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Journal of Clinical Endocrinology & Metabolism
Journal Prestige (SJR): 2.941
Citation Impact (citeScore): 5
Number of Followers: 182  
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ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
Published by Endocrine Society, The Homepage  [3 journals]
  • The Effects of Dapagliflozin on Systemic and Renal Vascular Function
           Display an Epigenetic Signature
    • Authors: Solini A; Seghieri M, Giannini L, et al.
      Pages: 4253 - 4263
      Abstract: ContextMechanisms mediating the cardiovascular and renal protection exerted by SGLT2 inhibitors are still partially unknown. We investigated whether dapagliflozin modulates systemic and renal vascular function and structure, and induces epigenetic modifications.Subjects and MethodsForty hypertensive patients with type 2 diabetes were randomly assigned to 4-week treatment with dapagliflozin 10 mg or hydrochlorothiazide (HCT) 12.5 mg. Routine analyses; plasma renin activity; aldosterone, catecholamine, and 24-hour urinary electrolyte levels; flow-mediated dilation (FMD) of the brachial artery; carotid-femoral pulse-wave velocity (PWV); augmentation index; and resistive index and dynamic renal resistive index (DRIN) were measured at baseline and after treatment. Circulating miRNAs (miRs) related to heart failure (miR30e-5p, miR199a-3p), endothelial dysfunction (miR27b and miR200b), and renal function (miR130b-3p, miR21-5p) were assessed and related to the effects of treatments.ResultsDapagliflozin and HCT marginally lowered blood pressure. Fasting glucose was lowered, whereas 24-hour diuresis, glycosuria, and osmolar clearance were increased by dapagliflozin (P < 0.001 for all), without affecting sodium excretion and glomerular filtration rate. Magnesium levels significantly increased after dapagliflozin treatment (P = 0.02). Neither dapagliflozin nor HCT modified FMD or PWV. DRIN did not vary in the dapagliflozin group, whereas it increased in the HCT group (P = 0.047 for time by treatment interaction). Both treatments induced variations in the expression of some miRs; dapagliflozin, but not HCT, significantly up-regulated miR30e-5p and downregulated miR199a-3p.ConclusionA putative epigenetic regulation of the protecting cardiovascular effect exerted by SGLT2 inhibitors was found. Dapagliflozin might exert nephroprotection by preserving renal vasodilating capacity.
      PubDate: Tue, 04 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00706
      Issue No: Vol. 104, No. 10 (2019)
  • Long-Term Outcomes and Aggressiveness of Hereditary Medullary Thyroid
           Carcinoma: 40 Years of Experience at One Center
    • Authors: Raue F; Bruckner T, Frank-Raue K.
      Pages: 4264 - 4272
      Abstract: ContextRecent data on long-term outcomes and aggressiveness of medullary thyroid carcinoma (MTC) are lacking for patients with multiple endocrine neoplasia type 2 (MEN2).ObjectivesTo analyze the long-term outcomes in MEN2 and compare MTC aggressiveness in three defined RET mutation-risk categories: moderate risk (MOD), high risk (H), and highest risk (HST).Design, SettingRetrospective study of 263 operated patients with MEN2 from one German tertiary referral center from 1979 to 2017 comparing demographic, biochemical, genetic, and outcome parametersInterventionNone (observational study)Main Outcome MeasureLong-term survival and outcomes in three risk groupsResultsSurgery was performed at a mean age of 35.3 ± 18.8 (MOD, n = 122), 23.0 ± 15.7 years (H, n = 120), and 14.9 ± 9.3 (HST, n = 21) years (P < 0.05). The mean follow-up was 12.9 ± 9.8 years. Age and tumor stage at diagnosis differed among the three risk groups (P < 0.0001). Multivariate analysis of disease-specific survival (DSS) showed that increasing age [hazard ratio (HR), 1.06; 95% CI, 1.02 to 1.09], stage III/IV at diagnosis (HR, 7.39; 95% CI, 2.39 to 22.8), and HST group (HR, 14.4; 95% CI, 3.32 to 62.6) were significantly associated with worse DSS; the H group was not (P = 0.175). The DSS rates and outcomes were not different between the MOD and H groups (P = 0.179 and P = 0.893, respectively) but were significantly inferior in the HST group (P < 0.0008 and P < 0.0001, respectively).ConclusionMTC in patients with MEN2 showed a clearly different age of onset in the different risk groups. DSS and outcomes after MTC diagnosis were similar in the MOD and H groups, suggesting similar tumor behavior. The HST group had inferior outcomes and survival vs the MOD and or H groups.
      PubDate: Thu, 30 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00516
      Issue No: Vol. 104, No. 10 (2019)
  • High Prevalence of Growth Plate Gene Variants in Children With Familial
           Short Stature Treated With GH
    • Authors: Plachy L; Strakova V, Elblova L, et al.
      Pages: 4273 - 4281
      Abstract: ContextFamilial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date.ObjectivesTo identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD).Design, Settings, and PatientsOf 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height −2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines.ResultsIn 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1).ConclusionsSingle-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.
      PubDate: Thu, 07 Feb 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02288
      Issue No: Vol. 104, No. 10 (2019)
  • Unique Inflammatory Changes in Exocrine and Endocrine Pancreas in
           Enterovirus-Induced Fulminant Type 1 Diabetes
    • Authors: Takita M; Jimbo E, Fukui T, et al.
      Pages: 4282 - 4294
      Abstract: ContextThere are scant reports on the pathological changes of the exocrine and endocrine pancreas in fulminant type 1 diabetes mellitus (FT1DM).ObjectiveTo clarify the distinct pathological changes in the exocrine as well as the endocrine pancreas shortly after onset of diabetes in FT1DM.DesignThe exocrine and endocrine pancreases of 3 patients with FT1DM and 17 nondiabetic controls were immunohistochemically examined for islet and exocrine tissue inflammation, infiltrating mononuclear cell (MNC) CD subtype, enterovirus capsid protein 1 (VP1) localization, and CXC chemokine ligand 10 (CXCL10) and CXC chemokine receptor 3 (CXCR3) expressions.ResultsThe median frequency of insulitis in the 3 FT1DM pancreases was 60%. In the nondiabetic control pancreases, no insulitis was observed. In the islets of FT1DM, the numbers of CD45+, CD3+, CD8+, CD68+, and CD11c+ MNCs were significantly higher than those of the control group. In the exocrine pancreas of FT1DM, the numbers of CD3+ T cells, CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were significantly higher than those of the control group. Infiltrating CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were observed around exocrine acinar cells in FT1DM. There was a close association between VP1 and CXCL10 expression in pancreatic exocrine ductal cells and acinar cells as well as islet cells in FT1DM. CXCL10+ exocrine cells were surrounded by CXCR3+ T cells.ConclusionThe pathological findings suggested that suppression of the activated CXCL10–CXCR3 axis in the exocrine as well as the endocrine pancreas is a novel therapeutic target in FT1DM and possibly in enterovirus-associated acute-onset type 1 diabetes.
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02672
      Issue No: Vol. 104, No. 10 (2019)
  • A Prospective Study of Early Pregnancy Essential Metal(loid)s and Glucose
           Levels Late in the Second Trimester
    • Authors: Zheng Y; Zhang C, Weisskopf M, et al.
      Pages: 4295 - 4303
      Abstract: ContextStudies suggest many essential trace metal(loid)s are involved in glucose metabolism, but the associations among pregnant women are unclear.ObjectiveTo assess associations between early pregnancy plasma zinc, selenium, copper, and molybdenum levels and blood glucose levels later in the second trimester.DesignThe Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies‒Singleton Cohort is a prospective cohort study conducted between July 2009 and January 2013.SettingTwelve academic research hospitals in the United States.PatientsA total of 1857 multiracial, nonobese, healthy women.Main Outcome MeasureBlood glucose levels from 1-hour 50-g gestational load test (GLT) at 24 to 28 weeks of gestation.ResultsHigher concentrations of first-trimester copper were associated with higher glucose levels from the GLT (i.e., every 50% increase in copper concentration was related to 4.9 mg/dL higher glucose level; 95% CI: 2.2, 7.5 mg/dL) adjusted for maternal sociodemographic characteristics and reproductive history. In contrast, every 50% increase in molybdenum concentration was associated with 1.2 mg/dL lower mean glucose level (95% CI: −2.3, −0.1 mg/dL). The magnitude of these associations was greater at the upper tails of glucose level distribution based on quantile regressions of the 10th, 50th, and 90th percentiles.ConclusionsHigher copper and lower molybdenum concentrations could increase the risk of glucose dysregulation during pregnancy, with women at higher risk of gestational diabetes mellitus potentially affected to a greater extent. Further work is needed to understand the mechanisms involved with early pregnancy essential metal(loid)s to inform clinical diagnosis and prevention of glucose intolerance during pregnancy.
      PubDate: Thu, 16 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00109
      Issue No: Vol. 104, No. 10 (2019)
  • Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent
           of Neurokinin B and Dynorphin Signaling
    • Authors: Lippincott M; León S, Chan Y, et al.
      Pages: 4304 - 4318
      Abstract: ContextKisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear.ObjectiveTo probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB.DesignCase/control.SettingAcademic medical center.ParticipantsMembers of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice.InterventionsFrequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin.Main Outcome MeasuresLH pulse characteristics.ResultsHumans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin.ConclusionThe preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
      PubDate: Mon, 27 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00146
      Issue No: Vol. 104, No. 10 (2019)
  • Letter to the Editor: “A Meta-Analysis of the Prevalence of Cardiac
           Valvulopathy in Patients With Hyperprolactinemia Treated With
    • Authors: Caputo C; Inder W.
      Pages: 4319 - 4320
      Abstract: We are writing in response to the article by Stiles et al. (1) published in Journal of Clinical Endocrinology & Metabolism. The authors examined 13 case-control studies and concluded that low-dose cabergoline appears to be associated with increased prevalence of tricuspid regurgitation. Furthermore, Stiles et al. (1) wrote that publication of large-scale, prospective, controlled, quality-assured echocardiographic studies with centralized standardized interpretation are needed to provide data and that additional cross-sectional studies drawn from routine practice are unlikely to inform the field significantly. We disagree with this conclusion and suggest that meta-analysis is not the most appropriate means to determine the specific effects of cabergoline on cardiac valve morphology.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00577
      Issue No: Vol. 104, No. 10 (2019)
  • Response to Letter to the Editor: “A Meta-Analysis of the Prevalence of
           Cardiac Valvulopathy in Patients With Hyperprolactinemia Treated With
    • Authors: Stiles C; Steeds R, Drake W.
      Pages: 4321 - 4322
      Abstract: We welcome Caputo and Inder’s view that cabergoline-associated valvulopathy (CAV) is an “uncommon complication” (1) of cabergoline treatment and point to our recent joint position statement (2) regarding the use of echocardiography for surveillance of patients with this condition. We have proposed (3) a far less stringent surveillance strategy than that laid out by the Medicines and Healthcare Products Regulatory Agency in 2008 (4), in recognition of the rarity of clinically significant valve lesions. We share the view that CAV is much less of a clinical issue than is implied by the Medicines and Healthcare Products Regulatory Agency guidelines, but as yet, there are insufficient data to completely exonerate cabergoline.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00704
      Issue No: Vol. 104, No. 10 (2019)
  • The Low-Dose ACTH Test: Usefulness of Combined Analysis of Serum and
           Salivary Maximum Cortisol Response in Pediatrics
    • Authors: Vaiani E; Lazzati J, Ramirez P, et al.
