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Journal Cover Journal of Clinical Endocrinology & Metabolism
  [SJR: 2.94]   [H-I: 287]   [165 followers]  Follow
   Full-text available via subscription Subscription journal
   ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
   Published by Endocrine Society, The Homepage  [4 journals]
  • Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine
           Society* Clinical Practice Guideline
    • Authors: Martin K; Anderson R, Chang R, et al.
      Pages: 1233 - 1257
      Abstract: ObjectiveTo update the “Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2008.ParticipantsThe participants include an Endocrine Society–appointed task force of seven medical experts and a methodologist.EvidenceThis evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.Consensus ProcessGroup meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines.ConclusionWe suggest testing for elevated androgen levels in all women with an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen–progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation.
      PubDate: Wed, 07 Mar 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00241
      Issue No: Vol. 103, No. 4 (2018)
  • Treatment Options for Hirsutism: A Systematic Review and Network
    • Authors: Barrionuevo P; Nabhan M, Altayar O, et al.
      Pages: 1258 - 1264
      Abstract: BackgroundSeveral pharmacologic treatments for hirsutism are used in practice; however, their relative efficacy is unclear.MethodsWe searched MEDLINE, EMBASE, and CENTRAL through January 2017 for randomized controlled trials (RCTs) with follow-up of at least 6 months that evaluated antiandrogens, insulin sensitizers, and oral contraceptives in women with hirsutism. Independent pairs of reviewers selected and appraised trials. Random-effects network meta-analysis was used to compare individual drugs and classes.ResultsWe included 43 trials. Estrogen-progestin oral contraceptives pills (OCPs), antiandrogens, and insulin sensitizers were superior to placebo, with standardized mean reductions (95% confidence intervals) of −0.94 (−1.49 to −0.38), −1.29 (−1.80 to −0.79), and −0.62 (−1.00 to −0.23), respectively. Antiandrogen monotherapy, the combination of OCP and antiandrogen, the combination of OCPs and insulin sensitizer, and the combination of antiandrogen and insulin sensitizer were superior to insulin sensitizer monotherapy. The combination of OCPs and antiandrogen was superior to OCPs. Antiandrogen monotherapy with flutamide, finasteride, and spironolactone were each superior to placebo but similar to each other in efficacy. OCPs containing levonorgestrel, cyproterone acetate, or drospirenone were similar in effectiveness to other OCPs or had trivial differences. The certainty in comparisons with placebo was moderate and for head-to-head comparisons was low.ConclusionsEstrogen-progestin OCPs, antiandrogens, and insulin sensitizers are superior to placebo for the treatment of hirsutism.
      PubDate: Wed, 07 Mar 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02052
      Issue No: Vol. 103, No. 4 (2018)
  • Preventing Hypoglycemia in Type 2 Diabetes
    • Authors: Lash R; Lucas D, Illes J.
      Pages: 1265 - 1268
      Abstract: The Society and Avalere Health are working to develop and test interventions in clinical settings that will improve early identification and management of T2D patients at high risk for hypoglycemia.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02804
      Issue No: Vol. 103, No. 4 (2018)
  • A Homozygous RET K666N Genotype With an MEN2A Phenotype
    • Authors: Jaber T; Hyde S, Cote G, et al.
      Pages: 1269 - 1272
      Abstract: ContextGermline RET K666N mutation has been described as a pathogenic mutation with low disease penetrance for medullary thyroid cancer (MTC) without other features of multiple endocrine neoplasia type 2A. We describe a patient with homozygous RET K666N mutation with MTC and bilateral pheochromocytoma (PHEO).Case DescriptionA 59-year-old woman received a diagnosis of MTC after biopsy of two thyroid nodules. Coincident biochemical and radiologic testing was suspicious for bilateral PHEO, confirmed after bilateral adrenalectomy. There was no evidence of primary hyperparathyroidism (PHPT). She had a total thyroidectomy with neck dissection revealing bilateral MTC with lymph node metastases. Germline RET testing identified homozygous K666N mutations. Genetic testing of family members showed that both adult children harbor a heterozygous K666N mutation. Her 32-year-old son had an elevated calcitonin level and underwent thyroidectomy, which identified MTC. Her 30-year-old daughter had a normal calcitonin level. Prophylactic thyroidectomy showed C-cell hyperplasia only. Three of seven other family members were tested and found to carry the mutation. All had normal calcitonin levels, and none had biochemical evidence of PHEO or PHPT. Given the absence of PHEO in reported RET K666N families, our proband underwent genetic testing for causes of hereditary paragangliomas or PHEO. No additional mutations were identified.ConclusionsHere we report a case of a homozygous RET K666N mutation leading to coincident MTC and PHEO. Heterozygous presentations of RET K666N mutations have low penetrance for isolated MTC. We believe that the gene dosage associated with the homozygosity of this variant contributed to the occurrence of bilateral PHEO.
      PubDate: Fri, 02 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02402
      Issue No: Vol. 103, No. 4 (2018)
  • Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs
           Adolescent Puberty: Human Genetic Evidence
    • Authors: Shahab M; Lippincott M, Chan Y, et al.
      Pages: 1273 - 1276
      Abstract: ContextHypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders.Case DescriptionA missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone.ConclusionThis case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone–induced luteinizing hormone secretion than does adolescent puberty.
      PubDate: Wed, 14 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02636
      Issue No: Vol. 103, No. 4 (2018)
  • Pioglitazone Therapy of PAX8-PPARγ Fusion Protein Thyroid Carcinoma
    • Authors: Giordano T; Haugen B, Sherman S, et al.
      Pages: 1277 - 1281
      Abstract: ContextA subset of thyroid carcinomas expresses an oncogenic paired box 8 (PAX8) and peroxisome proliferator activated receptor γ (PPARγ) fusion protein (PPFP). The PPARγ/PPFP ligand pioglitazone is highly therapeutic in a transgenic mouse model of PPFP thyroid carcinoma, but whether pioglitazone is therapeutic in patients with PPFP thyroid carcinoma is unknown.Case DescriptionTumor blocks from 40 patients with progressive thyroid cancer despite standard-of-care therapy were screened for PPFP, and the tumor from only one patient (2.5%) was positive. The patient had a 6.0-cm acetabular soft tissue metastasis from Hürthle cell carcinoma that caused severe pain on weight bearing and had a serum thyroglobulin level of 1974 ng/mL. After 24 weeks of therapy with pioglitazone, the metastatic lesion was 3.9 cm, the thyroglobulin level was 49.4 ng/mL, and the patient was pain-free. Thirteen months after discontinuation of pioglitazone, the metastatic lesion was 3.6 cm, the thyroglobulin level was 4.7 ng/mL, and the patient remained pain-free.ConclusionsPioglitazone may be therapeutic in patients with PPFP thyroid cancer. However, thyroid cancers that are progressive despite standard-of-care therapy appear to only rarely express PPFP.
      PubDate: Wed, 24 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02533
      Issue No: Vol. 103, No. 4 (2018)
  • Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related
    • Authors: Khosla S; Farr J, Kirkland J.
      Pages: 1282 - 1290
      Abstract: ContextWith the aging of the population and projected increase in osteoporotic fractures coupled with the declining use of osteoporosis medications, there is a compelling need for new approaches to treat osteoporosis. Given that age-related osteoporosis generally coexists with multiple other comorbidities (e.g., atherosclerosis, diabetes, frailty) that share aging as the leading risk factor, there is growing interest in the “Geroscience Hypothesis,” which posits that manipulation of fundamental aging mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share aging as the underlying risk factor. In this context, one fundamental aging mechanism that has received considerable attention recently as contributing to multiple age-related morbidities is cellular senescence. This mini-review provides an overview on cellular senescence with a focus on its role in mediating age-related bone loss.MethodsThis summary is based on the authors’ knowledge of the field supplemented by a PubMed search using the terms “senescence,” “aging,” and “bone.”ResultsThere is compelling evidence from preclinical models and supportive human data demonstrating an increase in senescent cells in the bone microenvironment with aging. These cells produce a proinflammatory secretome that leads to increased bone resorption and decreased bone formation, and approaches that either eliminate senescent cells or impair the production of their proinflammatory secretome have been shown to prevent age-related bone loss in mice.ConclusionsTargeting cellular senescence represents a novel therapeutic strategy to prevent not only bone loss but potentially multiple age-related diseases simultaneously.
      PubDate: Wed, 07 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02694
      Issue No: Vol. 103, No. 4 (2018)
  • Nonthyroidal Illness Syndrome and Thyroid Hormone Actions at Integrin
    • Authors: Hercbergs A; Mousa S, Davis P.
      Pages: 1291 - 1295
      Abstract: ContextThe nonthyroidal illness syndrome (NTIS) is a constellation of changes in circulating thyroid hormone levels that occur in euthyroid patients with acute or chronic systemic diseases. The changes that occur include a reduction in serum T3, an increase in serum rT3, and variable changes in circulating T4 levels. No consensus exists regarding therapeutic intervention for NTIS.MethodsWe briefly review the published literature on the physiological actions of T4 and of rT3—hormones that until recently have been seen to have little or no bioactivity—and analyze the apparent significance of changes in circulating T4 and T3 encountered in the setting of NTIS in patients with cancer. In the case of T4, these actions may be initiated at a cancer or endothelial cell plasma membrane receptor on integrin αvβ3 or at the cytoskeleton.ResultsThis review examines possible therapeutic intervention in NTIS in patients with cancer in terms of T4 reduction and T3 support. Evidence also exists that rT3 may support cancer.ConclusionsProspective study is proposed of pharmacological reduction of normal or elevated T4 in cancer-associated NTIS. We also support investigation of normally circulating levels of T3 in such patients.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01939
      Issue No: Vol. 103, No. 4 (2018)
  • Recent Topics Around Multiple Endocrine Neoplasia Type 1
    • Authors: Marx S.
