The 50 most-cited articles in The Journal of Clinical Endocrinology & Metabolism, 2016

OBJECTIVE: To develop clinical practice guidelines for the management of patients with primary aldosteronism. PARTICIPANTS: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration. EVIDENCE: We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak…

OBJECTIVE: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. PARTICIPANTS: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical…

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within…

OBJECTIVE: To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline. EVIDENCE: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.…

CONTEXT: Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. OBJECTIVE: To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). DESIGN: Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. SETTING: Twenty-seven study centers in the United States. PATIENTS: DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. INTERVENTION: Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). MAIN OUTCOME MEASURES: B12 deficiency, anemia, and peripheral neuropathy. RESULTS: Low B12 (≤…

OBJECTIVE: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. PARTICIPANTS: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. EVIDENCE: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. CONSENSUS PROCESS: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group…

OBJECTIVE: Hypoparathyroidism is a rare disorder characterized by hypocalcemia and absent or deficient PTH. This report presents a summary of current information about epidemiology, presentation, diagnosis, clinical features, and management and proposes guidelines to help clinicians diagnose, evaluate, and manage this disorder. PARTICIPANTS: Participants in the First International Conference on the Management of Hypoparathyroidism represented a worldwide constituency with acknowledged interest and expertise in key basic, translational, and clinical aspects of hypoparathyroidism. Three Workshop Panels were constituted to address questions for presentation and discussion at the Conference held in Florence, Italy, May 7-9, 2015. At that time, a series of presentations were made, followed by in-depth discussions in an open forum. Each Workshop Panel also met in closed sessions to formulate the three evidence-based reports that accompany this summary statement. An Expert Panel then considered this information, developed summaries, guidelines, and a research agenda that constitutes this…

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…

CONTEXT: For health care planning and allocation of resources, realistic estimation of the prevalence of primary aldosteronism is necessary. Reported prevalences of primary aldosteronism are highly variable, possibly due to study heterogeneity. OBJECTIVE: Our objective was to identify and explain heterogeneity in studies that aimed to establish the prevalence of primary aldosteronism in hypertensive patients. DATA SOURCES: PubMed, EMBASE, Web of Science, Cochrane Library, and reference lists from January 1, 1990, to January 31, 2015, were used as data sources. STUDY SELECTION: Description of an adult hypertensive patient population with confirmed diagnosis of primary aldosteronism was included in this study. DATA EXTRACTION: Dual extraction and quality assessment were the forms of data extraction. DATA SYNTHESIS: Thirty-nine studies provided data on 42 510 patients (nine studies, 5896 patients from primary care). Prevalence estimates varied from 3.2% to 12.7% in primary care and from 1% to 29.8% in referral centers. Heterogeneity was too high to establish point estimates (I(2) =…

CONTEXT: Understanding the etiology, diagnosis, and symptoms of hypoparathyroidism may help to improve quality of life and long-term disease outcomes. This paper summarizes the results of the findings and recommendations of the Working Group on Presentation of Hypoparathyroidism. EVIDENCE ACQUISITION: Experts convened in Florence, Italy, in May 2015 and evaluated the literature and recent data on the presentation and long-term outcomes of patients with hypoparathyroidism. EVIDENCE SYNTHESIS: The most frequent etiology is surgical removal or loss of viability of parathyroid glands. Despite precautions and expertise, about 20-30% of patients develop transient and 1-7% develop permanent postsurgical hypoparathyroidism after total thyroidectomy. Autoimmune destruction is the main reason for nonsurgical hypoparathyroidism. Severe magnesium deficiency is an uncommon but correctable cause of hypoparathyroidism. Several genetic etiologies can result in the loss of parathyroid function or action causing isolated hypoparathyroidism or a complex syndrome with other symptoms apart from those of…

