Rose G. Radin, L. Sjaarda, N. Perkins, R. Silver, Zhen Chen, Laurie L. Lesher, N. Galai, J. Wactawski‐Wende, S. Mumford, E. Schisterman
Context Among women with a single, recent pregnancy loss, daily preconception low-dose aspirin (LDA) increased the live birth rate with no effect on pregnancy loss. Ovulation is a potential mechanism underlying this effect. Objective We estimated the effect of LDA on the per-cycle risk of anovulation among eumenorrheic women. Design Multicenter, randomized, double-blind, placebo-controlled trial of daily LDA on reproductive outcomes. Preconception follow-up lasted 1 to 6 menstrual cycles (ClinicalTrials.gov, NCT00467363). Setting Four US medical centers during 2007 to 2011. Patients or Other Participants Healthy women (n = 1214), age 18 to 40, were attempting pregnancy, had regular menstrual cycles (21 to 42 days), and had a history of 1 to 2 documented pregnancy losses, ≤2 live births, and no infertility. All participants completed at least 1 menstrual cycle of follow-up; none withdrew due to adverse events. Intervention Aspirin (81 mg) daily for 1 to 6 menstrual cycles. Main Outcome Measure Per-cycle risk of anovulation, defined as the absence of both a positive spot-urine pregnancy test and a luteinizing hormone (LH) peak (2.5-fold increase in daily urinary LH). Hypothesis formulation preceded data collection. Results Among 4340 cycles, LDA was not associated with anovulation (LDA: 13.4%, placebo: 11.1%; risk ratio = 1.16, 95% confidence interval, 0.88 to 1.52). Results were similar among women with a single, recent loss. Conclusions Daily LDA had no effect on anovulation among women with a history of 1 to 2 pregnancy losses. LDA may affect fertility via other pathways, and these warrant further study.
{"title":"Low-Dose Aspirin and Sporadic Anovulation in the EAGeR Randomized Trial","authors":"Rose G. Radin, L. Sjaarda, N. Perkins, R. Silver, Zhen Chen, Laurie L. Lesher, N. Galai, J. Wactawski‐Wende, S. Mumford, E. Schisterman","doi":"10.1210/jc.2016-2095","DOIUrl":"https://doi.org/10.1210/jc.2016-2095","url":null,"abstract":"Context Among women with a single, recent pregnancy loss, daily preconception low-dose aspirin (LDA) increased the live birth rate with no effect on pregnancy loss. Ovulation is a potential mechanism underlying this effect. Objective We estimated the effect of LDA on the per-cycle risk of anovulation among eumenorrheic women. Design Multicenter, randomized, double-blind, placebo-controlled trial of daily LDA on reproductive outcomes. Preconception follow-up lasted 1 to 6 menstrual cycles (ClinicalTrials.gov, NCT00467363). Setting Four US medical centers during 2007 to 2011. Patients or Other Participants Healthy women (n = 1214), age 18 to 40, were attempting pregnancy, had regular menstrual cycles (21 to 42 days), and had a history of 1 to 2 documented pregnancy losses, ≤2 live births, and no infertility. All participants completed at least 1 menstrual cycle of follow-up; none withdrew due to adverse events. Intervention Aspirin (81 mg) daily for 1 to 6 menstrual cycles. Main Outcome Measure Per-cycle risk of anovulation, defined as the absence of both a positive spot-urine pregnancy test and a luteinizing hormone (LH) peak (2.5-fold increase in daily urinary LH). Hypothesis formulation preceded data collection. Results Among 4340 cycles, LDA was not associated with anovulation (LDA: 13.4%, placebo: 11.1%; risk ratio = 1.16, 95% confidence interval, 0.88 to 1.52). Results were similar among women with a single, recent loss. Conclusions Daily LDA had no effect on anovulation among women with a history of 1 to 2 pregnancy losses. LDA may affect fertility via other pathways, and these warrant further study.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"17 1","pages":"86–92"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84465948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Kaplan, G. Strizich, Chino Aneke-Nash, Clara P Domínguez-Islas, P. Bůžková, H. Strickler, T. Rohan, M. Pollak, L. Kuller, J. Kizer, A. Cappola, Christopher I. Li, B. Psaty, A. Newman
Context Multiple diseases may explain the association of the growth hormone/insulinlike growth factor-I (GH/IGF-I) axis with longevity. Objective To relate circulating GH/IGF-I system protein levels with major health events. Design and Setting This is a cohort study set in 4 US communities. Participants Adults (N = 2268) 65 years and older free of diabetes and cardiovascular disease. Measurements We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiological covariates. Results During 13,930 person-years of follow-up, 48.1% of individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-hour ghrelin were associated with 27% higher (95% confidence interval [CI]: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-hour IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite end point. Similarly, higher mortality was significantly associated with higher fasting and 2-hour ghrelin levels and with 2-hour IGFBP-1 level. When examined together, 2-hour post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels. Conclusions Circulating IGFBP-1 and ghrelin measured during an OGTT predicted major health events and death in older adults, which may explain the influence of the GH/IGF-I axis on lifespan and health.