      Pages: 1296 - 1301
      Abstract: IntroductionMultiple endocrine neoplasia type 1 (MEN1) is complex with regard to clinical expressions, management, and molecular pathways. Advances are being made broadly and in focused aspects. Selected topics are presented for their developments since publication of the most recent MEN1 consensus guidelines 6 years ago.MethodsTopics were selected for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews.ResultsThe selected topics are as follows: tumor behavior and breast cancer in MEN1; foregut neuroectoderm tumor screening, biomarkers periodically to detect tumor emergence of foregut neuroectoderm tumors, 68Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal neuroectodermal tumor imaging, and glucagon-like peptide-1 receptor scintigraphy for insulinoma; therapy, the size of pancreatic neuroendocrine tumor (NET) as one criterion for surgery, minimally invasive surgery of pancreatic NETs, and 177Lu dotatate therapy; MEN1 gene, the search for the MEN1/menin pathway and MEN1 or GCM2 mutation in familial isolated hyperparathyroidism, and MEN1 mutation-positive vs mutation-negative cases of MEN1 are different.ConclusionsMEN1 topics are a rich and fast-moving area. Important highlights stand out, and major and rapid advances will continue into the near future.
      PubDate: Fri, 06 Apr 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02340
      Issue No: Vol. 103, No. 4 (2018)
  • Effect of Teriparatide Treatment on Circulating Periostin and Its
           Relationship to Regulators of Bone Formation and BMD in Postmenopausal
           Women With Osteoporosis
    • Authors: Gossiel F; Scott J, Paggiosi M, et al.
      Pages: 1302 - 1309
      Abstract: ContextTreatment of postmenopausal osteoporosis with teriparatide parathyroid hormone amino terminal 1-34 increases bone formation and improves bone microarchitecture. A possible modulator of action is periostin. In vitro experiments have shown that periostin might regulate osteoblast differentiation and bone formation through Wnt signaling. The effect of teriparatide on periostin is not currently known.ObjectivesTo determine the effect of teriparatide treatment on circulating levels of periostin and other regulators of bone formation and investigate how changes in periostin relate to changes in bone turnover markers, regulators of bone formation, and bone mineral density (BMD).Participants and DesignTwenty women with osteoporosis; a 2-year open-label single-arm study.InterventionTeriparatide 20 µg was administered by subcutaneous injection daily for 104 weeks. Periostin, sclerostin, and Dickkopf-related protein 1, procollagen type I N-terminal propeptide (PINP), and C-telopeptide of type I collagen were measured in fasting serum collected at baseline (two visits) and then at weeks 1, 2, 4, 12, 26, 52, 78, and 104. BMD was measured at the lumbar spine, total hip, and femoral neck using dual energy x-ray absorptiometry.ResultsPeriostin levels increased by 6.6% [95% confidence interval (CI), −0.4 to 13.5] after 26 weeks of teriparatide treatment and significantly by 12.5% (95% CI, 3.3 to 21.0; P < 0.01) after 52 weeks. The change in periostin correlated positively with the change in the lumbar spine BMD at week 52 (r = 0.567; 95% CI, 0.137 to 0.817; P < 0.05) and femoral neck BMD at week 104 (r = 0.682; 95% CI, 0.261 to 0.885; P < 0.01).ConclusionsTeriparatide therapy increases periostin secretion; it is unclear whether this increase mediates the effect of the drug on bone.
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-00283
      Issue No: Vol. 103, No. 4 (2018)
  • The Second Phase of Insulin Secretion in Nondiabetic Islet-Grafted
           Recipients Is Altered and Can Predict Graft Outcome
    • Authors: Villard O; Brun J, Bories L, et al.
      Pages: 1310 - 1319
      Abstract: ContextIslet transplantation (IT) can treat patients with severely unstable type 1 diabetes. Prehepatic kinetics of insulin secretion (ISec) in two phases can be calculated by C-peptide levels during meal tests. We proposed to describe the ISec profile after a mixed-meal tolerance test (MMTT) in IT recipients and to determine whether the calculated ISec indexes can predict graft outcome.MethodsWe analyzed 34 MMTT among 11 patients who underwent IT between 2011 and 2016 and compared them with healthy controls and patients with type 2 diabetes (T2D). ISec indexes and insulin sensitivity were calculated from models of Van Cauter, Breda, and Mari after MMTT. Graft success was defined by total insulin independence without any criteria for diabetes.ResultsIn patients with successful IT, the first- and second-phase ISec indexes were lower than those of controls (P < 0.001) and did not differ from those of the T2D group. Nevertheless, insulin sensitivity of IT recipients was similar to that of the control group and higher than that of the T2D group. The index of the second phase of ISec ɸS was correlated with total infused islet equivalents (IEQs), was a good predictor of diabetes (re)occurrence, and allowed us to calculate 9500 IEQ/kg as the minimum needed to reach insulin independence.ConclusionWe showed that indexes from the first and second phases of ISec are altered in insulin-independent IT recipients. Higher sensitivity distinguishes them from patients with T2D. Even in insulin-independent patients, IT remains a marginal mass model. Moreover, ɸS can estimate transplanted islet mass and predict IT recipient outcomes.
      PubDate: Mon, 08 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01342
      Issue No: Vol. 103, No. 4 (2018)
  • Two Novel MicroRNA Biomarkers Related to β-Cell Damage and Their
           Potential Values for Early Diagnosis of Type 1 Diabetes
    • Authors: Liu L; Yan J, Xu H, et al.
      Pages: 1320 - 1329
      Abstract: ContextNew strategies and biomarkers are needed in the early detection of β-cell damage in the progress of type 1 diabetes mellitus (T1DM).ObjectiveTo explore whether serum microRNAs (miRNA) should be served as biomarkers for T1DM.Design, Settings, and PatientsThe miRNA profile was established with miRNA microarray in discovery phase (six T1DM, six controls). A miRNA-based model for T1DM diagnosis was developed using logistic regression analysis in the training dataset (40 T1DM, 56 controls) and then validated with leave-one-out cross validation and another independent validation dataset (33 T1DM, 29 controls).Main Outcome MeasuresQuantitative reverse transcription polymerase chain reaction was applied to confirm the differences of candidate miRNAs between T1DM and controls. Area under the receiver-operating characteristic (ROC) curve (AUC) was used to evaluate diagnostic accuracy. INS-1 cells, streptozotocin-treated mice (n = 4), and nonobese diabetic (NOD) mice (n = 12) were used to evaluate the association of miRNAs with β-cell damage.ResultsA miRNA -based model was established in the training dataset with high diagnostic accuracy for T1DM (AUC = 0.817) based on six candidate differential expressed miRNAs identified in discovery phase. The validation dataset showed the model’s satisfactory diagnostic performance (AUC = 0.804). Secretions of miR-1225-5p and miR-320c were significantly increased in streptozotocin-treated mice and INS-1 cells. Noteworthy, the elevation of these two miRNAs was observed before glucose elevation in the progress of diabetes in NOD mice.ConclusionsTwo miRNA biomarkers (miR-1225-5p and miR-320c) related to β-cell damage were identified in patients with recent-onset T1DM. The miRNA-based model established in this study exhibited a good performance in diagnosis of T1DM.
      PubDate: Tue, 23 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01417
      Issue No: Vol. 103, No. 4 (2018)
  • TSH and FT4 Concentrations in Congenital Central Hypothyroidism and Mild
           Congenital Thyroidal Hypothyroidism
    • Authors: Zwaveling-Soonawala N; van Trotsenburg A, Verkerk P.
      Pages: 1342 - 1348
      Abstract: ContextIn central hypothyroidism (CeH), free thyroxine (FT4) concentrations are low, whereas thyrotropin (TSH) concentrations may be low, normal, or even slightly elevated due to reduced bioactivity. Congenital CeH (CCeH) may be isolated or part of multiple pituitary hormone deficiencies (MPHD).ObjectiveWe tested our hypotheses that (1) TSH concentrations have a more U-shaped distribution in children with CCeH compared with children with a normally functioning hypothalamic-pituitary-thyroid axis and (2) TSH concentrations in children with CCeH with MPHD are higher compared with children with isolated CCeH. We also studied whether FT4 levels are helpful in distinguishing CCeH from mild congenital hypothyroidism of thyroidal origin (CH-T).MethodsDutch neonatal screening TSH and first diagnostic TSH and FT4 were analyzed in all children diagnosed with permanent CCeH between 1995 and 2012. Controls were children with T4-binding globulin deficiency. FT4 concentrations in CCeH were compared with those in CH-T with TSH values in the same range as those of CCeH.ResultsWe studied 120 children with CCeH (isolated CCeH, n = 50; MPHD, n = 70) and 350 control subjects. Screening TSH concentrations were not significantly different (P = 0.055), but diagnostic TSH values were significantly different between the CCeH group and the control group (P = 0.037). TSH was significantly higher in MPHD compared with isolated CCeH (P = 0.004). FT4 concentrations were significantly lower in CCeH compared with mild CH-T (P < 0.0005).ConclusionTSH values in CCeH have a more U-shaped distribution compared with controls with the highest TSH concentrations in MPHD. FT4 levels were significantly lower in CCeH compared with CH-T.
      PubDate: Tue, 09 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01577
      Issue No: Vol. 103, No. 4 (2018)
  • Predictive Value of Malignancy of Thyroid Nodule Ultrasound Classification
           Systems: A Prospective Study
    • Authors: Persichetti A; Di Stasio E, Guglielmi R, et al.
      Pages: 1359 - 1368
      Abstract: ContextBritish Thyroid Association (BTA), American Thyroid Association (ATA), and American Association of Clinical Endocrinologists (AACE/ACE/AME) recommend for thyroid nodules an ultrasound (US)-based stratification of risk of malignancy. Aim of our study was to assess the diagnostic accuracy of US classification systems and their reliability for indication to fine-needle aspiration (FNA).DesignProspective study on 987 thyroid nodules consecutively referred for FNA. US images were independently reviewed by four experts for assignment of malignancy risk. Cytologically benign nodules had confirmation with a second FNA, whereas Bethesda class IV, V, and VI nodules were operated upon. Class III nodules had surgery or follow-up on the basis of clinical, immunocytochemical, and US features.ResultsBTA: Malignancy rate was 2.8% in benign, 10.0% in indeterminate, 51.3% in suspicion, and 80.9% in malignant US class. Sensitivity was 0.74, specificity was 0.92, and accuracy was 0.89. ATA: Malignancy rate was 0.0% in benign, 2.2% in very low suspicion, 3.0% in low suspicion, 5.8% in intermediate, and 55.0% in high suspicion US class. Sensitivity was 0.81, specificity was 0.87, and accuracy was 0.86. AACE/ACE/AME: Malignancy rate was 1.1% in low-risk, 4.4% in intermediate-risk, and 54.9% in high-risk US class. Sensitivity was 0.82, specificity was 0.87, and accuracy was 0.86. K correlation coefficient was 78.9%, 76.9%, and 82.0% for BTA, ATA, and AACE/ACE/AME classifications.ConclusionsClassification systems had elevated predictive value of malignancy in high-risk classes. ATA and AACE/ACE/AME systems were effective for ruling out indication to FNA in low-US-risk nodules. A similar diagnostic accuracy and a substantial interobserver agreement was provided by the three- and the five-category classifications.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01708
      Issue No: Vol. 103, No. 4 (2018)
  • Transethnic Evaluation Identifies Low-Frequency Loci Associated With
           25-Hydroxyvitamin D Concentrations
    • Authors: Hong J; Hatchell K, Bradfield J, et al.