      Pages: 4323 - 4330
      Abstract: ContextThe low-dose (1 µg) ACTH test (LDT) is widely used to assess central adrenal insufficiency (CAI); however, the serum cortisol cutoff value is controversial. Salivary cortisol (SC) may be a more accurate measurement for CAI.ObjectiveTo assess a new maximum cutoff value of serum cortisol after LDT in pediatric patients, taking into account serum and SC measurements.Design and SettingProspective study in a pediatric tertiary referral center.Working HypothesisThe combined analysis of serum and SC response to LDT might improve LDT for CAI diagnosis.Participant and Outcome MeasurementA total of 145 pediatric patients underwent LDT. Serum and SC levels were measured. A central adrenal sufficient (CAS) response was established according to the reference serum cortisol cutoff value of ≥497 nmol/L.ResultsThe LDT study showed central adrenal sufficiency in 72 patients and CAI in 73 patients. Considering the lower quartile of maximum SC value (21 nmol/L) in the CAS group, an intermediate CAI (InCAI) group and a real CAI (RCAI) group were defined. Regarding the median maximum value of serum cortisol levels in the InCAI group, a new serum cortisol cutoff value of 450 nmol/L was established. Furthermore, 91% of the patients in the RCAI group were below this cutoff value.ConclusionThe combined evaluation of maximum serum and SC levels to LDT might be useful to define an InCAI group and to avoid unnecessary hormone replacement therapy. However, rigorous patient follow-up is required
      PubDate: Tue, 28 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00304
      Issue No: Vol. 104, No. 10 (2019)
  • Plasma Steroid Profiles in Subclinical Compared With Overt Adrenal Cushing
    • Authors: Masjkur J; Gruber M, Peitzsch M, et al.
      Pages: 4331 - 4340
      Abstract: ContextDiagnosis of subclinical adrenal hypercortisolism is based on several tests of the hypothalamic-pituitary-adrenal axis to establish mild alterations of cortisol secretion and dysregulated cortisol physiology.ObjectiveWe assessed whether plasma steroid profiles might assist diagnosis of subclinical Cushing syndrome (SC).DesignRetrospective cross-sectional study.SettingTwo tertiary medical centers.PatientsOf 208 patients tested for hypercortisolism, disease was excluded in 152 and confirmed in 21 with overt adrenal Cushing syndrome (AC) compared to 35 with SC. Another 277 age- and sex-matched hypertensive and normotensive volunteers were included for reference.Main Outcome MeasuresA panel of 15 plasma steroids was measured by mass spectrometry, with classification by discriminant analysis.ResultsPatients with SC had lower plasma concentrations of dehydroepiandrosterone and dehydroepiandrosterone-sulfate than subjects without SC (P < 0.05). The largest increases (P < 0.001) in plasma steroids among patients with SC were observed for 11-deoxycortisol and 11-deoxycorticosterone. Nevertheless, concentrations of 11-deoxycorticosterone, 11-deoxycortisol, and pregnenolone in patients with AC were higher (P < 0.05) than in those with SC. Patients with SC or AC could be distinguished from subjects without disease using this combination of steroids as precisely as with use of measurements of serum cortisol after administration of dexamethasone. The steroid combination provided superior diagnostic performance compared with each of the other routine biochemical tests.ConclusionDistinct plasma steroid profiles in patients with SC may provide a simple and reliable screening method for establishing the diagnosis.
      PubDate: Fri, 12 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02349
      Issue No: Vol. 104, No. 10 (2019)
  • Impaired Glucose-Stimulated Proinsulin Secretion Is an Early Marker of
           β-Cell Impairment Before Prediabetes Stage
    • Authors: Yang Y; Wang M, Tong J, et al.
      Pages: 4341 - 4346
      Abstract: ContextEvidence indicates that there is substantial impairment/loss of β-cell function/mass even before prediabetes. Elevated plasma proinsulin is a sign of β-cell dysfunction in patients with diabetes/prediabetes. However, the dynamic changes of glucose stimulated proinsulin secretion (GSPS) among nondiabetic individuals remain obscure.ObjectiveTo examine GSPS and glucose-stimulated insulin secretion (GSIS) among individuals with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) and to evaluate whether impaired GSPS is an early biomarker of β-cell impairment in individuals with NGT who have subthreshold postprandial plasma glucose (PPG).Design and ParticipantsWe evaluated GSPS and GSIS in 116 Chinese adults without diabetes (mean age ± SD, 33.31 ± 9.10 years; mean BMI, 25.24 ± 4.20 kg/m2) with fasting plasma glucose (FPG) < 5.6 mmol/L. Based on 2hPPG, the participants were divided into three groups: NGT1 (2hPPG < 6.67 mmol/L), NGT2 (6.67 ≤ 2hPPG < 7.78 mmol/L), and IGT (7.78 ≤ 2hPPG<11.1 mmol/L). We analyzed the association of GSIS and GSPS with commonly used indexes of β-cell function, insulin resistance and family history of diabetes.ResultsAlthough not diagnosed with prediabetes, the individuals with NGT2 have clinical characteristics and high diabetes risk factors similar to those of the IGT group. However, unlike individuals with IGT, NGT2 participants did not exhibit a delayed GSIS. Instead, GSPS was impaired in NGT2 groups but not in NGT1 group.ConclusionsThis study suggests that impaired GSPS, but not impaired GSIS, may serve as an early biomarker to identify a subpopulation of NGT with a high risk of diabetes.
      PubDate: Fri, 10 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00549
      Issue No: Vol. 104, No. 10 (2019)
  • A Randomized Placebo-Controlled Trial of Low-Dose Testosterone Therapy in
           Women With Anorexia Nervosa
    • Authors: Kimball A; Schorr M, Meenaghan E, et al.
      Pages: 4347 - 4355
      Abstract: ContextAnorexia nervosa (AN) is a psychiatric illness with considerable morbidity and no approved medical therapies. We have shown that relative androgen deficiency in AN is associated with greater depression and anxiety symptom severity.ObjectiveTo determine whether low-dose testosterone therapy is an effective endocrine-targeted therapy for AN.DesignDouble-blind, randomized, placebo-controlled trial.SettingClinical research center.ParticipantsNinety women, 18 to 45 years, with AN and free testosterone levels below the median for healthy women.InterventionTransdermal testosterone, 300 μg daily, or placebo patch for 24 weeks.Main Outcome MeasuresPrimary end point: body mass index (BMI). Secondary end points: depression symptom severity [Hamilton Depression Rating Scale (HAM-D)], anxiety symptom severity [Hamilton Anxiety Rating Scale (HAM-A)], and eating disorder psychopathology and behaviors.ResultsMean BMI increased by 0.0 ± 1.0 kg/m2 in the testosterone group and 0.5 ± 1.1 kg/m2 in the placebo group (P = 0.03) over 24 weeks. At 4 weeks, there was a trend toward a greater decrease in HAM-D score (P = 0.09) in the testosterone vs placebo group. At 24 weeks, mean HAM-D and HAM-A scores decreased similarly in both groups [HAM-D: −2.9 ± 4.9 (testosterone) vs −3.0 ± 5.0 (placebo), P = 0.72; HAM-A: −4.5 ± 5.3 (testosterone) vs −4.3 ± 4.4 (placebo), P = 0.25]. There were no significant differences in eating disorder scores between groups. Testosterone therapy was safe and well tolerated with no increase in androgenic side effects compared with placebo.ConclusionLow-dose testosterone therapy for 24 weeks was associated with less weight gain—and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms—compared with placebo in women with AN.
      PubDate: Thu, 20 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00828
      Issue No: Vol. 104, No. 10 (2019)
  • Continuous Glucose Monitoring Profiles in Healthy Nondiabetic
           Participants: A Multicenter Prospective Study
    • Authors: Shah V; DuBose S, Li Z, et al.
      Pages: 4356 - 4364
      Abstract: ContextUse of continuous glucose monitoring (CGM) is increasing for insulin-requiring patients with diabetes. Although data on glycemic profiles of healthy, nondiabetic individuals exist for older sensors, assessment of glycemic metrics with new-generation CGM devices is lacking.ObjectiveTo establish reference sensor glucose ranges in healthy, nondiabetic individuals across different age groups using a current generation CGM sensor.DesignMulticenter, prospective study.SettingTwelve centers within the T1D Exchange Clinic Network.Patients or ParticipantsNonpregnant, healthy, nondiabetic children and adults (age ≥6 years) with nonobese body mass index.InterventionEach participant wore a blinded Dexcom G6 CGM, with once-daily calibration, for up to 10 days.Main Outcome MeasuresCGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability.ResultsA total of 153 participants (age 7 to 80 years) were included in the analyses. Mean average glucose was 98 to 99 mg/dL (5.4 to 5.5 mmol/L) for all age groups except those over 60 years, in whom mean average glucose was 104 mg/dL (5.8 mmol/L). The median time between 70 to 140 mg/dL (3.9 to 7.8 mmol/L) was 96% (interquartile range, 93 to 98). Mean within-individual coefficient of variation was 17 ± 3%. Median time spent with glucose levels >140 mg/dL was 2.1% (30 min/d), and median time spent with glucose levels <70 mg/dL (3.9 mmol/L) was 1.1% (15 min/d).ConclusionBy assessing across age groups in a healthy, nondiabetic population, normative sensor glucose data have been derived and will be useful as a benchmark for future research studies.
      PubDate: Thu, 25 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02763
      Issue No: Vol. 104, No. 10 (2019)
  • ERRATUM FOR “Increased Incidence Rate of Hypothyroidism After Iodine
    • Pages: 4365 - 4365
      Abstract: In the above-named article by Petersen M, Knudsen N, Carlé A, Andersen S, Jørgensen T, Perrild H, Ovesen L, Rasmussen LB, Thuesen BH, and Pedersen IB (J Clin Endocrinol Metab. 2019;104(5):1833–1840; doi: 10.1210/jc.2018-01993), the following error occurred during the production process of the accepted manuscript: two instances of the word “iodine” were replaced with “iron” in the introduction section of the article.
      PubDate: Mon, 12 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-01993) the following error occurred during the production process of the accepted ma
      Issue No: Vol. 104, No. 10 (2019)
  • Clinical but Not Histological Outcomes in Males With 45,X/46,XY Mosaicism
           Vary Depending on Reason for Diagnosis
    • Authors: Ljubicic M; Jørgensen A, Acerini C, et al.
      Pages: 4366 - 4381
      Abstract: ContextLarger studies on outcomes in males with 45,X/46,XY mosaicism are rare.ObjectiveTo compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life.DesignA retrospective, multicenter study.SettingSixteen tertiary centers.Patients or Other ParticipantsSixty-three males older than 13 years with 45,X/46,XY mosaicism.Main Outcome MeasuresHealth outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia.ResultsThirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm.ConclusionPatients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.
      PubDate: Thu, 25 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02752
      Issue No: Vol. 104, No. 10 (2019)
  • Latent Autonomous Cortisol Secretion From Apparently Nonfunctioning
           Adrenal Tumor in Nonlateralized Hyperaldosteronism
    • Authors: Ohno Y; Sone M, Inagaki N, et al.
      Pages: 4382 - 4389
      Abstract: ContextAdrenal tumors (ATs), even those diagnosed as nonfunctioning, may cause metabolic disorders. Some primary aldosteronism (PA) patients with ATs are diagnosed with bilateral PA based on adrenal venous sampling (AVS), and their ATs are apparently nonfunctioning.ObjectiveTo clarify the influence of apparently nonfunctioning ATs, we compared hormone levels and clinical complications between bilateral PA cases with and without ATs.Design, setting, and participantsAfter retrospectively assessing 2814 patients with PA in the multicenter Japan PA study, bilateral PA cases on AVS were divided into cases with and without ATs by computed tomography findings. Importantly, patients with cortisol levels >1.8 µg/dL after the 1-mg dexamethasone suppression test (DST) were excluded. Clinical characteristics and biochemical data were compared between them. The correlation between AT size and hormone levels was also analyzed.Main outcome measuresAnalyzed were 196 bilateral PA patients with ATs and 331 those without ATs. Although basal cortisol and aldosterone levels were similar between them, cortisol levels after the 1-mg DST and the prevalences of diabetes mellitus and proteinuria were significantly higher and ACTH levels and plasma renin activity were significantly lower in cases with ATs than in those without. After adjusting for patients’ backgrounds, cortisol levels after the 1-mg DST and plasma renin activity remained significantly different between them. Moreover, cortisol levels after the 1-mg DST and ACTH levels correlated with AT size.ConclusionsApparently nonfunctioning ATs in bilateral PA cases may cause latent autonomous cortisol secretion, inducing diabetes and proteinuria.
      PubDate: Mon, 06 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02790
      Issue No: Vol. 104, No. 10 (2019)
  • Sex Differences in Effects of Obesity on Reproductive Hormones and Glucose
           Metabolism in Early Puberty
    • Authors: Nokoff N; Thurston J, Hilkin A, et al.