{"title":"Insulinlike Growth Factor Binding Protein-1 and Ghrelin Predict Health Outcomes Among Older Adults: Cardiovascular Health Study Cohort","authors":"R. Kaplan, G. Strizich, Chino Aneke-Nash, Clara P Domínguez-Islas, P. Bůžková, H. Strickler, T. Rohan, M. Pollak, L. Kuller, J. Kizer, A. Cappola, Christopher I. Li, B. Psaty, A. Newman","doi":"10.1210/jc.2016-2779","DOIUrl":"https://doi.org/10.1210/jc.2016-2779","url":null,"abstract":"Context Multiple diseases may explain the association of the growth hormone/insulinlike growth factor-I (GH/IGF-I) axis with longevity. Objective To relate circulating GH/IGF-I system protein levels with major health events. Design and Setting This is a cohort study set in 4 US communities. Participants Adults (N = 2268) 65 years and older free of diabetes and cardiovascular disease. Measurements We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiological covariates. Results During 13,930 person-years of follow-up, 48.1% of individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-hour ghrelin were associated with 27% higher (95% confidence interval [CI]: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-hour IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite end point. Similarly, higher mortality was significantly associated with higher fasting and 2-hour ghrelin levels and with 2-hour IGFBP-1 level. When examined together, 2-hour post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels. Conclusions Circulating IGFBP-1 and ghrelin measured during an OGTT predicted major health events and death in older adults, which may explain the influence of the GH/IGF-I axis on lifespan and health.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"40 1","pages":"267–278"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75457832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Context Hypercalciuria is an adverse event of postsurgical hypoparathyroidism treatment that can lead to renal complications. The collection of 24-hour urine to detect hypercalciuria is often considered unreliable. Objective The purpose of this study was to find useful predictive biomarkers of hypercalciuria in patients with permanent postsurgical hypoparathyroidism receiving treatment with oral calcium and calcitriol supplements. Design and Setting The investigation was designed as a prospective cross-sectional study. An outpatient hospital clinic served as the study setting. Patients Fifty-four consecutive observations were made of 34 stable outpatients with postsurgical hypoparathyroidism taking oral calcium and calcitriol supplements, and 17 adult controls without hypoparathyroidism. Intervention There were no interventions. Main Outcome Measure Hypercalciuria was defined as 24-hour urine calcium >300 mg. Results Patients without hypercalciuria (n = 21) vs those with hypercalciuria (n = 33) had lower levels of serum 1,25-dihydroxyvitamin D (33.5 ± 11.9 pg/mL vs 45.8 ± 9.5 pg/mL; P < 0.001), similar albumin-corrected serum calcium (8.3 ± 0.5 vs 8.6 ± 0.5 mg/dL; P = nonsignificant), and serum parathyroid hormone (12.5 ± 5.7 vs 10.7 ± 6.8 pg/mL; P = nonsignificant). Multiple linear regression analysis showed an independent relationship between 1,25-dihydroxyvitamin D and urinary calcium excretion (B = 6.2 ± 1.423; P < 0.001). A cutoff value of 33.5 pg/mL for serum 1,25-dihydroxyvitamin D to predict the absence of hypercalciuria had 100% sensitivity and 63.6% specificity, and the area under the receiver operating characteristic curve was 0.797. No patients with serum 1,25-dihydroxyvitamin D levels of <33.5 pg/mL presented with hypercalciuria, regardless of the level of albumin-corrected serum calcium. Conclusions Routine measurement of serum 1,25-dihydroxyvitamin D may be useful as a biomarker to predict the absence of hypercalciuria in patients with permanent postsurgical hypoparathyroidism who are receiving treatment with oral calcium and calcitriol supplements.