      Pages: 1380 - 1392
      Abstract: ContextVitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry.ObjectiveThe Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries.DesignAncestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL).Patients or Other ParticipantsIn total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study.Main Outcome MeasuresBlood concentrations of 25(OH)D were measured for all participants.ResultsAncestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.ConclusionsAncestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
      PubDate: Tue, 09 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01802
      Issue No: Vol. 103, No. 4 (2018)
  • Insulin and Estrogen Independently and Differentially Reduce Macronutrient
           Intake in Healthy Men
    • Authors: Krug R; Mohwinkel L, Drotleff B, et al.
      Pages: 1393 - 1401
      Abstract: ContextInsulin administration to the central nervous system inhibits food intake, but this effect has been found to be less pronounced in female compared with male organisms. This sex-specific pattern has been suggested to arise from a modulating influence of estrogen signaling on the insulin effect.ObjectiveWe assessed in healthy young men whether pretreatment with transdermal estradiol interacts with the hypophagic effect of central nervous insulin administration via the intranasal pathway.Design, Setting, Participants, and InterventionAccording to a 2×2 design, two groups of men (n = 16 in each group) received a 3-day transdermal estradiol (100 µg/24 h) or placebo pretreatment and on two separate mornings were intranasally administered 160 IU regular human insulin or placebo.Main Outcome MeasuresWe assessed free-choice ad libitum calorie intake from a rich breakfast buffet and relevant blood parameters in samples collected before and after breakfast.ResultsEstrogen treatment induced a 3.5-fold increase in serum estradiol concentrations and suppressed serum testosterone concentrations by 70%. Independent of estradiol administration, intranasal insulin reduced the intake of carbohydrates during breakfast, attenuating in particular the consumption of sweet, palatable foods. Estradiol treatment per se decreased protein consumption. We did not find indicators of eating-related interactions between both hormones.ConclusionsResults indicate that, in an acute setting, estrogen does not interact with central nervous insulin signaling in the control of eating behavior in healthy men. Insulin and estradiol rather exert independent inhibiting effects on macronutrient intake.
      PubDate: Fri, 12 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01835
      Issue No: Vol. 103, No. 4 (2018)
  • Empagliflozin Treatment Is Associated With Improved β-Cell Function
           in Type 2 Diabetes Mellitus
    • Authors: Al Jobori H; Daniele G, Adams J, et al.
      Pages: 1402 - 1407
      Abstract: ObjectiveTo examine whether lowering plasma glucose concentration with the sodium-glucose transporter-2 inhibitor empagliflozin improves β-cell function in patients with type 2 diabetes mellitus (T2DM).MethodsPatients with T2DM (N = 15) received empagliflozin (25 mg/d) for 2 weeks. β-Cell function was measured with a nine-step hyperglycemic clamp (each step, 40 mg/dL) before and at 48 hours and at 14 days after initiating empagliflozin.ResultsGlucosuria was recorded on days 1 and 14 [mean ± standard error of the mean (SEM), 101 ± 10 g and 117 ± 11 g, respectively] after initiating empagliflozin, as were reductions in fasting plasma glucose levels (25 ± 6 mg/dL and 38 ± 8 mg/dL, respectively; both P < 0.05). After initiating empagliflozin and during the stepped hyperglycemic clamp, the incremental area under the plasma C-peptide concentration curve increased by 48% ± 12% at 48 hours and 61% ± 10% at 14 days (both P < 0.01); glucose infusion rate increased by 15% on day 3 and 16% on day 14, compared with baseline (both P < 0.05); and β-cell function, measured with the insulin secretion/insulin resistance index, increased by 73% ± 21% at 48 hours and 112% ± 20% at 14 days (both P < 0.01). β-cell glucose sensitivity during the hyperglycemic clamp was enhanced by 42% at 14 hours and 54% at 14 days after initiating empagliflozin (both P < 0.01).ConclusionLowering the plasma glucose concentration with empagliflozin in patients with T2DM augmented β-cell glucose sensitivity and improved β-cell function.
      PubDate: Fri, 12 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01838
      Issue No: Vol. 103, No. 4 (2018)
  • Impact of C-Peptide Status on the Response of Glucagon and Endogenous
           Glucose Production to Induced Hypoglycemia in T1DM
    • Authors: Zenz S; Mader J, Regittnig W, et al.
      Pages: 1408 - 1417
      Abstract: ContextComplete loss of β-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia.ObjectiveWe aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycemia in patients with T1DM.Design and SettingWe conducted an open, comparative trial.PatientsTen C-peptide positive (C-pos) and 11 matched C-peptide negative (C-neg) patients with T1DM were enrolled.InterventionPlasma glucose was normalized over the night fast, and after a steady-state (baseline) plateau all patients underwent a hyperinsulinemic, stepwise hypoglycemic clamp with glucose plateaus of 5.5, 3.5, and 2.5 mmol/L and a recovery phase of 4.0 mmol/L. Blood glucagon was measured with a specific and highly sensitive glucagon assay. EGP was determined with a stable isotope tracer technique.Main Outcome MeasureImpact of C-peptide status on glucagon response and EGP during hypoglycemia.ResultsGlucagon concentrations were significantly lower in C-pos and C-neg patients than previously reported. At baseline, C-pos patients had higher glucagon concentrations than C-neg patients (8.39 ± 4.6 vs 4.19 ± 2.4 pmol/L, P = 0.016, mean ± standard deviation) but comparable EGP rates (2.13 ± 0.2 vs 2.04 ± 0.3 mg/kg/min, P < 0.391). In both groups, insulin suppressed glucagon levels, but hypoglycemia revealed significantly higher glucagon concentrations in C-pos than in C-neg patients. EGP was significantly higher in C-pos patients at hypoglycemia (2.5 mmol/L) compared with C-neg patients.ConclusionsGlucagon concentrations and EGP during hypoglycemia were more pronounced in C-pos than in C-neg patients, which indicates that preserved β-cell function may contribute to counterregulation during hypoglycemia in patients with T1DM.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01836
      Issue No: Vol. 103, No. 4 (2018)
  • Postnatal Changes in Testicular Position Are Associated With IGF-I and
           Function of Sertoli and Leydig Cells
    • Authors: Koskenniemi J; Virtanen H, Wohlfahrt-Veje C, et al.
      Pages: 1429 - 1437
      Abstract: ContextDespite clinical guidelines calling for repetitive examination of testicular position during childhood, little is known of normal changes in testicular position during childhood, let alone factors that control it.ObjectiveTo assess changes in and factors associated with testicular position during childhood.DesignTesticular position (the distance from the pubic bone to the upper pole of the testes) at birth, 3 months, 18 months, 36 months, and 7 years and reproductive hormones at 3 months were measured.SettingPrenatally recruited, prospective longitudinal birth cohort.ParticipantsA total of 2545 boys were recruited prenatally in a Danish-Finnish birth cohort and had a testicular position examination available. A subset of 680 Danish and 362 Finnish boys had serum reproductive hormone concentrations and insulin-like growth factor I (IGF-I) determined at 3 months.Main Outcome MeasuresTesticular distance to pubic bone (TDP), serum reproductive hormone, and IGF-I concentrations.ResultsTDP increased from birth to 3 months and decreased thereafter. Length, gestational age, weight for gestational age, and penile length were positively associated with larger TDP and thus lower testicular position in a linear mixed-effect model. Furthermore, IGF-I concentration, inhibin B/follicle-stimulating hormone ratio, and testosterone/luteinizing hormone ratio were all independently and positively associated with longer TDP.ConclusionsWe provide longitudinal data on postnatal changes in TDP. TDP is dynamic and associated with Leydig and Sertoli cell function as well as with IGF-I levels during the first months of life at mini-puberty of infancy. TDP may thus be a useful biomarker of postnatal testicular function.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01889
      Issue No: Vol. 103, No. 4 (2018)
  • Postprandial Saturated Fatty Acids Increase the Risk of Type 2 Diabetes: A
           Cohort Study in a Chinese Population
    • Authors: Wang Y; Meng X, Deng X, et al.
      Pages: 1438 - 1446
      Abstract: ContextExperimental evidence suggests saturated fatty acids (SFAs) are associated with insulin resistance, but results from epidemiological studies on fasting SFAs-diabetes risk are inconsistent.ObjectiveWe investigated SFA (fasting and 2-hour postprandial) profiles and diabetes risk.Design SettingA total of 8940 participants were recruited for the Harbin People’s Health Study in 2008. Serum SFAs (fasting and 2-hour postprandial) at baseline in Chinese men and women without diabetes were profiled, and type 2 diabetes was ascertained using World Health Organization criteria after 4 to 7 years of follow-up.OutcomeAssociations between 2-hour postprandial SFA (2h-SFA) and diabetes.ResultsAt baseline, incident cases of diabetes were older with a higher body mass index and waist circumference. After a mean follow-up of 6.7 years, 658 incident cases of diabetes occurred. After propensity score computation and inverse probability of treatment weighting (IPTW) estimation, fasting SFAs were unrelated to diabetes risk but IPTW-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the highest tertile of 2-hour postprandial stearic acid (2h-SA), 2-hour postprandial palmitic acid (2h-PA), and 2h-SFA for diabetes risk were 2.50 (2.08 to 3.16), 1.56 (1.23 to 2.02), and 1.70 (1.34 to 2.17), respectively (P-trend < 0.0001). Similarly, 2h-SA/fasting SA, 2h-PA/fasting PA, and 2h-SFA/fasting SFA ratios [IPTW-adjusted OR (95% CI): 2.94 (2.39 to 3.58), 2.31 (1.80 to 2.93), and 2.42 (1.91 to 3.11), respectively; P-trend < 0.0001] predicted the diabetes risk.ConclusionsHigher serum 2h-SFA (but not fasting SFA) independently predicted diabetes risk.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01904
      Issue No: Vol. 103, No. 4 (2018)
  • Altered Expression of miR-181a-5p and miR-23a-3p Is Associated With
           Obesity and TNFα-Induced Insulin Resistance
    • Authors: Lozano-Bartolomé J; Llauradó G, Portero-Otin M, et al.