      Pages: 4390 - 4397
      Abstract: ContextObesity is known to impact reproductive function in adults, but little is known about its effects on reproductive hormones during puberty.ObjectiveTo assess sex differences in effects of obesity on reproductive hormones and their relation to insulin sensitivity and secretion.DesignCross-sectional study including anthropometrics, serum and urine reproductive hormone concentrations, and intravenous glucose tolerance testing (IVGTT) to assess acute insulin response to glucose (AIRg), and insulin sensitivity (Si).SettingOutpatient academic clinical research center.PatientsGirls (52%) and boys (48%) who were normal weight (NW; n = 51, BMI-Z score = −0.11 ± 0.77, age = 11.5 ± 1.7 years) and obese (n = 53, BMI-Z score = 2.22 ± 0.33, age = 10.9 ± 1.5 years), Tanner stage 2 to 3.ResultsBoys with obesity had lower total testosterone (P < 0.0001) and higher concentrations of the urinary estradiol metabolite, E1c, (P = 0.046) than boys with NW. Girls with obesity had higher free androgen index (FAI; P = 0.03) than NW girls. Both boys and girls with obesity had lower sex hormone-binding globulin (SHBG; P < 0.0001) than NW. AIRg was inversely related to SHBG in boys (R = 0.6, P < 0.0001) and girls (R = 0.53, P = 0.0001). Si correlated with higher SHBG in boys (R2 = 0.67, P < 0.0001) and girls (R = 0.5, P = 0.0003), higher total testosterone for boys (R = 0.39, P = 0.01), and lower FAI for girls (R = −0.2, P = 0.04).ConclusionYouth with obesity have lower SHBG than youth with NW, but obesity has differential effects on reproductive hormones in girls versus boys, which are apparent early in puberty. Ongoing longitudinal studies will evaluate the impact of obesity on reproductive hormones in girls and boys as puberty progresses.
      PubDate: Mon, 15 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02747
      Issue No: Vol. 104, No. 10 (2019)
  • A Clinical Perspective of Sleep and Andrological Health: Assessment,
           Treatment Considerations, and Future Research
    • Authors: Liu P.
      Pages: 4398 - 4417
      Abstract: ContextSleep that is insufficient, misaligned, or disrupted causes hypersomnolence and neuropsychological deficits, adversely affects cardiometabolic health, and is increasingly recognized to impair other biological processes that lead to conditions important to men, such as hypogonadism, erectile dysfunction, and infertility.Evidence AcquisitionLiterature review from 1970 to December 2018.Evidence SynthesisHigh-quality and complementary epidemiological and interventional studies establish that abnormal sleep is associated with increased mortality, hypertension, and other cardiometabolic disorders (insufficient, disrupted, and misaligned sleep), as well as reduced fecundity and total sperm count (insufficient sleep), erectile dysfunction (disrupted sleep), and low testosterone (both). Circadian misalignment shifts the peak of testosterone’s diurnal rhythm to occur soon after waking up, irrespective of the biological clock time, but it does not change the mean concentration. Preliminary studies show that extending sleep in individuals who are chronically sleep deprived may become a strategy to reduce insulin resistance and hypertension. Continuous positive airway pressure therapy can improve erectile function, and possibly systemic testosterone exposure, but only when used adherently by men with obstructive sleep apnea. Both high-dose and replacement-dose testosterone therapies modestly worsen sleep-disordered breathing, but they also improve cardiometabolic function and sexual desire. Persistence of either the adverse or beneficial outcomes over the longer term requires further investigation.ConclusionsSleep is increasingly recognized to be essential for healthy living. Establishing the effect of abnormal sleep, and of improving sleep, on andrological issues of prime interest to men will promote prioritization of sleep, and may thereby improve overall long-term health outcomes.
      PubDate: Wed, 01 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00683
      Issue No: Vol. 104, No. 10 (2019)
  • Letter to the Editor: “Genetic Link Between Gender Dysphoria and Sex
           Hormone Signaling”
    • Authors: White P.
      Pages: 4418 - 4419
      Abstract: Foreman et al. (1) tested the interesting hypothesis that transgender women (formerly called male-to-female transsexuals) have frequencies of polymorphisms in genes for several steroid metabolizing enzymes and hormone receptors that differ from those of male controls. They concluded that gender dysphoria, at least in natal males, may have a genetic basis.
      PubDate: Wed, 03 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00487
      Issue No: Vol. 104, No. 10 (2019)
  • Response to Letter to the Editor: “Genetic Link Between Gender Dysphoria
           and Sex Hormone Signaling”
    • Authors: Foreman M; Vilain E, Harley V.
      Pages: 4420 - 4420
      Abstract: We appreciate Dr. White’s interest in our work. We formulated the hypothesis that genes in the sex steroid pathway are associated with gender identity. A priori experimental data to analyze genes in this single pathway, and correlation of genetic variants with gender, provided a strong case that this pathway is a good candidate. In our article (1) we put arguments forward about gender identity differences in congenital adrenal hyperplasia and partial androgen insensitivity syndrome intersex conditions, positron emission tomography response of transwomen (known historically as male-to-female transsexuals) to sex steroid odor, neuroimaging studies, heritability studies, blood analysis of dehydroepiandrosterone and dehydroepiandrosterone sulfate levels, and genetic association studies of transmen (female-to-male transsexuals) that also link gender dysphoria to sex steroid signaling. Furthermore, the gene polymorphisms we studied are functional in other disease contexts, rather than neutral.
      PubDate: Wed, 03 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00701
      Issue No: Vol. 104, No. 10 (2019)
  • Improving Long-Term Outcomes of Youth With Lipid Abnormalities—Expanding
           the Role of Pediatric Endocrinologists
    • Authors: Ashraf A; Kohn B, Wilson D.
      Pages: 4421 - 4426
      Abstract: ContextThere is a disturbingly high prevalence of dyslipidemia in youth. Although pediatric endocrinologists are aware of the substantial cardiovascular (CV) risk associated with monogenic disorders of lipid and lipoprotein metabolism, relatively few recognize the CV disease (CVD)-related morbidity and premature mortality incurred by common endocrine disorders associated with dyslipidemia, such as diabetes mellitus, growth hormone deficiency, congenital adrenal hyperplasia, and hypopituitarism.ObjectiveIn this article, we discuss the expanding role of pediatric endocrinologists in CV health and risk prevention.DesignWe reviewed available literature and summarized discussions with opinion leaders in pediatric endocrinology to accomplish the following: (i) provide an overview of this timely topic; (ii) identify opportunities for targeted education; and (iii) discuss ways of expanding clinical services to improve outcomes.ResultsIn addition to well-known genetic disorders of lipid and lipoprotein metabolism, youth with common endocrine disorders, including type 1 and type 2 diabetes, would benefit from cholesterol screening and in some, early intervention, including use of lipid-lowering medications. Despite the growing need, the location and extent of services available to youth with dyslipidemia and the availability of providers with experience in treatment of dyslipidemia are largely unknown but likely inadequate to provide accessible, timely, and cost-effective intervention.ConclusionWith a new awareness of opportunities to prevent premature CVD in youth, including those with common endocrine disorders and CVD-related events during adulthood, there is an urgent need for additional clinical services and targeted education of current as well as future pediatric endocrinologists.
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00150
      Issue No: Vol. 104, No. 10 (2019)
  • Effect of Prebiotic on Microbiota, Intestinal Permeability, and Glycemic
           Control in Children With Type 1 Diabetes
    • Authors: Ho J; Nicolucci A, Virtanen H, et al.
      Pages: 4427 - 4440
      Abstract: ContextPatients with type 1 diabetes (T1D) have lower microbiota diversity and distinct gut microbial profiles that have been linked to changes in intestinal permeability. Prebiotics are nondigestible carbohydrates that alter gut microbiota and could potentially improve glycemic control and reduce intestinal permeability and thereby insulin sensitivity.ObjectiveTo determine the effect of prebiotics on glycemic control, gut microbiota, and intestinal permeability in children with T1D.DesignA randomized, placebo-controlled trial in children 8 to 17 years of age with T1D using placebo or prebiotic oligofructose-enriched inulin for 12 weeks. Baseline, 3-month, and 6-month assessments included HbA1c, C-peptide, gut microbiota, intestinal permeability, frequency of diabetic ketoacidosis (DKA), and severe hypoglycemia.ResultsForty-three subjects were randomized and 38 completed the study. The groups were similar at baseline: prebiotic (N = 17), age 12.5 years (SD of 2.8), HbA1c 8.02% (SD of 0.82); placebo (N = 21), age 12.0 years (SD of 2.6), HbA1c 8.08% (SD of 0.91). No significant differences were found in the frequency of DKA or severe hypoglycemia. At 3-months, C-peptide was significantly higher (P = 0.029) in the group who received prebiotics, which was accompanied by a modest improvement in intestinal permeability (P = 0.076). There was a significant increase in the relative abundance of Bifidobacterium within the prebiotic group at 3 months that was no longer present after the 3-month washout. The placebo group had significantly higher relative abundance of Streptococcus, Roseburia inulinivorans, Terrisporobacter, and Faecalitalea compared with the prebiotic group at 3 months.ConclusionPrebiotics are a potentially novel, inexpensive, low-risk treatment addition for T1D that may improve glycemic control. Further larger-scale trials are needed.
      PubDate: Wed, 12 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00481
      Issue No: Vol. 104, No. 10 (2019)
  • Cortisol Secretion, Sensitivity, and Activity Are Associated With
           Hypertension in Postmenopausal Eucortisolemic Women
    • Authors: Chiodini I; Gaudio A, Eller-Vainicher C, et al.
      Pages: 4441 - 4448
      Abstract: ContextPrevious data suggest a possible association between type 2 diabetes (T2D) and fragility fractures (FX) with the degree of glucocorticoid suppressibility (GCS) and peripheral activation or sensitivity even in persons without hypercortisolemia.ObjectiveTo investigate whether the degree of GCS, GC sensitivity, and peripheral activation in persons without overt or mild hypercortisolism are associated with hypertension and with the number of the possible consequences of cortisol excess among patients with T2D, fragility FX, and hypertension.DesignCase-control study.SettingOutpatient clinic.PatientsA total of 216 postmenopausal women without hypercortisolemia (age, 50 to 80 years; 108 with hypertension); 68 and 99 patients had fragility FX and T2D, respectivelyMain outcome measuresWe assessed 24-hour urinary free cortisol (UFF), cortisone (UFE), their ratio (R-UFF/UFE), (F-1mgDST), and the GC receptor N363S single-nucleotide polymorphism (N363S-SNP).ResultsHypertension was associated with F-1 mgDST [odds ratio (OR), 3.3; 95% CI, 1.5 to 7.5; P = 0.004) and R-UFF/UFE (OR, 101.7; 95% CI, 2.6 to 4004.1; P = 0.014), regardless of age, body mass index, and presence of the N363S single nucleotide polymorphism and of T2D. The progressive increase in the number of possible consequences of cortisol excess was significantly associated with F-1mgDST levels (R2 = 0.125; P = 0.04), R-UFF/UFE (R2 = 0.46; P = 0.02), and the prevalence of N363S heterozygous variant (T = 0.46; P = 0.015), after adjustment for age.ConclusionsIn postmenopausal women without hypercortisolemia, hypertension is associated with GCS and GC peripheral activation. The number of possible consequences of cortisol excess (among patients with hypertension, T2D, and fragility FX) is associated with GCS, GC peripheral activation, and the prevalence of the N363S heterozygous variant.
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00037
      Issue No: Vol. 104, No. 10 (2019)
  • Association of Galectin-3 With Diabetes Mellitus in the Dallas Heart Study
    • Authors: Vora A; de Lemos J, Ayers C, et al.