高钙尿症是术后甲状旁腺功能减退治疗的不良事件，可导致肾脏并发症。收集24小时尿液来检测高钙尿通常被认为是不可靠的。目的:本研究的目的是在接受口服钙和骨化三醇补充剂治疗的永久性术后甲状旁腺功能低下患者中寻找有用的高钙尿的预测性生物标志物。本研究设计为前瞻性横断面研究。一家医院门诊作为研究场所。患者:34例稳定的术后甲状旁腺功能减退门诊患者口服钙和骨化三醇补充剂，以及17例无甲状旁腺功能减退的成人对照，进行了54次连续观察。干预没有干预。主要观察指标高钙尿定义为24小时尿钙>300 mg。结果无高钙尿症患者(n = 21)比高钙尿症患者(n = 33)血清1,25-二羟基维生素D水平低(33.5±11.9 pg/mL vs 45.8±9.5 pg/mL);P < 0.001)，相似的白蛋白校正血清钙(8.3±0.5 vs 8.6±0.5 mg/dL;P =无统计学意义)，血清甲状旁腺激素(12.5±5.7 vs 10.7±6.8 pg/mL;P =无显著性)。多元线性回归分析显示1,25-二羟基维生素D与尿钙排泄量之间存在独立关系(B = 6.2±1.423;P < 0.001)。血清1,25-二羟基维生素D预测无高钙尿症的临界值为33.5 pg/mL，敏感性为100%，特异性为63.6%，受试者工作特征曲线下面积为0.797。无论白蛋白校正的血清钙水平如何，血清1,25-二羟基维生素D水平<33.5 pg/mL的患者均未出现高钙尿。结论血清1,25-二羟基维生素D的常规测定可作为预测永久性术后甲状旁腺功能低下患者是否存在高钙尿的生物标志物，这些患者接受口服钙和骨化三醇补充剂治疗。
{"title":"Serum 1,25-Dihydroxyvitamin D as a Biomarker of the Absence of Hypercalciuria in Postsurgical Hypoparathyroidism","authors":"L. García-Pascual, M. Barahona, V. Perea, R. Simó","doi":"10.1210/jc.2016-2987","DOIUrl":"https://doi.org/10.1210/jc.2016-2987","url":null,"abstract":"Context Hypercalciuria is an adverse event of postsurgical hypoparathyroidism treatment that can lead to renal complications. The collection of 24-hour urine to detect hypercalciuria is often considered unreliable. Objective The purpose of this study was to find useful predictive biomarkers of hypercalciuria in patients with permanent postsurgical hypoparathyroidism receiving treatment with oral calcium and calcitriol supplements. Design and Setting The investigation was designed as a prospective cross-sectional study. An outpatient hospital clinic served as the study setting. Patients Fifty-four consecutive observations were made of 34 stable outpatients with postsurgical hypoparathyroidism taking oral calcium and calcitriol supplements, and 17 adult controls without hypoparathyroidism. Intervention There were no interventions. Main Outcome Measure Hypercalciuria was defined as 24-hour urine calcium >300 mg. Results Patients without hypercalciuria (n = 21) vs those with hypercalciuria (n = 33) had lower levels of serum 1,25-dihydroxyvitamin D (33.5 ± 11.9 pg/mL vs 45.8 ± 9.5 pg/mL; P < 0.001), similar albumin-corrected serum calcium (8.3 ± 0.5 vs 8.6 ± 0.5 mg/dL; P = nonsignificant), and serum parathyroid hormone (12.5 ± 5.7 vs 10.7 ± 6.8 pg/mL; P = nonsignificant). Multiple linear regression analysis showed an independent relationship between 1,25-dihydroxyvitamin D and urinary calcium excretion (B = 6.2 ± 1.423; P < 0.001). A cutoff value of 33.5 pg/mL for serum 1,25-dihydroxyvitamin D to predict the absence of hypercalciuria had 100% sensitivity and 63.6% specificity, and the area under the receiver operating characteristic curve was 0.797. No patients with serum 1,25-dihydroxyvitamin D levels of <33.5 pg/mL presented with hypercalciuria, regardless of the level of albumin-corrected serum calcium. Conclusions Routine measurement of serum 1,25-dihydroxyvitamin D may be useful as a biomarker to predict the absence of hypercalciuria in patients with permanent postsurgical hypoparathyroidism who are receiving treatment with oral calcium and calcitriol supplements.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"4 1","pages":"259–266"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78499751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Enzo Cohen, M. Maghnie, N. Collot, J. Léger, F. Dastot, M. Polak, S. Rose, P. Touraine, P. Duquesnoy, M. Tauber, B. Copin, A. Bertrand, F. Brioude, D. Larizza, T. Edouard, Laura G González Briceño, I. Netchine, I. Oliver-Petit, M. Sobrier, S. Amselem, M. Legendre
Context LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.