      Pages: 1447 - 1458
      Abstract: ContextThe proinflammatory cytokine TNFα is a key player in insulin resistance (IR). The role of miRNAs in inflammation associated with IR is poorly understood.ObjectiveTo investigate miR-181a-5p and miR-23a-3p expression profiles in obesity and to study their role in TNFα-induced IR in adipocytes.DesignTwo separate cohorts were used. Cohort 1 was used in adipose tissue (AT) expression studies and included 28 subjects with body mass index (BMI) <30 kg/m2 and 30 with BMI ≥30 kg/m2. Cohort 2 was used in circulating serum miRNA studies and included 101 subjects with 4 years of follow-up (48 case subjects and 53 control subjects). miR-181a-5p and miR-23a-3p expression was assessed in subcutaneous and visceral AT. Functional analysis was performed in adipocytes, using miRNA mimics and inhibitors. Key molecules of the insulin pathway, AKT, PTEN, AS160, and S6K, were analyzed.ResultsExpression of miR-181a-5p and miR-23a-3p was reduced in adipose tissue from obese and diabetic subjects and was inversely correlated to adiposity and homeostasis model assessment of IR index. Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin-stimulated AKT activation and reduced TNFα-induced IR, regulating PTEN and S6K expression. Serum levels of miR-181a-5p were reduced in case vs control subjects at baseline, suggesting a prognostic value. Variable importance in projection scores revealed miR-181a-5p had more effect on the model than insulin or glucose at 120 minutes.ConclusionmiR-181a-5p and miR-23a-3p may prevent TNFα-induced IR in adipocytes through modulation of PTEN and S6K expression.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01909
      Issue No: Vol. 103, No. 4 (2018)
  • Mean High-Dose l-Thyroxine Treatment Is Efficient and Safe to Achieve a
           Normal IQ in Young Adult Patients With Congenital Hypothyroidism
    • Authors: Aleksander P; Brückner-Spieler M, Stoehr A, et al.
      Pages: 1459 - 1469
      Abstract: ContextThe optimal levothyroxine (LT4) dose to treat congenital hypothyroidism (CH) remains unclear, with debate over whether higher starting doses (>10 µg/kg) are necessary and safe for a normal intelligence quotient (IQ).ObjectiveTo examine psychomotor, metabolic, and quality of life (QoL) outcomes in patients with CH treated with a mean high initial LT4 dose.Design, settings, participantsA cross-sectional cohort study of patients with CH identified in the Berlin newborn screening program from 1979 to 2003; 76 patients with CH (mean age, 18 years; mean initial LT4 dose, 13.5 µg/kg) and 40 siblings completed the study.Main outcome measuresPsychomotor (Wechsler Intelligence Test, CNS Vital Signs), QoL (short form-36 Health Survey), anthropometric (body mass index, height), and metabolic (intima media thickness, laboratory parameters) outcomes were compared with those of healthy siblings. Mean values and percentage of episodes of elevated thyroxine (T4) and tri-jod-thyronin (T3) and suppressed thyrotropin (TSH) before age 2 years were analyzed. A meta-analysis of CH treatment studies was performed.ResultsThere were no significant differences in IQ, QoL, or other outcome measures in patients with CH compared with controls. Most T4 levels were high before age 2 years and during subsequent testing, but mean T3 and TSH levels remained normal. The meta-analysis showed a significant IQ difference in severe vs mild CH cases only when treatment started with an LT4 dose <10 µg/kg.ConclusionsHigh initial LT4 dosing was effective and safely achieved optimal cognitive development in patients with CH, including those severely affected. Supranormal T4 values during infancy were not associated with impaired IQ in adolescence.
      PubDate: Tue, 09 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01937
      Issue No: Vol. 103, No. 4 (2018)
  • Connection Between BMI-Related Plasma Metabolite Profile and Gut
    • Authors: Ottosson F; Brunkwall L, Ericson U, et al.
      Pages: 1491 - 1501
      Abstract: ContextEmerging evidence has related the gut microbiome and circulating metabolites to human obesity. Gut microbiota is responsible for several metabolic functions, and altered plasma metabolome might reflect differences in the gut microbiome.ObjectiveTo identify a plasma metabolite profile associated with body mass index (BMI) in a general population and investigate whether such metabolite profile is associated with distinct composition of the gut microbiota.DesignTargeted profiling of 48 plasma metabolites was performed in a population of 920 Swedish adults (mean age, 39 years; 53% women) from the ongoing Malmö Offspring Study using targeted liquid chromatography–mass spectrometry. Gut microbiota was analyzed by sequencing the 16S ribosomal RNA gene (V1-V3 region) in fecal samples of 674 study participants.ResultsBMI was associated with 19 metabolites (P < 0.001 for all), of which glutamate provided the strongest direct association (P = 5.2e-53). By orthogonal partial least squares regression, a metabolite principal component predictive of BMI was constructed (PCBMI). In addition to glutamate, PCBMI was dominated by branched-chain amino acids (BCAAs) and related metabolites. Four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) were associated with both BMI and PCBMI (P < 8.0e-4 for all). When simultaneously regressing PCBMI and metabolite-associated gut bacteria against BMI, only PCBMI remained statistically significant.ConclusionsWe discovered associations between four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) and BMI-predictive plasma metabolites, including glutamate and BCAAs. Thus, these metabolites could be mediators between gut microbiota and obesity, pointing to potential future opportunities for targeting the gut microbiota in prevention of obesity.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02114
      Issue No: Vol. 103, No. 4 (2018)
  • Gut Microbial Diversity in Women With Polycystic Ovary Syndrome Correlates
           With Hyperandrogenism
    • Authors: Torres P; Siakowska M, Banaszewska B, et al.
      Pages: 1502 - 1511
      Abstract: ContextA majority of women with polycystic ovary syndrome (PCOS) have metabolic abnormalities that result in an increased risk of developing type 2 diabetes and heart disease. Correlative studies have shown an association between changes in the gut microbiome and metabolic disorders. Two recent studies reported a decrease in α diversity of the gut microbiome in women with PCOS compared with healthy women.ObjectiveWe investigated whether changes in the gut microbiome correlated with specific clinical parameters in women with PCOS compared with healthy women. We also investigated whether there were changes in the gut microbiome in women with polycystic ovarian morphology (PCOM) who lacked the other diagnostic criteria of PCOS.ParticipantsSubjects were recruited at the Poznan University of Medical Sciences. Fecal microbial diversity profiles of healthy women (n = 48), women with PCOM (n = 42), and women diagnosed with PCOS using the Rotterdam criteria (n = 73) were analyzed using 16S ribosomal RNA gene sequencing.ResultsLower α diversity was observed in women with PCOS compared with healthy women. Women with PCOM had a change in α diversity that was intermediate between that of the other two groups. Regression analyses showed that hyperandrogenism, total testosterone, and hirsutism were negatively correlated with α diversity. Permutational multivariate analysis of variance in UniFrac distances showed that hyperandrogenism was also correlated with β diversity. A random forest identified bacteria that discriminated between healthy women and women with PCOS.ConclusionThese results suggest that hyperandrogenism may play a critical role in altering the gut microbiome in women with PCOS.
      PubDate: Tue, 23 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02153
      Issue No: Vol. 103, No. 4 (2018)
  • Trabecular Bone Score in Obese and Nonobese Subjects With Primary
           Hyperparathyroidism Before and After Parathyroidectomy
    • Authors: Tay Y; Cusano N, Rubin M, et al.
      Pages: 1512 - 1521
      Abstract: ContextObesity has been shown to be unfavorable to skeletal microarchitecture when assessed by trabecular bone score (TBS). The influence of adiposity on skeletal microstructure in primary hyperparathyroidism (PHPT) has not yet been evaluated.ObjectiveTo investigate the effect of obesity on TBS and bone mineral density (BMD) in subjects with PHPT at baseline and through 2 years after parathyroidectomy.DesignProspective observational study.SettingReferral center.Patients or Other ParticipantsThirty men and women with PHPT undergoing parathyroid surgery.Main Outcome MeasuresTBS and BMD by dual-energy X-ray absorptiometry (DXA).ResultsThere were notable improvements in lumbar spine and femoral neck BMD in the obese (lumbar spine: 4.3 ± 4.7%, femoral neck: 3.8 ± 6.6%; P < 0.05 for both) and nonobese subjects (lumbar spine: 3.8 ± 5.6%, femoral neck 3.1 ± 5.0%; P < 0.05 for both) but no marked change in TBS in either group at 24 months postparathyroidectomy. Obese subjects had fully degraded TBS values compared with the nonobese subjects, whose TBS values were minimally below normal throughout the study (baseline: 1.199 ± 0.086 vs 1.327 ± 0.099, respectively; P = 0.003; 24 months: 1.181 ± 0.061 vs 1.352 ± 0.114, respectively; P = 0.001), despite improvements in BMD.ConclusionsThe detrimental effect of obesity on TBS, an index of bone quality, was demonstrated in subjects with PHPT. Obesity was associated with fully degraded skeletal microarchitecture as measured by TBS in PHPT, despite similar values in bone density by DXA compared with nonobese subjects. TBS values did not improve postparathyroidectomy in either obese or nonobese subjects.
      PubDate: Wed, 24 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02169
      Issue No: Vol. 103, No. 4 (2018)
  • Deficient Glucagon Response to Hypoglycemia During a Mixed Meal in Total
           Pancreatectomy/Islet Autotransplantation Recipients
    • Authors: Bogachus L; Bellin M, Vella A, et al.