      Pages: 4449 - 4458
      Abstract: ContextGalectin-3 is a biomarker associated with inflammation and fibrosis in cardiac, liver, and renal disease. Galectin-3 is higher in overweight and obese individuals; whether an association with diabetes exists independent of weight is unknown.ObjectiveTo evaluate if galectin-3 is associated with diabetes mellitus.DesignWe performed measurements of galectin-3 among participants in the Dallas Heart Study (DHS) Phases 1 and 2 (DHS-1 and DHS-2; n = 3392, and n = 3194, respectively). Of these, 1989 participants were evaluated longitudinally in both studies. Associations of galectin-3 with prevalent and incident type 2 diabetes were determined using logistic regression models. Associations of galectin-3 with relevant biomarkers and fat compartments were evaluated using Spearman correlation coefficients and multivariable linear regression models, respectively.Setting and ParticipantsDHS is a population-based, single-site, multiethnic study conducted in Dallas County, Texas, with oversampling to comprise 50% blacks.ResultsGalectin-3 levels were associated with diabetes prevalence in DHS-1 [OR 1.56 per SD change in log-galectin (95% CI 1.41 to 1.73)] and DHS-2 [OR 1.86 (95% CI 1.67 to 2.06)]. Galectin-3 levels in DHS-1 also associated with incident diabetes mellitus over the 7.1 (interquartile range 6.6 to 7.6)-year follow-up period [OR 1.34 (95% CI 1.14 to 1.58)]. These associations maintained significance in models adjusted for traditional metabolic risk factors (age, sex, race, body mass index, and hypertension) and renal function. Galectin-3 levels correlated with levels of biomarkers implicated in inflammation (high-sensitivity C-reactive peptide, IL-18, monocyte chemoattractant protein 1, soluble TNF receptor 1A, myeloperoxidase), insulin secretion (C-peptide and C-peptide/homeostatic model assessment for insulin resistance), and subcutaneous adiposity.ConclusionsGalectin-3 is associated with diabetes prevalence and incidence, possibly through the inflammatory pathway contributing to β-cell fibrosis and impaired insulin secretion.
      PubDate: Tue, 04 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00398
      Issue No: Vol. 104, No. 10 (2019)
  • Cord Blood Metabolomics: Association With Newborn Anthropometrics and
           C-Peptide Across Ancestries
    • Authors: Kadakia R; Talbot O, Kuang A, et al.
      Pages: 4459 - 4472
      Abstract: ContextNewborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance.ObjectiveTo determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns.DesignCross-sectional, observational study.SettingHyperglycemia and Adverse Pregnancy Outcome study.ParticipantsOne thousand six hundred multiethnic mother–newborn pairs.Main Outcome MeasureCord blood C-peptide, birthweight, and newborn sum of skinfolds.ResultsMeta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes.ConclusionsCord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.
      PubDate: Thu, 04 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00238
      Issue No: Vol. 104, No. 10 (2019)
  • Persistently Elevated PTH After Parathyroidectomy at One Year: Experience
           in a Tertiary Referral Center
    • Authors: Caldwell M; Laux J, Clark M, et al.
      Pages: 4473 - 4480
      Abstract: Context/ObjectiveIncreased PTH after successful parathyroid surgery represents a clinical conundrum. We aimed to determine the prevalence of persistently elevated PTH (PePTH) postsurgery, along with predisposing factors.Designand Setting: Patients ≥ age 18 with parathyroidectomy performed at University of North Carolina Hospitals for primary hyperparathyroidism (PHPT) over a 12-year period were identified from the Carolina Data Warehouse. Clinical and demographic characteristics were collected, transformed, and analyzed.ResultsFive hundred seventy patients met initial criteria for PHPT, and of those 407 had postoperative values. One hundred forty-four had laboratory results within 3 to 18 months post operatively. There was no clinical difference between those with and without long-term laboratory follow-up. Presurgery, patients had average calcium of 11 mg/dL and PTH 125.4 pg/mL. Ninety-seven percent of patients had normalized calcium after surgery, but 30% had PePTH, which can be predicted at 3 months. Patients with PePTH (persistent elevation of PTH) after surgery did not differ from those with normalized PTH in terms of sex, age, body mass index, or excised gland weight; presurgery 25-vitamin D was slightly lower, but not abnormal (26 ± 15 vs 36 ± 11). The presurgical PTH was significantly higher (P < 0.001) in those with PePTH (156.5 pg/mL compared with presurgical level of 102.5 in those whose PTH normalized).ConclusionsNearly one-third of PHPT patients have elevated PTH levels postsurgery in a tertiary hospital setting. At presentation, patients with PePTH tend to have higher PTH relative to calcium levels. Whether PePTH after surgical treatment of PHPT has pathological consequences is unknown.
      PubDate: Wed, 12 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00705
      Issue No: Vol. 104, No. 10 (2019)
  • Appetite Control Is Improved by Acute Increases in Energy Turnover at
           Different Levels of Energy Balance
    • Authors: Hägele F; Büsing F, Nas A, et al.
      Pages: 4481 - 4491
      Abstract: BackgroundWeight control is hypothesized to be improved when physical activity and energy intake are both high [high energy turnover (ET)].ObjectiveThe impact of three levels of ET on short-term appetite control is therefore investigated at fixed levels of energy balance.DesignIn a randomized crossover trial, 16 healthy adults (25.1 ± 3.9 y of age; body mass index, 24.0 ± 3.2 kg/m2) spent three daylong protocols for four times in a metabolic chamber. Four conditions of energy balance (ad libitum energy intake, zero energy balance, −25% caloric restriction, and +25% overfeeding) were each performed at three levels of ET (PAL 1.3 low, 1.6 medium, and 1.8 high ET; by walking on a treadmill). Levels of appetite hormones ghrelin, GLP-1, and insulin (total area under the curve) were measured during 14 hours. Subjective appetite ratings were assessed by visual analog scales.ResultsCompared with high ET, low ET led to decreased GLP-1 (at all energy balance conditions: P < 0.001) and increased ghrelin concentrations (caloric restriction and overfeeding: P < 0.001), which was consistent with higher feelings of hunger (zero energy balance: P < 0.001) and desire to eat (all energy balance conditions: P < 0.05) and a positive energy balance during ad libitum intake (+17.5%; P < 0.001).ConclusionAppetite is regulated more effectively at a high level of ET, whereas overeating and consequently weight gain are likely to occur at low levels of ET. In contrast to the prevailing concept of body weight control, the positive impact of physical activity is independent from burning up more calories and is explained by improved appetite sensations.
      PubDate: Mon, 15 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01164
      Issue No: Vol. 104, No. 10 (2019)
  • High-Normal Adolescent Fasting Plasma Glucose Is Associated With Poorer
           Midlife Brain Health: Bogalusa Heart Study
    • Authors: Carmichael O; Stuchlik P, Pillai S, et al.
      Pages: 4492 - 4500
      Abstract: ContextIt is unclear how adolescent glycemic status relates to brain health in adulthood.ObjectiveTo assess the association between adolescent fasting plasma glucose (FPG) and MRI-based brain measures in midlife.DesignBetween 1973 and 1992, the Bogalusa Heart Study (BHS) collected FPG from children, 3 to 18 years old, and followed up between 1992 and 2018. Cognitive tests and brain MRI were collected in 2013 to 2016 and 2018.SettingObservational longitudinal cohort study.ParticipantsOf 1298 contacted BHS participants, 74 completed screening, and 50 completed MRI.Main Outcome MeasuresMean FPG per participant at ages <20, 20 to 40, and over 40 years old; brain white matter hyperintensity (WMH) volume, gray matter volume, and functional MRI (fMRI) activation to a Stroop task; tests of logical and working memory, executive function, and semantic fluency.ResultsAt MRI, participants were middle aged (51.3 ± 4.4 years) and predominantly female (74%) and white (74%). Mean FPG was impaired for zero, two, and nine participants in pre-20, 20 to 40, and over-40 periods. The pre-20 mean FPG above the pre-20 median value (i.e., above 83.5 mg/dL) was associated with greater WMH volume [mean difference: 0.029% of total cranial volume, CI: (0.0059, 0.052), P = 0.015] and less fMRI activation [−1.41 units (−2.78, −0.05), P = 0.043] on midlife MRI compared with below-median mean FPG. In controlling for over-40 mean FPG status did not substantially modify the associations. Cognitive scores did not differ by pre-20 mean FPG.ConclusionsHigh-normal adolescent FPG may be associated with preclinical brain changes in midlife.
      PubDate: Mon, 06 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02750
      Issue No: Vol. 104, No. 10 (2019)
  • Differences in Trabecular Plate and Rod Structure in Premenopausal Women
           Across the Weight Spectrum
    • Authors: Schorr M; Fazeli P, Bachmann K, et al.
      Pages: 4501 - 4510
      Abstract: ContextPremenopausal women with anorexia nervosa (AN) and obesity (OB) have elevated fracture risk. More plate-like and axially aligned trabecular bone, assessed by individual trabeculae segmentation (ITS), is associated with higher estimated bone strength. Trabecular plate and rod structure has not been reported across the weight spectrum.ObjectiveTo investigate trabecular plate and rod structure in premenopausal women.DesignCross-sectional study.SettingClinical research center.ParticipantsA total of 105 women age 21 to 46 years: (i) women with AN (n = 46), (ii) eumenorrheic lean healthy controls (HCs) (n = 29), and (iii) eumenorrheic women with OB (n = 30).MeasuresTrabecular microarchitecture by ITS.ResultsMean age (±SD) was similar (28.9 ± 6.3 years) and body mass index differed (16.7 ± 1.8 vs 22.6 ± 1.4 vs 35.1 ± 3.3 kg/m2; P < 0.0001) across groups. Bone was less plate-like and axially aligned in AN (P ≤ 0.01) and did not differ between OB and HC. After controlling for weight, plate and axial bone volume fraction and plate number density were lower in OB vs HC; some were lower in OB than AN (P < 0.05). The relationship between weight and plate variables was quadratic (R = 0.39 to 0.70; P ≤ 0.0006) (i.e., positive associations were attenuated at high weight). Appendicular lean mass and IGF-1 levels were positively associated with plate variables (R = 0.27 to 0.67; P < 0.05). Amenorrhea was associated with lower radial plate variables than eumenorrhea in AN (P < 0.05).ConclusionsIn women with AN, trabecular bone is less plate-like. In women with OB, trabecular plates do not adapt to high weight. This is relevant because trabecular plates are associated with greater estimated bone strength. Higher muscle mass and IGF-1 levels may mitigate some of the adverse effects of low weight or excess adiposity on bone.
      PubDate: Thu, 20 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00843
      Issue No: Vol. 104, No. 10 (2019)
  • Poor Glycemic Control Is Associated With Impaired Bone Accrual in the Year
           Following a Diagnosis of Type 1 Diabetes
    • Authors: Weber D; Gordon R, Kelley J, et al.
      Pages: 4511 - 4520
      Abstract: ContextType 1 diabetes (T1D) is associated with an increased fracture risk across the life course. The effects on bone accrual early in the disease are unknown.ObjectiveTo characterize changes in bone density and structure over the year following diagnosis of T1D and to identify contributors to impaired bone accrual.DesignProspective cohort study.SettingAcademic children’s hospital.ParticipantsThirty-six children, ages 7 to 17 years, enrolled at diagnosis of T1D.OutcomesWhole body and regional dual-energy X-ray absorptiometry and tibia peripheral quantitative computed tomography obtained at baseline and 12 months. The primary outcome was bone accrual assessed by bone mineral content (BMC) and areal bone mineral density (aBMD) velocity z score.ResultsParticipants had low total body less head (TBLH) BMC (z = −0.46 ± 0.76), femoral neck aBMD (z = −0.57 ± 0.99), and tibia cortical volumetric BMD (z = −0.44 ± 1.11) at diagnosis, compared with reference data, P < 0.05. TBLH BMC velocity in the year following diagnosis was lower in participants with poor (hemoglobin A1c ≥7.5%) vs good (hemoglobin A1c <7.5%) glycemic control at 12 months, z = −0.36 ± 0.84 vs 0.58 ± 0.71, P = 0.003. TBLH BMC velocity was correlated with gains in tibia cortical area (R = 0.71, P = 0.003) and periosteal circumference (R = 0.67, P = 0.007) z scores in participants with good, but not poor control.ConclusionsOur results suggest that the adverse effects of T1D on BMD develop early in the disease. Bone accrual following diagnosis was impaired in participants with poor glycemic control and appeared to be mediated by diminished bone formation on the periosteal surface.
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00035
      Issue No: Vol. 104, No. 10 (2019)
  • Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in
           Progression of Islet Autoimmunity in Childhood
    • Authors: Bauer W; Veijola R, Lempainen J, et al.
