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A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis.
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A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):681-688

Authors: Smirin-Yosef P, Zuckerman-Levin N, Tzur S, Granot Y, Cohen L, Sachsenweger J, Borck G, Lagovsky I, Salmon-Divon M, Wiesmüller L, Basel-Vanagaite L

Context: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty.
Objective: To elucidate the cause of ovarian dysfunction in a family with POI.
Design: We performed whole-exome sequencing in 2 affected individuals. To evaluate whether DNA double-strand break (DSB) repair activities are altered in biallelic mutation carriers, we applied an enhanced green fluorescent protein-based assay for the detection of specific DSB repair pathways in blood-derived cells.
Setting: Diagnoses were made at the Pediatric Endocrine Clinic, Clalit Health Services, Sharon-Shomron District, Israel. Genetic counseling and sample collection were performed at the Pediatric Genetics Unit, Schneider Children's Medical Center Israel, Petah Tikva, Israel.
Patients and Intervention: Two sisters born to consanguineous parents of Israeli Muslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples for DNA extraction were obtained from all family members.
Main Outcome Measure: Exome analysis to elucidate the cause of POI in 2 affected sisters.
Results: Analysis revealed a stop-gain homozygous mutation in the SPIDR gene (KIAA0146) c.839G>A, p.W280*. This mutation altered SPIDR activity in homologous recombination, resulting in the accumulation of 53BP1-labeled DSBs postionizing radiation and γH2AX-labeled damage during unperturbed growth.
Conclusions: SPIDR is important for ovarian function in humans. A biallelic mutation in this gene may be associated with ovarian dysgenesis in cases of autosomal recessive inheritance.

PMID: 27967308 [PubMed - indexed for MEDLINE]

Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome.
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Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):604-612

Authors: Gibson-Helm M, Teede H, Dunaif A, Dokras A

Context: Polycystic ovary syndrome (PCOS) is a complex, chronic, and under-recognized disorder. Diagnosis experience may have lasting effects on well-being and self-management.
Objective: To investigate PCOS diagnosis experiences, information provided, and concerns about PCOS.
Design: Cross-sectional study using an online questionnaire.
Setting: Recruitment via support group web sites in 2015 to 2016.
Participants: There were 1385 women with a reported diagnosis of PCOS who were living in North America (53.0%), Europe (42.2%), or other world regions (4.9%); of these, 64.8% were 18 to 35 years of age.
Main Outcome Measures: Satisfaction with PCOS diagnosis experience, satisfaction with PCOS information received at the time of diagnosis, and current concerns about PCOS.
Results: One-third or more of women reported >2 years (33.6%) and ≥3 health professionals (47.1%) before a diagnosis was established. Few were satisfied with their diagnosis experience (35.2%) or with the information they received (15.6%). Satisfaction with information received was positively associated with diagnosis satisfaction [odds ratio (OR), 7.0; 95% confidence interval (CI), 4.9 to 9.9]; seeing ≥5 health professionals (OR, 0.5; 95% CI, 0.3 to 0.8) and longer time to diagnosis (>2 years; OR, 0.4; 95% CI, 0.3 to 0.6) were negatively associated with diagnosis satisfaction (independent of time since diagnosis, age, and world region). Women's most common concerns were difficulty losing weight (53.6%), irregular menstrual cycles (50.8%), and infertility (44.5%).
Conclusions: In the largest study of PCOS diagnosis experiences, many women reported delayed diagnosis and inadequate information. These gaps in early diagnosis, education, and support are clear opportunities for improving patient experience.

PMID: 27906550 [PubMed - indexed for MEDLINE]

Metabolic Syndrome Among Adults in China: The 2010 China Noncommunicable Disease Surveillance.
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Metabolic Syndrome Among Adults in China: The 2010 China Noncommunicable Disease Surveillance.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):507-515

Authors: Lu J, Wang L, Li M, Xu Y, Jiang Y, Wang W, Li J, Mi S, Zhang M, Li Y, Wang T, Xu M, Zhao Z, Dai M, Lai S, Zhao W, Wang L, Bi Y, Ning G, 2010 China Noncommunicable Disease Surveillance Group

Context: In China, data on the prevalence of metabolic syndrome have been rare recently.
Objective: The objective of the study was to evaluate the prevalence of metabolic syndrome and its components in 2010.
Design, Setting, and Participants: The study covered all 31 provinces of mainland China and consisted of a nationally representative population sample of 98,658 Chinese adults aged ≥18 years. Of these, 97,098 participants were eligible for the data analysis reported here.
Main Outcome Measures: Estimates of the prevalence of metabolic syndrome and its components were calculated. To further explore whether metabolic syndrome is associated with the 10-year coronary heart disease risk, sex-stratified logistic regression models were used.
Results: The prevalence of the metabolic syndrome was 33.9% (31.0% in men and 36.8% in women), which indicates that metabolic syndrome affects approximately 454 million adults in China. More than half of total adult population was suffering from low high-density lipoprotein cholesterol (HDL-C), and nearly half of participants had high blood pressure. Abdominal obesity and low HDL-C were more prevalent in women than in men, whereas high blood pressure, high blood glucose, and high triglycerides were more common in men. Metabolic syndrome was associated with a higher 10-year coronary heart disease risk after adjustment for potential risk factors and each component of metabolic syndrome as continuous variables.
Conclusion: Our results showed a high prevalence of metabolic syndrome and its components in the general adult population in mainland China. Metabolic syndrome was independently associated with a higher 10-year risk of developing coronary heart disease.

PMID: 27898293 [PubMed - indexed for MEDLINE]

Teriparatide Treatment in Elderly Patients With Sacral Insufficiency Fracture.
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Teriparatide Treatment in Elderly Patients With Sacral Insufficiency Fracture.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):560-565

Authors: Yoo JI, Ha YC, Ryu HJ, Chang GW, Lee YK, Yoo MJ, Koo KH

Context and Objective: Pain-related immobility because of insufficiency fractures may result in serious complications and a high mortality rate in senile patients with preexisting comorbidities. This study aimed to evaluate the efficacy of teriparatide in patients with sacral insufficiency fractures.
Design, Setting, and Participants: This retrospective, case-controlled, single center study, performed from 2009 to 2014, included 41 patients who underwent radiographs, magnetic resonance imaging, and/or bone scans to document sacral insufficiency fractures.
Intervention: The intervention involved teriparatide at a once-daily subcutaneous dose of 20 μg within 2 days of hospital admission (21 patients). Twenty patients (control group) did not receive teriparatide.
Main Outcome Measures: Functional outcome was assessed using a visual analog scale for pain and the time to mobilization. Pelvic anteroposterior radiographs were repeated at 0, 1, 4, 8, 12, and 16 weeks until radiographic evidence of cortical bridging at the fracture site was confirmed.
Results: From the date of admission to 4 weeks, the mean visual analog scale score improved between the 2 groups. The mean time to mobilization was 1.2 ± 0.4 weeks in patients who received teriparatide treatment, compared with 2.0 ± 0.3 weeks in controls (P < 0.001). At 8 weeks, all fractures in the teriparatide treatment group and 4 fractures in the control group had healed.
Conclusions: In senile patients with preexisting comorbidities who have sacral insufficiency fractures, teriparatide treatment may achieve earlier pain reduction and mobilization and reduce healing time.

PMID: 27880077 [PubMed - indexed for MEDLINE]

Influence of Premature Mortality on the Link Between Type 2 Diabetes and Hip Fracture: The Fremantle Diabetes Study.
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Influence of Premature Mortality on the Link Between Type 2 Diabetes and Hip Fracture: The Fremantle Diabetes Study.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):551-559

Authors: Hamilton E, Davis WA, Bruce DG, Davis TM

Context: Studies of hip fracture complicating diabetes have not considered the effect of premature mortality.
Objective: The aim of our study was to determine influence of the competing risk of death on the association between type 2 diabetes and hip fracture.
Design: The study was designed as a longitudinal observational study.
Setting: The study setting was an urban community.
Patients: Participants included 1291 patients with type 2 diabetes (mean age 64.0 years) and 5159 matched residents without diabetes.
Main Outcome Measures: Primary outcome measures were incident hip fracture hospitalizations and deaths. Hip fracture risk was assessed using proportional hazards and competing risk regression modeling.
Results: During a mean of 14.1 years of follow-up, the incidence rate ratio for first hip fracture hospitalization in participants with vs without diabetes was 1.33 [95% confidence interval (CI), 1.05 to 1.68; P = 0.013]. Type 2 diabetes was associated with a cause-specific hazard ratio (csHR) for hip fracture of 1.50 (95% CI, 1.19 to 1.89; P < 0.001) and a subdistribution hazard ratio (sdHR) of 1.21 (95% CI, 0.96 to 1.52; P = 0.11) after adjustment for age, sex, and comorbidities. In patients with diabetes, significant csHRs for incident hip fracture were male sex (protective), body mass index (protective), insulin use, and renal impairment. These variables, with increasing age, also had significant sdHRs.
Conclusions: The diabetes-associated risk of hip fracture is attenuated after allowing for the competing risk of death. Risk factors for hip fracture in diabetes were those in reported in general population studies plus insulin use.

PMID: 27880070 [PubMed - indexed for MEDLINE]

Cortical Bone Area Predicts Incident Fractures Independently of Areal Bone Mineral Density in Older Men.
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Cortical Bone Area Predicts Incident Fractures Independently of Areal Bone Mineral Density in Older Men.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):516-524

Authors: Ohlsson C, Sundh D, Wallerek A, Nilsson M, Karlsson M, Johansson H, Mellström D, Lorentzon M

Context: Areal bone mineral density (aBMD) measured using dual-energy X-ray absorptiometry (DXA) is used clinically to predict fracture but does not discriminate between trabecular and cortical bone assessment.
Objective: This study aimed to investigate whether information on cortical and trabecular bone predict fracture risk independently of aBMD and clinical risk factors.
Design and Participants: Cortical area, bone mass, porosity, and trabecular bone volume fraction (BVTV) were measured at the tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT) in 456 men (80.2 ± 3.5 years) recruited from the general population in Gothenburg, Sweden. aBMD was measured using DXA. Incident fractures (71 men) were X-ray verified. Associations were evaluated using Cox regression.
Results: Cortical area [hazard ratio (HR) per standard deviation (SD) decrease, 2.05; 95% confidence interval (CI), 1.58 to 2.65], cortical bone mass (HR, 2.07; 95% CI, 1.58 to 2.70), and BVTV (HR, 1.62; 95% CI, 1.26 to 2.07), but not cortical porosity, were independently associated with fracture risk. These associations remained after adjustment for femoral neck aBMD and Fracture Risk Assessment risk factors (area: HR 1.96, 95% CI, 1.44 to 2.66; mass: HR 1.99, 95% CI, 1.45 to 2.74; BV/TV: HR 1.46, 95% CI, 1.09 to 1.96). After entering BV/TV and cortical area or bone mass simultaneously in the adjusted models, only the cortical parameters remained important predictors of fracture.
Conclusion: HR-pQCT measurement of cortical area and mass might add clinically useful information for the evaluation of fracture risk.

PMID: 27875059 [PubMed - indexed for MEDLINE]

17β-Estradiol Enhances Vascular Endothelial Ets-1/miR-126-3p Expression: The Possible Mechanism for Attenuation of Atherosclerosis.
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17β-Estradiol Enhances Vascular Endothelial Ets-1/miR-126-3p Expression: The Possible Mechanism for Attenuation of Atherosclerosis.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):594-603

Authors: Li P, Wei J, Li X, Cheng Y, Chen W, Cui Y, Simoncini T, Gu Z, Yang J, Fu X

Context: Endothelial microRNA 126 (miR-126) attenuates the development of atherosclerosis (AS). However, there is no evidence showing the role of miR-126 in estrogen's antiatherogenic effects.
Objective: We hypothesized that 17β-estradiol (E2) modulates miR-126 expression and thus may improve endothelial function and retard AS development.
Design/Setting/Participants: This was a prospective cohort study of 12 healthy regularly menstruating female volunteers. ApoE-/- mice were used as the atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as the cell model.
Main Outcome Measures: Serum hormones and miR-126-3p levels were measured up to 3 times for 1 cycle. Real-time polymerase chain reaction, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, cell proliferation, migration and tube formation assay, and western blot were performed.
Results: Serum concentrations of miR-126-3p in cycling women were higher at the ovulatory and luteal phases than in the follicular phase, and they were positively correlated with E2 values. Administration of miR-126-3p mimics to ApoE-/- mice-attenuated atherogenesis, and antagomir-126-3p partially reversed the protective effect of E2 on atherogenesis. In HUVECs, E2 increased miR-126-3p expression via upregulation of Ets-1 (a transcription factor for miR-126). c-Src/Akt signaling was important for E2-mediated expression of Ets-1/miR-126. E2 decreased expression of miR-126-3p target Spred1 (a protein that inhibits mitogenic signaling). Overexpression of Spred1 partially blocked enhancement of endothelial cell proliferation, migration, and tube formation by E2. Additionally, E2 regulates miR-126-3p-mediated expression of vascular cell adhesion molecule-1 to inhibit monocyte adhesion into HUVECs.
Conclusions: E2 protection against atherogenesis is possibly mediated by Ets-1/miR-126.

PMID: 27870587 [PubMed - indexed for MEDLINE]

Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial.
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Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):698-707

Authors: Schneider TC, de Wit D, Links TP, van Erp NP, van der Hoeven JJ, Gelderblom H, Roozen IC, Bos M, Corver WE, van Wezel T, Smit JW, Morreau H, Guchelaar HJ, Kapiteijn E

Background: Mammalian target of rapamycin (mTOR) upregulation has been reported to be involved in the pathogenesis of thyroid tumors, and treatment with the mTOR inhibitor everolimus has shown promising results in endocrine tumors. We conducted a prospective phase II clinical trial to determine the efficacy and safety of everolimus in patients with advanced follicular-derived thyroid cancer.
Patients and Methods: Twenty-eight patients with progressive metastatic or locally advanced radioactive refractory differentiated thyroid cancer and 7 patients with anaplastic thyroid cancer were included and received everolimus 10 mg orally once daily. The primary endpoint was disease control rate [complete (CR) + partial response (PR) + stable disease (SD) > 24 weeks]. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and mutational and pharmacokinetic-related outcomes.
Results: Median follow-up duration was 38 months (2-64). Seventeen patients (65%) showed SD, of which 15 (58%) showed SD >24 weeks. No CR or PR was observed. Median PFS and OS were 9 [95% confidence interval (CI): 4 to 14] and 18 (95% CI: 7 to 29) months, respectively. Survival was negatively influenced by the presence of bone metastases. Toxicity was predominantly grade 1/2 and included anemia (64%), cough (64%), stomatitis (61%), and hyperglycemia (61%). Duration of SD was related to everolimus exposure. The presence of somatic gene variants related to mTOR signaling did not clearly stratify for responses.
Conclusion: Everolimus has clinically relevant antitumor activity in patients with advanced differentiated thyroid cancer. Given the observed disease control rate and the relatively low toxicity profile, further investigation of everolimus in sequential or combination therapy in these patients is warranted.