      Pages: 1522 - 1529
      Abstract: ContextTotal pancreatectomy and intrahepatic islet autotransplantation (TP/IAT) is performed to alleviate severe abdominal pain, avoid narcotic use, maintain islet function, and avoid diabetes in patients with chronic pancreatitis. However, many TP/IAT recipients complain of postprandial hypoglycemia.ObjectiveThis study was designed to discover the mechanisms of this problem.DesignParticipants consumed a triple-isotope mixed meal.SettingThis study was performed in a hospital research unit.ParticipantsWe studied 10 TP/IAT recipients and 10 age- and body mass index–matched control subjects. Seven of 10 recipients had a history of postprandial hypoglycemia.InterventionsParticipants were given a [1-13C]-labeled mixed meal and two tracer infusions ([6,6-2H2]- and [6-3H]-glucose).Main Outcome MeasuresGlucose kinetics and concentrations of regulatory hormones were determined.ResultsImmediately after the meal, peak glucose was elevated in recipients compared with control subjects [266 ± 20 mg/dL (14.8 ± 1.1 mmol/L) vs 185 ± 13 mg/dL (10.3 ± 0.7 mmol/L); P = 0.01]. However, mean Δ glucose for TP/IAT recipients between minutes 240 and 360 postprandially was significantly lower than for control subjects (P < 0.05); six of the seven recipients with a history of hypoglycemia experienced abnormally low postprandial Δ glucose. Δ Glucagon remained unchanged (minutes 240 to 360; P = 0.58) in TP/IAT recipients despite abnormal decreases in postprandial glucose. Radioisotopic studies revealed that meal appearance, glucose disappearance, and endogenous glucose production in TP/IAT recipients were not different from control subjects.ConclusionInitially high glucose levels followed by hypoglycemia with an absent glucagon response is a mechanistic sequence that contributes to postprandial hypoglycemia after TP/IAT.
      PubDate: Wed, 17 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02182
      Issue No: Vol. 103, No. 4 (2018)
  • Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression
           in Preeclampsia
    • Authors: Alahari S; Post M, Rolfo A, et al.
      Pages: 1545 - 1557
      Abstract: ContextThe von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5% to 7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive.ObjectiveWe examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia.Design, Setting, and ParticipantsPlacentae were obtained from early-onset preeclampsia (n = 56; <34 weeks of gestation) and late-onset preeclampsia (n = 19; ≥34 weeks of gestation). Placentae from healthy normotensive age-matched preterm control (n = 43) and term control (n = 23) pregnancies were included as controls.Main Outcome Measure(s)We measured the activity of Jumonji domain containing protein 6 (JMJD6), a ferrous iron (Fe2+)– and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL.ResultsJMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592–treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592–treated mice.ConclusionsOur study uncovers epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia.
      PubDate: Wed, 24 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02197
      Issue No: Vol. 103, No. 4 (2018)
  • Excessive Adiposity and Metabolic Dysfunction Relate to Reduced
           Natriuretic Peptide During RAAS Activation in HIV
    • Authors: Murphy C; Fitch K, Feldpausch M, et al.
      Pages: 1558 - 1565
      Abstract: PurposeNatriuretic peptides (NPs) negatively feedback on the renin-angiotensin-aldosterone system (RAAS) and play a critical role in preserving cardiac structure and maintaining metabolic homeostasis. Well-treated HIV-infected individuals are at risk for fat redistribution and demonstrate evidence of RAAS dysregulation, which relates to metabolic dysfunction. We investigated circulating NPs in relation to RAAS physiology and metrics of body composition in HIV.MethodsWe assessed atrial natriuretic peptide, brain natriuretic peptide (BNP), and amino terminal pro B-type natriuretic peptide (NT-proBNP) during acute activation of the RAAS using a low-sodium controlled diet among 20 HIV-infected and 10 non–HIV-infected individuals well phenotyped for body composition.ResultsBNP was significantly lower [median, 60 (interquartile range, 44, 152) pg/mL vs 196 (91, 251) pg/mL, respectively; P = 0.04], and serum aldosterone was higher, among HIV-infected than among non–HIV-infected individuals. BNP was significantly and inversely associated with body composition [waist circumference: r = −0.46 (P = 0.04); BMI: r = −0.55 (P = 0.01); body adiposity index: r = −0.49 (P = 0.03)], metabolic indices [total cholesterol: r = −0.44 (P = 0.05), insulin resistance calculated by using homeostatic model assessment: r = −0.44 (P = 0.05); mean arterial pressure: r = −0.44 (P = 0.05)], and serum aldosterone (r = −0.49; P = 0.03) among the HIV-infected group. These relationships were not demonstrated in the non–HIV-infected group. In a four-group comparison stratifying by HIV serostatus and above or below a body mass index (BMI) of 25 kg/m2, BNP decreased significantly across groups; it was highest in non–HIV-infected patients with a BMI <25 kg/m2 and lowest in HIV-infected patients with a BMI ≥25 kg/m2 (overall P = 0.01).ConclusionRelatively reduced NP, particularly BNP, among HIV-infected individuals with excess adiposity may contribute to reduced suppression of aldosterone and potentially drive aldosterone-mediated metabolic complications. Strategies that target RAAS blockade and/or augment NPs may be useful to reduce cardiometabolic disease among HIV-infected individuals in whom these systems are perturbed.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02198
      Issue No: Vol. 103, No. 4 (2018)
  • Matrix Metalloproteinase Activity Correlates With Uterine Myoma Volume
           Reduction After Ulipristal Acetate Treatment
    • Authors: Courtoy G; Henriet P, Marbaix E, et al.
      Pages: 1566 - 1573
      Abstract: ContextUlipristal acetate (UPA), a selective progesterone receptor modulator, clinically reduces uterine myoma size in 80% of cases. However, the molecular mechanism of action is still poorly understood, as is the reason why 20% of myomas do not respond to treatment.ObjectiveTo elucidate whether matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are associated with myoma volume shrinkage after UPA therapy.DesignProspective study.SettingAcademic research unit of a university hospital.PatientsUterine biopsies were obtained from 59 patients with symptomatic myomas undergoing myomectomy, 45 of whom were treated preoperatively with either one or greater than or equal to two, 3-month courses of UPA and 14 not given any hormone therapy to serve as controls. Myoma volume was individually monitored during UPA therapy to determine any substantial clinical response (defined as a reduction in volume of >25%). Three groups were established based on the response to treatment: responsive (R) after one course (n = 12); R after two to four courses (n = 15); and nonresponsive (NR; n = 18).InterventionsUPA treatment given as preoperative management for symptomatic myomas.Main Outcome MeasuresMMP and TIMP expression assessed by zymography and immunohistochemistry.ResultsCompared with controls and NR myomas, responders showed significantly higher expression levels for MMP-1 (P < 0.0001) and MMP-2 (P = 0.009) and significantly lower expression levels for TIMP-1 (P = 0.040).ConclusionsThe correlation found between MMP expression and volume fold change supports the notion that MMPs play a key role in UPA-induced myoma shrinkage.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02295
      Issue No: Vol. 103, No. 4 (2018)
  • 18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma
    • Authors: Taïeb D; Jha A, Guerin C, et al.
      Pages: 1574 - 1582
      Abstract: ContextMYC-associated factor X (MAX) has been recently described as a new susceptibility pheochromocytoma (PHEO) gene with a total of ~40 reported cases. At present, no study has specifically described the functional imaging phenotype of MAX-related PHEO.Objective, Patients, and DesignThe objective of the present study was to present our experience with contrast-enhanced computed tomography (CT) and 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET)/CT in six consecutive patients (four at the initial diagnosis and two at the follow-up evaluation) with rare, but clinically important, MAX-related PHEOs. In five patients, 18F-FDOPA was also compared with other radiopharmaceutical agents.ResultsThe patients had five different mutations in the MAX gene that caused disruption of Max/Myc interaction and/or abolished interaction with DNA based on in silico analyses. All but one patient developed bilateral PHEOs during their lifetime. In all cases, 18F-FDOPA PET/CT accurately visualized PHEOs that were often multiple within the same gland or bilaterally and detected more adrenal and extra-adrenal lesions than did CT (per-lesion sensitivity, 90.9% vs 52.4% for CT/magnetic resonance imaging). The two PHEOs missed on 18F-FDOPA PET/CT were <1 cm, corresponding to nodular adrenomedullary hyperplasia. 68Ga-DOTA,Tyr3-octreotate PET/CT detected fewer lesions than did 18F-FDOPA PET/CT in one of three patients, and 18F-fluorodeoxyglucose PET/CT was only faintly positive in two of four patients with underestimation of extra-adrenal lesions in one patient.ConclusionsMAX-related PHEOs exhibit a marked 18F-FDOPA uptake, a finding that illustrates the common well-differentiated chromaffin pattern of PHEOs associated with activation of kinase signaling pathways. 18F-FDOPA PET/CT should be considered as the first-line functional imaging modality for diagnostic or follow-up evaluations for these patients.
      PubDate: Thu, 08 Mar 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02324
      Issue No: Vol. 103, No. 4 (2018)
  • Controlled Antenatal Thyroid Screening II: Effect of Treating Maternal
           Suboptimal Thyroid Function on Child Cognition
    • Authors: Hales C; Taylor P, Channon S, et al.
      Pages: 1583 - 1591
      Abstract: Context and ObjectiveThe Controlled Antenatal Thyroid Screening (CATS) study investigated treatment of suboptimal gestational thyroid function (SGTF) on childhood cognition and found no difference in intelligence quotient (IQ) at 3 years between children of treated and untreated SGTF mothers. We have measured IQ in the same children at age 9.5 years and included children from normal gestational thyroid function (normal-GTF) mothers.Design, Setting, and ParticipantsOne examiner, blinded to participant group, assessed children’s IQ (Wechsler Intelligence Scale for Children, Fourth Edition UK), long-term memory, and motor function (Developmental Neuropsychological Assessment II) from children of 119 treated and 98 untreated SGTF mothers plus children of 232 mothers with normal-GTF. Logistic regression explored the odds and percentages of an IQ < 85 in the groups.ResultsThere was no difference in IQ < 85 between children of mothers with normal-GTF and combined SGTF, i.e., treated and untreated (fully adjusted odds ratio [OR] = 1.15 [95% confidence interval (CI) 0.52, 2.51]; P = 0.731). Furthermore, there was no significant effect of treatment [untreated OR = 1.33 (95% CI 0.53, 3.34); treated OR = 0.75 (95% CI 0.27, 2.06) P = 0.576]. IQ < 85 was 6.03% in normal-GTF, 7.56% in treated, and 11.22% in untreated groups. Analyses accounting for treated-SGTF women with free thyroxine > 97.5th percentile of the entire CATS-I cohort revealed no significant effect on a child’s IQ < 85 in CATS-II. IQ at age 3 predicted IQ at age 9.5 (P < 0.0001) and accounted for 45% of the variation.ConclusionsMaternal thyroxine during pregnancy did not improve child cognition at age 9.5 years. Our findings confirmed CATS-I and suggest that the lack of treatment effect may be a result of the similar proportion of IQ < 85 in children of women with normal-GTF and SGTF.