      Pages: 4521 - 4530
      Abstract: ContextChildren with initial autoantibodies to either insulin (IAA) or glutamic acid decarboxylase (GADA) differ in peak age of seroconversion and have different type 1 diabetes (T1D) risk gene associations, suggesting heterogeneity in the disease process.ObjectiveTo compare the associations of age at seroconversion, HLA risk, and specificity of secondary autoantibodies with the progression of islet autoimmunity between children with either IAA or GADA as their first autoantibody.Design and methodsA cohort of 15,253 children with HLA-associated increased risk of T1D participated in a follow-up program in which islet autoantibodies were regularly measured. The median follow-up time was 6.7 years. Spearman correlation, Kaplan-Meier survival plots, and Cox proportional-hazard models were used for statistical analyses.ResultsPersistent positivity for at least one of the tested autoantibodies was detected in 998 children; 388 of children progressed to clinical T1D. Young age at initial seroconversion was associated with a high probability of expansion of IAA-initiated autoimmunity and progression to clinical diabetes, whereas expansion of GADA-initiated autoimmunity and progression to diabetes were not dependent on initial seroconversion age. The strength of HLA risk affected the progression of both IAA- and GADA-initiated autoimmunity. The simultaneous appearance of two other autoantibodies increased the rate of progression to diabetes compared with that of a single secondary autoantibody among subjects with GADA-initiated autoimmunity but not among those with IAA as the first autoantibody.ConclusionsFindings emphasize the differences in the course of islet autoimmunity initiated by either IAA or GADA supporting heterogeneity in the pathogenic process.
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00421
      Issue No: Vol. 104, No. 10 (2019)
  • Association Between Urinary Triclosan With Bone Mass Density and
           Osteoporosis in US Adult Women, 2005‒2010
    • Authors: Cai S; Zhu J, Sun L, et al.
      Pages: 4531 - 4538
      Abstract: ContextLaboratory studies have demonstrated that triclosan (TCS) can cause significant interstitial collagen accumulation and an increase in trabecular bone. However, little is known about the relationship between TCS exposure and human bone health.MethodsWe used 2005 to 2010 National Health and Nutrition Examination Survey data to examine the association between urinary TCS concentration and bone mineral density (BMD) and osteoporosis in US adult women aged ≥20 years. After inclusion and exclusion, 1848 women were analyzed.ResultsAfter adjustment for other covariates, we observed significant associations between tertile 3 of TCS concentration and lower BMD in regions of the total femur (β = −0.016; 95% CI = −0.032, −0.000), intertrochanteric region (β = −0.022; 95% CI = −0.042, −0.002), and lumbar spine (β = −0.014; 95% CI = −0.029, 0.001), respectively, relative to tertile 1. Compared with women at tertile 1, those at tertile 3 were more likely to have increased prevalence of osteoporosis in the intertrochanteric region (OR = 2.464; 95% CI = 1.190, 5.105).ConclusionThis epidemiological study investigated the association between urinary TCS concentration and BMD and osteoporosis in US adult women. We found urinary TCS concentration was negatively associated with BMD and was positively associated with the prevalence of osteoporosis. The evidence was stronger in postmenopausal women than in premenopausal women. Future prospective studies are needed to validate these findings.
      PubDate: Tue, 25 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00576
      Issue No: Vol. 104, No. 10 (2019)
  • Sex-Specific Association of Circulating Ferritin Level and Risk of Type 2
           Diabetes: A Dose-Response Meta-Analysis of Prospective Studies
    • Authors: Jiang L; Wang K, Lo K, et al.
      Pages: 4539 - 4551
      Abstract: ContextAlthough the role of iron in the development of type 2 diabetes (T2D) has long been a concern, prospective studies directly linking body iron stores to T2D risk in a sex-dependent context have been inconsistent.ObjectiveA systematic meta-analysis was conducted to explore the sex-specific association of circulating ferritin with T2D risk.Data SourcesWe searched PubMed, Web of Science, and EMBASE databases to identify available prospective studies through 1 August 2018.ResultsFifteen prospective studies comprising 77,352 participants and 18,404 patients with T2D, aged 20 to 80 years, and with ∼3 to 17 years of follow-up were identified. For each 100-μg/L increment in ferritin levels of overall participants, T2D risk increased by 22% (RR, 1.22; 95% CI, 1.14 to 1.31). Of note, major heterogeneities by sex were identified, with increased ferritin level having an apparently greater effect on T2D risk in women (RR, 1.53; 95% CI, 1.29 to 1.82) than in men (RR, 1.21; 95% CI, 1.15 to 1.27) after exclusion of a study with high heterogeneity (41,512 men and 6974 women for sex-specific analyses; P = 0.020 for sex difference). Further nonlinear analysis between circulating ferritin and T2D risk also showed sex-dimorphic association in that the T2D risk of women was twice as strong in magnitude as that of men at the same ferritin level.ConclusionsGreater circulating ferritin levels were independently associated with increased T2D risk, which appeared stronger among women than men. Our findings provide prospective evidence for further testing of the utility of ferritin levels in predicting T2D risk in a sex-specific manner.
      PubDate: Fri, 10 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00495
      Issue No: Vol. 104, No. 10 (2019)
  • Human-Specific Function of IL-10 in Adipose Tissue Linked to Insulin
    • Authors: Acosta J; Tavira B, Douagi I, et al.
      Pages: 4552 - 4562
      Abstract: ObjectiveAlthough IL-10 is generally considered as an anti-inflammatory cytokine, it was recently shown to have detrimental effects on insulin sensitivity and fat cell metabolism in rodents. Whether this also pertains to human white adipose tissue (hWAT) is unclear. We therefore determined the main cellular source and effects of IL-10 on human adipocytes and hWAT-resident immune cells and its link to insulin resistance.MethodsAssociations between hWAT IL-10 production and metabolic parameters were investigated in 216 participants with large interindividual variations in body mass index and insulin sensitivity. Adipose cells expressing or secreting IL-10 and the cognate IL-10 receptor α (IL10RA) were identified by flow cytometry sorting. Effects on adipogenesis, lipolysis, and inflammatory/metabolic gene expression were measured in two human primary adipocyte models. Secretion of inflammatory cytokines was investigated in cultures of IL-10–treated hWAT macrophages and leukocytes by Luminex analysis (Luminex Corp.).ResultsIL-10 gene expression and protein secretion in hWAT correlated positively with body mass index (BMI) and homeostasis model assessment-insulin resistance (HOMA-IR). Gene expression analyses in mature fat cells and flow cytometry–sorted hWAT-resident adipocyte progenitors, macrophages, and leukocytes demonstrated that the expression of IL-10 and the IL10RA were significantly enriched in proinflammatory M1 macrophages. In contrast to murine data, functional studies showed that recombinant IL-10 had no effect on adipocyte phenotype. In hWAT-derived macrophages and leukocytes, it induced an anti-inflammatory profile.ConclusionIn hWAT, IL-10 is upregulated in proinflammatory macrophages of obese and insulin-resistant persons. However, in contrast to findings in mice, IL-10 does not directly affect human adipocyte function.
      PubDate: Mon, 27 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00341
      Issue No: Vol. 104, No. 10 (2019)
  • Hippocampal Volume, Cognitive Functions, Depression, Anxiety, and Quality
           of Life in Patients With Cushing Syndrome
    • Authors: Frimodt-Møller K; Møllegaard Jepsen J, Feldt-Rasmussen U, et al.
      Pages: 4563 - 4577
      Abstract: ContextCushing syndrome (CS) is associated with hippocampal atrophy and psychopathology.ObjectiveThe primary objective of this systematic review was to assess hippocampal volume (HV) in patients with CS. The secondary objectives were to assess patients’ cognitive functioning, depressive and anxiety symptoms, and quality of life.Data SourcesPubMed, Embase, Cochrane, LILACs, and Scopus databases were searched for relevant studies until 1 May 2019.Study SelectionCase-control studies comparing patients with CS with healthy control subjects, or studies assessing patients with CS before and after surgery were included. The initial search resulted in 18 studies fulfilling the inclusion criteria.Data ExtractionData extraction regarding all outcomes was performed independently by two reviewers. Quality assessment was assessed with the Newcastle-Ottawa Scale for case-control studies.Data SynthesisMeta-analysis was performed using a random effect model. The right-side HV in patients with CS was reduced by a standard mean difference of 0.68 (95% CI, −1.12 to −0.24; P = 0.002; I2 = 0%) compared with healthy control subjects, but with no increase in HV after surgery. Patients had more depressive symptoms, impaired cognitive functions, and reduced health-related QoL (HRQoL), which all responded favorably to surgery. The data did not support the presence of anxiety in patients with CS.ConclusionAn overall reduction of HV in patients with CS was not suggested by the study findings. However, most cognitive domains were significantly affected and responded favorably to surgery. Depressive symptoms and reduced HRQoL were present in patients with CS and improved after surgery.
      PubDate: Wed, 19 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00749
      Issue No: Vol. 104, No. 10 (2019)
  • Effects of the Timing of Sex-Steroid Exposure in Adolescence on Adult
           Health Outcomes
    • Authors: Chan Y; Feld A, Jonsdottir-Lewis E.
      Pages: 4578 - 4586
      Abstract: ContextVariation in pubertal timing is associated with a wide range of adult risks and outcomes, but it is unclear whether these associations are causal, and it is largely unknown whether these associations can be modified by treatment.Evidence AcquisitionWe conducted PubMed searches to identify Mendelian randomization (MR) studies on the influence of pubertal timing on adult health and studies on sex-steroid treatment of the following conditions associated with reduced reproductive endocrine function in adolescence: constitutional delay, Turner syndrome, and Klinefelter syndrome.Evidence SynthesisResults of MR studies suggest that earlier pubertal timing increases body mass index; increases risk for breast, ovarian, endometrial, and prostate cancers; elevates fasting glucose levels and blood pressure; impairs lung capacity and increases risk for asthma; leads to earlier sexual intercourse and first birth; decreases time spent in education; and increases depressive symptoms in adolescence. Later pubertal timing appears to lower bone mineral density (BMD). Although studies of constitutional delay have not shown that sex-steroid treatment alters adult height or BMD, studies of girls with Turner syndrome and boys with Klinefelter syndrome suggest that earlier initiation of sex-steroid treatment improves physical and neurocognitive outcomes.ConclusionsDespite having some limitations, MR studies suggest that pubertal timing causally influences many adult conditions and disease risks. Studies of Turner syndrome and Klinefelter syndrome suggest that earlier sex-steroid exposure may have short- and long-term benefits. The mechanisms underlying these findings and the effects of trends and treatments affecting pubertal timing remain to be determined.
      PubDate: Thu, 13 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00569
      Issue No: Vol. 104, No. 10 (2019)
  • Evaluating the Low-Dose ACTH Stimulation Test in Children: Ideal Times for
           Cortisol Measurement
    • Authors: Gill H; Barrowman N, Webster R, et al.
      Pages: 4587 - 4593
      Abstract: ContextCentral adrenal insufficiency (AI) can be diagnosed with the low-dose ACTH stimulation test (LDST). Protocols determining timing of cortisol sampling vary, with 30 minutes after stimulation being most common.ObjectivesTo determine optimal times to draw cortisol levels and factors predicting timing of peak cortisol levels in children undergoing LDST.DesignRetrospective chart review of LDSTs between February 2014 and September 2017.SettingThe Children’s Hospital of Eastern Ontario.PatientsPatients 3 months to 20 years who underwent LDSTs.InterventionLDSTs were performed with cortisol levels at 0, 15, 30, and 60 minutes after 1 μg cosyntropin. Cortisol values <18 μg/dL (500 nmol/L) determined AI.Main Outcome MeasuresThe incremental value of testing cortisol at 15 or 60 minutes, in addition to the standard 30-minute sample, was estimated.ResultsA total of 221 patients met inclusion criteria. The mean age was 9.7 years, and 32% were female. Peak cortisol levels were 19%, 67%, and 14% at 15, 30, and 60 minutes, respectively. One false positive LDST result would be prevented for every 24 (95% CI, 13 to 46) or 55 (95% CI, 22 to 141) patients tested at 15 or 60 minutes in addition to the standard 30-minute test. Of the 122 patients who passed the LDST, discontinuing the 15- and 60-minute samples would have misdiagnosed 12 patients (9.8%). Glucocorticoid exposure, age, and body mass index z scores were independent predictors of peak cortisol timing.ConclusionAlthough the majority of patients peak 30 minutes after cosyntropin administration, testing cortisol levels at 15 and 60 minutes reduces the risk of false positive LDSTs.
