sperm injection.ParticipantsWe collected hSAF GCs from 31 women (98 follicles): 10 with polycystic ovaries (PCO) and 21 without. GLCs were collected from 6 women with PCOS and 6 controls undergoing IVF.Main Outcome MeasuresExpression of the following genes: LHCGR, FSHR, AR, INSR, HSD3B2, CYP11A1, CYP19, STAR, AMH, AMHR2, FST, INHBA, INHBB in GCs and GLCs were compared between women with PCO and controls.ResultsGCs in hSAFs from women with PCO showed higher expression of LHCGR in a subset (20%) of follicles. Expression of FSHR (P < 0.05), AR (P < 0.05), and CYP11A1 (P < 0.05) was lower, and expression of CYP19A1 (P < 0.05), STAR (P < 0.05), HSD3B2 (P = NS), and INHBA (P < 0.05) was higher in PCO GCs. Gene expression in GL cells differed between women with and without PCOS but also differed from that in GCs.ConclusionsFollicle arrest in PCO is characterized in GCs by differential regulation of key genes involved in follicle growth and function.
      PubDate: Fri, 05 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00780
      Issue No: Vol. 104, No. 12 (2019)
       
  • Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2
           Trial
    • Authors: Carneiro B; Konda B, Costa R, et al.
      Pages: 6193 - 6200
      Abstract: ContextSystemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti–PD-1 nivolumab.ObjectiveThe primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety.DesignSingle-arm, multicenter, phase 2 clinical trial with two-stage design.SettingComprehensive cancer center.PatientsTen adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy.InterventionNivolumab (240 mg) IV every 2 weeks.ResultsTen patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia.ConclusionNivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.
      PubDate: Fri, 05 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00600
      Issue No: Vol. 104, No. 12 (2019)
       
  • Longitudinal Changes in Fasting and Glucose-Stimulated GLP-1 and GIP in
           Healthy Older Subjects
    • Authors: Pham H; Marathe C, Phillips L, et al.
      Pages: 6201 - 6206
      Abstract: ContextIt is not known whether glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels correlate within individuals, nor whether levels change with age. Previous studies have all been cross-sectional in design.ObjectiveTo evaluate longitudinal changes in fasting and glucose-stimulated incretin hormone concentrations in healthy older subjects.Patients and DesignForty-one healthy older subjects had measurements of plasma GLP-1 and GIP while fasting and after a 75-g oral glucose load on two occasions separated by 5.9 ± 0.1 years [mean age at the initial study: 71.2 ± 3.8 (SD) years]. Breath samples were collected to calculate the gastric 50% emptying time (T50).ResultsFor GLP-1, both fasting concentrations (P < 0.001) and area under the curve 0 to 120 minutes (P = 0.001) were decreased at followup. Fasting GIP was also lower (P = 0.03) at follow up, but there was no change in the area under the curve 0 to 120 minutes (P = 0.26). The gastric emptying T50 was slower at followup (P = 0.008). Neither the change in T50 nor the body mass index at the initial study was a determinant of the change in incretin responses. Between the two study days, fasting GIP (r = 0.72, P < 0.001) correlated well, but not fasting GLP-1 (r = 0.23, P = 0.18). However, both glucose-stimulated GLP-1 (r = 0.50, P = 0.002) and GIP (r = 0.60, P < 0.001) showed correlations between the initial and follow-up studies.ConclusionsFasting GIP and glucose-stimulated GLP-1 and GIP concentrations correlate within individuals over a follow-up period of ∼5.9 years. Aging is associated with reductions in fasting GLP-1 and GIP, and glucose-stimulated GLP-1, which may predispose to the development of glucose intolerance and type 2 diabetes.
      PubDate: Thu, 08 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01262
      Issue No: Vol. 104, No. 12 (2019)
       
  • Overeating Saturated Fat Promotes Fatty Liver and Ceramides Compared With
           Polyunsaturated Fat: A Randomized Trial
    • Authors: Rosqvist F; Kullberg J, Ståhlman M, et al.
      Pages: 6207 - 6219
      Abstract: ContextSaturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms.ObjectiveTo investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans.DesignDouble-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction.SettingGeneral community.ParticipantsMen and women who are overweight or have obesity (n = 61).InterventionMuffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet.Main Outcome MeasuresLean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots.ResultsBy design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat, or total body fat compared with PUFA. SFA consistently increased, whereas PUFA reduced circulating ceramides, changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction.ConclusionsSFA markedly induces liver fat and serum ceramides, whereas dietary PUFA prevents liver fat accumulation and reduces ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.
      PubDate: Thu, 01 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00160
      Issue No: Vol. 104, No. 12 (2019)
       
  • Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless
           Diabetic Neuropathy
    • Authors: Püttgen S; Bönhof G, Strom A, et al.
      Pages: 6220 - 6228
      Abstract: ContextThe factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.ObjectiveWe hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.Design and MethodsIn this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.ResultsAfter adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.ConclusionDespite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.
      PubDate: Wed, 07 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01072
      Issue No: Vol. 104, No. 12 (2019)
       
  • Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the
           Known Causative Genes and a Literature Review
    • Authors: Sugisawa C; Takamizawa T, Abe K, et al.
      Pages: 6229 - 6237
      Abstract: ContextCongenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified.ObjectivesTo define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations.Patients and MethodsThirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed.ResultsGenetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap.ConclusionsThe mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.
      PubDate: Wed, 24 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00657
      Issue No: Vol. 104, No. 12 (2019)
       
  • Prostate-Specific Antigen Levels During Testosterone Treatment of
           Hypogonadal Older Men: Data from a Controlled Trial
    • Authors: Cunningham G; Ellenberg S, Bhasin S, et al.
      Pages: 6238 - 6246
      Abstract: ContextProstate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated.DesignDouble-blinded, placebo-controlled trial.SettingTwelve US academic medical centers.ParticipantsSeven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded.InterventionsTestosterone or placebo gel for 12 months.Main OutcomesPercentile changes in PSA during testosterone treatment of 12 months.ResultsTestosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8.ConclusionsWhen hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.
      PubDate: Tue, 23 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00806
      Issue No: Vol. 104, No. 12 (2019)
       
  • Apolipoprotein(a) Kinetics in Statin-Treated Patients With Elevated Plasma
           Lipoprotein(a) Concentration
    • Authors: Ma L; Chan D, Ooi E, et al.
      Pages: 6247 - 6255
      Abstract: BackgroundLipoprotein(a) [Lp(a)] is a low-density lipoprotein‒like particle containing apolipoprotein(a) [apo(a)]. Patients with elevated Lp(a), even when treated with statins, are at increased risk of cardiovascular disease. We investigated the kinetic basis for elevated Lp(a) in these patients.ObjectivesApo(a) production rate (PR) and fractional catabolic rate (FCR) were compared between statin-treated patients with and without elevated Lp(a).MethodsThe kinetics of apo(a) were investigated in 14 patients with elevated Lp(a) and 15 patients with normal Lp(a) levels matched for age, sex, and body mass index using stable isotope techniques and compartmental modeling. All 29 patients were on background statin treatment. Plasma apo(a) concentration was measured using liquid chromatography–mass spectrometry.ResultsThe plasma concentration and PR of apo(a) were significantly higher in patients with elevated Lp(a) than in patients with normal Lp(a) concentration (all P < 0.01). The FCR of apo(a) was not significantly different between the groups. In univariate analysis, plasma concentration of apo(a) was significantly associated with apo(a) PR in both patient groups (r = 0.699 and r = 0.949, respectively; all P < 0.01). There was no significant association between plasma apo(a) concentration and FCR in either of the groups (r = 0.160 and r = −0.137, respectively).ConclusionElevated plasma Lp(a) concentration is a consequence of increased hepatic production of Lp(a) particles in these patients. Our findings provide a kinetic rationale for the use of therapies that target the synthesis of apo(a) and production of Lp(a) particles in patients with elevated Lp(a).
      PubDate: Thu, 08 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01382
      Issue No: Vol. 104, No. 12 (2019)
       