PMID: 27870581 [PubMed - indexed for MEDLINE]

Hepatitis C Virus E2 Protein Induces Upregulation of IL-8 Pathways and Production of Heat Shock Proteins in Human Thyroid Cells.
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Hepatitis C Virus E2 Protein Induces Upregulation of IL-8 Pathways and Production of Heat Shock Proteins in Human Thyroid Cells.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):689-697

Authors: Hammerstad SS, Stefan M, Blackard J, Owen RP, Lee HJ, Concepcion E, Yi Z, Zhang W, Tomer Y

Context: Thyroiditis is one of the most common extrahepatic manifestations of hepatitis C virus (HCV) infection. By binding to surface cell receptor CD81, HCV envelope glycoprotein E2 mediates entry of HCV into cells. Studies have shown that different viral proteins may individually induce host responses to infection. We hypothesized that HCV E2 protein binding to CD81 expressed on thyroid cells activates a cascade of inflammatory responses that can trigger autoimmune thyroiditis in susceptible individuals.
Setting: Human thyroid cell lines ML-1 and human thyrocytes in primary cell culture were treated with HCV recombinant E2 protein. The expression of major proinflammatory cytokines was measured at the messenger RNA and protein levels. Next-generation transcriptome analysis was used to identify early changes in gene expression in thyroid cells induced by E2.
Results: HCV envelope protein E2 induced strong inflammatory responses in human thyrocytes, resulting in production of interleukin (IL)-8, IL-6, and tumor necrosis factor-α. Furthermore, the E2 protein induced production of several heat shock proteins including HSP60, HSP70p12A, and HSP10, in human primary thyrocytes. In thyroid cell line ML-1, RNA sequencing identified upregulation of molecules involved in innate immune pathways with high levels of proinflammatory cytokines and chemokines and increased expression of costimulatory molecules, specifically CD40, known to be a major thyroid autoimmunity gene.
Conclusion: Our data support a key role for HCV envelope protein E2 in triggering thyroid autoimmunity through activation of cytokine pathways by bystander mechanisms.

PMID: 27860532 [PubMed - indexed for MEDLINE]

Whole-Exome Sequencing Study of Thyrotropin-Secreting Pituitary Adenomas.
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Whole-Exome Sequencing Study of Thyrotropin-Secreting Pituitary Adenomas.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):566-575

Authors: Sapkota S, Horiguchi K, Tosaka M, Yamada S, Yamada M

Context: Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism, and the genetic aberrations responsible remain unknown.
Objective: To identify somatic genetic abnormalities in TSHomas.
Design and Setting: A single-nucleotide polymorphism (SNP) array analysis was performed on 8 TSHomas. Four tumors with no allelic losses or limited loss of heterozygosity were selected, and whole-exome sequencing was performed, including their corresponding blood samples. Somatic variants were confirmed by Sanger sequencing. A set of 8 tumors was also assessed to validate candidate genes.
Patients: Twelve patients with sporadic TSHomas were examined.
Results: The overall performance of whole-exome sequencing was good, with an average coverage of each base in the targeted region of 97.6%. Six DNA variants were confirmed as candidate driver mutations, with an average of 1.5 somatic mutations per tumor. No mutations were recurrent. Two of these mutations were found in genes with an established role in malignant tumorigenesis (SMOX and SYTL3), and 4 had unknown roles (ZSCAN23, ASTN2, R3HDM2, and CWH43). Similarly, an SNP array analysis revealed frequent chromosomal regions of copy number gains, including recurrent gains at loci harboring 4 of these 6 genes.
Conclusions: Several candidate somatic mutations and changes in copy numbers for TSHomas were identified. The results showed no recurrence of mutations in the tumors studied but a low number of mutations, thereby highlighting their benign nature. Further studies on a larger cohort of TSHomas, along with the use of epigenetic and transcriptomic approaches, may reveal the underlying genetic lesions.

PMID: 27854551 [PubMed - indexed for MEDLINE]

Expression and Function of the Costimulatory Receptor SLAMF1 Is Altered in Lymphocytes From Patients With Autoimmune Thyroiditis.
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Expression and Function of the Costimulatory Receptor SLAMF1 Is Altered in Lymphocytes From Patients With Autoimmune Thyroiditis.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):672-680

Authors: Vitales-Noyola M, Ramos-Levi AM, Serrano-Somavilla A, Martínez-Hernández R, Sampedro-Nuñez M, Di Pasquale C, González-Amaro R, Marazuela M

Context: Signaling lymphocytic activation molecule family 1 (SLAMF1) is a costimulatory receptor expressed by most immune cells. Its role in autoimmune thyroid disease (AITD) is not well known.
Objective: To analyze the expression and function of the costimulatory receptor SLAMF1 in lymphocytes of patients with AITD.
Design: Cross-sectional, prospective, single-center study.
Setting: Department of Endocrinology, Hospital Universitario de la Princesa, Madrid.
Patients: Twenty-eight patients with AITD (17 with Graves disease and 11 with Hashimoto thyroiditis) and 21 controls.
Intervention: Multiparametric flow cytometry and immunofluorescence techniques to analyze the expression of SLAMF1 in peripheral blood (n = 28) and thyroid tissue (n = 5) mononuclear cells. Assay of inhibition of cellular proliferation to study the function of SLAMF1 in CD4+CD25+ T regulatory (Treg) cells.
Main Outcome Measure: Expression levels and the function of SLAMF1 in lymphocytes in AITD patients and controls.
Results: Expression of SLAMF1 was significantly increased in peripheral blood CD4+, T helper 17, and CD19+ B cells from AITD patients. Immunofluorescence microscopy detected the presence of SLAMF1+ lymphocytes in thyroid inflammatory cell infiltrate. Functional studies showed that SLAMF1 engagement in Treg cells increased their suppressive function in healthy controls but not in AITD patients.
Conclusions: The altered expression of SLAMF1, as well as its defective function observed in patients with AITD, may have a relevant role in the defective immune-regulatory function observed in this condition.

PMID: 27854550 [PubMed - indexed for MEDLINE]

The Benefit of Menopausal Hormone Therapy on Bone Density and Microarchitecture Persists After its Withdrawal.
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The Benefit of Menopausal Hormone Therapy on Bone Density and Microarchitecture Persists After its Withdrawal.

J Clin Endocrinol Metab. 2016 Dec;101(12):5004-5011

Authors: Papadakis G, Hans D, Gonzalez-Rodriguez E, Vollenweider P, Waeber G, Marques-Vidal PM, Lamy O

CONTEXT: Menopausal hormone therapy (MHT) favorably affects bone mineral density (BMD). Whether MHT also affects bone microarchitecture, as assessed by trabecular bone score (TBS), has never been evaluated.
OBJECTIVE: Our objective was to assess the effect of MHT on TBS and BMD before and after its withdrawal.
DESIGN: This was a cross-sectional study.
SETTING: This study included the general community.
PATIENTS OR OTHER PARTICIPANTS: Data were collected from the OsteoLaus cohort (1500 women aged 50-80 years). After exclusion of women with bone-modulating treatments, 1279 women were categorized according to MHT status into current (CU), past (PU), and never (NU) users.
MAIN OUTCOME MEASURE(S): Spine TBS and BMD at lumbar spine, femoral neck, and total hip were assessed by dual X-ray absorptiometry.
RESULTS: Age- and body mass index-adjusted analysis showed higher TBS values in CU vs PU or NU (1.31 ± 0.01, 1.29 ± 0.01, and 1.27 ± 0.01, respectively; P < .001). All BMD values were significantly higher in CU vs PU or NU. Compared to NU, PU exhibited higher lumbar spine (0.94 ± 0.01 vs 0.91 ± 0.01 g/cm(2); P = .017) and total hip (0.86 ± 0.01 vs 0.84 ± 0.01 g/cm(2); P = .026) BMD and a trend for higher TBS (P = .066). The 10-year loss of TBS and BMD at lumbar spine and total hip was significantly lower for both CU and PU vs NU. MHT duration had no effect on bone parameters. In PU, the residual effect on TBS and BMD was significantly more prominent in early discontinuers (<2 years).
CONCLUSION: MHT is associated with bone microarchitecture preservation, as assessed by TBS. The effect of MHT on TBS and BMD persists at least 2 years after withdrawal.

PMID: 27854548 [PubMed - indexed for MEDLINE]

Germline Polymorphisms of the VEGF Pathway Predict Recurrence in Nonadvanced Differentiated Thyroid Cancer.
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Germline Polymorphisms of the VEGF Pathway Predict Recurrence in Nonadvanced Differentiated Thyroid Cancer.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):661-671

Authors: Marotta V, Sciammarella C, Capasso M, Testori A, Pivonello C, Chiofalo MG, Gambardella C, Grasso M, Antonino A, Annunziata A, Macchia PE, Pivonello R, Santini L, Botti G, Losito S, Pezzullo L, Colao A, Faggiano A

Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors.
Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD).
Design: Multicenter, retrospective, observational study.
Setting: Four referral centers.
Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (-2578C>A, -460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining.
Outcome Measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype.
Results: Two hundred four patients with stage I-II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two "risk" genotypes were identified by combining VEGF-A SNPs -2578 C>A, -460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I-II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I-II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024).
Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.

PMID: 27849428 [PubMed - indexed for MEDLINE]

ITM2A Expands Evidence for Genetic and Environmental Interaction in Graves Disease Pathogenesis.
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ITM2A Expands Evidence for Genetic and Environmental Interaction in Graves Disease Pathogenesis.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):652-660

Authors: Ye XP, Yuan FF, Zhang LL, Ma YR, Zhang MM, Liu W, Sun F, Wu J, Lu M, Xue LQ, Shi JY, Zhao SX, Song HD, Liang J, Zheng CX, China Consortium for the Genetics of Autoimmune Thyroid Disease

Context: Graves disease (GD) is a common autoimmune disease triggered by genetic predisposition and environmental factors. However, the mechanisms of interaction between genetic and environmental factors contributing to the development of GD remain unknown.
Objective: We aimed to identify GD susceptibility variants and genes on Xq21.1 locus and interpret the contribution of interaction between genetic predisposition on Xq21.1 and environmental factors to GD.
Design: We performed refining study on Xq21.1 in a 2-stage study and carried out expression quantitative trait locus analysis of the best association signal with GD.
Setting and Participants: A total of 4316 GD patients and 4374 sex-matched controls were collected from the Chinese Han population by cooperation with multiple hospitals.
Results: We identified that rs3827440 or its linkage single nucleotide polymorphisms (SNPs) were probably the causal variant in the Xq21.1 locus, with the most substantial association with GD in our combined cohorts (P = 2.45 × 10-15). The genotypes of rs3827440 were correlated with the expression of ITM2A in monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Notably, the expression of ITM2A in monocytes after lipopolysaccharide (LPS) and interferon-γ (INF-γ) stimulation showed substantial difference among the volunteers that carried different genotypes of rs3827440 (P = 9.40 × 10-7 and P = 1.26 × 10-5 for 24 hours' LPS and INF-γ stimulation, respectively). Moreover, ITM2A expression was significantly decreased in PBMCs from untreated GD patients than that from controls.
Conclusion: The results suggest that ITM2A might be a susceptibility gene for GD in the Xq21.1 locus, and environmental factors, such as viral and bacterial infections, probably contribute to GD pathogenesis by interacting with the risk SNP rs3827440 mediating the regulation of ITM2A expression.

PMID: 27809695 [PubMed - indexed for MEDLINE]

Scoring System for Identifying Impending Complete Fractures in Incomplete Atypical Femoral Fractures.
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Scoring System for Identifying Impending Complete Fractures in Incomplete Atypical Femoral Fractures.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):545-550

Authors: Min BW, Koo KH, Park YS, Oh CW, Lim SJ, Kim JW, Lee KJ, Lee YK

Context: Although impending incomplete atypical femoral fractures (AFFs) require prophylactic fixation, there is still a lack of study on predicting complete fracture among the incomplete AFFs.
Objective: Our purposes are to develop a scoring system to predict progression into complete fracture and to evaluate its reliability and validity.
Design, Setting, and Patients: We reviewed 46 incomplete AFFs in 44 patients who did not undergo prophylactic fixation. A weighted scoring system, including four identified risk factors (the site, severity of pain, status of the contralateral femur, and the extent of radiolucent line), was developed. We evaluated its interobserver reliability by using intraclass correlation coefficiency (ICC) and its accuracy using receiver operator characteristic (ROC) curve. The validity of the scoring system was tested in a different cohort.
Intervention: Observational study.
Main Outcome Measure: Progression to complete fracture within 6 months.
Results: Among 46 incomplete fractures, 13 developed a complete fracture within 6 months. The probability of complete fracture increased abruptly when the score was 8 points or more. The proposed scoring system showed an almost perfect reliability (ICC, 0.997; 95% confidence interval, 0.995 to 0.998) and higher accuracy than any single risk factor in ROC curve. In the different series, the positive predictive value was 100% and the sensitivity was 75%, when cutoff value was 8 points.
Conclusion: The progression to complete fracture could be predicted by using our scoring system. Incomplete AFF with scores <8 points can be treated conservatively, whereas lesions with scores ≥8 require prophylactic fixation.

PMID: 27802096 [PubMed - indexed for MEDLINE]

MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.
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MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):576-582

Authors: Desai S, Wood-Trageser M, Matic J, Chipkin J, Jiang H, Bachelot A, Dulon J, Sala C, Barbieri C, Cocca M, Toniolo D, Touraine P, Witchel S, Rajkovic A

Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI).
Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants.
Setting: Academic research institution.
Participants: All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels.
Interventions: None.
Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging.
Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway.
Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.

PMID: 27802094 [PubMed - indexed for MEDLINE]

Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy.
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Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy.

J Clin Endocrinol Metab. 2016 Dec;101(12):5012-5020

Authors: Moon RJ, Harvey NC, Cooper C, D'Angelo S, Crozier SR, Inskip HM, Schoenmakers I, Prentice A, Arden NK, Bishop NJ, Carr A, Dennison EM, Eastell R, Fraser R, Gandhi SV, Godfrey KM, Kennedy S, Mughal MZ, Papageorghiou AT, Reid DM, Robinson SM, Javaid MK

CONTEXT: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.
OBJECTIVE: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.
DESIGN: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.
SETTING: Hospital antenatal clinics.
PARTICIPANTS: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.
INTERVENTIONS: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.
MAIN OUTCOME MEASURE: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).
RESULTS: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (β = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation.
CONCLUSIONS: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.

PMID: 27788053 [PubMed - indexed for MEDLINE]

Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men.
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Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men.

J Clin Endocrinol Metab. 2016 Dec;101(12):4779-4788

Authors: Behre HM, Zitzmann M, Anderson RA, Handelsman DJ, Lestari SW, McLachlan RI, Meriggiola MC, Misro MM, Noe G, Wu FC, Festin MP, Habib NA, Vogelsong KM, Callahan MM, Linton KA, Colvard DS

CONTEXT: The development of a safe and effective reversible method of male contraception is still an unmet need.
OBJECTIVE: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone.
DESIGN: Prospective multicentre study.
SETTING: Ten study centers.
PARTICIPANTS: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems.
INTERVENTION: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks.
MAIN OUTCOMES MEASURES: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate.
RESULTS: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early.
CONCLUSIONS: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.