      PubDate: Thu, 20 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00295
      Issue No: Vol. 104, No. 10 (2019)
  • The Incremental Risk of Pancreatic Cancer According to Fasting Glucose
           Levels: Nationwide Population-Based Cohort Study
    • Authors: Koo D; Han K, Park C.
      Pages: 4594 - 4599
      Abstract: ContextIt has been unclear whether the risk of pancreatic cancer is different according to glucose levels.ObjectiveTo determine the association between fasting glucose levels and pancreatic cancer risk using prospectively collected nationwide population-based cohort data in Korea.DesignThe National Health Insurance Service database of claims and preventive health check-up data recorded was used between 2009 and 2015.Setting and ParticipantsA total of 25.4 million patients who had participated in a preventive health check-up between 2009 and 2013 were evaluated for pancreatic cancer incidence rates according to fasting glucose level.Main Outcomes MeasuresThe cumulative incidence rate for pancreatic cancer was calculated after grouping according to fasting glucose levels as follows: (i) low normal (<90 mg/dL), (ii) high normal (90 to 99 mg/dL), (iii) prediabetes level 1 (100 to 109 mg/dL), (iv) prediabetes level 2 (110 to 125 mg/dL), (v) diabetes (≥126 mg/dL), and (vi) diabetes on anti-diabetic medications.ResultsThe 5-year cumulative incidence rates (per 100,000) were as follows: (i) low normal = 32; (ii) high normal = 41; (iii) prediabetes level 1 = 50; (iv) prediabetes level 2 = 64; (v) diabetes = 75; and (vi) on anti-diabetic medications = 121. The risk of pancreatic cancer increased continuously with elevating fasting glucose levels (P < 0.0001). The incidence of pancreatic cancer increased significantly with increasing fasting blood glucose levels even after adjusting for age, sex, smoking, drinking, exercise, body mass index, and diabetes duration (P < 0.0001).ConclusionsThe cumulative incidence rate of pancreatic cancer significantly increased as the fasting glucose level elevated, even in populations with a normal glucose level range.
      PubDate: Wed, 24 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00033
      Issue No: Vol. 104, No. 10 (2019)
  • Association Between Statin Use and Sex Hormone in the Multi-Ethnic Study
           of Atherosclerosis Cohort
    • Authors: Oluleye O; Kronmal R, Folsom A, et al.
      Pages: 4600 - 4606
      Abstract: PurposeBased on the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, the number of individuals eligible for statin therapy to reduce atherosclerotic cardiovascular disease risk has greatly expanded. Statins inhibit cholesterol biosynthesis, which can impair gonadal steroidogenesis. We evaluated the effect of statins on endogenous sex hormones in a large epidemiological study.MethodsA total of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants underwent the baseline examination. Of these, 6171 had measurements of serum sex hormones available: dehydroepiandrosterone (DHEA), SHBG, estradiol, and total and bioavailable testosterone. Multivariable linear regression models were used to assess the relationship of statin use with each sex hormone.ResultsA total of 345 women (17.4%) and 464 men (14.7%) were statin users (mean age, 67 years; 41% white, 29% black, 11% Chinese, and 19% Hispanic). Among the users vs nonusers of statins, the mean SHBG was 3.54 nmol/L (P < 0.01) lower in women and 3.37 nmol/L (P < 0.001) lower in men; the mean DHEA was 1.06 nmol/L (P < 0.05) lower in women and 0.70 nmol/L (P < 0.01) lower in men, after adjustment for potential confounders. With further propensity score adjustment, the mean DHEA and SHBG levels were 0.67 nmol/L (P < 0.05) and 3.49 nmol/L (P < 0.001) lower, respectively, for statin users vs nonusers. No statistically significant association was noted between estradiol, total testosterone, and bioavailable testosterone and statin use.ConclusionStatin users have lower levels of SHBG and DHEA. This is especially relevant owing to the increasing use of statin therapy.
      PubDate: Mon, 03 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00530
      Issue No: Vol. 104, No. 10 (2019)
  • Circulating Exosomes Activate Dendritic Cells and Induce Unbalanced CD4+ T
           Cell Differentiation in Hashimoto Thyroiditis
    • Authors: Cui X; Liu Y, Wang S, et al.
      Pages: 4607 - 4618
      Abstract: ObjectiveThis study explored whether circulating exosomes effectively participate in the inflammatory response in Hashimoto thyroiditis (HT).DesignExosomes were extracted from the serum of 30 patients with HT and 30 healthy control (HC) subjects. The expression of thyroperoxidase (TPO), thyroglobulin, high mobility group box 1 (HMGB1), heat shock protein 60 (HSP60), major histocompatibility complex class II (MHC-II), and intercellular adhesion molecule 1 (ICAM1) in exosomes was determined by Western blotting. Flow cytometry and immunofluorescence were performed to confirm that exosomes were taken up by healthy peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs). Then, either DCs or PBMCs were stimulated with HT exosomes (serum exosomes from patients with HT) or HC exosomes (serum exosomes from HC subjects) in the presence or absence of Toll-like receptor (TLR)2/3 inhibitors.ResultsTPO, HSP60, and MHC-II expression was higher in HT exosomes than in HC exosomes. Exosomes were mainly taken up by CD14+ monocytes and CD11c+ DCs. After DCs were stimulated by HT exosomes, significant elevations were observed in MyD88, TRIF, and p-P65 expression; median fluorescence intensity of CD40 and CD83; and IL-6 production. After stimulating PBMCs with HT exosomes, CD11c+TLR2+/TLR3+ and CD4+IFN-γ+Th1/IL-17A+Th17A cell percentages were significantly elevated, and CD4+CD25+Foxp3+ Treg cell percentage was significantly decreased. HT exosomes induced increased IL-17A and IFN-γ production, whereas IL-10 production was suppressed. However, addition of TLR2 or TLR3 inhibitor reversed most of the abovementioned results.ConclusionsOur study demonstrates that HT exosomes can present antigens to DCs and bind TLR2/3, causing DC activation via the nuclear factor κB signaling pathway, leading to an imbalance in CD4+ T lymphocyte differentiation, and potentially contributing to HT onset.
      PubDate: Fri, 14 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00273
      Issue No: Vol. 104, No. 10 (2019)
  • Antidepressants Reduced Risk of Mortality in Patients With Diabetes
           Mellitus: A Population-Based Cohort Study in Taiwan
    • Authors: Chen H; Yang Y, Chen K, et al.
      Pages: 4619 - 4625
      Abstract: ContextThe effect of antidepressant (ATD) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied, although comorbid depression is common in this population.ObjectiveTo explore the impact of ATDs on mortality among DM patients.DesignA retrospective cohort study in a national database.SettingThis population-based study used the National Health Insurance Research Database in Taiwan. Since 2000, we identified 53,412 cases of newly diagnosed patients with DM and depression. Patient cases were followed for assessing mortality until 2013.Main Outcome MeasureThe association between mortality and ATD use was explored adjusting for cumulative dosing.ResultsUsing the time-dependent Cox regression model, ATD use was associated with significantly reduced mortality among patients with DM [in the highest dose group: hazard ratio (HR), 0.65; 95% CI, 0.59 to 0.71]. Further analysis showed that differences in mortality existed across ATD categories: selective serotonin reuptake inhibitors (HR, 0.63; 95% CI, 0.56 to 0.71), serotonin-norepinephrine reuptake inhibitors (HR, 0.58; 95% CI, 0.44 to 0.78), norepinephrine-dopamine reuptake inhibitors (HR, 0.20; 95% CI, 0.07 to 0.63), mirtazapine (HR, 0.60; 95% CI, 0.45 to 0.82), tricyclic/tetracyclic antidepressants (HR, 0.73; 95% CI, 0.54 to 0.97), and trazodone (HR, 0.52; 95% CI, 0.29 to 0.91). However, reversible inhibitor of monoamine oxidase A (RIMA) was found to be associated with an increase, rather than a decrease, in total mortality (HR, 1.48; 95% CI, 1.09 to 1.99).ConclusionMost ATDs, but not RIMA, were associated with significantly reduced mortality among a population with comorbid DM and depression.
      PubDate: Tue, 02 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02362
      Issue No: Vol. 104, No. 10 (2019)
  • Letter to the Editor: “Suppressed ACTH Is Frequently Unrelated to
           Autonomous Cortisol Secretion in Patients With Adrenal Incidentalomas”
    • Authors: Nakhleh A; Shehadeh N, Saiegh L.
      Pages: 4626 - 4627
      Abstract: We read with great interest the article by Olsen et al. (1) in Journal of Clinical Endocrinology & Metabolism. This study highlights a group of patients with unilateral adrenal incidentaloma (AI), defined by suppressed ACTH despite normal cortisol suppression after a 1-mg overnight dexamethasone dose (LowACTH/ONDST<50), indicating ACTH suppression by another factor than autonomous cortisol secretion (ACS). The authors suggest that this factor may be an increased sensitivity of AI to ACTH, resulting in suppressed ACTH due to negative feedback in an otherwise intact hypothalamic-pituitary-adrenal (HPA) axis. However, ACTH stimulation tests were not performed to support this hypothesis.
      PubDate: Tue, 09 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00444
      Issue No: Vol. 104, No. 10 (2019)
  • Response to Letter to the Editor: “Suppressed ACTH Is Frequently
           Unrelated to Autonomous Cortisol Secretion in Patients With Adrenal
    • Authors: Olsen H; Kjellbom A, Löndahl M, et al.
      Pages: 4628 - 4629
      Abstract: We thank Nakhleh et al. for their comments on our article (1). The lower ACTH in patients with cortisol following an overnight dexamethasone suppression test (cortisolONDST) < 50 nM, compared with controls, could theoretically be caused by glucocorticoid receptor (GR) polymorphisms causing increased sensitivity of the receptor (1). However, previous studies have not supported this possibility. Tzanela et al. (2) found that patients with normal suppression of cortisol following dexamethasone suppression more often were carriers of the BCL 1 variant than patients with impaired suppression. However, BCL 1 carriers had similar ACTH as noncarriers (2). Damjanovic et al. (3) reported that the GR gene variants C allele of BCL 1 and minor allele of 9β are associated with unilateral adrenal incidentalomas (AIs), although they did not find any differences in ACTH between carriers and noncarriers. Majnik et al. (4) found that the carrier frequency for the N363S variant was markedly higher in patients with bilateral AI but not in those with unilateral AI. Finally, in the largest study, Reimondo et al. (5) studied 411 patients with AI and 186 blood donors and found that there were no differences in the GR polymorphisms between the two groups. Taken together, we find GR polymorphism an unlikely explanation for the lower ACTH in our patients.
      PubDate: Tue, 09 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00669
      Issue No: Vol. 104, No. 10 (2019)
  • Reduced Androgen Receptor Expression in Genital Skin Fibroblasts From
           Patients With 45,X/46,XY Mosaicism
    • Authors: Hornig N; Demiri J, Rodens P, et al.
      Pages: 4630 - 4638
      Abstract: ContextMolecular mechanisms causing the broad phenotypic diversity of external masculinization in individuals with 45,X/46,XY mosaicism are poorly understood.ObjectiveAnalysis of androgen receptor (AR) expression and function as a putative influencing factor for the genital phenotype in patients with 45,X/46,XY mosaicism.DesignMeasurement of AR mRNA expression levels, AR activity [DHT-mediated APOD (apolipoprotein D) induction] and cellular 45,X/46,XY ratios in genital skin fibroblasts from individuals with 45,X/46,XY mosaicism and male reference individuals, and determination of the external virilization scale from individuals with 45,X/46,XY mosaicism.SettingUniversity hospital endocrine research laboratory.Patients or Other Participants: 30 genital skin fibroblast cultures (GFs) from male reference individuals and 15 GFs from individuals with 45,X/46,XY mosaicism.InterventionNoneMain Outcome MeasuresDetermination of AR mRNA expression and AR activity in male reference GFs and 45,X/46,XY GFs and correlation of the obtained data with the cellular 45,X/46,XY ratios and the patients’ external virilization scale.ResultsIn 6 of 15 45,X/46,XY GFs, AR mRNA expression and AR activity were significantly lower compared with those in the 46,XY reference GFs. In this subgroup of reduced AR mRNA expression, a positive trend was seen between AR mRNA expression and the percentage of XY-positive cells. Furthermore, we found a positive correlation between AR activity and the external virilization scale in the 15 45,X/46,XY GF samples (P = 0.03).ConclusionOur results suggest that AR expression and AR activity might influence the phenotypic variability seen in patients with 45,X/46,XY mosaicism.