{"title":"Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients","authors":"Enzo Cohen, M. Maghnie, N. Collot, J. Léger, F. Dastot, M. Polak, S. Rose, P. Touraine, P. Duquesnoy, M. Tauber, B. Copin, A. Bertrand, F. Brioude, D. Larizza, T. Edouard, Laura G González Briceño, I. Netchine, I. Oliver-Petit, M. Sobrier, S. Amselem, M. Legendre","doi":"10.1210/jc.2016-3158","DOIUrl":"https://doi.org/10.1210/jc.2016-3158","url":null,"abstract":"Context LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"48 1","pages":"290–301"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79093831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Grasemann, N. Unger, M. Hövel, D. Arweiler-Harbeck, R. Herrmann, Michael M. Schündeln, O. Müller, B. Schweiger, E. Lausch, T. Meissner, C. Kiewert, B. Hauffa, N. Shaw
Introduction Juvenile Paget's disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype-phenotype correlation spanning from mild to very severe forms is described. Aim This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.
{"title":"Loss of Functional Osteoprotegerin: More Than a Skeletal Problem","authors":"C. Grasemann, N. Unger, M. Hövel, D. Arweiler-Harbeck, R. Herrmann, Michael M. Schündeln, O. Müller, B. Schweiger, E. Lausch, T. Meissner, C. Kiewert, B. Hauffa, N. Shaw","doi":"10.1210/jc.2016-2905","DOIUrl":"https://doi.org/10.1210/jc.2016-2905","url":null,"abstract":"Introduction Juvenile Paget's disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype-phenotype correlation spanning from mild to very severe forms is described. Aim This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"2 1","pages":"210–219"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89959121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
W. Widdowson, A. McGowan, J. Phelan, G. Boran, J. Reynolds, J. Gibney
Context Intestinal cholesterol metabolism is important in influencing postprandial lipoprotein concentrations, and might be important in the development of vascular disease. Objective This study evaluated associations between expression of intestinal cholesterol metabolism genes, postprandial lipid metabolism, and endothelial function/early vascular disease in human subjects. Design/Patients One hundred patients undergoing routine oesophago-gastro-duodenoscopy were recruited. mRNA levels of Nieman-Pick C1-like 1 protein (NPC1L1), ABC-G5, ABC-G8, ABC-A1, microsomal tissue transport protein (MTTP), and sterol-regulatory element-binding protein (SREBP)-2 were measured in duodenal biopsies using quantitative reverse transcription polymerase chain reaction. Postprandially, serum lipid and glycemic profiles were measured, endothelial function was assessed using fasting, and postprandial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). Subjects were divided into those above and below the median value of relative expression of each gene, and results were compared between the groups. Results There were no between-group differences in demographic variables or classical cardiovascular risks. For all genes, the postprandial triglyceride incremental area under the curve was greater (P < 0.05) in the group with greater expression. Postprandial apolipoprotein B48 (ApoB48) levels were greater (P < 0.05) in groups with greater expression of NPC1L1, ABC-G8, and SREBP-2. For all genes, postprandial but not fasting FMD was lower (P < 0.01) in the group with greater expression. Triglyceride and ApoB48 levels correlated significantly with postprandial FMD. Carotid artery IMT was greater (P < 0.05) in groups with greater expression of MTTP, ABC-A1, and SREBP-2. Conclusion Intestinal cholesterol metabolism gene expression is significantly associated with postprandial increment in triglycerides, intestinal ApoB48, and reduced postprandial FMD. Some genes were also associated with increased IMT. These findings suggest a role of intestinal cholesterol metabolism in development of early vascular disease.