PMID: 27788052 [PubMed - indexed for MEDLINE]

Population Survey of Iodine Deficiency and Environmental Disruptors of Thyroid Function in Young Children in Haiti.
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Population Survey of Iodine Deficiency and Environmental Disruptors of Thyroid Function in Young Children in Haiti.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):644-651

Authors: von Oettingen JE, Brathwaite TD, Carpenter C, Bonnell R, He X, Braverman LE, Pearce EN, Larco P, Larco NC, Jean-Baptiste E, Brown RS

Context: Iodine deficiency is the leading cause of preventable neurodevelopmental delay in children worldwide and a possible public health concern in Haiti.
Objective: To determine the prevalence of iodine deficiency in Haitian young children and its influence by environmental factors.
Design: Cross-sectional study, March through June 2015.
Setting: Community churches in 3 geographical regions in Haiti.
Participants: 299 healthy Haitian children aged 9 months to 6 years; one-third each enrolled in a coastal, mountainous, and urban region.
Main Outcome Measures: Urinary iodide, serum thyrotropin (TSH), goiter assessment, and urinary perchlorate and thiocyanate.
Results: Mean age was 3.3±1.6 years, with 51% female, median family income USD 30/week, and 16% malnutrition. Median urinary iodide levels were normal in coastal (145 μg/L, interquartile range [IQR] 97 to 241) and urban regions (187 μg/L, IQR 92 to 316), but revealed mild iodine deficiency in a mountainous region (89 μg/L, IQR 56 to 129), P < 0.0001. Grade 1 goiters were palpated in 2 children, but TSH values were normal. Urinary thiocyanate and perchlorate concentrations were not elevated. Predictors of higher urinary iodide included higher urinary thiocyanate and perchlorate, breastfeeding, and not living in a mountainous region.
Conclusions: Areas of mild iodine deficiency persist in Haiti's mountainous regions. Exposure to two well-understood environmental thyroid function disruptors is limited.

PMID: 27768855 [PubMed - indexed for MEDLINE]

Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men.
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Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):583-593

Authors: Storer TW, Basaria S, Traustadottir T, Harman SM, Pencina K, Li Z, Travison TG, Miciek R, Tsitouras P, Hally K, Huang G, Bhasin S

Context: Findings of studies of testosterone's effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied.
Objective: To determine the effects of testosterone administration for 3 years in older men on muscle strength, power, fatigability, and physical function.
Design, Setting, and Participants: This was a double-blind, placebo-controlled, randomized trial of healthy men ≥60 years old with total testosterone levels of 100 to 400 ng/dL or free testosterone levels <50 pg/mL.
Interventions: Random assignment to 7.5 g of 1% testosterone or placebo gel daily for 3 years.
Outcome Measures: Loaded and unloaded stair-climbing power, muscle strength, power, and fatigability in leg press and chest press exercises, and lean mass at baseline, 6, 18, and 36 months.
Results: The groups were similar at baseline. Testosterone administration for 3 years was associated with significantly greater performance in unloaded and loaded stair-climbing power than placebo (mean estimated between-group difference, 10.7 W [95% confidence interval (CI), -4.0 to 25.5], P = 0.026; and 22.4 W [95% CI, 4.6 to 40.3], P = 0.027), respectively. Changes in chest-press strength (estimated mean difference, 16.3 N; 95% CI, 5.5 to 27.1; P < 0.001) and power (mean difference 22.5 W; 95% CI, 7.5 to 37.5; P < 0.001), and leg-press power were significantly greater in men randomized to testosterone than in those randomized to placebo. Lean body mass significantly increased more in the testosterone group.
Conclusion: Compared with placebo, testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in stair-climbing power, muscle mass, and power. Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.

PMID: 27754805 [PubMed - indexed for MEDLINE]

Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.
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Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):634-643

Authors: Wang W, Kang H, Zhao Y, Min I, Wyrwas B, Moore M, Teng L, Zarnegar R, Jiang X, Fahey TJ

Context: The RAF inhibitor vemurafenib has provided a major advance for the treatment of patients with BRAF-mutant metastatic melanoma. However, BRAF-mutant thyroid cancer is relatively resistant to vemurafenib, and the reason for this disparity remains unclear. Anticancer therapy-induced autophagy can trigger adaptive drug resistance in a variety of cancer types and treatments. To date, role of autophagy during BRAF inhibition in thyroid cancer remains unknown.
Objective: In this study, we investigate if autophagy is activated in vemurafenib-treated BRAF-mutant thyroid cancer cells, and whether autophagy inhibition improves or impairs the treatment efficacy of vemurafenib.
Design: Autophagy level was determined by western blot assay and transmission electron microscopy. The combined effects of autophagy inhibitor and vemurafenib were assessed in terms of cell viability in vitro and tumor growth rate in vivo. Whether the endoplasmic reticulum (ER) stress was in response to vemurafenib-induced autophagy was also analyzed.
Results: Vemurafenib induced a high level of autophagy in BRAF-mutant thyroid cancer cells. Inhibition of autophagy by either a pharmacological inhibitor or interfering RNA knockdown of essential autophagy genes augmented vemurafenib-induced cell death. Vemurafenib-induced autophagy was independent of MAPK signaling pathway and was mediated through the ER stress response. Finally, administration of vemurafenib with the autophagy inhibitor hydroxychloroquine promoted more pronounced tumor suppression in vivo.
Conclusions: Our data demonstrate that vemurafenib induces ER stress response-mediated autophagy in thyroid cancer and autophagy inhibition may be a beneficial strategy to sensitize BRAF-mutant thyroid cancer to vemurafenib.

PMID: 27754804 [PubMed - indexed for MEDLINE]

Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study.
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Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):535-544

Authors: Välimäki VV, Mäkitie O, Pereira R, Laine C, Wesseling-Perry K, Määttä J, Kirjavainen M, Viljakainen H, Välimäki MJ

Context: We previously identified 2 Finnish families with dominantly inherited, low-turnover osteoporosis caused by mutations in WNT1 or PLS3.
Objective, Design, and Setting: This prospective, longitudinal, uncontrolled study was undertaken to evaluate whether these patients respond to teriparatide.
Patients and Intervention: We recruited 6 adults (median age, 54 years); 3 with a WNT1 missense mutation, c.652T>G, and 3 with a PLS3 splice mutation, c.73-24T>A, to receive teriparatide 20 μg daily for 24 months. Five patients had previously used bisphosphonates.
Main Outcome Measures: Outcome measures included lumbar spine and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry, distal radius peripheral quantitative computed tomography, spinal radiography, serum bone turnover markers, paired iliac crest biopsies.
Results: All patients showed increases in formation markers procollagen type 1 amino-terminal propeptide (90% to 398%) and osteocalcin (50% to 280%) and in resorption markers cross-linked C-terminal telopeptide of type I collagen (58% to 457%) and tartrate-resistant acid phosphatase 5b (20% to 68%) in first 6 months. Lumbar spine BMD increased 5.2% to 7.9% in 5 patients and femoral neck BMD 2.6% to 7.8% in 4 patients in 24 months. Distal radius cortical volumetric BMD decreased 5.4% to 26.1%. In histomorphometric analyses, osteoid indices increased more consistently in patients with WNT1 vs PLS3 mutation. Eroded surface decreased 44% to 100% in all patients. Adipocyte number increased in 5 patients studied.
Conclusions: Patients with WNT1 or PLS3 mutation-related osteoporosis responded to teriparatide treatment. Future studies are needed to evaluate whether observed changes translate to fracture resistance.

PMID: 27732335 [PubMed - indexed for MEDLINE]

Positive Feedback Loops Between NrCAM and Major Signaling Pathways Contribute to Thyroid Tumorigenesis.
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Positive Feedback Loops Between NrCAM and Major Signaling Pathways Contribute to Thyroid Tumorigenesis.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):613-624

Authors: Zhang Y, Sui F, Ma J, Ren X, Guan H, Yang Q, Shi J, Ji M, Shi B, Sun Y, Hou P

Context: Although neuronal cell adhesion molecule (NrCAM) has been reported to be overexpressed in papillary thyroid cancer (PTCs), its role in this disease remains largely unclear.
Objectives: The aim of this study was to explore the biological functions of NrCAM and its potential as a diagnostic marker and therapeutic target in thyroid cancer.
Experimental Design: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate messenger RNA expression of investigated genes. The functions of knockdown and ectopic expression of NrCAM in thyroid cancer cells were determine by a series of in vitro and in vivo experiments.
Results: We found that NrCAM was highly expressed in PTCs and demonstrated that NrCAM might be a potential marker for preoperative diagnosis of PTC. Moreover, NrCAM depletion dramatically inhibited thyroid cancer cell growth, invasiveness and tumorigenic potential in nude mice. On the other hand, ectopic expression of NrCAM significantly enhanced its tumor-promoting effects. Mechanically, NrCAM exerted its oncogenic function by activating MAPK/Erk and PI3K/Akt pathways via its ectodomain shedding and binding to EGFR and α4β1 integrins. In turn, these 2 pathways were also responsible for NrCAM overexpression through GSK3β/β-catenin signaling axis in thyroid cancer cells. Similar results were also found in transgenic mice with thyroid-specific knock-in of oncogenic BrafV600E (TPO-Cre/LSL-BrafV600E).
Conclusions: Our data first reveal positive feedback loops between NrCAM and major signaling pathways contributing to thyroid tumorigenesis by modulating tumor microenvironment, and suggest that NrCAM may represent a potential diagnostic marker and therapeutic target for thyroid cancer.

PMID: 27732334 [PubMed - indexed for MEDLINE]

Long-Term Recurrence of Small Papillary Thyroid Cancer and Its Risk Factors in a Korean Multicenter Study.
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Long-Term Recurrence of Small Papillary Thyroid Cancer and Its Risk Factors in a Korean Multicenter Study.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):625-633

Authors: Hwangbo Y, Kim JM, Park YJ, Lee EK, Lee YJ, Park DJ, Choi YS, Lee KD, Sohn SY, Kim SW, Chung JH, Lim DJ, Kim MH, Kim MJ, Jo YS, Shong MH, Koong SS, Hahm JR, Jung JH, Yi KH

Context: Small papillary thyroid cancer (PTC) generally has an excellent prognosis. However, long-term recurrence is not uncommon and sometimes leads to morbidity or mortality.
Objective: To identify high-risk factors for long-term recurrence in patients with small PTC by stratifying their pathologic characteristics.
Design, Setting, and Patients: We conducted a nationwide, retrospective, multicenter study of 3282 patients with PTC sized ≤2 cm from 9 high-volume hospitals in Korea.
Main Outcome Measures: The maximally selected χ2 method was used to find the best cutoff points of tumor size, the number of metastatic lymph nodes (LNs), and the ratio of metastatic/examined LNs (LNR) to predict recurrence. Kaplan-Meier analysis and the Cox proportional hazards regression model were used to analyze recurrence and risk factors.
Results: The optimal tumor size cutoff was 1.8 cm (10-year recurrence rates for tumors sized 0.1 to 1.7 cm and 1.8 to 2.0 cm: 7.7% vs 17.2%, respectively). Metastatic LNs ≤1 and ≥2 provided optimal estimates of recurrence (10-year recurrence rates: 4.0% vs 16.8%, respectively). The LNR of 0.19 was the optimal cutoff point for predicting the risk of recurrence (10-year recurrence rates for LNRs of 0 to 0.18 and 0.19 to 1: 2.7% vs 16.2%, respectively). LN metastasis, lobectomy, tumor size ≥1.8 cm, and bilateral tumors were independent risk factors for recurrence.
Conclusions: Long-term recurrence was increased in patients who underwent lobectomy or with tumor sized ≥1.8 cm, 2 or more metastatic LNs, or bilateral tumors. For patients with these high-risk features, total thyroidectomy could be considered to avoid reoperation.

PMID: 27732329 [PubMed - indexed for MEDLINE]

Stress Fractures: Concepts and Therapeutics.
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Stress Fractures: Concepts and Therapeutics.

J Clin Endocrinol Metab. 2017 Feb 01;102(2):525-534

Authors: Moreira CA, Bilezikian JP

Context: Stress fractures are repetitive use injuries in which recurrent strains lead to material fatigue and microarchitectural discontinuities. They account for up to 20% of athletic injuries, more often in women and in the setting of track-and-field events. In women, menstrual disturbances, low body mass index, low energy intake, and sometimes low bone mass, may be contributing factors. There are no standard protocols for evaluation or management of stress fractures.
Evidence Acquisition: Available literature published in English was retrieved using the following terms: stress fractures; fractures; osteoporosis, athletes, premenopausal women, and athletic triad; through PubMed. Reviews, original reports, and case reports were all included.
Evidence Synthesis: Despite lack of consistency among the publications, a phenotype emerges, namely of individuals whose bone mineral density is reduced along with low intake of dietary calcium and low circulating levels of 25-hydroxy vitamin D. Limited experience suggests that calcium and vitamin D supplementation might be helpful. Bisphosphonates or teriparatide may accelerate fracture healing in special circumstances.
Conclusions: Most individuals who experience a stress fracture are young and healthy and do not appear to have an underlying metabolic bone disease. On the other hand, the presence of low bone mass and hormonal disturbances in some afflicted individuals might identify a cohort who needs endocrinological attention. Prospective, well-designed studies of stress fractures are needed to elucidate further underlying pathophysiological elements that predispose such individuals. Guidelines for prevention and treatment may follow from such well-controlled studies.

PMID: 27732325 [PubMed - indexed for MEDLINE]

Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis.
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Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis.

J Clin Endocrinol Metab. 2016 Dec;101(12):4752-4763

Authors: Rakhila H, Al-Akoum M, Doillon C, Lacroix-Pépin N, Leboeuf M, Lemyre M, Akoum A, Pouliot M

CONTEXT: Angiogenesis is required for ectopic endometrial tissue growth. Our previous studies showed that prostaglandin F2α (PGF2α) biosynthetic enzymes and receptor were markedly elevated in endometriotic lesions and that PGF2α is a potent angiogenic factor in endothelial cells.
OBJECTIVE: We sought to determine whether or not the F-prostanoid receptor modulates angiogenesis in ectopic stromal cells.
DESIGN: Release of angiogenic factors by ectopic endometrial stromal cell primary cultures stimulated with PGF2αand exposed to agents that target PGF2α signaling was assessed.
SETTING: The study was conducted in an immunology laboratory at the Centre Hospitalier Universitaire (Québec City) medical research center.
PATIENTS: Women found to have peritoneal endometriosis during laparoscopy were included in this study.
MAIN OUTCOME MEASURE(S): Prostaglandin E2, PGF2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression.
RESULTS: PGF2α markedly up-regulated prostaglandin E2, CXC chemokine ligand 8 and vascular endothelial cell growth factor secretion in endometriotic cells. This effect was suppressed in the presence of a specific F-prostanoid antagonist (AL8810) and its signaling pathway was dependent on F-prostanoid receptor variant. PGF2α can exert its proliferative and angiogenic activities either directly by stimulating endothelial cell proliferation, migration and angiogenesis through F-prostanoid receptor, or indirectly, by stimulating endometriotic stromal cells to produce potent angiogenic factors through either receptor variant.
CONCLUSION: These results show for the first time that PGF2α exerts an angiogenic effect on ectopic stromal cells, inducing the secretion of major angiogenic factors via different F-prostanoid signaling pathways. This study suggests a new interpretation of the mechanism underlying endometriosis development involving PGF2α in endometriosis-associated angio-inflammatory changes.