      PubDate: Mon, 15 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02378
      Issue No: Vol. 103, No. 4 (2018)
  • Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration
           and the Risk of Incident Diabetes Mellitus
    • Authors: Svensson T; Svensson A, Kitlinski M, et al.
      Pages: 1592 - 1600
      Abstract: ContextThe biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and caspase-8, a marker of apoptotic activity, have both been implicated in β-cell function.ObjectiveTo investigate the associations between sleep duration and plasma caspase-8 and incident DM, respectively.DesignProspective cohort study.SettingThe Malmö Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmö, Sweden.ParticipantsA total of 4023 individuals from the MDC Study aged 45 to 68 years at baseline without a history of prevalent DM and with information on habitual sleep duration.Main OutcomesIncident DM.ResultsMean follow-up time was 17.8 years. Sleep duration was the only behavioral variable significantly associated with plasma caspase-8. Plasma caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form [hazard ratio (HR) = 1.24; 95% confidence interval (CI), 1.13 to 1.36] and when dichotomized into high (quartile 4) (HR = 1.44; 95% CI, 1.19 to 1.74) compared with low (quartiles 1 to 3) concentrations. Caspase-8 interacted with sleep duration; compared with individuals who had 7 to 8 hours of sleep and low plasma caspase-8, those with high plasma caspase-8 and sleep duration <6 hours (HR = 3.54; 95% CI, 2.12 to 5.90), 6 to 7 hours (HR = 1.81; 95% CI, 1.24 to 2.65), and 8 to 9 hours (HR = 1.54; 95% CI, 1.09 to 2.18) were at significantly increased risks of incident DM.ConclusionsSleep duration is associated with plasma caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of caspase-8.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02374
      Issue No: Vol. 103, No. 4 (2018)
  • Randomized Trial of CPAP and Vardenafil on Erectile and Arterial Function
           in Men With Obstructive Sleep Apnea and Erectile Dysfunction
    • Authors: Melehan K; Hoyos C, Hamilton G, et al.
      Pages: 1601 - 1611
      Abstract: ContextErectile function is important for life satisfaction and often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g., vardenafil) are the first-line therapy for erectile dysfunction (ED), but may worsen OSA.ObjectiveTo assess the effects of CPAP and vardenafil on ED.DesignSixty-one men with moderate-to-severe OSA and ED were randomized to 12 weeks of CPAP or sham CPAP, and 10 mg daily vardenafil or placebo in a two-by-two factorial design.Main Outcome MeasuresInternational Index of Erectile Function (primary end point), treatment and relationship satisfaction, sleep-related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep-disordered breathing.ResultsCPAP increased the frequency of sleep-related erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness, or sleep-disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function, and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self-esteem, relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality.ConclusionCPAP improves overall sexual satisfaction, sleep-related erections, and arterial stiffness. Low-dose daily vardenafil improves certain aspects of sexual function and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02389
      Issue No: Vol. 103, No. 4 (2018)
  • Metformin Use in PCOS Pregnancies Increases the Risk of Offspring
           Overweight at 4 Years of Age: Follow-Up of Two RCTs
    • Authors: Hanem L; Stridsklev S, Júlíusson P, et al.
      Pages: 1612 - 1621
      Abstract: ContextMetformin is used in pregnancy in women with gestational diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity. Metformin passes the placenta.ObjectiveTo explore the effects of metformin use in PCOS pregnancies on offspring growth to 4 years of age.DesignFollow-up study of two randomized, double-blind, placebo-controlled trials.SettingSecondary care centers. Eleven public hospitals in Norway.ParticipantsOne hundred eighty-two children of mothers with PCOS who participated in two randomized controlled trials.InterventionMetformin 1700 or 2000 mg/d or placebo from first trimester to delivery in the original studies. No intervention in the current study.Main Outcome MeasuresHeight, weight, body mass index (BMI), and overweight/obesity at 4 years of age and head circumference at 1 year of age, converted to z scores.ResultsThe difference in height z score means between the groups at 4 years of age was nonsignificant (0.07 [95% confidence interval (CI): –0.22 to 0.36]; P = 0.651). At 4 years of age, the metformin group had higher weight z score than the placebo group [difference in means: 0.38 (0.07 to 0.69); P = 0.017] and higher BMI z score [difference in means: 0.45 (0.11 to 0.78); P = 0.010]. There were more overweight/obese children in the metformin group [26 (32%)] than in the placebo group [14 (18%)] at 4 years of age [odds ratio: 2.17 (1.04 to 4.61); P = 0.038]. The difference in mean head circumference z score at 1 year of age was 0.27 (–0.04 to 0.58; P = 0.093).ConclusionMetformin-exposed children had higher BMI and increased prevalence of overweight/obesity at 4 years of age.
      PubDate: Tue, 27 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02419
      Issue No: Vol. 103, No. 4 (2018)
  • High Androgens in Postmenopausal Women and the Risk for Atherosclerosis
           and Cardiovascular Disease: The Rotterdam Study
    • Authors: Meun C; Franco O, Dhana K, et al.
      Pages: 1622 - 1630
      Abstract: ContextPolycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular disease (CVD).ObjectiveTo assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women.DesignThe Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years.SettingGeneral community.ParticipantsA total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age <40 or >62).InterventionNone.Main Outcomes and MeasuresLinear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone–binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave velocity, peripheral artery disease, and incidence of coronary heart disease (CHD), stroke, and CVD.ResultsMean age (standard deviation) was 70.19 (8.71) years, and average time since menopause was 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity (β [95% confidence interval (CI)], 0.009 [0.000 to 0.018]). Highest quartile dehydroepiandrosterone [β (95% CI), −0.008 (−0.015 to −0.001)] and androstenedione [β (95% CI), −0.010 (−0.017 to −0.003)] levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, CHD, or CVD.ConclusionPostmenopausal high androgen levels were not associated with an elevated risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02421
      Issue No: Vol. 103, No. 4 (2018)
  • Characteristics of Follicular Variant Papillary Thyroid Carcinoma in a
           Pediatric Cohort
    • Authors: Samuels S; Surrey L, Hawkes C, et al.
      Pages: 1639 - 1648
      Abstract: ContextIn adults, noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) is considered a low risk for metastasis and persistent/recurrent disease.ObjectiveThe goal of this study was to assess the clinical, sonographic, and histopathologic features of FVPTC in a pediatric cohort.DesignA retrospective review of subjects <19 years of age with papillary thyroid carcinoma (PTC) who underwent thyroidectomy between January 2010 and July 2015.SettingMultidisciplinary academic referral center.PatientsPatients with FVPTC, defined as a tumor ≥1 cm in the largest dimension with predominant follicular growth, complete lack of well-formed papillae, and nuclear features of PTC.Main Outcome MeasuresTumor size and location, presence of a tumor capsule, capsule and vascular invasion, lymph node invasion, and distant metastasis.ResultsEighteen patients with FVPTC were identified from a case cohort of 110 patients with PTC. On histopathology, 13 (72%) had unifocal nodules and 14 (78%) had completely encapsulated FVPTC. Capsule invasion was frequent (nine of 14; 64%), and vascular invasion was found in one-third of patients (six of 18; 33%). No lymph node metastases were found in the 13 patients (72%) who had a central neck lymph node dissection. One patient with vascular invasion had distant metastases.ConclusionWhen strictly defined, FVPTC in pediatric patients has a low risk for bilateral disease and metastasis. Prospective studies are needed to confirm whether lobectomy with surveillance is sufficient to achieve remission in pediatric patients with low-risk FVPTC.
      PubDate: Thu, 08 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02454
      Issue No: Vol. 103, No. 4 (2018)
  • Letter to the Editor: “Myonectin Predicts the Development of Type 2
    • Authors: Gagliano-Jucá T.
      Pages: 1649 - 1649
      Abstract: Myonectin, also known as C1q/tumor necrosis factor α-related protein 15 (CTRP15), was first described in 2012 as a nutrient-responsive myokine, secreted by skeletal muscle to regulate the whole-body fatty acid metabolism (1). In that same year, Lim et al. (2) reported on CTRP5, a related but distinct C1q family member, and inadvertently also named it myonectin. As mouse CTRP15 cDNA and protein sequences had already been deposited in the GenBank database as myonectin, CTRP5 remains, to date, known solely as CTRP5. However, this seems to have confused Li et al. (3) in their recent, interesting report on the usefulness of serum myonectin levels in predicting the development of diabetes, as they compare their findings with CTRP5 levels reported by Lim et al. (2). Besides this mix-up, additional points need further clarification.