{"title":"Vascular Disease Is Associated With the Expression of Genes for Intestinal Cholesterol Transport and Metabolism","authors":"W. Widdowson, A. McGowan, J. Phelan, G. Boran, J. Reynolds, J. Gibney","doi":"10.1210/jc.2016-2728","DOIUrl":"https://doi.org/10.1210/jc.2016-2728","url":null,"abstract":"Context Intestinal cholesterol metabolism is important in influencing postprandial lipoprotein concentrations, and might be important in the development of vascular disease. Objective This study evaluated associations between expression of intestinal cholesterol metabolism genes, postprandial lipid metabolism, and endothelial function/early vascular disease in human subjects. Design/Patients One hundred patients undergoing routine oesophago-gastro-duodenoscopy were recruited. mRNA levels of Nieman-Pick C1-like 1 protein (NPC1L1), ABC-G5, ABC-G8, ABC-A1, microsomal tissue transport protein (MTTP), and sterol-regulatory element-binding protein (SREBP)-2 were measured in duodenal biopsies using quantitative reverse transcription polymerase chain reaction. Postprandially, serum lipid and glycemic profiles were measured, endothelial function was assessed using fasting, and postprandial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). Subjects were divided into those above and below the median value of relative expression of each gene, and results were compared between the groups. Results There were no between-group differences in demographic variables or classical cardiovascular risks. For all genes, the postprandial triglyceride incremental area under the curve was greater (P < 0.05) in the group with greater expression. Postprandial apolipoprotein B48 (ApoB48) levels were greater (P < 0.05) in groups with greater expression of NPC1L1, ABC-G8, and SREBP-2. For all genes, postprandial but not fasting FMD was lower (P < 0.01) in the group with greater expression. Triglyceride and ApoB48 levels correlated significantly with postprandial FMD. Carotid artery IMT was greater (P < 0.05) in groups with greater expression of MTTP, ABC-A1, and SREBP-2. Conclusion Intestinal cholesterol metabolism gene expression is significantly associated with postprandial increment in triglycerides, intestinal ApoB48, and reduced postprandial FMD. Some genes were also associated with increased IMT. These findings suggest a role of intestinal cholesterol metabolism in development of early vascular disease.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"1 1","pages":"326–335"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82114002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Nockel, Bruna Babic, C. Millo, P. Herscovitch, Dhaval Patel, N. Nilubol, S. Sadowski, Craig S. Cochran, P. Gorden, E. Kebebew
Context Reliable localization of insulinoma is critical for successful treatment. Objective This study compared the accuracy of 68Gallium DOTA-(Tyr3)-octreotate (Ga-DOTATATE) positron emission tomography (PET)/computed tomography (CT) to anatomic imaging modalities, selective arterial secretagogue injection (SASI), and intraoperative ultrasound (IO ultrasound) and palpation for localizing insulinoma in patients who were biochemically cured. Design, Setting, and Patients We conducted a retrospective analysis of 31 patients who had an insulinoma. The results of CT, magnetic resonance imaging (MRI), ultrasound, IO ultrasound, 68Ga-DOTATATE PET/CT, SASI, and operative findings were analyzed. Intervention, Main Outcome Measures, and Results The insulinomas were correctly localized in 17 out of 31 (55%) patients by CT, in 17 out of 28 (61%) by MRI, in 6 out of 28 (21%) by ultrasound, and in 9 out of 10 (90%) by 68Ga-DOTATATE. In 29 of 31 patients (93.5%) who had IO ultrasound, an insulinoma was successfully localized. Thirty patients underwent SASI, and the insulinoma was regionalized in 28 out of 30 patients (93%). In 19 out of 23 patients (83%), manual palpation identified insulinoma. In patients who had all 4 noninvasive imaging studies, CT was concordant with 68Ga-DOTATATE in 6 out of 9 patients (67%), MRI in 8 out of 9 (78%), ultrasound in 0 out of 9; the lesion was only seen by 68Ga-DOTATATE in 1 out of 9 (11%). Conclusions 68Ga-DOTATATE PET/CT identifies most insulinomas and may be considered as an adjunct imaging study when all imaging studies are negative and when a minimally invasive surgical approach is planned.