PMID: 27726474 [PubMed - indexed for MEDLINE]

Comparison of Early (2 Days) and Later (28 Days) Response of Adipose Tissue to Very Low-Calorie Diet in Obese Women.
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Comparison of Early (2 Days) and Later (28 Days) Response of Adipose Tissue to Very Low-Calorie Diet in Obese Women.

J Clin Endocrinol Metab. 2016 Dec;101(12):5021-5029

Authors: Šrámková V, Rossmeislová L, Krauzová E, Kračmerová J, Koc M, Langin D, Štich V, Šiklová M

CONTEXT: Beneficial metabolic effects of calorie restriction found in the early stage of hypocalorie diets may be caused by the modulation of metabolic and endocrine function of adipose tissue.
OBJECTIVE: The objective of the study was to compare metabolic and inflammation-related characteristics of sc adipose tissue (SAAT) in the early (2 d) and later (28 d) phase of a very low calorie diet (VLCD). Design, Setting, Intervention, and Patients: Seventeen moderately obese premenopausal women followed an 800 kcal/d VLCD for 28 days. Anthropometric measurements, blood sampling, and a biopsy of SAAT were performed before the diet and after 2 and 28 days of the VLCD.
MAIN OUTCOME MEASURE(S): mRNA expression of 50 genes related to lipid metabolism, inflammation, and fibrosis were analyzed in SAAT. Secretion of adipokines was determined in SAAT explants and adipokines, fibroblast growth factor 21 (FGF21) and C-reactive protein were measured in plasma.
RESULTS: In the early phase of the VLCD, the expression of lipolytic genes was increased, whereas the expression of lipogenic genes was significantly suppressed. The inflammatory markers in SAAT remained unchanged. At the later phase, expression of genes involved in lipogenesis and β-oxidation was markedly suppressed, whereas the expression of inflammatory markers was increased. The changes of lipogenic genes after 28 days of the VLCD correlated with FGF21 changes.
CONCLUSION: The early and later phases of a VLCD differ with respect to metabolic and inflammatory responses in SAAT. The expression changes in SAAT in the early phase of the VLCD could not explain the effect of short calorie restriction on the improvement of insulin sensitivity. An interplay of SAAT with liver function during VLCD mediated by FGF21 might be suggested.

PMID: 27715401 [PubMed - indexed for MEDLINE]

Genetic Variation in the 11β-hydroxysteroid-dehydrogenase 1 Gene Determines NAFLD and Visceral Obesity.
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Genetic Variation in the 11β-hydroxysteroid-dehydrogenase 1 Gene Determines NAFLD and Visceral Obesity.

J Clin Endocrinol Metab. 2016 Dec;101(12):4743-4751

Authors: Lutz SZ, Peter A, Machicao F, Lamprinou A, Machann J, Schick F, Königsrainer I, Königsrainer A, Fritsche A, Staiger H, Häring HU, Stefan N, Kantartzis K

CONTEXT/OBJECTIVE: Acute pharmacological inhibition of 11β-hydroxysteroid-dehydrogenase 1 (11β-HSD1), which converts cortisone into the much more potent cortisol in peripheral tissues, results in reduction of total, visceral, and liver fat but not insulin resistance. We now investigated whether lifelong alterations of 11β-HSD1 activity similarly affect these cardiometabolic risk parameters by studying single-nucleotide polymorphisms (SNPs) in the 11β-HSD1-coding gene (HSD11B1).
DESIGN/METHODS: Liver fat content was measured by (1)H-magnetic resonance spectroscopy and total and visceral fat mass by (1)H-magnetic resonance tomography in 327 subjects. Insulin sensitivity (IS) was estimated during an oral glucose tolerance test and the euglycemic, hyperinsulinemic clamp (n = 219). Nine SNPs covering the whole HSD11B1 gene were genotyped.
RESULTS: After correction for multiple testing, liver fat content strongly correlated with three SNPs, rs2235543, rs12565406, and rs4844880 (P = .0002, P = .001, and P = .0009, respectively), independently of gender and age. There was a nominal association of these SNPs with hepatic IS but only of rs4844880 with whole-body IS. Subjects homozygous for the major allele had an adjusted odds ratio of 2.16 (95% confidence interval [CI] 1.23-3.90) for rs2235543, 2.06 (95% CI 1.08-4.13) for rs12565406, and 1.95 (95% CI 1.13-3.49) for rs4844880 for having nonalcoholic fatty liver disease compared with carriers of the minor allele. Less strong associations of these SNPs with visceral fat mass were observed. In liver biopsies, carriers of the minor alleles of rs2235543 and rs12565406 had significantly lower HSD11B1 mRNA expression (n = 105, P = .034 and P = .0086, respectively).
CONCLUSIONS: 11β-HSD1 may be an important enzyme in the pathogenesis of fatty liver and visceral obesity and a promising target for their treatment.

PMID: 27715400 [PubMed - indexed for MEDLINE]

Metabolic Fingerprints of Circulating IGF-1 and the IGF-1/IGFBP-3 Ratio: A Multifluid Metabolomics Study.
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Metabolic Fingerprints of Circulating IGF-1 and the IGF-1/IGFBP-3 Ratio: A Multifluid Metabolomics Study.

J Clin Endocrinol Metab. 2016 Dec;101(12):4730-4742

Authors: Knacke H, Pietzner M, Do KT, Römisch-Margl W, Kastenmüller G, Völker U, Völzke H, Krumsiek J, Artati A, Wallaschofski H, Nauck M, Suhre K, Adamski J, Friedrich N

OBJECTIVE: IGF-1 is known for its various physiological and severe pathophysiological effects on human metabolism; however, underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time, we associated serum IGF-1 levels with multifluid untargeted metabolomics data.
METHODS: Plasma/urine samples of 995 nondiabetic participants of the Study of Health in Pomerania were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-1 and IGF-1/IGF binding protein 3 ratio with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-1 was assessed by orthogonal partial least squares analyses.
RESULTS AND CONCLUSIONS: We revealed a multifaceted image of associated metabolites with large sex differences. Confirming previous reports, we detected relations between IGF-1 and steroid hormones or related intermediates. Furthermore, various associated metabolites were previously mentioned regarding IGF-1-associated diseases, eg, betaine and cortisol in cardiovascular disease and metabolic syndrome, lipid disorders, and diabetes, or have previously been found to associate with differentiation and proliferation or mitochondrial functionality, eg, phospholipids. bradykinin, fatty acid derivatives, and cortisol, which were inversely associated with IGF-1, might establish a link of IGF-1 with inflammation. For the first time, we showed an association between IGF-1 and pipecolate, a metabolite linked to amino acid metabolism. Our study demonstrates that IGF-1 action on metabolism is tractable, even in healthy subjects, and that the findings provide a solid basis for further experimental/clinical investigation, eg, searching for inflammatory or cardiovascular disease- or metabolic syndrome-associated biomarkers and therapeutic targets.

PMID: 27710242 [PubMed - indexed for MEDLINE]

Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature.
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Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature.

J Clin Endocrinol Metab. 2016 Dec;101(12):4984-4993

Authors: Mauras N, Ross JL, Gagliardi P, Yu YM, Hossain J, Permuy J, Damaso L, Merinbaum D, Singh RJ, Gaete X, Mericq V

CONTEXT: Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion.
OBJECTIVES: To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups.
DESIGN: Randomized three-arm open-label comparator.
SETTING: Outpatient clinical research.
PATIENTS: Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)].
INTERVENTION: Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months.
OUTCOMES: Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs.
RESULTS: Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole.
CONCLUSIONS: Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24-36 months with a strong safety profile.

PMID: 27710241 [PubMed - indexed for MEDLINE]

Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals.
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Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals.

J Clin Endocrinol Metab. 2016 Dec;101(12):4994-5003

Authors: Sparks LM, Redman LM, Conley KE, Harper ME, Hodges A, Eroshkin A, Costford SR, Gabriel ME, Yi F, Shook C, Cornnell HH, Ravussin E, Smith SR

CONTEXT: Reduced mitochondrial coupling (ATP/O2 [P/O]) is associated with sedentariness and insulin resistance. Interpreting the physiological relevance of P/O measured in vitro is challenging.
OBJECTIVE: To evaluate muscle mitochondrial function and associated transcriptional profiles in nonobese healthy individuals distinguished by their in vivo P/O.
DESIGN: Individuals from an ancillary study of Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy phase 2 were assessed at baseline.
SETTING: The study was performed at Pennington Biomedical Research Center.
PARTICIPANTS: Forty-seven (18 males, 26-50 y of age) sedentary, healthy nonobese individuals were divided into 2 groups based on their in vivo P/O.
INTERVENTION: None. Main Outcome(s): Body composition by dual-energy x-ray absorptiometry, in vivo mitochondrial function (P/O and maximal ATP synthetic capacity) by (31)P-magnetic resonance spectroscopy and optical spectroscopy were measured. A muscle biopsy was performed to measure fiber type, transcriptional profiling (microarray), and protein expressions.
RESULTS: No differences in body composition, peak aerobic capacity, type I fiber content, or mitochondrial DNA copy number were observed between the 2 groups. Compared with the uncoupled group (lower P/O), the coupled group (higher P/O) had higher rates of maximal ATP synthetic capacity (maximal ATP synthetic capacity, P < .01). Transcriptomics analyses revealed higher expressions of genes involved in mitochondrial remodeling and the oxidative stress response in the coupled group. A trend for higher mitonuclear protein imbalance (P = .06) and an elevated mitochondrial unfolded protein response (heat shock protein 60 protein; P = .004) were also identified in the coupled group.
CONCLUSIONS: Higher muscle mitochondrial coupling is accompanied by an overall elevation in mitochondrial function, a novel transcriptional signature of oxidative stress and mitochondrial remodeling and indications of an mitochondrial unfolded protein response.

PMID: 27710240 [PubMed - indexed for MEDLINE]

Free Radical-derived Oxysterols: Novel Adipokines Modulating Adipogenic Differentiation of Adipose Precursor Cells.
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Free Radical-derived Oxysterols: Novel Adipokines Modulating Adipogenic Differentiation of Adipose Precursor Cells.

J Clin Endocrinol Metab. 2016 Dec;101(12):4974-4983

Authors: Murdolo G, Piroddi M, Tortoioli C, Bartolini D, Schmelz M, Luchetti F, Canonico B, Papa S, Zerbinati C, Iuliano L, Galli F

CONTEXT: Increased oxidative stress in adipose tissue emerges as an inducer of obesity-linked insulin resistance. Here we tested whether free-radical derived oxysterols are formed by, and accumulate in, human adipocytes. Moreover, we asked whether increased accumulation of oxysterols characterizes the adipose cells of obese patients with type 2 diabetes (T2D) (OBT2D) compared with lean, nondiabetic controls (CTRLs). Finally, we studied the effects of the free radical-derived oxysterols on adipogenic differentiation of adipose-derived stem cells (ASCs).
MAIN OUTCOME MEASURES: Adipocytes and ASCs were isolated from sc abdominal adipose tissue biopsy in four OBT2D and four CTRL subjects. Oxysterols in adipocytes were detected by gas chromatography/mass spectrometry. The cellular and molecular effects of oxysterols were then evaluated on primary cultures of ASCs focusing on cell viability, adipogenic differentiation, and "canonical" WNT and MAPK signaling pathways.
RESULTS: 7-ketocholesterol (7κ-C) and 7β-hydroxycholesterol were unambiguously detected in adipocytes, which showed higher oxysterol accumulation (P < .01) in OBT2D, as compared with CTRL individuals. Notably, the accumulation of oxysterols in adipocytes was predicted by the adipose cell size of the donor (R(2) = 0.582; P < .01). Challenging ASCs with free radical-derived type I (7κ-C) and type II (5,6-Secosterol) oxysterols led to a time- and concentration-dependent decrease of cell viability. Meaningfully, at a non-toxic concentration (1μM), these bioactive lipids hampered adipogenic differentiation of ASCs by sequential activation of WNT/β-catenin, p38-MAPK, ERK1/2, and JNK signaling pathways.
CONCLUSION: Free radical-derived oxysterols accumulate in the "diabetic" fat and may act as novel adipokines modulating the adipogenic potential of undifferentiated adipose precursor cells.

PMID: 27710239 [PubMed - indexed for MEDLINE]

A SDHC Founder Mutation Causes Paragangliomas (PGLs) in the French Canadians: New Insights on the SDHC-Related PGL.
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A SDHC Founder Mutation Causes Paragangliomas (PGLs) in the French Canadians: New Insights on the SDHC-Related PGL.

J Clin Endocrinol Metab. 2016 Dec;101(12):4710-4718

Authors: Bourdeau I, Grunenwald S, Burnichon N, Khalifa E, Dumas N, Binet MC, Nolet S, Gimenez-Roqueplo AP

BACKGROUND: More than 40% of patients with paragangliomas (PGLs) harbor a germline mutation of the known PGL susceptibility genes, mainly in the SDHB or SDHD genes.
OBJECTIVE: The objective of the study was to characterize the genetic background of the French Canadian (FC) patients with PGLs and provide new clinical and paraclinical insights on SDHC-related PGLs.
METHODS: Genetic testing has been offered to FC patients affected with PGLs followed up at the adrenal genetics clinic at Centre hospitalier de l'Université de Montréal. After genetic counseling, 29 FC patients consented for PGL genetic testing.
RESULTS: Thirteen of 29 patients (44.8%) carried a germline mutation. The same heterozygous nonsense mutation at codon 133 of exon 5 of the SDHC gene (c.397C>T, p.[Arg133Ter]) was found in nine patients, representing 69.2% of the patients having a germline mutation. Seventy percent of these patients had head and neck PGLs. Twenty percent had multiple and 30% had malignant PGLs. We traced back the ascending genealogy of 10 index cases (nine patients from our cohort and one patient referred to us) and found that this mutation was most probably introduced in Nouvelle France by a couple of French settlers who established themselves in the 17th century.
CONCLUSIONS: We found that 31% of the PGLs in the French Canadian can be explained by the SDHC mutation (c.397C>T, p.[Arg133Ter]). The dominance of the SDHC mutation is unique to the FCs and is most likely due to a French founder effect. SDHC gene analysis should be prioritized in FC patients with PGL.

PMID: 27700540 [PubMed - indexed for MEDLINE]

Is a Normal TSH Synonymous With "Euthyroidism" in Levothyroxine Monotherapy?
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Is a Normal TSH Synonymous With "Euthyroidism" in Levothyroxine Monotherapy?