  • PLIN2 Functions As a Novel Link Between Progesterone Signaling and
           Metabolism in Uterine Leiomyoma Cells
    • Authors: Okeigwe I; Bulun S, Liu S, et al.
      Pages: 6256 - 6264
      Abstract: ContextUterine leiomyoma (fibroids) are the most common tumors in women. Recently, perilipin-2 (PLIN2) was identified as a critical target gene of the progesterone receptor; however, its function in the pathogenesis of fibroids is unknown.ObjectiveTo determine the function of PLIN2 in leiomyoma cells.DesignTissue and primary cells from leiomyoma and myometrium were analyzed. PLIN2 function in leiomyoma was assessed using small interfering RNA. RNA-sequencing was performed to identify genome-wide effects of PLIN2 depletion. Metabolic activity was measured using the Seahorse XF96 analyzer. Real-time quantitative PCR and immunoblotting were also performed.SettingLaboratory.Patients or Other ParticipantsForty-one premenopausal women undergoing surgery for fibroids.Main Outcome MeasuresGene expression, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and cell proliferation.ResultsPLIN2 gene expression was 2.4-fold lower in leiomyoma compared with adjacent myometrium, suggesting a link between PLIN2 deficiency and fibroids. A total of 3877 genes were differentially expressed after PLIN2 knockdown. Gene ontology analysis identified metabolism as the second-highest biological process affected by PLIN2 depletion. OCR (mitochondrial respiration) and ECAR (glycolysis) were significantly upregulated after PLIN2 knockdown; PLIN2-depleted cells had a greater basal metabolic activity and higher metabolic stress response. Cell proliferation was also significantly increased after PLIN2 knockdown.ConclusionsPLIN2 depletion increases mitochondrial respiration and glycolysis, suggesting that PLIN2 is a critical regulator of metabolic function in leiomyoma cells. PLIN2 deficiency also reprograms leiomyoma cells to a proproliferative phenotype. These findings introduce metabolomics as an area to explore to better understand leiomyoma tumorigenesis.
      PubDate: Tue, 23 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00762
      Issue No: Vol. 104, No. 12 (2019)
       
  • Levothyroxine Replacement in Obese Adults: The Role of Metabolic Variables
           and Aging on Thyroid Testing Abnormalities
    • Authors: Mele C; Tagliaferri M, Pagano L, et al.
      Pages: 6265 - 6274
      Abstract: ContextGeneral rates of over- and underreplacement in levothyroxine (LT4) users with primary hypothyroidism are variably high. No information on LT4 adequacy exists in obesity.ObjectiveWe explored rates and factors relating to LT4 adequacy in obese patients with primary hypothyroidism.SettingTertiary care center.DesignAmong 4954 consecutive obese patients admitted between 2011 and 2014, 691 hypothyroid patients receiving LT4 therapy and 691 body mass index (BMI)-, age-, and sex-matched euthyroid controls underwent analysis of thyroid function, glucolipid profile, body composition, and indirect calorimetry. LT4 users were classified into low TSH (<0.27 mU/L), euthyroid (0.27 to 4.2 mU/L), and high TSH (>4.2 mU/L).ResultsLT4 users constituted 13.9% of the incident population. TSH was low in 7.5%, high in 17.2%, and normal in 75.2% of LT4 users. Overtreatment decreased with aging and more LT4 users ≥65 years of age had normal TSH than those <65 years of age (P < 0.05). Compared with the euthyroid obese group, LT4 users showed higher adiposity, similar insulin resistance, but a healthier lipid profile. In multivariable analyses, LT4 dose was predicted by fat-free mass, hypothyroidism cause, and sex (P < 0.0001 to < 0.05). Risk of LT4 overreplacement increased with younger age (OR 0.96; 95% CI 0.94 to 0.99), higher LT4 dose (OR 2.98; 95% CI 1.44 to 6.14), and lower BMI (OR 0.93; 95% CI 0.88 to 0.99). Male sex increased the likelihood of LT4 underreplacement (OR 2.37; 95% CI 1.10 to 5.11).ConclusionsObesity is associated with milder rates of inadequate LT4 treatment compared with nonobese populations. LT4 adequacy increases with aging. Age, body composition, and sex are main determinants of LT4 requirements in obesity.
      PubDate: Tue, 02 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00773
      Issue No: Vol. 104, No. 12 (2019)
       
  • JCEM Editor’s Swan Song: 2015–2019
    • Authors: Robertson R.
      Pages: 6275 - 6278
      Abstract: Almost 5 years have elapsed since the associate editors and I took the baton from Len Wartofsky and his associate editors to manage and edit JCEM. Almost 14,000 manuscripts later, it’s time to reflect on where we were when we started this journey and where we are at its end. The breadth and depth of the information coming from all over the world that we have reviewed continues to amaze me. It is what makes this journal such a rich depository of important clinical information, as has been the case for 78 years. Paul Stewart and his colleagues will carry the baton forward starting on 1 January 2020. We wish them well on the next lap of the journey.
      PubDate: Sat, 02 Nov 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01927
      Issue No: Vol. 104, No. 12 (2019)
       
 
 
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