{"title":"Localization of Insulinoma Using 68Ga-DOTATATE PET/CT Scan","authors":"P. Nockel, Bruna Babic, C. Millo, P. Herscovitch, Dhaval Patel, N. Nilubol, S. Sadowski, Craig S. Cochran, P. Gorden, E. Kebebew","doi":"10.1210/jc.2016-3445","DOIUrl":"https://doi.org/10.1210/jc.2016-3445","url":null,"abstract":"Context Reliable localization of insulinoma is critical for successful treatment. Objective This study compared the accuracy of 68Gallium DOTA-(Tyr3)-octreotate (Ga-DOTATATE) positron emission tomography (PET)/computed tomography (CT) to anatomic imaging modalities, selective arterial secretagogue injection (SASI), and intraoperative ultrasound (IO ultrasound) and palpation for localizing insulinoma in patients who were biochemically cured. Design, Setting, and Patients We conducted a retrospective analysis of 31 patients who had an insulinoma. The results of CT, magnetic resonance imaging (MRI), ultrasound, IO ultrasound, 68Ga-DOTATATE PET/CT, SASI, and operative findings were analyzed. Intervention, Main Outcome Measures, and Results The insulinomas were correctly localized in 17 out of 31 (55%) patients by CT, in 17 out of 28 (61%) by MRI, in 6 out of 28 (21%) by ultrasound, and in 9 out of 10 (90%) by 68Ga-DOTATATE. In 29 of 31 patients (93.5%) who had IO ultrasound, an insulinoma was successfully localized. Thirty patients underwent SASI, and the insulinoma was regionalized in 28 out of 30 patients (93%). In 19 out of 23 patients (83%), manual palpation identified insulinoma. In patients who had all 4 noninvasive imaging studies, CT was concordant with 68Ga-DOTATATE in 6 out of 9 patients (67%), MRI in 8 out of 9 (78%), ultrasound in 0 out of 9; the lesion was only seen by 68Ga-DOTATATE in 1 out of 9 (11%). Conclusions 68Ga-DOTATATE PET/CT identifies most insulinomas and may be considered as an adjunct imaging study when all imaging studies are negative and when a minimally invasive surgical approach is planned.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"26 1","pages":"195–199"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81092364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Kulle, T. Reinehr, G. Šimić-Schleicher, N. Hornig, P. Holterhus
Background Dehydroepiandrosterone sulfate (DHEAS) and 17-hydroxypregnenolone (17OHPreg) are important for understanding the Δ5 pathway (e.g., in adrenarche and obesity). Although mass spectrometry has become the state-of-the-art method for quantifying steroids, there are few comprehensive age-, sex-, and pubertal stage-specific reference ranges for children. Aims To develop a sensitive and reliable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of DHEAS and 17OHPreg and to establish entire age-, sex- and pubertal stage-specific reference ranges in children. Methods A total of 684 children, 453 (243 female, 210 male) with normal body mass index (BMI; <90th) and 231 (132 female, 99 male) obese subjects (>97th), were categorized into 11 age groups, and age- and Tanner stage (PH)-specific reference ranges were determined. Results The limit of detection was 0.05 nmol/L for 17OHPreg and 0.5 nmol/L for DHEAS. Levels of both steroids declined after the neonatal period. Comparisons with RIA assays (Siemens, Munich, Germany) (DHEAS) and an in-house kit (17OHPreg) revealed 0.95 and 0.93, respectively, as coefficients of determination. Although DHEAS-generally higher in boys-increased continuously starting at 3 to 6 years, 17OHPreg remained largely constant. In obese patients, both were significantly elevated, also in part after alignment to Tanner stages (PH). Conclusions UPLC-MS/MS is sensitive and reliable for quantifying DHEAS and 17OHPreg. Our data support differential maturation of CYP17 during adrenarche with successively increasing 17,20-lyase activity but largely constant 17α-hydroxylation activity. Endocrine interpretation of 17OHPreg and DHEAS must consider differential patterns for age, sex, pubertal stage, and BMI.