J Clin Endocrinol Metab. 2016 Dec;101(12):4964-4973

Authors: Peterson SJ, McAninch EA, Bianco AC

CONTEXT: Levothyroxine (LT4) monotherapy is the standard of care for hypothyroidism.
OBJECTIVE: To determine whether LT4 at doses that normalize the serum TSH is associated with normal markers of thyroid status.
DESIGN: Cross-sectional data from the US National Health and Nutrition Examination Survey (2001-2012) was used to evaluate 52 clinical parameters. LT4 users were compared to healthy controls and controls matched for age, sex, race, and serum TSH. Regression was used to evaluate for correlation with T4 and T3 levels.
PARTICIPANTS: A total of 9981 participants with normal serum TSH were identified; 469 were LT4-treated.
RESULTS: Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to approximately 15-20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants had higher body mass index despite report of consuming fewer calories/day/kg; were more likely to be taking beta-blockers, statins, and antidepressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum high-density lipoprotein and lower serum low-density lipoprotein, triglycerides, and C-reactive protein. Age was negatively associated with serum free T3:free T4 ratio in all participants; caloric intake was positively associated in LT4-treated individuals.
CONCLUSIONS: In a large population study, participants using LT4 exhibited lower serum T3:T4 ratios and differed in 12/52 objective and subjective measures.

PMID: 27700539 [PubMed - indexed for MEDLINE]

mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success.
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mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success.

J Clin Endocrinol Metab. 2016 Dec;101(12):4719-4729

Authors: Szymanowski M, Estebanez MS, Padidela R, Han B, Mosinska K, Stevens A, Damaj L, Pihan-Le Bars F, Lascouts E, Reynaud R, Ferreira C, Bansept C, de Lonlay P, Saint-Martin C, Dunne MJ, Banerjee I, Arnoux JB

CONTEXT: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to obviate the need for pancreatectomy, but experience is limited.
OBJECTIVE: We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI.
DESIGN, SETTING, AND PATIENTS: This was an observational review of 10 severe CHI patients treated with mTOR inhibitors, in France and the United Kingdom, with the intention of achieving glycemic control without pancreatectomy. Safety information was recorded.
MAIN OUTCOME MEASURE(S): We examined whether mTOR inhibitors achieved glycemic control, fasting tolerance, and weaning of supportive medical therapy.
RESULTS: mTOR inhibition achieved euglycemia, fasting tolerance, and reduced medical therapy in only three patients (30%). Triglyceride levels were elevated in five patients (50%). One child required a blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the CHI pancreas.
CONCLUSION: mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.

PMID: 27691052 [PubMed - indexed for MEDLINE]

Clinical, Sonographic, and Pathological Characteristics of RAS-Positive Versus BRAF-Positive Thyroid Carcinoma.
Related Articles Clinical, Sonographic, and Pathological Characteristics of RAS-Positive Versus BRAF-Positive Thyroid Carcinoma. J Clin Endocrinol Metab. 2016 Dec;101(12):4938-4944 Authors: Kakarmath S, Heller HT, Alexander CA, Cibas ES, Krane JF, Barletta JA, Lindeman NI, Frates MC, Benson CB, Gawande AA, Cho NL, Nehs M, Moore FD, Marqusee E, Kim MI, Larsen PR, Kwong N, Angell TE, Alexander EK Abstract CONTEXT: Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid cancer. Yet, our clinical understanding of how BRAF-positive and RAS-positive thyroid cancers differ is incomplete. OBJECTIVE: We correlated clinical, radiographic, and pathological findings from patients with thyroid cancer harboring a BRAF or RAS mutation. DESIGN: Prospective cohort study. SETTING: Academic, tertiary care hospital. PATIENTS: A total of 101 consecutive patients with well-differentiated thyroid cancer. MAIN OUTCOME MEASURE: We compared the clinical, sonographic, and pathological characteristics of patients with BRAF-positive cancer to those with RAS-positive cancer. RESULTS: Of 101 patients harboring these mutations, 71 were BRAF-positive, whereas 30 were RAS-positive. Upon sonographic evaluation, RAS-positive nodules were significantly larger (P = .04), although BRAF-positive nodules were more likely to harbor concerning sonographic characteristics (hypoechogenicity [P < .001]; irregular margins [P = .04]). Cytologically, 70% of BRAF-positive nodules were classified positive for PTC, whereas 87% of RAS-positive nodules were indeterminate (P < .001). Histologically, 96% of RAS-positive PTC malignancies were follicular variants of PTC, whereas 70% of BRAF-positive malignancies were classical variants of PTC. BRAF-positive malignancies were more likely to demonstrate extrathyroidal extension (P = .003), lymphovascular invasion (P = .02), and lymph node metastasis (P < .001). CONCLUSIONS: BRAF-positive malignant nodules most often demonstrate worrisome sonographic features and are frequently associated with positive or suspicious Bethesda cytology. In contrast, RAS-positive malignancy most often demonstrates indolent sonographic features and more commonly associates with lower risk, "indeterminate" cytology. Because BRAF and RAS mutations are the most common molecular perturbations associated with well-differentiated thyroid cancer, these findings may assist with improved preoperative risk assessment by suggesting the likely molecular profile of a thyroid cancer, even when postsurgical molecular analysis is unavailable. PMID: 27689252 [PubMed - indexed for MEDLINE] [...]

miR-146a, miR-155, miR-370, and miR-708 Are CFTR-Dependent, Predicted FOXO1 Regulators and Change at Onset of CFRDs.
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miR-146a, miR-155, miR-370, and miR-708 Are CFTR-Dependent, Predicted FOXO1 Regulators and Change at Onset of CFRDs.

J Clin Endocrinol Metab. 2016 Dec;101(12):4955-4963

Authors: Montanini L, Smerieri A, Gullì M, Cirillo F, Pisi G, Sartori C, Amarri S, Bernasconi S, Marmiroli N, Street ME

CONTEXT: Cystic fibrosis-related diabetes (CFRD) is the most frequent and severe co-morbidity in cystic fibrosis (CF). Presentation and severity are quite variable.
OBJECTIVE: To investigate changes in microRNAs (miRNAs) due to CF transmembrane conductance regulator malfunctioning in vitro, to study the circulating levels of selected miRNAs in serum samples from patients, and to assess their relationships in different age groups with genotype, glucose tolerance state, and at onset of CFRD. Design/Setting/Patients/Interventions: Transcriptional profiling of all known miRNAs in CFBE41o- cells, in their normal counterparts (16HBE14o- cells), and in IB3 cells was performed. A set of miRNAs was differentially expressed in the CF cells. By in silico analysis, four miRNAs (miR-146a, miR-155, miR-370, and miR-708) were selected as potential regulators of the FOXO1 gene. Seventy-four CF patients and 50 healthy subjects whose glucose tolerance was characterized by an oral glucose tolerance test were enrolled in the study, and the identified miRNAs were quantified in serum by quantitative RT-PCR. Main Outcome Measurements/Results: A total of 111 miRNAs were differentially expressed in the two CF cell lines. miR-155, miR-370, and miR-708 were up-regulated and miR-146a was down-regulated in vitro, whereas in vivo, miR-146a, miR-155, and miR-370 were up-regulated, and miR-708 was down-regulated. These changes showed relationships with genotype, glucose tolerance state, and onset of CFRD.
CONCLUSIONS: The data showed significant changes in miRNAs dependent on genotype and glucose tolerance state in CF patients and highlighted some miRNAs of importance in CFRD at onset. miRNAs could explain some of the variability observed in CF.

PMID: 27689251 [PubMed - indexed for MEDLINE]

Subclinical Thyroid Dysfunction and the Risk of Cognitive Decline: a Meta-Analysis of Prospective Cohort Studies.
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Subclinical Thyroid Dysfunction and the Risk of Cognitive Decline: a Meta-Analysis of Prospective Cohort Studies.

J Clin Endocrinol Metab. 2016 Dec;101(12):4945-4954

Authors: Rieben C, Segna D, da Costa BR, Collet TH, Chaker L, Aubert CE, Baumgartner C, Almeida OP, Hogervorst E, Trompet S, Masaki K, Mooijaart SP, Gussekloo J, Peeters RP, Bauer DC, Aujesky D, Rodondi N

CONTEXT: Although both overt hyper- and hypothyroidism are known to lead to cognitive impairment, data on the association between subclinical thyroid dysfunction and cognitive function are conflicting.
OBJECTIVE: This study sought to determine the risk of dementia and cognitive decline associated with subclinical thyroid dysfunction among prospective cohorts.
DATA SOURCES: We searched in MEDLINE and EMBASE from inception until November 2014.
STUDY SELECTION: Two physicians identified prospective cohorts that assessed thyroid function and cognitive outcomes (dementia; Mini-Mental State Examination [MMSE]).
DATA EXTRACTION: Data were extracted by one reviewer following standardized protocols and verified by a second reviewer. The primary outcome was dementia and decline in cognitive function was the secondary outcome.
DATA SYNTHESIS: Eleven prospective cohorts followed 16,805 participants during a median followup of 44.4 months. Five studies analyzed the risk of dementia in subclinical hyperthyroidism (SHyper) (n = 6410), six in subclinical hypothyroidism (SHypo) (n = 7401). Five studies analyzed MMSE decline in SHyper (n = 7895), seven in SHypo (n = 8960). In random-effects models, the pooled adjusted risk ratio for dementia in SHyper was 1.67 (95% confidence interval, 1.04; 2.69) and 1.14 (95% confidence interval, 0.84; 1.55) in SHypo vs euthyroidism, both without evidence of significant heterogeneity (I(2) = 0.0%). The pooled mean MMSE decline from baseline to followup (mean 32 mo) did not significantly differ between SHyper or SHypo vs euthyroidism.
CONCLUSIONS: SHyper might be associated with an elevated risk for dementia, whereas SHypo is not, and both conditions are not associated with faster decline in MMSE over time. Available data are limited, and additional large, high-quality studies are needed.

PMID: 27689250 [PubMed - indexed for MEDLINE]

Nuchal Skinfold Thickness: A Novel Parameter for Assessment of Body Composition in Childhood Craniopharyngioma.
Related Articles Nuchal Skinfold Thickness: A Novel Parameter for Assessment of Body Composition in Childhood Craniopharyngioma. J Clin Endocrinol Metab. 2016 Dec;101(12):4922-4930 Authors: Sterkenburg AS, Hoffmann A, Reichel J, Lohle K, Eveslage M, Warmuth-Metz M, Müller HL Abstract CONTEXT: Hypothalamic obesity, cardiovascular disease (CVD), and relapse/progression have a major impact on prognosis in childhood-onset craniopharyngioma (CP). We analyzed nuchal skinfold thickness (NST) on magnetic resonance imaging performed for follow-up monitoring as a novel parameter for body composition (BC) and CVD in CP. OBJECTIVE: The objective of the study was to identify the association of NST with body mass index (BMI), waist to height ratio (WHtR), functional capacity, and blood pressure (BP) in CP and controls. DESIGN: This was a cross-sectional and longitudinal prospective study in CP patients. SETTING: The study was conducted at HIT-Endo, KRANIOPHARYNGEOM 2000/2007. PATIENTS: Participants included 94 CP patients and 75 controls. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Association of NST with BC and BP in 43 CP and 43 controls was measured. RESULTS: NST correlated with BMI SD score (SDS; r = 0.78; P < .001; n = 169) and WHtR (r = 0.85; P < .001; n = 86) in the total cohort and CP patients (NST-BMI SDS: r = 0.77, P < .001, n = 94); NST-WHtR: r = 0.835, P < .001, n=43) and controls (NST-BMI SDS: r = 0.792, P < .001, n = 75; NST-WHtR: r = 0.671, P < .001, n = 43). In CP, systolic BP correlated with NST (r = 0.575, P < .001), BMI SDS (r = 0.434, P = .004), and WHtR (r = 0.386, P = .011). Similar results were observed for diastolic BP in CP. In multivariate analyses, NST had a predictive value for hypertension in postpubertal CP and controls (odds ratio 6.98, 95% confidence interval [1.65, 29.5], P = .008). During a longitudinal follow-up, changes in NST correlated with changes in BMI SDS (P < .001) and WHtR (P = .01) but not with changes in BP and functional capacity. CONCLUSIONS: Because monitoring of magnetic resonance imaging and BC is essential for follow-up in CP, NST could serve as a novel and clinically relevant parameter for longitudinal assessment of BC and CVD risk in CP. PMID: 27680877 [PubMed - indexed for MEDLINE] [...]

The MITF, p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma.
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The MITF, p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma.

J Clin Endocrinol Metab. 2016 Dec;101(12):4764-4768

Authors: Castro-Vega LJ, Kiando SR, Burnichon N, Buffet A, Amar L, Simian C, Berdelou A, Galan P, Schlumberger M, Bouatia-Naji N, Favier J, Bressac-de Paillerets B, Gimenez-Roqueplo AP

CONTEXT: The microphthalmia-associated transcription factor (MITF) regulates the survival, proliferation, and differentiation of neural crest-derived lineages. Recent studies reported an increased risk of melanoma in individuals carrying the rare variant MITF, p.E318K (rs149617956). Whether this variant plays a role in other neural crest-derived tumors is unknown.
OBJECTIVE: In the present study, we aimed at determining the prevalence of the MITF, p.E318K variant, in a well-characterized French cohort of pheochromocytomas/paragangliomas (PCC/PGL).
DESIGN AND METHODS: Genomic DNA from 555 unrelated patients with PCC/PGL was genotyped for the p.E318K variant in MITF using Sanger sequencing.
MAIN OUTCOME MEASURE: The prevalence of the mutation in the PCC/PGL cohort was compared with a population-based sample of 2348 ethnically matched controls.
RESULTS: We identified seven carriers (five patients with sporadic PCCs, two with PGLs). The prevalence of the MITF, p.E318K variant, was higher in the PCC/PGL cohort than in controls, and appears to be a significant risk factor (odds ratio, 3.19; 95% confidence interval, 1.34-7.59; P = .005). Noteworthy, two patients were homozygous for the p.E318K risk allele, a patient with metastatic PCC and an SDHB-mutated patient with PGL.
CONCLUSION: Our results indicate that the germline variant MITF, p.E318K is associated with an increased risk of other neural crest-derived tumors such as PCC/PGL.

PMID: 27680874 [PubMed - indexed for MEDLINE]

A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia.
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A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab. 2016 Dec;101(12):4690-4698

Authors: Nella AA, Mallappa A, Perritt AF, Gounden V, Kumar P, Sinaii N, Daley LA, Ling A, Liu CY, Soldin SJ, Merke DP

CONTEXT: Classic congenital adrenal hyperplasia (CAH) management remains challenging, given that supraphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven adrenal androgen overproduction.
OBJECTIVE: This study sought to approximate physiologic cortisol secretion via continuous subcutaneous hydrocortisone infusion (CSHI) and evaluate the safety and efficacy of CSHI in patients with difficult-to-treat CAH.
DESIGN: Eight adult patients with classic CAH participated in a single-center open-label phase I-II study comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevated adrenal steroids and one or more comorbidities at study entry. Assessment while receiving conventional therapy at baseline and 6 months following CSHI included: 24-hour hormonal sampling, metabolic and radiologic evaluation, health-related quality-of-life (HRQoL), and fatigue questionnaires.
MAIN OUTCOME MEASURES: The ability of CSHI to approximate physiologic cortisol secretion and the percent of patients with 0700-hour 17-hydroxyprogesterone (17-OHP) ≤1200 ng/dL was measured.
RESULTS: CSHI approximated physiologic cortisol secretion. Compared with baseline, 6 months of CSHI resulted in decreased 0700-hour and 24-hour area under the curve 17-OHP, androstenedione, ACTH, and progesterone, increased osteocalcin, c-telopeptide and lean mass, and improved HRQoL (and SF-36 Vitality Score), and fatigue. One of three amenorrheic women resumed menses. One man had reduction of testicular adrenal rest tissue.
CONCLUSIONS: CSHI is a safe and well-tolerated modality of cortisol replacement that effectively approximates physiologic cortisol secretion in patients with classic CAH poorly controlled on conventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest that CSHI should be considered a treatment option for classic CAH. The long-term effect on established comorbidities requires further study.