      PubDate: Mon, 10 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00108
      Issue No: Vol. 104, No. 10 (2019)
  • Exercise Mitigates Bone Loss in Women With Severe Obesity After Roux-en-Y
           Gastric Bypass: A Randomized Controlled Trial
    • Authors: Murai I; Roschel H, Dantas W, et al.
      Pages: 4639 - 4650
      Abstract: ContextBone loss after bariatric surgery potentially could be mitigated by exercise.ObjectiveTo investigate the role of exercise training (ET) in attenuating bariatric surgery–induced bone loss.DesignRandomized, controlled trial.SettingReferral center for bariatric surgery.PatientsSeventy women with severe obesity, aged 25 to 55 years, who underwent Roux-en-Y gastric bypass (RYGB).InterventionSupervised, 6-month, ET program after RYGB vs. standard of care (RYGB only).OutcomesAreal bone mineral density (aBMD) was the primary outcome. Bone microarchitecture, bone turnover, and biochemical markers were secondary outcomes.ResultsSurgery significantly decreased femoral neck, total hip, distal radius, and whole body aBMD (P < 0.001); and increased bone turnover markers, including collagen type I C-telopeptide (CTX), procollagen type I N-propeptide (P1NP), sclerostin, and osteopontin (P < 0.05). Compared with RYGB only, exercise mitigated the percent loss of aBMD at femoral neck [estimated mean difference (EMD), −2.91%; P = 0.007;], total hip (EMD, −2.26%; P = 0.009), distal radius (EMD, −1.87%; P = 0.038), and cortical volumetric bone mineral density at distal radius (EMD, −2.09%; P = 0.024). Exercise also attenuated CTX (EMD, −0.20 ng/mL; P = 0.002), P1NP (EMD, −17.59 ng/mL; P = 0.024), and sclerostin levels (EMD, −610 pg/mL; P = 0.046) in comparison with RYGB. Exercise did not affect biochemical markers (e.g., 25(OH)D, calcium, intact PTH, phosphorus, and magnesium).ConclusionExercise mitigated bariatric surgery–induced bone loss, possibly through mechanisms involving suppression in bone turnover and sclerostin. Exercise should be incorporated in postsurgery care to preserve bone mass.
      PubDate: Fri, 19 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00074
      Issue No: Vol. 104, No. 10 (2019)
  • Unique Pattern of N-Glycosylation, Sialylation, and Sulfonation on TSH
           Molecules in Serum of Children Up to 18 Months
    • Authors: Wide L; Eriksson K.
      Pages: 4651 - 4659
      Abstract: ContextN-glycosylation and glycan composition of human TSH molecules modulate the biological properties of TSH in different physiological and clinical situations. The degree of sialylation of serum TSH was reported to be very low in normal third-trimester fetuses compared with normal adults. The circulating TSH glycoforms and their glycan compositions in young children have hitherto not been determined.ObjectiveTo characterize N-glycosylation and glycan composition of circulating TSH molecules in young children.Design, Participants, Main Outcome MeasuresSerum samples were obtained from euthyroid individuals: 33 children, age 2 weeks to 3 years, and 264 adults. The di-glycosylated TSH and tri-glycosylated TSH glycoforms were determined and characterized with respect to sialylation and sulfonation. The TSH N-glycosylation was also examined in pituitary extracts of 75 individuals.ResultsIn children up to 18 months of age, most TSH molecules were low-N-glycosylated, high-sulfonated, and low-sialylated compared with older children and adults. The degree of N-glycosylation was similar in serum and pituitary extracts up to 3 months of age and after that was higher in serum than in pituitary extracts.ConclusionsChildren up to age 18 months had low-sialylated TSH molecules, similar to those reported for third-trimester fetuses. Most TSH molecules in young children were of smaller size and less negatively charged, favoring transport into their target tissues. The low sialylation favors a high biopotency at thyroid and extrathyroidal TSH receptors. A delayed development of the liver SO3-N-acetylgalactosamine receptor function after birth is a likely explanation of the highly sulfonated TSH molecules in serum samples of infants.
      PubDate: Thu, 06 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02576
      Issue No: Vol. 104, No. 10 (2019)
  • Global Consensus Position Statement on the Use of Testosterone Therapy for
    • Authors: Davis S; Baber R, Panay N, et al.
      Pages: 4660 - 4666
      Abstract: This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynecologists.**
      PubDate: Mon, 02 Sep 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-01603
      Issue No: Vol. 104, No. 10 (2019)
  • Familial X-Linked Acrogigantism: Postnatal Outcomes and Tumor Pathology in
           a Prenatally Diagnosed Infant and His Mother
    • Authors: Wise-Oringer B; Zanazzi G, Gordon R, et al.
      Pages: 4667 - 4675
      Abstract: ContextX-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs.Case DescriptionThe patient’s mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For more than 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During preconception planning, X-LAG was diagnosed: single-nucleotide polymorphism microarray showed chromosome Xq26.3 microduplication. After conception, single-nucleotide polymorphism microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother’s pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and pituitary-specific transcription factor-1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and octamer-binding transcription factor 4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index, 5.6% in the mother and 8.5% in the infant, the highest reported in X-LAG.ConclusionsThis is a prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.
      PubDate: Wed, 05 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00817
      Issue No: Vol. 104, No. 10 (2019)
  • Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other
           Clinical Features: A New Syndrome
    • Authors: Cohen M; Persky R, Stegemann R, et al.
      Pages: 4676 - 4682
      Abstract: BackgroundSomatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing genetic syndrome.Case DescriptionWe describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal surgery. Despite initial improvement, she developed recurrent CD.MethodsDNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma.ResultsA de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hot spot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma.ConclusionSomatic USP8 mutations are common in adenomas causing CD, but to date, no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8.
      PubDate: Tue, 04 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00697
      Issue No: Vol. 104, No. 10 (2019)
  • Bones and Joints: The Effects of Cannabinoids on the Skeleton
    • Authors: Ehrenkranz J; Levine M.
      Pages: 4683 - 4694
      Abstract: ContextThe endocannabinoid system uses tissue-specific lipid ligands and G protein‒coupled transmembrane receptors to regulate neurologic, metabolic, and immune responses. Recent studies demonstrate that the endocannabinoid system influences bone metabolism. With the increasing use of endocannabinoid mimetics (e.g., tetrahydrocannabinol and cannabidiol), the involvement of endocannabinoids in bone growth and remodeling has become clinically relevant.Evidence AcquisitionThis literature review is based on a search of PubMed and Google Scholar databases as of June 2019 for all English-language publications relating to cannabinoids and bone. We evaluated retrieved articles for relevance, experimental design, data acquisition, statistical analysis, and conclusions.Evidence SynthesisPreclinical studies establish a role for endocannabinoids in bone metabolism. These studies yield complex and often contradictory results attributed to differences in the specific experimental model examined. Studies using human cells or subjects are limited.ConclusionsIn vitro and animal models document that endocannabinoids are involved in bone biology. The relevance of these observations to humans is not clear. The increasing long-term use of medical and recreational cannabis underscores the need to better understand the role of endocannabinoids in human bone metabolism. Moreover, it is important to evaluate the role of endocannabinoids as a therapeutic target to prevent and treat disorders associated with bone loss.
      PubDate: Thu, 08 Aug 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00665
      Issue No: Vol. 104, No. 10 (2019)
  • KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After
           Adrenalectomy for Unilateral Primary Aldosteronism
    • Authors: Vilela L; Rassi-Cruz M, Guimaraes A, et al.
      Pages: 4695 - 4702
      Abstract: ContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear.ObjectiveTo determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.MethodsWe retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.ResultsKCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004).ConclusionThe presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.
      PubDate: Wed, 19 Jun 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00531
      Issue No: Vol. 104, No. 10 (2019)
  • Treatment of Primary Aldosteronism With mTORC1 Inhibitors
    • Authors: Trinh B; Hepprich M, Betz M, et al.
      Pages: 4703 - 4714
      Abstract: ContextMammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA.ObjectiveTo investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA.Design(i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout.Main Outcome Measures(i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters.ResultsTreatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients.ConclusionIn mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients.
      PubDate: Tue, 14 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00563
      Issue No: Vol. 104, No. 10 (2019)
  • Differential Levels of Regulatory T Cells and T-Helper-17 Cells in Women
           With Early and Advanced Endometriosis
    • Authors: Khan K; Yamamoto K, Fujishita A, et al.
      Pages: 4715 - 4729
      Abstract: ContextRegulatory T (Treg) cells and T-helper-17 (Th17) cells may be involved in endometriosis. Information on the pattern of change in the percentages of Treg and Th17 cells in the peripheral blood (PB) and peritoneal fluid (PF) of women with early and advanced endometriosis is unclear.ObjectiveTo investigate the pattern of change in the percentages of Treg and Th17 cells in the PB and PF of women with early and advanced endometriosis.MethodsWe recruited 31 women with laparoscopically and histologically confirmed, revised American Society of Reproductive Medicine stage I-II endometriosis, 39 women with stage III-IV endometriosis, and 36 control subjects without visible endometriosis. PB and PF samples were collected and T-cell subpopulations analyzed by flow cytometry using specific monoclonal antibodies recognizing CD4+, CD25+, FOXP3+, and IL-17A+ markers. PF concentrations of TGF-β and IL-17 were measured by ELISA.ResultsThe percentages of CD25+FOXP3+ Treg cells within the CD4+ T-cell population were significantly higher in the PF of women with advanced endometriosis than in either early endometriosis or in control subjects (P < 0.05 for both). A persistently lower percentage of CD4+IL-17A+ Th17 cells was found in both PB and PF of women with early and advanced endometriosis. Compared with IL-17 levels, PF levels of TGF-β were significantly higher in women with endometriosis (P = 0.01).ConclusionOur findings reconfirmed the current speculation that endometriosis is related to alteration of Treg and Th17 cells in the pelvis causing survival and implantation of ectopic endometrial lesions.
      PubDate: Wed, 01 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00350
      Issue No: Vol. 104, No. 10 (2019)
  • Treatment of Children With GH in the United States and Europe: Long-Term
           Follow-Up From NordiNet® IOS and ANSWER Program
    • Authors: Sävendahl L; Polak M, Backeljauw P, et al.
      Pages: 4730 - 4742
      Abstract: ContextUnderstanding real-world prescribing of GH may help improve treatment of eligible patients.ObjectiveOverall: to assess real-world effectiveness and safety of GH (Norditropin). This analysis: to compare clinical characteristics of GH-treated children in the United States and Europe.DesignThe American Norditropin Studies: Web-Enabled Research Program (ANSWER; 2002 to 2016, United States) and the NordiNet International Outcome Study (NordiNet IOS; 2006 to 2016, Europe) were multicenter longitudinal observational cohort studies.SettingData were recorded in 207 (United States) and 469 (Europe) clinics.ParticipantsPatients with GH deficiency, Turner syndrome, Noonan syndrome, idiopathic short stature, Prader–Willi syndrome, or born small for gestational age, who commenced GH treatment aged <1 year.InterventionGH was prescribed by treating physicians according to local practice.Main Outcomes MeasuresBaseline data and drug doses were recorded. Data on effectiveness and safety were collected.ResultsANSWER had 19,847 patients in the full analysis set (FAS; patients with birthdate information and one or more GH prescription) and 12,660 in the effectiveness analysis set (EAS; GH-naive patients with valid baseline information). NordiNet IOS had 17,711 (FAS) and 11,967 (EAS). Boys accounted for 69% (ANSWER) and 57% (NordiNet IOS). Treatment start occurred later than optimal to improve growth. The proportion of boys treated was generally larger, children were older at treatment start, and GH doses were higher in the United States vs Europe. No new safety signals of concern were noted.ConclusionsIn most indications, more boys than girls were treated, and treatment started late. Earlier diagnosis of GH-related disorders is needed. The data support a favorable benefit–risk profile of GH therapy in children.