{"title":"Determination of 17OHPreg and DHEAS by LC-MS/MS: Impact of Age, Sex, Pubertal Stage, and BMI on the &Dgr;5 Steroid Pathway","authors":"A. Kulle, T. Reinehr, G. Šimić-Schleicher, N. Hornig, P. Holterhus","doi":"10.1210/jc.2016-2849","DOIUrl":"https://doi.org/10.1210/jc.2016-2849","url":null,"abstract":"Background Dehydroepiandrosterone sulfate (DHEAS) and 17-hydroxypregnenolone (17OHPreg) are important for understanding the Δ5 pathway (e.g., in adrenarche and obesity). Although mass spectrometry has become the state-of-the-art method for quantifying steroids, there are few comprehensive age-, sex-, and pubertal stage-specific reference ranges for children. Aims To develop a sensitive and reliable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of DHEAS and 17OHPreg and to establish entire age-, sex- and pubertal stage-specific reference ranges in children. Methods A total of 684 children, 453 (243 female, 210 male) with normal body mass index (BMI; <90th) and 231 (132 female, 99 male) obese subjects (>97th), were categorized into 11 age groups, and age- and Tanner stage (PH)-specific reference ranges were determined. Results The limit of detection was 0.05 nmol/L for 17OHPreg and 0.5 nmol/L for DHEAS. Levels of both steroids declined after the neonatal period. Comparisons with RIA assays (Siemens, Munich, Germany) (DHEAS) and an in-house kit (17OHPreg) revealed 0.95 and 0.93, respectively, as coefficients of determination. Although DHEAS-generally higher in boys-increased continuously starting at 3 to 6 years, 17OHPreg remained largely constant. In obese patients, both were significantly elevated, also in part after alignment to Tanner stages (PH). Conclusions UPLC-MS/MS is sensitive and reliable for quantifying DHEAS and 17OHPreg. Our data support differential maturation of CYP17 during adrenarche with successively increasing 17,20-lyase activity but largely constant 17α-hydroxylation activity. Endocrine interpretation of 17OHPreg and DHEAS must consider differential patterns for age, sex, pubertal stage, and BMI.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"12 1","pages":"232–241"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90509508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Stinca, M. Andersson, S. Weibel, I. Herter-Aeberli, R. Fingerhut, S. Gowachirapant, S. Hess, N. Jaiswal, T. Jukić, Z. Kusic, N. Mabapa, A. Nepal, Teofilo O L San Luis, J. Zhen, M. Zimmermann
Context Thyroglobulin (Tg) could be a sensitive biomarker of iodine nutrition in pregnant women (PW). A dried blood spot (DBS) assay would simplify collection and transport in field studies. Objectives Our aims were to (1) establish and test a reference range for DBS-Tg in PW; (2) determine whether co-measurement of Tg antibodies (Abs) is necessary to define population iodine status. Design, Setting, and Participants Standardized cross-sectional studies of 3870 PW from 11 countries. For the DBS-Tg reference range, we included TgAb-negative PW (n = 599) from 3 countries with sufficient iodine intake. Main Outcome Measures We measured the urinary iodine concentration and DBS thyroid-stimulating hormone, total thyroxin, Tg, and TgAb. Results In the reference population, the median DBS-Tg was 9.2 μg/L (95% confidence interval, 8.7 to 9.8 μg/L) and was not significantly different among trimesters. The reference range was 0.3 to 43.5 μg/L. Over a range of iodine intake, the Tg concentrations were U-shaped. Within countries, the median DBS-Tg and the presence of elevated DBS-Tg did not differ significantly between all PW and PW who were TgAb-negative. Conclusions A median DBS-Tg of ∼10 μg/L with <3% of values ≥44 μg/L indicated population iodine sufficiency. Concurrent measurement of TgAb did not appear necessary to assess the population iodine status.
{"title":"Dried Blood Spot Thyroglobulin as a Biomarker of Iodine Status in Pregnant Women","authors":"S. Stinca, M. Andersson, S. Weibel, I. Herter-Aeberli, R. Fingerhut, S. Gowachirapant, S. Hess, N. Jaiswal, T. Jukić, Z. Kusic, N. Mabapa, A. Nepal, Teofilo O L San Luis, J. Zhen, M. Zimmermann","doi":"10.1210/jc.2016-2829","DOIUrl":"https://doi.org/10.1210/jc.2016-2829","url":null,"abstract":"Context Thyroglobulin (Tg) could be a sensitive biomarker of iodine nutrition in pregnant women (PW). A dried blood spot (DBS) assay would simplify collection and transport in field studies. Objectives Our aims were to (1) establish and test a reference range for DBS-Tg in PW; (2) determine whether co-measurement of Tg antibodies (Abs) is necessary to define population iodine status. Design, Setting, and Participants Standardized cross-sectional studies of 3870 PW from 11 countries. For the DBS-Tg reference range, we included TgAb-negative PW (n = 599) from 3 countries with sufficient iodine intake. Main Outcome Measures We measured the urinary iodine concentration and DBS thyroid-stimulating hormone, total thyroxin, Tg, and TgAb. Results In the reference population, the median DBS-Tg was 9.2 μg/L (95% confidence interval, 8.7 to 9.8 μg/L) and was not significantly different among trimesters. The reference range was 0.3 to 43.5 μg/L. Over a range of iodine intake, the Tg concentrations were U-shaped. Within countries, the median DBS-Tg and the presence of elevated DBS-Tg did not differ significantly between all PW and PW who were TgAb-negative. Conclusions A median DBS-Tg of ∼10 μg/L with <3% of values ≥44 μg/L indicated population iodine sufficiency. Concurrent measurement of TgAb did not appear necessary to assess the population iodine status.