PMID: 27680873 [PubMed - indexed for MEDLINE]

The Dual Role of PEDF in the Pathogenesis of OHSS: Negating Both Angiogenic and Inflammatory Pathways.
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The Dual Role of PEDF in the Pathogenesis of OHSS: Negating Both Angiogenic and Inflammatory Pathways.

J Clin Endocrinol Metab. 2016 Dec;101(12):4699-4709

Authors: Miller I, Chuderland D, Grossman H, Ron-El R, Ben-Ami I, Shalgi R

CONTEXT: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproductive technologies. This complex syndrome is known to involve massive angiogenesis and inflammation. We have previously established the anti-angiogenic involvement of pigment epithelium-derived factor (PEDF) in the pathophysiology and treatment of OHSS.
OBJECTIVE: Evaluate the anti-inflammatory role of PEDF in OHSS.
DESIGN: In vivo mouse OHSS model and in vitro cultures of granulosa cells.
MAIN OUTCOME: Changes in the expression of PEDF, IL-6, IL-8, and vascular endothelial growth factor (VEGF) were measured by quantitative PCR and ELISA; OHSS symptoms were recorded (body and ovarian weight gain and peritoneal vascular leakage quantified by the modified Miles's assay).
RESULTS: Rat granulosa cell-line stimulated with lysophosphatidic acid (LPA), exhibited a significant increase in IL-6 expression, concomitantly with a decrease in PEDF level (P < .01). Co-stimulation with recombinant PEDF (rPEDF) decreased the expression of IL-6 significantly (P < .05). Furthermore, the expression of IL-6 and IL-8 increased in LPA-stimulated human primary granulosa cells (P < .01). Co-stimulation with rPEDF decreased the expression of LPA-induced IL-6 and IL-8 mRNA and protein by 4- and 2- to 5-fold, respectively. IL-8-stimulated human primary granulosa cells exhibited increased expression of VEGF mRNA; co-stimulation with hCG induced a significantly higher increase in the expression of VEGF mRNA (P < .001), which was counteracted by rPEDF. Subcutaneous injection of 0.5 mg/kg rPEDF to OHSS-induced mice reduced the increased expression of IL-6 in the ovary (P < .01) and alleviated the severity of all OHSS parameters.
CONCLUSIONS: Our findings provide a framework that correlates down-regulation of OHSS symptoms caused by PEDF with both angiogenic and inflammatory pathways.

PMID: 27680872 [PubMed - indexed for MEDLINE]

The Relationship Between Calciotropic Hormones, IGF-1, and Bone Mass Across Pubertal Stages.
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The Relationship Between Calciotropic Hormones, IGF-1, and Bone Mass Across Pubertal Stages.

J Clin Endocrinol Metab. 2016 Dec;101(12):4860-4870

Authors: Matar M, Al-Shaar L, Maalouf J, Nabulsi M, Arabi A, Choucair M, Tamim H, El-Hajj Fuleihan G

BACKGROUND: Little is known about the changes in calciotropic hormones during puberty and their relationship to bone mass during this critical period for skeletal accretion.
OBJECTIVES: Investigate changes in calciotropic hormones, IGF-1, body composition, and their associations with bone metabolism in adolescents.
METHODS: Post hoc analyses were performed from data on 335 healthy school children, ages 10-17 years, with hypovitaminosis D who participated in a vitamin D randomized controlled trial. Baseline serum biochemistries; hormonal studies; densitometry at the spine, hip, and total body; and body composition were used. ANOVA and regression analyses were implemented to evaluate changes in variables of interest across pubertal stages, within and between genders.
RESULTS: Bone mass and body composition parameters increased substantially across Tanner stages in both genders. Serum calcium, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D levels did not vary by Tanner stages in both genders. Conversely, serum phosphorus, alkaline phosphatase, IGF-1, PTH, and osteocalcin peaked for the most part at Tanner stage II in girls and stage III in boys. 1,25-Dihydroxyvitamin D correlations with bone mass were not consistent, whereas IGF-1 was the most robust correlate of bone mass at several skeletal sites in early Tanner stages in both genders (R = 0.3-0.6).
CONCLUSION: Serum phosphorus, alkaline phosphatase, IGF-1, PTH, and osteocalcin, but not calcium or 1,25-dihydroxyvitamin D, increased significantly in early puberty, with gender difference except for PTH, peaking earlier in girls than in boys. IGF-1 is a robust predictor of bone mass, an effect mediated in large part by increments in lean mass.

PMID: 27676398 [PubMed - indexed for MEDLINE]

Impact of Parity on Body Size Phenotype in Postmenopausal Women: KNHANES 2010-2012.
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Impact of Parity on Body Size Phenotype in Postmenopausal Women: KNHANES 2010-2012.

J Clin Endocrinol Metab. 2016 Dec;101(12):4904-4913

Authors: Kim JH, Kim J, Ahn HJ, Kim SY, Bae HY

CONTEXT: Parity has been implicated in many health consequences for women in later life.
OBJECTIVE: To determine whether there is an association between parity and body size phenotypes in postmenopausal women.
DESIGN AND PARTICIPANTS: This study was based on data from the Korean National Health and Nutrition Examination Survey, conducted during 2010-2012. Of the 25 534 participants, data from 3347 postmenopausal women were included in the analysis.
RESULTS: In analyses stratified by the metabolically abnormal obese (MAO) and metabolically healthy and normal weight phenotypes, women with parities of 3-4 births or more than or equal to 5 births were significantly associated with the MAO phenotype (odds ratio [OR] 1.396 [95% confidence interval (CI) 1.077-1.810] and OR 1.978 [1.392-2.811], respectively) compared with those with a parity of 1-2 births after adjusting for age, sociodemographic factors, lifestyle behaviors, and reproductive factors. A similar significant association of parity with the MAO phenotype was also found when we analyzed the parity number as a continuous variable in a comparison of the MAO and metabolically abnormal but normal weight phenotypes (OR 1.116 [1.012-1.232]). In grouping of the MAO and metabolically healthy but obese phenotypes, women who had experienced a parity of 3-4 births or more than or equal to 5 births were significantly associated with the MAO phenotype (OR 1.459 [1.025-2.076] and OR 1.989 [1.211-3.265], respectively) after adjustment for the above covariates.
CONCLUSIONS: Parity influenced the body size phenotype in postmenopausal women, and higher parity was independently associated with a higher risk of the MAO phenotype in postmenopausal women.

PMID: 27676397 [PubMed - indexed for MEDLINE]

Urinary Citrate, an Index of Acid-Base Status, Predicts Bone Strength in Youths and Fracture Risk in Adult Females.
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Urinary Citrate, an Index of Acid-Base Status, Predicts Bone Strength in Youths and Fracture Risk in Adult Females.

J Clin Endocrinol Metab. 2016 Dec;101(12):4914-4921

Authors: Esche J, Johner S, Shi L, Schönau E, Remer T

CONTEXT: Diet can impact on bone strength via metabolic shifts in acid-base status. In contrast to the strongly diet-dependent biomarker urinary potential renal acid load (uPRAL), the amount of renally excreted citrate integrates nutritional and systemic influences on acid-base homeostasis with high citrate indicating prevailing alkalization.
OBJECTIVE: To examine the association between urinary citrate excretion and bone strength as well as long-term fracture risk.
DESIGN AND PARTICIPANTS: Prospective cross-sectional analysis; 231 healthy children (6-18 y) of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study were included, with at least 2 urine collections available during the 4 years preceding peripheral quantitative computed tomography (pQCT) of the nondominant proximal forearm. uPRAL, urinary citrate, and urinary nitrogen excretion were quantified in 857 24-hour urine samples. Data on overall fracture incidence were collected within a 15-year follow-up after pQCT measurement.
MAIN OUTCOME MEASURES: Parameters of bone quality and geometry (pQCT) as well as long-term fracture incidence.
RESULTS: After controlling for confounders, especially forearm length, muscle area, and urinary nitrogen (biomarker of protein intake), urinary citrate excretion was positively associated with various parameters of bone quality and geometry (P < .05). Fracture risk in adult females, but not in males, was inversely associated with urinary citrate and positively with uPRAL (P < .05).
CONCLUSIONS: Although urinary citrate has to be confirmed as an integrated noninvasive biomarker of systemic acid-base status in further studies, our results substantiate dietary and metabolic acidity as potentially adverse for bone health in the long run from childhood onward.

PMID: 27676395 [PubMed - indexed for MEDLINE]

Autoimmune Diseases in Children and Adults With Type 1 Diabetes From the T1D Exchange Clinic Registry.
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Autoimmune Diseases in Children and Adults With Type 1 Diabetes From the T1D Exchange Clinic Registry.

J Clin Endocrinol Metab. 2016 Dec;101(12):4931-4937

Authors: Hughes JW, Riddlesworth TD, DiMeglio LA, Miller KM, Rickels MR, McGill JB, T1D Exchange Clinic Network

BACKGROUND AND AIMS: Type 1 diabetes (T1D) is associated with other autoimmune diseases (AIDs), but the prevalence and associated predictive factors for these comorbidities of T1D across all age groups have not been fully characterized.
MATERIALS AND METHODS: Data obtained from 25 759 participants with T1D enrolled in the T1D Exchange Registry were used to analyze the types and frequency of AIDs as well as their relationships to gender, age, and race/ethnicity. Diagnoses of autoimmune diseases, represented as ordinal categories (0, 1, 2, 3, or more AIDs) were obtained from medical records of Exchange Registry participants.
RESULTS: Among the 25 759 T1D Exchange participants, 50% were female, 82% non-Hispanic white, mean age was 23.0 ± 16.9 years and mean duration of diabetes was 11 years. Of these participants, 6876 (27%) were diagnosed with at least one AID. Frequency of two or more AIDs increased from 4.3% in participants aged younger than 13 years to 10.4% in those aged 50 years or older. The most common AIDs were thyroid (6097, 24%), gastrointestinal (1530, 6%), and collagen vascular diseases (432, 2%). Addison's disease was rare (75, 0.3%). The prevalence of one or more AIDs was increased in females and non-Hispanic whites and with older age.
CONCLUSIONS: In the T1D Exchange Clinic Registry, a diagnosis of one or more AIDs in addition to T1D is common, particularly in women, non-Hispanic whites, and older individuals. Results of this study have implications for both primary care and endocrine practice and will allow clinicians to better anticipate and manage the additional AIDs that develop in patients with T1D.

PMID: 27676394 [PubMed - indexed for MEDLINE]

Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma.
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Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma.

J Clin Endocrinol Metab. 2016 Dec;101(12):4871-4877

Authors: Xu JY, Murphy WA, Milton DR, Jimenez C, Rao SN, Habra MA, Waguespack SG, Dadu R, Gagel RF, Ying AK, Cabanillas ME, Weitzman SP, Busaidy NL, Sellin RV, Grubbs E, Sherman SI, Hu MI

CONTEXT: Bone metastases (BM) can lead to devastating skeletal-related events (SREs) in cancer patients. Data regarding medullary thyroid carcinoma (MTC) with BM are lacking.
OBJECTIVE: We evaluated the natural history of BM and SREs in MTC patients identified by a cancer center tumor registry.
SETTING: The study was conducted at a tertiary cancer center.
PATIENTS AND MAIN OUTCOME MEASURES: We retrospectively reviewed the charts of MTC patients with BM who received care from 1991 to 2014 to characterize BM and SREs.
RESULTS: Of 1008 MTC patients treated, 188 were confirmed to have BM (19%), of whom 89% (168 of 188) had nonosseous distant metastases. Median time from MTC to BM diagnosis was 30.9 months (range 0-533 mo); 25% (45 of 180) had BM identified within 3 months of MTC diagnosis. Median follow-up after detecting BM was 1.6 years (range 0-23.2 y). Most patients (77%) had six or more BM lesions, most often affecting the spine (92%) and pelvis (69%). Many patients (90 of 188, 48%) experienced one or more SREs, most commonly radiotherapy (67 of 90, 74%) followed by pathological fracture (21 of 90, 23%). Only three patients had spinal cord compression. Patients with more than 10 BM lesions were more likely to experience SREs (odds ratio 2.4; P = .007), with no difference in 5-year mortality after MTC diagnosis between patients with (31%) and without SREs (23%) (P = .11).
CONCLUSIONS: In this large retrospective series, BM in MTC was multifocal, primarily involving the spine and pelvis, supporting screening these regions for metastases in at-risk patients. SREs were common but spinal cord compression was rare. Antiresorptive therapies in this population should be investigated further with prospective trials.

PMID: 27662441 [PubMed - indexed for MEDLINE]

The Desmopressin Test Predicts Better Than Basal Cortisol the Long-Term Surgical Outcome of Cushing's Disease.
Related Articles The Desmopressin Test Predicts Better Than Basal Cortisol the Long-Term Surgical Outcome of Cushing's Disease. J Clin Endocrinol Metab. 2016 Dec;101(12):4878-4885 Authors: Vassiliadi DA, Balomenaki M, Asimakopoulou A, Botoula E, Tzanela M, Tsagarakis S Abstract CONTEXT: Cushing's disease (CD) has a significant relapse rate after successful transsphenoidal surgery (TSS). Many CD patients respond aberrantly to the desmopressin test (DT). Disappearance of this response after surgery may suggest complete removal of abnormal corticotrophs and a lower possibility of recurrence. OBJECTIVE: The utility of postoperative DT to predict long-term outcome compared to the widely used postoperative cortisol level. DESIGN: Retrospective analysis. SETTING: Tertiary hospital. PATIENTS: Seventy-three patients underwent TSS and postoperative DT; 51 had sustained remission, defined as normal dexamethasone suppression and urinary free cortisol at 6 months. After excluding 12 patients with short follow-up, negative or no preoperative DT, we analyzed 39 patients. INTERVENTION(S): Measurements of morning cortisol at 1-2 weeks and DT within 6 months after TSS. MAIN OUTCOME MEASURE(S): Recurrence or remission at latest follow-up. RESULTS: Mean follow-up was 63 ± 50 months. Recurrence occurred in seven patients. In logistic regression analysis, postoperative cortisol levels were not associated with remission. Apart from the percentage increment of cortisol, all other DT criteria (peak cortisol, peak ACTH, absolute cortisol increment [ΔCort], absolute ACTH change, and percentage absolute ACTH change) were significant predictors of outcome. In receiver operating characteristic analysis, the ΔCort had the best diagnostic performance. ΔCort <7.4 μg/dL had a sensitivity of 97% to detect remission. Comparison of Kaplan-Meier curves showed that ΔCort <7.4 μg/dL was associated with remission, whereas ΔCort ≥7.4 μg/dL had a hazard ratio of recurrence of 24.7 (95% confidence interval, 10.6-448.5) at 60 months (median). CONCLUSION: Loss of desmopressin response indicates favorable prognosis and, if used in addition to basal cortisol levels, improves the accuracy of the postoperative assessment of CD. PMID: 27662440 [PubMed - indexed for MEDLINE] [...]