      PubDate: Mon, 15 Jul 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00775
      Issue No: Vol. 104, No. 10 (2019)
  • Obesity, Bariatric Surgery, and Fractures
    • Authors: Lespessailles E; Paccou J, Javier R, et al.
      Pages: 4756 - 4768
      Abstract: ContextObesity and its associated comorbidities are a recognized and growing public health problem. For a long time, obesity-associated effects on bone were considered to strengthen the bone, mainly because of the known relationship between body weight and bone mass and the long-term weight-bearing load effect on bone. However, recent epidemiologic studies have shown that obesity may not have a fully protective effect on the occurrence of fragility fractures. The goal of this article is to review updated information on the link between obesity, bariatric surgery, and fractures.MethodsThe primary source literature for this review was acquired by searching a published database for reviews and articles up to January 2018. Additional references were selected through the in-depth analysis of the relevant studies.ResultsWe present data showing that overweight and obesity are often encountered in fracture cases. We also analyzed possible reasons and risk factors for fractures associated with overweight and patients with obesity. In addition, this review focuses on the complex effects of dramatic changes in body composition when interpreting dual-energy X-ray absorptiometry readings and findings. Finally, we review the data on the effects and consequences of bariatric surgery on bone metabolism and the risk of fractures in patients undergoing these procedures.ConclusionBecause of various adiposity-induced effects, patients with obesity are at risk for fracture in certain sites. Bariatric surgery increases the risk of fractures in patients undergoing malabsorptive procedures.
      PubDate: Fri, 22 Mar 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02084
      Issue No: Vol. 104, No. 10 (2019)
  • Autoimmune Polyendocrinopathy
    • Authors: Frommer L; Kahaly G.
      Pages: 4769 - 4782
      Abstract: ContextThis mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments.Design and ResultsSystematic search for studies related to pathogenesis, immunogenetics, screening, diagnosis, clinical spectrum, and epidemiology of AP. AP (orphan code ORPHA 282196) is defined as the autoimmune-induced failure of at least two glands. AP is divided into the rare juvenile type I and the adult types II to IV. The prevalence is 1:100,000 and 1:20,000 for types I and types II to IV, respectively. Whereas type I (ORPHA 3453) is a monogenetic syndrome with an autosomal recessive transmission related to mutations in the autoimmune regulator (AIRE) gene, types II to IV are genetically complex multifactorial syndromes that are strongly associated with certain alleles of HLA genes within the major histocompatibility complex located on chromosome 6, as well as the cytotoxic T lymphocyte antigen 4 and the protein tyrosine phosphatase nonreceptor type 22 genes. Addison disease is the major endocrine component of type II (ORPHA 3143), whereas the coexistence of type 1 diabetes and autoimmune thyroid disease is characteristic for type III (ORPHA 227982). Genetic screening for the AIRE gene is useful in patients with suspected type I, whereas serological screening (i.e., diabetes/adrenal antibodies) is required in patients with monoglandular autoimmunity and suspected AP. If positive, functional endocrine testing of the antibody-positive patients as well as serological screening of their first-degree relatives is recommended.ConclusionTimely diagnosis, genetic counseling, and optimal long-term management of AP is best offered in specialized centers.
      PubDate: Fri, 26 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00602
      Issue No: Vol. 104, No. 10 (2019)
  • Elevated Lipoprotein(a) Levels Lower ABCA1 Cholesterol Efflux Capacity
    • Authors: Tavori H; Fenton A, Plubell D, et al.
      Pages: 4793 - 4803
      Abstract: ContextElevated serum lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular disease risk. ABCA1-mediated cholesterol efflux from macrophages may be an antiatherogenic process. Plasminogen (PLG) is a driver of ABCA1-mediated cholesterol efflux, and its action is inhibited by purified human Lp(a).ObjectiveTo determine the effects of Lp(a) in human serum on ABCA1 cholesterol efflux.MethodsCholesterol efflux capacity (CEC) was measured with two different cell-culture models using serum from 76 patients with either low (<50 mg/dL) or high (>50 mg/dL) Lp(a) levels.ResultsUsing cAMP-stimulated J774 macrophages or baby hamster kidney fibroblasts overexpressing human ABCA1, we show that CEC was lower in patients with high Lp(a) levels compared with patients with low levels (−30.6%, P = 0.002 vs −24.1%, P < 0.001, respectively). Total-serum CEC negatively correlated with Lp(a) levels (r = −0.433, P = 0.0007 vs r = −0.505, P = 0.0011, respectively). These negative associations persisted after adjusting for serum cholesterol, age, sex, and statin use in a multiple linear regression model (adjusted R2 = 0.413 or 0.405, respectively) and were strengthened when further adjusting for the interaction between Lp(a) and PLG levels (adjusted R2 = 0.465 and 0.409, respectively). Total-serum and isolated Lp(a) from patients with high Lp(a) inhibited PLG-mediated ABCA1 cholesterol efflux.ConclusionTotal-serum CEC is reduced in patients with high Lp(a) levels. This is in part due to the inhibition of PLG-mediated ABCA1 cholesterol efflux by Lp(a). Our findings suggest an atherogenic role for Lp(a) through its ability to inhibit CEC.
      PubDate: Tue, 09 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02708
      Issue No: Vol. 104, No. 10 (2019)
  • Acute Exercise Increases Plasma Levels of Muscle-Derived Microvesicles
           Carrying Fatty Acid Transport Proteins
    • Authors: Nielsen M; Sabaratnam R, Pedersen A, et al.
      Pages: 4804 - 4814
      Abstract: ContextMicrovesicles (MVs) are a class of membrane particles shed by any cell in the body in physiological and pathological conditions. They are considered to be key players in intercellular communication, and with a molecular content reflecting the composition of the cell of origin, they have recently emerged as a promising source of biomarkers in a number of diseases.ObjectiveThe effects of acute exercise on the plasma concentration of skeletal muscle-derived MVs (SkMVs) carrying metabolically important membrane proteins were examined.ParticipantsThirteen men with obesity and type 2 diabetes mellitus (T2DM) and 14 healthy male controls with obesity exercised on a cycle ergometer for 60 minutes.InterventionsMuscle biopsies and blood samples—obtained before exercise, immediately after exercise, and 3 hours into recovery—were collected for the analysis of long-chain fatty acid (LCFA) transport proteins CD36 (a scavenger receptor class B protein) and fatty acid transport protein 4 (FATP4) mRNA content in muscle and for flow cytometric studies on circulating SkMVs carrying either LCFA transport protein.ResultsBesides establishing a flow cytometric approach for the detection of circulating SkMVs and subpopulations carrying either CD36 or FATP4 and thereby adding proof to their existence, we demonstrated an overall exercise-induced change of SkMVs carrying these LCFA transport proteins. A positive correlation between exercise-induced changes in skeletal muscle CD36 mRNA expression and concentrations of SkMVs carrying CD36 was found in T2DM only.ConclusionsThis approach could add important real-time information about the abundance of LCFA transport proteins present on activated muscle cells in subjects with impaired glucose metabolism.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-02547
      Issue No: Vol. 104, No. 10 (2019)
  • Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in
           Relation to the Risk of Latent Autoimmune Diabetes in Adults and Type 2
    • Authors: Hjort R; Löfvenborg J, Ahlqvist E, et al.
      Pages: 4815 - 4826
      Abstract: ObjectiveWe investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes.MethodsWe pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI ≥ 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP).ResultsThe combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO.ConclusionsOverweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.
      PubDate: Fri, 24 May 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00183
      Issue No: Vol. 104, No. 10 (2019)
  • Plasma Free Cortisol in States of Normal and Altered Binding Globulins:
           Implications for Adrenal Insufficiency Diagnosis
    • Authors: Dichtel L; Schorr M, Loures de Assis C, et al.
      Pages: 4827 - 4836
      Abstract: ContextAccurate diagnosis of adrenal insufficiency is critical because there are risks associated with overdiagnosis and underdiagnosis. Data using liquid chromatography tandem mass spectrometry (LC/MS/MS) free cortisol (FC) assays in states of high or low cortisol-binding globulin (CBG) levels, including cirrhosis, critical illness, and oral estrogen use, are needed.DesignCross-sectional.ObjectiveDetermine the relationship between CBG and albumin as well as total cortisol (TC) and FC in states of normal and abnormal CBG. Establish the FC level by LC/MS/MS that best predicts TC of <18 μg/dL (497 nmol/L) (standard adrenal insufficiency diagnostic cutoff) in healthy individuals.SubjectsThis study included a total of 338 subjects in four groups: healthy control (HC) subjects (n = 243), patients with cirrhosis (n = 38), intensive care unit patients (ICU) (n = 26), and oral contraceptive (OCP) users (n = 31).Main Outcome Measure(s)FC and TC by LC/MS/MS, albumin by spectrophotometry, and CBG by ELISA.ResultsTC correlated with FC in the ICU (R = 0.91), HC (R = 0.90), cirrhosis (R = 0.86), and OCP (R = 0.70) groups (all P < 0.0001). In receiver operator curve analysis in the HC group, FC of 0.9 μg/dL (24.8 nmol/L) predicted TC of <18 μg/dL (497 nmol/L; 98% sensitivity, 91% specificity; AUC, 0.98; P < 0.0001). Decreasing the cutoff to 0.7 μg/dL led to a small decrease in sensitivity (92%) with similar specificity (91%).ConclusionsA cutoff FC of <0.9 μg/dL (25 nmol/L) in this LC/MS/MS assay predicts TC of <18 μg/dL (497 nmol/L) with excellent sensitivity and specificity. This FC cutoff may be helpful in ruling out adrenal insufficiency in patients with binding globulin derangements.
      PubDate: Mon, 22 Apr 2019 00:00:00 GMT
      DOI: 10.1210/jc.2019-00022
      Issue No: Vol. 104, No. 10 (2019)
  • Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency
           and Cognitive Dysfunction in Older Adults
    • Authors: Porter K; Ward M, Hughes C, et al.
      Pages: 4837 - 4847
      Abstract: ContextEmerging evidence suggests that deficiencies of folate-related B vitamins can arise with metformin treatment and are independently linked with cognitive dysfunction, a comorbidity of diabetes.ObjectiveTo determine the impact of hyperglycemia and metformin use on relevant B vitamin biomarkers and cognitive outcomes in older adults.Setting and ParticipantsCommunity-dwelling older adults (74.1 ± 8.3 years, n = 4160) without dementia, recruited to the Trinity, Ulster and Department of Agriculture cohort study in 2008 to 2012, were classified as normoglycemic (n = 1856) or hyperglycemic, based on HbA1c ≥5.7% (39 mmol/mol), either with (n = 318) or without (n = 1986) metformin treatment.Main Outcome MeasuresBiomarkers of folate, vitamin B12, vitamin B6, and riboflavin were measured. Cognitive assessments included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and the Frontal Assessment Battery (FAB).ResultsMetformin use was associated with higher risk of deficiency of vitamin B12 (combined B12 index ≤−1; OR 1.45; 95% CI, 1.03 to 2.02) and vitamin B6 (plasma pyridoxal 5-phosphate <30.0 nmol/L; OR 1.48; 95% CI, 1.02 to 2.15). Fortified foods when eaten regularly had a positive impact on all relevant B vitamin biomarkers, even with hyperglycemia. After adjustment for relevant covariates, metformin use was associated with an increased risk of cognitive dysfunction as assessed with the RBANS (OR 1.36; 95% CI, 1.03 to 1.80) and FAB (OR 1.34; 95% CI, 1.03 to 1.74).ConclusionsUse of metformin by older adults is associated with poorer cognitive performance; B vitamin deficiency may be implicated. Fortified foods can optimize B vitamin status and may be beneficial for maintaining better cognitive health in older people with or at risk for diabetes.
      PubDate: Thu, 28 Mar 2019 00:00:00 GMT
      DOI: 10.1210/jc.2018-01791
      Issue No: Vol. 104, No. 10 (2019)
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