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"7 1","pages":"23–32"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89961261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Entringer, C. Buss, J. Rasmussen, K. Lindsay, D. Gillen, D. Cooper, P. Wadhwa
Context Glucocorticoids play a key role during intrauterine development in cellular growth and differentiation. Evidence suggests that exposure to inappropriate concentrations of glucocorticoids during sensitive developmental periods may produce alterations in physiological systems that impact obesity risk. Objective To elucidate the magnitude and stage-of-gestation-specific association of maternal cortisol concentrations during pregnancy with infant adiposity. Design, Participants, and Setting Sixty-seven mother-child dyads recruited in early pregnancy at university-based obstetric clinics in Southern California were followed with serial assessments from early gestation through birth until 6 months postnatal age. Maternal cumulative cortisol production was assessed over each of 4 consecutive days in early (≅13 weeks), mid (≅24 weeks), and late pregnancy (≅30 weeks) (5 saliva samples/d × 4 days × 3 trimesters = 60 saliva samples/subject). Infant body composition was serially assessed in newborns (at ∼25 days postnatal age) and at ∼6 months age with dual-energy X-ray absorptiometry imaging. Results After adjusting for key prenatal, birth, and postnatal covariates, higher maternal cortisol during the early third trimester (conditioned on prior early and midgestation cortisol concentrations) was significantly associated with a greater change in infant percent body fat from 1 to 6 months of age [partial r (adjusted for covariates) = 0.379, P = 0.007], accounting for ∼14% of the variance in this measure of childhood obesity risk. Conclusion The present findings suggest a stage-of-gestation-specific effect of maternal cortisol on infant adiposity gain in early postnatal life and provide evidence in humans to support the role of glucocorticoids in fetal programming of childhood obesity risk.
{"title":"Maternal Cortisol During Pregnancy and Infant Adiposity: A Prospective Investigation","authors":"S. Entringer, C. Buss, J. Rasmussen, K. Lindsay, D. Gillen, D. Cooper, P. Wadhwa","doi":"10.1210/jc.2016-3025","DOIUrl":"https://doi.org/10.1210/jc.2016-3025","url":null,"abstract":"Context\u0000Glucocorticoids play a key role during intrauterine development in cellular growth and differentiation. Evidence suggests that exposure to inappropriate concentrations of glucocorticoids during sensitive developmental periods may produce alterations in physiological systems that impact obesity risk.\u0000\u0000\u0000Objective\u0000To elucidate the magnitude and stage-of-gestation-specific association of maternal cortisol concentrations during pregnancy with infant adiposity.\u0000\u0000\u0000Design, Participants, and Setting\u0000Sixty-seven mother-child dyads recruited in early pregnancy at university-based obstetric clinics in Southern California were followed with serial assessments from early gestation through birth until 6 months postnatal age. Maternal cumulative cortisol production was assessed over each of 4 consecutive days in early (≅13 weeks), mid (≅24 weeks), and late pregnancy (≅30 weeks) (5 saliva samples/d × 4 days × 3 trimesters = 60 saliva samples/subject). Infant body composition was serially assessed in newborns (at ∼25 days postnatal age) and at ∼6 months age with dual-energy X-ray absorptiometry imaging.\u0000\u0000\u0000Results\u0000After adjusting for key prenatal, birth, and postnatal covariates, higher maternal cortisol during the early third trimester (conditioned on prior early and midgestation cortisol concentrations) was significantly associated with a greater change in infant percent body fat from 1 to 6 months of age [partial r (adjusted for covariates) = 0.379, P = 0.007], accounting for ∼14% of the variance in this measure of childhood obesity risk.\u0000\u0000\u0000Conclusion\u0000The present findings suggest a stage-of-gestation-specific effect of maternal cortisol on infant adiposity gain in early postnatal life and provide evidence in humans to support the role of glucocorticoids in fetal programming of childhood obesity risk.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"115 1","pages":"1366–1374"},"PeriodicalIF":0.0,"publicationDate":"2016-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88819109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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