Association Between Serum Fibroblast Growth Factor 21 and Mortality Among Patients With Coronary Artery Disease.
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Association Between Serum Fibroblast Growth Factor 21 and Mortality Among Patients With Coronary Artery Disease.

J Clin Endocrinol Metab. 2016 Dec;101(12):4886-4894

Authors: Li Q, Zhang Y, Ding D, Yang Y, Chen Q, Su D, Chen X, Yang W, Qiu J, Ling W

OBJECTIVES: Epidemiological studies have shown that serum fibroblast growth factor 21 (FGF21) levels were elevated in obesity and its related metabolic disorders. This prospective study assessed whether there was an independent association of serum FGF21 levels with all-cause and cardiovascular disease (CVD) mortality among patients with coronary artery disease (CAD).
METHODS: A prospective cohort study of 1668 CAD patients was conducted. Their serum FGF21 levels were measured with ELISA kits. Cox regression models were used to estimate the association of serum FGF21 levels with the risk of mortality.
RESULTS: During a median follow-up of 4.9 years, there were 194 deaths recorded and 130 of them were CVD deaths. Serum FGF21 levels positively correlated with age, body mass index, waist circumference, and adverse lipid profiles. Spline plots displayed a U-shaped association between serum FGF21 levels and all-cause as well as CVD mortality among CAD patients. Compared with serum FGF21 quartile 2, groups at quartiles 1, 3, and 4 had higher risk for all-cause and CVD mortality. Patients in the serum FGF21 quartile 4 had a 1.95-fold (95% confidence interval 1.25-3.02) risk of all-cause mortality and a 2.50-fold (95% confidence interval 1.43-4.38) risk of CVD mortality compared with those in quartile 2.
CONCLUSIONS: The present study is the first to demonstrate that both higher and lower serum FGF21 levels were associated with increased risks for all-cause and CVD mortality, independent of traditional CVD risk factors.

PMID: 27662438 [PubMed - indexed for MEDLINE]

Effect of Genotype and Previous GH Treatment on Adiposity in Adults With Prader-Willi Syndrome.
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Effect of Genotype and Previous GH Treatment on Adiposity in Adults With Prader-Willi Syndrome.

J Clin Endocrinol Metab. 2016 Dec;101(12):4895-4903

Authors: Coupaye M, Tauber M, Cuisset L, Laurier V, Bieth E, Lacorte JM, Oppert JM, Clément K, Poitou C

CONTEXT: Adults with Prader-Willi syndrome (PWS) have an increased proportion of sc fat mass compared with body mass index (BMI)-matched controls, but whether the genotype influences body composition and metabolic profile remains controversial.
OBJECTIVE: To assess body composition and metabolic features in adults with PWS, according to genetic subtype. In addition, the effect of previous GH treatment was assessed. Main Outcomes and Measures: Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire.
RESULTS: In the whole sample, the deletion group had a higher BMI compared with UPD (40.9 ± 11.5 vs 34.6 ± 9.6 kg/m(2), P = .02), but there was no difference between groups in percent body fat, metabolic profile, adipocyte size, resting energy expenditure, hyperphagia score, or ghrelin levels. In subjects previously treated with GH, BMI was not different between UPD and deletion groups (33.0 ± 9.7 vs 33.5 ± 11.1 kg/m(2)). In addition, previous GH treatment was associated with decreased percent body fat and adipocyte volume only in the deletion group.
CONCLUSION: A deletion genotype in adults with PWS is associated with increased BMI. GH treatment in childhood and/or adolescence limits this deleterious phenotypic effect with improved adiposity markers. This study suggests relationships between the molecular phenotype of PWS and adipose tissue development as well as sensitivity to GH.

PMID: 27662437 [PubMed - indexed for MEDLINE]

The Risk of Preeclampsia According to High Thyroid Function in Pregnancy Differs by hCG Concentration.
Related Articles The Risk of Preeclampsia According to High Thyroid Function in Pregnancy Differs by hCG Concentration. J Clin Endocrinol Metab. 2016 Dec;101(12):5037-5043 Authors: Korevaar TI, Steegers EA, Chaker L, Medici M, Jaddoe VW, Visser TJ, de Rijke YB, Peeters RP Abstract CONTEXT: During pregnancy, there is an increased demand for thyroid hormone. The pregnancy hormone human chorionic gonadotropin (hCG) is an important physiological stimulator of thyroid function. Already high-normal maternal free T4 concentrations are associated with a higher risk of preeclampsia. OBJECTIVE: The objective of the investigation was to study our hypothesis that hCG concentrations can distinguish a physiological form of high thyroid function from a more pathological form of high thyroid function and that the risk of preeclampsia would differ accordingly. DESIGN: TSH, free T4, hCG, or thyroperoxidase antibody concentrations were determined in pregnant women participating in a population-based prospective cohort study. SETTING: The study was conducted in the general community. PARTICIPANTS: A nonselected sample of 5146 pregnant women participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE(S): Preeclampsia was measured. RESULTS: Women with high hCG-associated high thyroid function did not have a higher risk of preeclampsia than women with normal thyroid function. In contrast, women with low hCG and high thyroid function had a 3.4- to 11.1-fold higher risk of preeclampsia. These risk estimates were amplified in women with a high body mass index. Women with a low hCG and suppressed TSH (<0.10 mU/L) had a 3.2- to 8.9-fold higher risk of preeclampsia. hCG was not associated with preeclampsia, and results remained similar after exclusion of thyroperoxidase antibody-positive women. CONCLUSION: This study suggests that, in contrast to women with a high hCG associated high thyroid function, women with low hCG and high thyroid function during pregnancy are at a higher risk of developing preeclampsia. The additional measurement of hCG may therefore help to distinguish a more pathological form of high thyroid function and women at a high risk of preeclampsia. PMID: 27648965 [PubMed - indexed for MEDLINE] [...]

Thyroid Function and Cancer Risk: The Rotterdam Study.
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Thyroid Function and Cancer Risk: The Rotterdam Study.

J Clin Endocrinol Metab. 2016 Dec;101(12):5030-5036

Authors: Khan SR, Chaker L, Ruiter R, Aerts JG, Hofman A, Dehghan A, Franco OH, Stricker BH, Peeters RP

CONTEXT: In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results.
OBJECTIVE: We aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting.
DESIGN, SETTING, AND PARTICIPANTS: The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T4 (FT4) and/or TSH were available.
MAIN OUTCOME MEASURES: Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically.
RESULTS: Higher FT4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval [CI], 1.12-1.79), lung cancer (HR, 2.33; 95% CI, 1.39-3.92) and breast (HR, 1.77; 95% CI, 1.10-2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk.
CONCLUSIONS: Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.

PMID: 27648963 [PubMed - indexed for MEDLINE]

Liver and Muscle Contribute Differently to the Plasma Acylcarnitine Pool During Fasting and Exercise in Humans.
Related Articles Liver and Muscle Contribute Differently to the Plasma Acylcarnitine Pool During Fasting and Exercise in Humans. J Clin Endocrinol Metab. 2016 Dec;101(12):5044-5052 Authors: Xu G, Hansen JS, Zhao XJ, Chen S, Hoene M, Wang XL, Clemmesen JO, Secher NH, Häring HU, Pedersen BK, Lehmann R, Weigert C, Plomgaard P Abstract BACKGROUND: Plasma acylcarnitine levels are elevated by physiological conditions such as fasting and exercise but also in states of insulin resistance and obesity. AIM: To elucidate the contribution of liver and skeletal muscle to plasma acylcarnitines in the fasting state and during exercise in humans. METHODS: In 2 independent studies, young healthy males were fasted overnight and performed an acute bout of exercise to investigate either acylcarnitines in skeletal muscle biopsies and arterial-to-venous plasma differences over the exercising and resting leg (n = 9) or the flux over the hepato-splanchnic bed (n = 10). RESULTS: In the fasting state, a pronounced release of C2- and C3-carnitines from the hepato-splanchnic bed and an uptake of free carnitine by the legs were detected. Exercise further increased the release of C3-carnitine from the hepato-splanchnic bed and the uptake of free carnitine in the exercising leg. In plasma and in the exercising muscle, exercise induced an increase of most acylcarnitines followed by a rapid decline to preexercise values during recovery. In contrast, free carnitine was decreased in the exercising muscle and quickly restored thereafter. C8-, C10-, C10:1-, C12-, and C12:1-carnitines were released from the exercising leg and simultaneously; C6, C8, C10, C10:1, C14, and C16:1 were taken up by the hepato-splanchnic. CONCLUSION: These data provide novel insight to the organo-specific release/uptake of acylcarnitines. The liver is a major contributor to systemic short chain acylcarnitines, whereas the muscle tissue releases mostly medium chain acylcarnitines during exercise, indicating that other tissues are contributing to the systemic increase in long chain acylcarnitines. PMID: 27648961 [PubMed - indexed for MEDLINE] [...]

Racial Differences in Association of Serum Calcium with Mortality and Incident Cardio- and Cerebrovascular Events.
Related Articles Racial Differences in Association of Serum Calcium with Mortality and Incident Cardio- and Cerebrovascular Events. J Clin Endocrinol Metab. 2016 Dec;101(12):4851-4859 Authors: Lu JL, Molnar MZ, Ma JZ, George LK, Sumida K, Kalantar-Zadeh K, Kovesdy CP Abstract CONTEXT: Abnormalities in calcium metabolism may potentially contribute to the development of vascular disease. Calcium metabolism may be different in African American (AA) vs white individuals, but the effect of race on the association of serum calcium with clinical outcomes remains unclear. OBJECTIVE: This study sought to examine race-specific associations of serum calcium levels with mortality and with major incident cardiovascular events. DESIGN AND SETTING: This was a historical cohort study in the U.S. Department of Veterans Affairs health care facilities. PARTICIPANTS: Participants included veterans (n = 1 967 622) with estimated glomerular filtration rate ≥ 60 mL/min/1.73 m(2). MAIN OUTCOME MEASURES: The association between serum calcium levels with all-cause mortality, incident coronary heart disease (CHD), and ischemic stroke incidence was examined in multivariable adjusted Cox proportional hazards models, including an interaction term for calcium and race. RESULTS: The association of calcium with all-cause mortality was U-shaped in both AA and white patients, but race modified the association of calcium with all-cause mortality. Compared with white patients, AA patients experienced lower risk of mortality when calcium was ≥ 8.8 mg/dL, with a statistically significant interaction (P < .001). Conversely, AA vs white race was associated with higher mortality when calcium was < 8.8 mg/dL. Calcium showed no significant association with ischemic stroke or CHD in both races; and race did not modify these associations (P = .37 and 0.11, respectively for interaction term). CONCLUSIONS: Race modified the U-shaped association between calcium and all-cause mortality. Serum calcium is not associated with incident stroke or CHD in either AA or white patients. The race-specific difference in the association of calcium levels with mortality warrants further examination. PMID: 27631543 [PubMed - indexed for MEDLINE] [...]

Exploring Inpatient Hospitalizations and Morbidity in Patients With Adrenal Insufficiency.
Related Articles Exploring Inpatient Hospitalizations and Morbidity in Patients With Adrenal Insufficiency. J Clin Endocrinol Metab. 2016 Dec;101(12):4843-4850 Authors: Stewart PM, Biller BM, Marelli C, Gunnarsson C, Ryan MP, Johannsson G Abstract CONTEXT: Patients with adrenal insufficiency (AI) (primary AI [PAI], secondary AI due to a pituitary disorder [PIT] and congenital adrenal hyperplasia [CAH]) have reduced life expectancy; however, the underlying explanation remains unknown. OBJECTIVE: To evaluate characteristics, comorbidities, and hospitalizations in AI patients. DESIGN: Retrospective observational. SETTING AND POPULATION: Using a United States-based national payer database comprising of more than 108 million members, strict inclusion criteria including diagnostic codes and steroid prescription records were used to identify 10 383 adults with AI; 1014 with PAI, 8818 with PIT, and 551 with CAH. Patients were matched 1:1 to controls, based on age (±5 y), gender, insurance, and region and followed for more than 12 months. INTERVENTION: None. MAIN OUTCOME MEASURES: Demographic variables, comorbidities (diabetes mellitus [DM] types 1 and 2, depression, anxiety, hyperlipidemia, hypertension) and hospitalization incidence. RESULTS: Compared with controls, patients with AI had higher odds of DM, hypertension, hyperlipidaemia, depression, and anxiety, ranging from an odds ratio (OR) of 1.51 for hyperlipidaemia in PAI to 3.85 for DM in CAH. Odds of having DM (OR, 3.85; 95% confidence interval, 2.52-5.90) or anxiety (OR, 2.99; 95% confidence interval, 2.02-4.42) compared with controls were highest in CAH, whereas depression was highest in PAI and PIT (OR, 2.40 and 2.55). ORs of hyperlipidaemia and hypertension (OR, 1.98 and 2.24) were highest in the PIT cohort. Inpatient admissions were more frequent in PAI (4.64:1; P < .0001) and PIT (4.00:1; P < .0001) than controls; infection was the most common cause for admission. CONCLUSION: Patients with AI carry a significant metabolic and psychiatric burden, with higher risk of comorbidities and hospital admissions than matched controls. PMID: 27623069 [PubMed - indexed for MEDLINE] [...]

Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Graves' Ophthalmopathy-Implications for Smoking.
Related Articles Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Graves' Ophthalmopathy-Implications for Smoking. J Clin Endocrinol Metab. 2016 Dec;101(12):4834-4842 Authors: Görtz GE, Horstmann M, Aniol B, Reyes BD, Fandrey J, Eckstein A, Berchner-Pfannschmidt U Abstract CONTEXT: In Graves' ophthalmopathy (GO), inflammation with tissue expansion in a closed compartment like the bony orbit and smoking may cause tissue hypoxia. OBJECTIVES: In this study, we investigated whether hypoxia-inducible factor-1 (HIF-1) action impacts on tissue remodeling in GO with the aim to identify possible new therapeutic targets. DESIGN/SETTING/PARTICIPANTS: Orbital fibroblasts (OFs) were derived from GO patients and control (Ctrl) persons. We analyzed HIF-1α levels in response to hypoxia and cigarette smoke extract, as well as HIF-1-dependent vascular endothelial growth factor (VEGF) release and adipogenic differentiation, by using HIF-1α small interfering RNA, or HIF-1 inhibitor BAY 87-2243. MAIN OUTCOME MEASURES: Western blot, real-time PCR, ELISA, and immunohistochemistry were used to analyze HIF-1α, VEGF, CD31, and adiponectin. Adipogenic differentiation was measured with Nile red assay. RESULTS: Higher HIF-1α levels in OFs were correlated with the clinical activity score of GO patients. Cigarette smoke extract elevated HIF-1α levels. HIF-1-dependent VEGF secretion was enhanced in GO-OF compared to Ctrl-OF, and as an in vivo consequence, we found a higher vessel density in GO tissue than in Ctrl tissue. Hypoxia strongly stimulated HIF-1-dependent adipogenesis and adiponectin release of GO-OF and enhanced TSH receptor-mediated adipogenesis. CONCLUSIONS: Hypoxia impacts on tissue remodeling in GO by stimulating angiogenesis and adipogenesis through activation of HIF-1-dependent pathways in OFs. Our results offer a molecular mechanism for the detrimental influence of smoking on GO and an explanation as to why decompression can improve the outcome of patients. Drug-targeted inhibition of HIF-1/VEGF may provide a therapeutic option to control tissue expansion in GO. PMID: 27610652 [PubMed - indexed for MEDLINE] [...]