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02542
      Issue No: Vol. 103, No. 4 (2018)
  • CORRIGENDUM FOR “Complement C3 Associates With Incidence of Diabetes,
           but No Evidence of a Causal Relationship”
    • Pages: 1650 - 1650
      Abstract: In the above-named article by Borné Y, Muhammad IF, Lorés-Motta L, Hedblad B, Nilsson PM, Melander O, de Jong EK, Blom AM, den Hollander AI, and Engström G (J Clin Endocrinol Metab. 2017;102(12):4477–4485; doi: 10.1210/jc.2017-00948) in Subsection GWAS of C3, paragraph 1, line 4, the following inaccuracy occurred:
      PubDate: Fri, 05 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02806
      Issue No: Vol. 103, No. 4 (2018)
  • CORRIGENDUM FOR “The Role of Episodic Postprandial Peptides in
           Exercise-Induced Compensatory Eating”
    • Pages: 1651 - 1651
      Abstract: In the above-named article by Gibbons C, Blundell JE, Caudwell P, Webb D-L, Hellström PM, Näslund E, and Finlayson G (J Clin Endocrinol Metab. 2017;102(11):4051–4059; doi: 10.1210/jc.2017-00817) the author affiliations had the following inaccuracy:
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00140
      Issue No: Vol. 103, No. 4 (2018)
  • CORRIGENDUM FOR “Identification of Novel Potentially Pleiotropic
           Variants Associated With Osteoporosis and Obesity Using the cFDR Method”
    • Pages: 1652 - 1652
      Abstract: In the above-named article by Hu Y, Tan L-J, Chen X-D, Liu Z, Min S-S, Zeng Q, Shen H, and Deng H-W (J Clin Endocrinol Metab. 2018;103(1):125–138; doi: 10.1210/jc.2017-01531) in Acknowledgments, paragraph 3, the following inaccuracy occurred:
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00141
      Issue No: Vol. 103, No. 4 (2018)
  • CORRIGENDUM FOR “Assessment of β Cell Mass and Function by AIRmax and
           Intravenous Glucose in High-Risk Subjects for Type 1 Diabetes”
    • Pages: 1653 - 1653
      Abstract: In the above-named article by Hao W, Woodwyk A, Beam C, Bahnson HT, Palmer JP, Greenbaum CJ (J Clin Endocrinol Metab. 2017;102(12):4428–4434; doi: 10.1210/jc.2017-01713) the following omission occurred in the published paper:
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00226
      Issue No: Vol. 103, No. 4 (2018)
  • Vitamin D Status and Intakes and Their Association With Cognitive
           Trajectory in a Longitudinal Study of Urban Adults
    • Authors: Beydoun M; Hossain S, Fanelli-Kuczmarski M, et al.
      Pages: 1654 - 1668
      Abstract: ContextSerum 25-hydroxyvitamin D [25(OH)D], and dietary and supplemental vitamin D may influence cognitive outcomes.ObjectivesSex-, age-, and race-specific associations of vitamin D status and intake with longitudinal change in various cognitive domains were examined in a large sample of ethnically and socioeconomically diverse US urban adults.DesignTwo prospective waves of data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study were used.ParticipantsAdults in Baltimore, Maryland, aged 30 to 64 years at baseline (n = 1231 to 1803), were followed for a mean (± standard deviation) of 4.64 ± 0.93 years. Visit 1 occurred between 2004 and 2009; visit 2, between 2009 and 2013; there were 1.5 to 2.0 visits per participant.Main outcome and exposure measuresCognitive performance was assessed using 11 test scores covering domains of global cognition, attention, learning/memory, executive function, visuospatial/visuoconstruction ability, psychomotor speed, and language/verbal. Serum 25(OH)D, vitamin D intake, and use of supplements containing vitamin D were the key exposures.ResultsA consistent relationship was found between vitamin D status (overall) and supplemental intake (older women and black adults), with a slower rate of decline in the domain of verbal fluency. Higher dietary intake of vitamin D was linked to slower rate of decline in verbal memory among younger women, and a slower rate of decline in visual memory/visuoconstructive abilities among white adults. All other associations were inconsistent.ConclusionsVitamin D status and intakes were inversely related to domain-specific cognitive decline in US urban adults.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02462
      Issue No: Vol. 103, No. 4 (2018)
  • Effects of a Lifestyle Intervention During Pregnancy and First Postpartum
           Year: Findings From the RADIEL Study
    • Authors: Huvinen E; Koivusalo S, Meinilä J, et al.
      Pages: 1669 - 1677
      Abstract: ContextWomen with a history of gestational diabetes (GDM) have a sevenfold risk of developing type 2 diabetes.ObjectiveTo assess the effects of a lifestyle intervention during pregnancy and first postpartum year on glucose regulation, weight retention, and metabolic characteristics among women at high GDM risk.DesignIn the Finnish Gestational Diabetes Prevention study, trained study nurses provided lifestyle counseling in each trimester and 6 weeks, 6 months, and 12 months postpartum.SettingThree maternity hospitals in the Helsinki area and one in Lappeenranta.PatientsIn total, 269 women with previous GDM and/or a prepregnancy body mass index ≥30 kg/m2 were enrolled before 20 gestational weeks and allocated to either a control or an intervention group. This study includes the 200 participants who attended study visits 6 weeks and/or 12 months postpartum.InterventionThe lifestyle intervention followed Nordic diet recommendations and at least 150 minutes of moderate exercise was recommended weekly.Main Outcome MeasureThe incidence of impaired glucose regulation (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes) during the first postpartum year.ResultsImpaired glucose regulation was present in 13.3% of the women in the control and in 2.7% in the intervention group [age-adjusted odds ratio, 0.18 (95% confidence interval, 0.05 to 0.65), P = 0.009] during the first postpartum year. There were no differences between the groups in weight retention, physical activity, or diet at 12 months postpartum.ConclusionsA lifestyle intervention during pregnancy and the first postpartum year successfully reduced the incidence of postpartum impairment in glucose regulation.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02477
      Issue No: Vol. 103, No. 4 (2018)
  • Long-Term Testosterone Administration on Insulin Sensitivity in Older Men
           With Low or Low-Normal Testosterone Levels
    • Authors: Huang G; Pencina K, Li Z, et al.
      Pages: 1678 - 1685
      Abstract: BackgroundSerum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. However, the effects of long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels remain unknown.MethodsThe Testosterone Effects on Atherosclerosis in Aging Men Trial was a placebo-controlled, randomized, double-blind trial. The participants were 308 community-dwelling men, ≥60 years old, with total testosterone 100 to 400 ng/dL or free testosterone <50 pg/mL. A subset of 134 nondiabetic men (mean age, 66.7 ± 5.1 years) underwent an octreotide insulin suppression test at baseline and at 3 and 36 months after randomization to measure insulin sensitivity. Insulin sensitivity was estimated as the steady-state plasma glucose (SSPG) concentration at equilibrium during octreotide and insulin administration. Secondary outcomes included total lean mass (TLM) and total fat mass (TFM) by dual energy x-ray absorptiometry.ResultsThere was a significant (P = 0.003) increase in SSPG in the placebo group, whereas no change was seen in testosterone-treated subjects from baseline to 36 months; however, the between-group differences in change in SSPG over 3 years were not statistically significant (+15.3 ± 6.9 mg/dL in the placebo group vs +6.2 ± 6.4 mg/dL in the testosterone group; mixed-model effect, P = 0.17). Changes in SSPG with testosterone treatment were not associated with changes in serum total or free testosterone concentrations. Changes in TFM but not TLM were associated with increases in SSPG. Stratification by age or baseline total testosterone level did not show significant intervention effects.ConclusionTestosterone administration for 36 months in older men with low or low-normal testosterone levels did not improve insulin sensitivity.
      PubDate: Wed, 24 Jan 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02545
      Issue No: Vol. 103, No. 4 (2018)
  • Mitotane Monotherapy in Patients With Advanced Adrenocortical Carcinoma
    • Authors: Megerle F; Herrmann W, Schloetelburg W, et al.
      Pages: 1686 - 1695
      Abstract: ContextAlthough mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce.ObjectiveTo assess the efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors.Design and SettingMulticenter cohort study of three German referral centers.PatientsOne hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy.Outcome MeasuresResponse Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression.ResultsTwenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P = 0.017); and initiation of mitotane at delayed advanced recurrence, HR 0.35(P < 0.001) and 0.34 (P < 0.001), respectively. Accordingly, 67% of patients with low tumor burden and mitotane initiation ≥360 days after primary diagnosis experienced a clinical benefit (stable disease >180 days). Patients who achieved mitotane levels >14 mg/L had significantly longer OS (HR 0.42; P = 0.003).ConclusionsAt 20.5% the objective response rate was slightly lower than previously reported. However, >20% of patients experienced long-term disease control at >1 year. In general, patients with late diagnosis of advanced disease and low tumor burden might especially benefit from mitotane monotherapy, whereas patients with early advanced disease and high tumor burden are probably better candidates for combined therapy of mitotane and cytotoxic drugs.
      PubDate: Wed, 14 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02591
      Issue No: Vol. 103, No. 4 (2018)
  • The Short Cosyntropin Test Revisited: New Normal Reference Range Using
    • Authors: Ueland G; Methlie P, Øksnes M, et al.
      Pages: 1696 - 1703
      Abstract: BackgroundThe cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges.ObjectiveThe goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays.MethodsCosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile.ResultsCortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively.ConclusionsLC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.
      PubDate: Wed, 14 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02602
      Issue No: Vol. 103, No. 4 (2018)
  • A Comparative Analysis of Phenotypic Predictors of Mutations in Familial
    • Authors: Chan D; Pang J, Hooper A, et al.
      Pages: 1704 - 1714
      Abstract: ContextThe gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available.ObjectiveTo compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation.Design, Setting, and PatientsAn adult cohort of unrelated patients referred to a lipid clinic for genetic testing.Main Outcome MeasuresOdds ratio (OR), area under the curve (AUC), sensitivity, and specificity.ResultsA pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274), and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P < 0.05). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation.ConclusionsThe DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.
      PubDate: Fri, 02 Feb 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02622
      Issue No: Vol. 103, No. 4 (2018)
  • Quantitative Brain MRI in Congenital Adrenal Hyperplasia: In Vivo
           Assessment of the Cognitive and Structural Impact of Steroid Hormones
    • Authors: Webb E; Elliott L, Carlin D, et al.
      Pages: 1330 - 1341
      Abstract: ContextBrain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis.ObjectiveTo examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure.Design, Setting, and ParticipantsA cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age-matched healthy women.Main Outcome MeasureRecruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes.ResultsPatients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance.ConclusionWe demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment.
      PubDate: Mon, 20 Nov 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-01481
      Issue No: Vol. 103, No. 4 (2017)
  • Subclinical Changes in Maternal Thyroid Function Parameters in Pregnancy
           and Fetal Growth
    • Authors: Johns L; Ferguson K, Cantonwine D, et al.