The Association of Weight Loss and Cardiometabolic Outcomes in Obese Children: Systematic Review and Meta-regression.
Related Articles The Association of Weight Loss and Cardiometabolic Outcomes in Obese Children: Systematic Review and Meta-regression. J Clin Endocrinol Metab. 2016 Dec;101(12):4764-4768 Authors: Rajjo T, Almasri J, Al Nofal A, Farah W, Alsawas M, Ahmed AT, Mohammed K, Kanwar A, Asi N, Wang Z, Prokop LJ, Murad MH Abstract BACKGROUND: Excess body weight in children is associated with multiple immediate and long-term medical comorbidities. We aimed to identify the degree of reduction in excess body weight associated with cardiometabolic changes (lipid panel, liver function tests, systolic blood pressure (SBP), diastolic blood pressure, glycosylated hemoglobin, and fasting blood glucose) in overweight and obese children. METHODS: We conducted a comprehensive search of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus through February 12, 2015. We included randomized controlled trials and cohort studies that evaluated interventions to treat pediatric obesity (medication, surgery, lifestyle, and community-based interventions) with ≥ a 6-month follow-up. We used a random effects meta-regression approach to assess the association between body mass index (BMI)/weight and cardiometabolic changes. RESULTS: We included 42 studies (37 randomized controlled trials and five cohorts) enrolling 3807 children (mean age, 12.2 years; weight, 74.7 kg; and BMI, 31.7 kg/m(2)). Studies had overall moderate to low risk of bias. A 1-mm Hg decrease in SBP was significantly associated with a decrease of 0.16 kg/m(2) (P = .04) in BMI. A 1-mg/dL increase in HDL was significantly associated with a 0.74-kg decrease in weight (P = .02). A 1-mg/dL decrease in triglycerides was significantly associated with a 0.1-kg decrease in weight (P = .03). The remaining associations were not statistically significant. CONCLUSIONS: Weight reduction in children is associated with significant changes in several cardiometabolic outcomes, particularly HDL, SBP, and triglycerides. The magnitude of improvement may help in setting expectations and may inform shared decision-making and counseling. PMID: 27603909 [PubMed - indexed for MEDLINE] [...]

Diazoxide in Children With Obesity After Hypothalamic-Pituitary Lesions: A Randomized, Placebo-Controlled Trial.
Related Articles Diazoxide in Children With Obesity After Hypothalamic-Pituitary Lesions: A Randomized, Placebo-Controlled Trial. J Clin Endocrinol Metab. 2016 Dec;101(12):4825-4833 Authors: Brauner R, Serreau R, Souberbielle JC, Pouillot M, Grouazel S, Recasens C, Zerah M, Sainte-Rose C, Treluyer JM Abstract OBJECTIVE: The objective was to evaluate the safety and efficacy of diazoxide (DZX) for decreasing obesity with hyperinsulinemia in patients treated for hypothalamic-pituitary lesions during childhood. DESIGN: This was a double-blind, placebo-controlled trial in parallel groups using a centralized randomization process (PEDIAC). SETTING: This was a single-center study. PATIENTS: Among the 40 patients included, 35 fulfilled the study requirements. INTERVENTIONS: Interventions included six-month treatment with DZX (4 mg/kg/d) or placebo. MAIN OUTCOME MEASURES: The primary outcome was relative weight change at 2 months. Secondary outcomes were changes in absolute weight, plasma insulin concentrations, glucose peak after oral glucose tolerance test (OGTT), and glycosylated hemoglobin after 2 months. RESULTS: Eighteen participants were randomized to the DZX group; three withdrew their consent or were excluded after the occurrence of diabetes mellitus at days 10, 10, and 35, respectively; and two dropped out because of protocol non-compliance at day 10. No statistically significant differences in baseline characteristics were observed among the 13 DZX patients and the 17 placebo patients. The relative weight changes at 2 months in the DZX and placebo groups were -0.9 and -0.5%, respectively (P = nonsignificant). No statistically significant differences were observed between the groups concerning the change in absolute weight or glycosylated hemoglobin after 2 months, but the plasma glucose concentrations (basal and after OGTT) were significantly greater in the patients receiving DZX treatment vs those receiving the placebo, whereas the plasma increases in insulin after OGTT were lower. CONCLUSIONS: The 2-month treatment with DZX was not associated with a significant change in weight compared with placebo; however, it was associated with the occurrence of diabetes mellitus in three of 18 patients. PMID: 27603903 [PubMed - indexed for MEDLINE] [...]

Mechanisms Underlying the Pathogenesis of Isolated Impaired Glucose Tolerance in Humans.
Related Articles Mechanisms Underlying the Pathogenesis of Isolated Impaired Glucose Tolerance in Humans. J Clin Endocrinol Metab. 2016 Dec;101(12):4816-4824 Authors: Varghese RT, Dalla Man C, Sharma A, Viegas I, Barosa C, Marques C, Shah M, Miles JM, Rizza RA, Jones JG, Cobelli C, Vella A Abstract CONTEXT: Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance. OBJECTIVE: We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT). DESIGN: The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance. SETTING: An inpatient clinical research unit at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study. INTERVENTION(S): Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin. MAIN OUTCOME MEASURES: We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT. RESULTS: Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 μmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10(-14) dL/kg/min(2) per pmol/L; P < .001). CONCLUSIONS: We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in β-cell function. PMID: 27603902 [PubMed - indexed for MEDLINE] [...]

P450 Oxidoreductase Deficiency: Loss of Activity Caused by Protein Instability From a Novel L374H Mutation.
Related Articles P450 Oxidoreductase Deficiency: Loss of Activity Caused by Protein Instability From a Novel L374H Mutation. J Clin Endocrinol Metab. 2016 Dec;101(12):4789-4798 Authors: Parween S, Roucher-Boulez F, Flück CE, Lienhardt-Roussie A, Mallet D, Morel Y, Pandey AV Abstract CONTEXT: P450 oxidoreductase (POR) is required for the activities of steroid-metabolizing cytochrome P450 enzymes in the endoplasmic reticulum. POR deficiency (PORD) is a form of congenital adrenal hyperplasia. Objective and Aim: Enzymatic and structural analysis of a novel L374H POR mutation from a patient with 46,XX disorder of sexual development. Design, Setting, Patient, and Intervention: The patient was a 46,XX girl with nonconsanguineous Turkish parents. She had virilized external genitalia at birth, a uterus and ovaries, and no sign of Antley-Bixler syndrome. The initial diagnosis was CYP21A2 deficiency with no mutations in CYP21A2, but POR mutations were found. Functional testing was done after producing recombinant POR proteins for analyzing enzymatic and structural properties. MAIN OUTCOME: Novel mutations were causing severe loss of POR activities for metabolism of steroids and small molecules. RESULTS: The L374H mutation reduced activities by 80% in cytochrome c, 97% in thiazolyl blue tetrazolium bromide, and 86% in ferricyanide reduction assays. The catalytic efficiency of the 17 α-hydroxylation of progesterone and the 17,20-lyase reaction of 17-OH pregnenolone was decreased by 87 and 90%, respectively; 21-hydroxylation of progesterone was decreased by 96%, and androstenedione aromatization was decreased by 90%. Analysis of the mutant structure by molecular dynamics simulations revealed structural instability. Flavin release and fast proteolysis assays showed that the L374H mutant is less stable than wild-type POR, confirming the bioinformatics prediction. CONCLUSIONS: This is the first report of a mutation causing PORD by affecting protein stability that causes severe reduction in POR activities. Detailed characterization of individual mutations in POR is required for understanding novel molecular mechanisms causing PORD. PMID: 27603900 [PubMed - indexed for MEDLINE] [...]

Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators.
Related Articles Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators. J Clin Endocrinol Metab. 2016 Dec;101(12):4799-4807 Authors: Juhanson P, Rull K, Kikas T, Laivuori H, Vaas P, Kajantie E, Heinonen S, Laan M Abstract CONTEXT AND OBJECTIVES: The study represents the first comprehensive analysis of Stanniocalcin-1 (STC1) hormone in human pregnancy, assessing clinical, lifestyle, and genetic determinants of circulating STC1 at term. DESIGN, SETTING, AND PARTICIPANTS: Participants included women with (n = 50) and without (n = 316) preeclampsia (PE) at delivery, recruited in the REPROgrammed fetal and/or maternal METAbolism (REPROMETA) study (2006-2011, Estonia). Genetic association analysis combined PE cases (n = 597) and controls (n = 623) from the REPROMETA and Finnish Genetics of Preeclampsia Consortium (2008-2011) studies. MAIN OUTCOME MEASURE(S): Maternal postpartum plasma STC1 was measured by ELISA (n = 366) and placental STC1 gene expression by TaqMan quantitative RT-PCR (n = 120). Genotyping was performed using Sequenom MassArray. RESULTS: Significantly higher STC1 plasma level was measured for the PE (median, 1952 pg/mL; 1030-4284 pg/mL) compared with non-PE group (median, 1562 pg/mL; 423-3781 pg/mL; P = 3.7 × 10(-4), Mann-Whitney U test). Statistical significance was enhanced after adjustment for cofactors (linear regression, P = 1.8 × 10(-6)). STC1 measurements were negatively correlated with maternal smoking. Prepregnancy body mass index had a positive correlation with STC1 only among PE patients (r = 0.45; P = .001). The strongest genetic association with hormone concentrations was detected for STC1 single nucleotide polymorphisms rs3758089 (C allele: minor allele frequency, 5%; linear regression: β = 249.2 pg/mL; P = .014) and rs12678447 (G allele: minor allele frequency, 7%; β = 147.0 pg/mL; P = .082). rs12678447 placental genotypes were significantly associated with STC1 gene expression (P = .014). The REPROMETA/Finnish Genetics of Preeclampsia Consortium meta-analysis suggested an increased risk to develop late-onset PE for the rs12678447 G allele carriers (P = .05; odds ratio = 1.38 [0.98-1.93]). CONCLUSIONS: Increased STC1 hormone represents a hallmark of late-onset PE. STC1 gene variants modulate placental gene expression and maternal hormone [...]

Ethnic and Sex Differences in Adiponectin: From Childhood to Adulthood.
Related Articles Ethnic and Sex Differences in Adiponectin: From Childhood to Adulthood. J Clin Endocrinol Metab. 2016 Dec;101(12):4808-4815 Authors: Ohman-Hanson RA, Cree-Green M, Kelsey MM, Bessesen DH, Sharp TA, Pyle L, Pereira RI, Nadeau KJ Abstract CONTEXT: Insulin resistance (IR) and type 2 diabetes are increasing, particularly in Hispanic (H) vs non-Hispanic White (NHW) populations. Adiponectin has a known role in IR, and therefore, understanding ethnic and sex-specific behavior of adiponectin across the lifespan is of clinical significance. OBJECTIVE: To compare ethnic and sex differences in adiponectin, independent of body mass index, across the lifespan and relationship to IR. DESIGN: Cross-sectional. SETTING: Primary care, referral center. PATIENTS: A total of 187 NHW and 117 H participants (8-57 y) without diabetes. Life stage: pre-/early puberty (Tanner 1/2), midpubertal (Tanner 3/4), late pubertal (Tanner 5, <21 years), and adult (Tanner 5, ≥21). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Fasting adiponectin, insulin, glucose, and revised homeostatic model assessment of insulin resistance. RESULTS: Adiponectin was significantly inversely correlated with revised homeostatic model assessment of insulin resistance. Regarding puberty, adiponectin trended downward in late puberty, but only males were significantly lower in adulthood. By sex, adiponectin was lower in adult males vs females of both ethnicities. Regarding ethnicity, H adults of both sexes had lower adiponectin than NHW adults. Of note, in NHW females, adiponectin trended highest in adulthood, whereas in H females, adiponectin fell in late puberty and remained lower in adulthood. CONCLUSIONS: Adiponectin inversely correlated with IR, trended down in late puberty, and was lowest in adult males. H adults of both sexes had lower adiponectin than NHW adults, and H females followed a more "male pattern," lacking the rebound in adiponectin seen in NHW females after puberty. These data suggest that adiponectin, independent of body mass index, may relate to the greater cardiometabolic risk seen in H populations and in particular H females. PMID: 27603898 [PubMed - indexed for MEDLINE] [...]

Small Intestinal Glucose Delivery Affects the Lowering of Blood Glucose by Acute Vildagliptin in Type 2 Diabetes.
Related Articles Small Intestinal Glucose Delivery Affects the Lowering of Blood Glucose by Acute Vildagliptin in Type 2 Diabetes. J Clin Endocrinol Metab. 2016 Dec;101(12):4769-4778 Authors: Wu T, Zhang X, Trahair LG, Bound MJ, Little TJ, Deacon CF, Horowitz M, Jones KL, Rayner CK Abstract CONTEXT: The rate of gastric emptying is an important determinant of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion and may influence the magnitude of glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors. OBJECTIVE: To evaluate the effects of the DPP-4 inhibitor, vildagliptin (VILD), during intraduodenal (ID) glucose infusion at 2 different rates within the physiological range of gastric emptying, in type 2 diabetes. PARTICIPANTS AND DESIGN: A total of 16 diet-controlled type 2 diabetic patients were studied on 4 separate days in double-blind, randomized, fashion. On each day, either 5-mg VILD or placebo (PLBO) was given 60 minutes before a 120-minute ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4). Plasma glucose and hormones were measured frequently. RESULTS: Plasma glucose, insulin, C-peptide, glucagon, total GIP, and total and intact GLP-1 concentrations were higher during ID4 than ID2 (P < .01 for each). Compared with PLBO, VILD was associated with higher intact GLP-1, insulin, and C-peptide and lower glucose and total GIP and GLP-1 (P < .01 for each), without affecting glucagon. There were significant interactions between the rate of ID glucose and VILD treatment on plasma glucose, intact and total GLP-1, and GIP (P < .05 for each) but not insulin, C-peptide, or glucagon. The reduction in glucose and the increment in intact GLP-1 after VILD vs PLBO were 3.3- and 3.8-fold greater, respectively, during ID4 compared with ID2. CONCLUSIONS/INTERPRETATION: These observations warrant further study to clarify whether type 2 diabetic patients with relatively more rapid gastric emptying have greater glucose lowering during treatment with DPP-4 inhibitors. PMID: 27598511 [PubMed - indexed for MEDLINE] [...]