      Pages: 1349 - 1358
      Abstract: ContextOvert thyroid disease in pregnancy is a known risk factor for abnormal fetal growth and development. Data on the effects of milder forms of variation in maternal thyroid function on intrauterine growth are less well examined.ObjectiveWe explored these associations using repeated thyroid hormone and ultrasound measurements.Design, Setting, and ParticipantsData were obtained from 439 pregnant women without diagnosed thyroid disease who were participants in a case-control study of preterm birth nested within an ongoing prospective birth cohort in Boston, Massachusetts.Main Outcome MeasuresUltrasound and delivery indices of fetal growth were standardized to those measured in a larger population.ResultsAt median 10, 18, and 26 weeks of gestation, we observed significant inverse associations between free thyroxine (FT4) and birth weight z scores, with the strongest association detected at median 10 weeks, at which time a 10% increase in FT4 was associated with a 0.02 z score decrease (∼8.5 g) in birth weight (β = −0.41 for ln-transformed FT4; 95% confidence interval, −0.64 to −0.18). FT4 was also inversely associated with repeated measurements of estimated fetal weight, head circumference, and abdominal circumference. We observed weaker inverse associations for total T4 and a positive relationship between total triiodothyronine and birth weight z scores. We did not observe any associations for thyroid-stimulating hormone.ConclusionIn pregnant women without overt thyroid disease, subclinical changes in thyroid function parameters may influence fetal growth.
      PubDate: Tue, 26 Dec 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-01698
      Issue No: Vol. 103, No. 4 (2017)
  • The Role of NRG1 in the Predisposition to Papillary Thyroid Carcinoma
    • Authors: He H; Li W, Liyanarachchi S, et al.
      Pages: 1369 - 1379
      Abstract: ContextPrevious genome-wide association studies have shown that single-nucleotide polymorphism (SNP) rs2439302 in chromosome 8p12 is significantly associated with papillary thyroid carcinoma (PTC) risk and dysregulated NRG1 expression. The underlying mechanisms remain to be discovered.ObjectiveTo evaluate the expression of NRG1 isoforms, candidate functional variants, and potential genes downstream of NRG1 in thyroid tissue.MethodsQuantitative reverse transcription polymerase chain reaction was applied for gene expression analysis. SNaPshot assay, haplotype, and computer analyses were performed to evaluate candidate functional variants. Other functional assays [chromatin immunoprecipitation (ChIP) assay, luciferase assay, small interfering RNA knockdown, and RNA sequencing] were performed.ResultsThree NRG1 isoforms (NM_004495, NM_013958, and NM_001160008) tested were highly expressed in thyroid tissue. The expression levels of the three isoforms were significantly correlated with the genotypes of rs2439302. A DNA block of ~32 kb containing the risk G allele of rs2439302 was revealed, harboring multiple candidate functional variants. ChIP assay for active chromatin markers indicated at least nine regions in the DNA block showing strong H3Kme1 and H3K27Ac signals in thyroid tissue. Luciferase reporter assays revealed differential allelic activities associated with seven SNPs. Knocking down NRG1 in primary thyroid cells revealed downstream or interacting genes related to NRG1.ConclusionsOur data suggest a role for transcriptional regulation of NRG1 in the predisposition to PTC.
      PubDate: Tue, 07 Nov 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-01798
      Issue No: Vol. 103, No. 4 (2017)
  • Morbidity, Mortality, and Socioeconomics in Females With 46,XY Disorders
           of Sex Development: A Nationwide Study
    • Authors: Berglund A; Johannsen T, Stochholm K, et al.
      Pages: 1418 - 1428
      Abstract: ContextLittle is known about long-term health outcomes in phenotypic females with 46,XY disorders of sex development (XY females), and the socioeconomic profile has not been described in detail.ObjectiveTo describe morbidity, mortality, and socioeconomic status in XY females in a comparison to the general population.DesignNationwide registry study with complete follow-up.SettingUniform public health care system.ParticipantsA total of 123 XY females karyotyped in Denmark during 1960 to 2012 and a randomly selected age-matched control cohort of 12,300 females and 12,300 males from the general population.Main Outcome MeasuresOverall mortality and morbidity as well as cause-specific morbidity; medicine use and socioeconomics (education, income, cohabitation, motherhood, and retirement).ResultsCompared with female controls, overall morbidity was increased in XY females [hazard ratio (HR), 1.72; 95% confidence interval (CI), 1.43 to 2.08] but not when excluding diagnoses associated with the specific disorder of sex development (DSD) diagnosis or pregnancy and birth (HR, 1.13; CI, 0.93 to 1.37). Mortality was similar to controls (HR, 0.79; CI, 0.35 to 1.77). Cohabitation (HR, 0.44; CI, 0.33 to 0.58) and motherhood (HR, 0.10; CI, 0.05 to 0.18) were reduced in XY females but education (HR, 0.92; CI, 0.61 to 1.37) was similar to controls. Income was higher than among controls in the older years.ConclusionsMorbidity was not increased in XY females when excluding diagnoses associated to the DSD condition per se. Judged on education and income, XY females perform well in the labor market. However, DSD seems to impact on the prospects of family life.
      PubDate: Mon, 20 Nov 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-01888
      Issue No: Vol. 103, No. 4 (2017)
  • Ezh2 Mutations Found in the Weaver Overgrowth Syndrome Cause a Partial
           Loss of H3K27 Histone Methyltransferase Activity
    • Authors: Lui J; Barnes K, Dong L, et al.
      Pages: 1470 - 1478
      Abstract: ContextWeaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.ObjectiveTo test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function.DesignExome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.ResultsA de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.ConclusionWe generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.
      PubDate: Wed, 13 Dec 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-01948
      Issue No: Vol. 103, No. 4 (2017)
  • High-Intensity Exercise Decreases IP6K1 Muscle Content and Improves
           Insulin Sensitivity (SI2*) in Glucose-Intolerant Individuals
    • Authors: Naufahu J; Elliott B, Markiv A, et al.
      Pages: 1479 - 1490
      Abstract: ContextInsulin resistance (IR) in skeletal muscle contributes to whole body hyperglycemia and the secondary complications associated with type 2 diabetes. Inositol hexakisphosphate kinase-1 (IP6K1) may inhibit insulin-stimulated glucose transport in this tissue type.ObjectiveMuscle and plasma IP6K1 were correlated with two-compartment models of glucose control in insulin-resistant hyperinsulinemic individuals. Muscle IP6K1 was also compared after two different exercise trials.DesignNine prediabetic [hemoglobin A1c; 6.1% (0.2%)] patients were recruited to take part in a resting control, a continuous exercise (90% of lactate threshold), and a high-intensity exercise trial (6 30-second sprints). Muscle biopsies were drawn before and after each 60-minute trial. A labeled ([6,62H2]glucose) intravenous glucose tolerance test was performed immediately after the second muscle sample.ResultsFasting muscle IP6K1 content did not correlate with insulin sensitivity (SI2*) (P = 0.961). High-intensity exercise reduced IP6K1 muscle protein and messenger RNA expression (P = 0.001). There was no effect on protein IP6K1 content after continuous exercise. Akt308 phosphorylation of was significantly greater after high-intensity exercise. Intermittent exercise reduced hepatic glucose production after the same trial. The same intervention also increased SI2*, and this effect was significantly greater compared with the effect of continuous exercise improvements. Our in vitro experiment demonstrated that the chemical inhibition of IP6K1 increased insulin signaling in C2C12 myotubes.ConclusionsThe in vivo and in vitro approaches used in the current study suggest that a decrease in muscle IP6K1 may be linked to whole body increases in SI2*. In addition, high-intensity exercise reduces hepatic glucose production in insulin-resistant individuals.
      PubDate: Fri, 29 Dec 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-02019
      Issue No: Vol. 103, No. 4 (2017)
  • Downregulation of SKP2 in Papillary Thyroid Cancer Acts Synergistically
           With TRAIL on Inducing Apoptosis via ROS
    • Authors: Pratheeshkumar P; Siraj A, Divya S, et al.
      Pages: 1530 - 1544
      Abstract: Context and ObjectiveS-phase kinase protein 2 (SKP2) is an F-box protein with proteasomal properties and has been found to be overexpressed in a variety of cancers. However, its role in papillary thyroid cancer (PTC) has not been fully elucidated.Experimental DesignSKP2 expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of >1000 PTC samples. In vitro and in vivo studies were performed using proteasome inhibitor bortezomib and proapoptopic death ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) either alone or in combination on PTC cell lines.ResultsSKP2 was overexpressed in 45.5% of PTC cases and was significantly associated with extrathyroidal extension (P = 0.0451), distant metastasis (P = 0.0435), and tall cell variant (P = 0.0271). SKP2 overexpression was also directly associated with X-linked inhibitor of apoptosis protein overexpression (P < 0.0001) and Bcl-xL overexpression (P = 0.0005) and inversely associated with death receptor 5 (P < 0.0001). The cotreatment of bortezomib and TRAIL synergistically induced apoptosis via mitochondrial apoptotic pathway in PTC cell lines. Furthermore, bortezomib and TRAIL synergistically induced reactive oxygen species (ROS) generation and caused death receptor 5 upregulation through activation of the extracellular signal-regulated kinase–C/EBP homologous protein signaling cascade. Finally, bortezomib treatment augmented the TRAIL-mediated anticancer effect on PTC xenograft tumor growth in nude mice.ConclusionThese data suggest that SKP2 is a potential therapeutic target in PTC and that a combination of bortezomib and TRAIL might be a viable therapeutic option for the treatment of patients with aggressive PTC.
      PubDate: Thu, 28 Dec 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-02178
      Issue No: Vol. 103, No. 4 (2017)
  • In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic
           Neuroendocrine Tumors in von Hippel–Lindau Disease
    • Authors: Tirosh A; el Lakis M, Green P, et al.
      Pages: 1631 - 1638
      Abstract: ContextPatients with von Hippel–Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types.ObjectiveTo define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype.DesignA prospective natural history study.SettingThe National Institutes of Health clinical center.PatientsPatients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations.InterventionIn-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)].Main Outcome MeasureRates of metastases, surgical intervention, and disease progression.ResultsSixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients.ConclusionsComputational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.
      PubDate: Tue, 26 Dec 2017 00:00:00 GMT
      DOI: 10.1210/jc.2017-02434
      Issue No: Vol. 103, No. 4 (2017)
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