CONTEXT: Hypoparathyroidism is a disorder characterized by hypocalcemia due to insufficient secretion of PTH. Pseudohypoparathyroidism is a less common disorder due to target organ resistance to PTH. This report summarizes the results of the findings and recommendations of the Working Group on Epidemiology and Diagnosis of Hypoparathyroidism. EVIDENCE ACQUISITION: Each contributing author reviewed the recent published literature regarding epidemiology and diagnosis of hypoparathyroidism using PubMed and other medical literature search engines. EVIDENCE SYNTHESIS: The prevalence of hypoparathyroidism is an estimated 37 per 100 000 person-years in the United States and 22 per 100 000 person-years in Denmark. The incidence in Denmark is approximately 0.8 per 100 000 person-years. Estimates of prevalence and incidence of hypoparathyroidism are currently lacking in most other countries. Hypoparathyroidism increases the risk of renal insufficiency, kidney stones, posterior subcapsular cataracts, and intracerebral calcifications, but it does not appear to increase overall mortality,…

CONTEXT: We have previously found that visceral fat is a stronger predictor for cardiovascular risk factors than body mass index (BMI). OBJECTIVE: This study sought to investigate the prevalence of diabetes in elderly men and women in relation to objectively assessed visceral fat volume. DESIGN AND SETTING: The cohort consisted of a population-based sample of 705 men and 688 women, all age 70 y at the time of examination. MAIN OUTCOME MEASURES: Associations between body fat estimates, plasma glucose level, and diabetes prevalence were investigated using multivariable-adjusted statistical models. RESULTS: ; P = .01), with a greater difference in mean visceral fat mass (1987 vs 1077 g; P < .001). After adjustment for physical activity and smoking, men had about/approximately twice the odds of having type 2 diabetes compared with women (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.38-2.76). The inclusion of BMI in this model did not change the risk associated with male sex (OR, 1.93; 95% CI, 1.34-2.77). However, when visceral fat was included as a covariate, male sex was not…

Context: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. Methods: One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four-hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. Results: As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens…

CONTEXT: Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and 24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown. OBJECTIVE: The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects. DESIGN: A randomized, crossover study with two 3-day laboratory visits. SETTING: Center for Clinical Investigation at Brigham and Women's Hospital. PATIENTS: Healthy chronic shift workers. INTERVENTION: The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment). MAIN OUTCOME MEASURES: Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols. RESULTS:…

OBJECTIVE: To formulate clinical practice guidelines for the use of continuous glucose monitoring and continuous subcutaneous insulin infusion in adults with diabetes. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of seven experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the American Association of Diabetes Educators, and the European Society of Endocrinology co-sponsored this guideline. EVIDENCE: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned one systematic review and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the American Association of Diabetes…

Context: Immune checkpoint blockade is associated with endocrine-related adverse events.Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized.Objective: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction.Design and Setting: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center.18 Fluorodeoxyglucose uptake on positron emission tomography/computed tomography ( 18 FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis.Patients: Ninety-nine patients with advanced melanoma (age, 26.3-93.6 years; 63.6% females) who received at least one administration of pembrolizumab.Main Outcome Measures: Patient characteristics, thyroid function (TSH, free T 4 ), thyroid autoantibodies, and 18 FDG-PET/CT.Results: Eighteen adverse events of thyroid dysfunction were observed in 17 patients.Thyrotoxicosis occurred in 12 patients, of which nine…

CONTEXT: Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis. OBJECTIVE: The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover. DESIGN AND SETTING: This was an international, multicenter, randomized, double-blind trial. PARTICIPANTS: A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study. INTERVENTIONS: Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months. MAIN OUTCOME MEASURES: Changes in BMD and bone turnover markers were measured. RESULTS: BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs -0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater…

OBJECTIVE: The epidemiology of hypoparathyroidism (HP) is largely unknown. We aimed to determine prevalence, etiologies, health related quality of life (HRQOL) and treatment pattern of HP. METHODS: Patients with HP and 22q11 deletion syndrome (DiGeorge syndrome) were identified in electronic hospital registries. All identified patients were invited to participate in a survey. Among patients who responded, HRQOL was determined by Short Form 36 and Hospital Anxiety and Depression scale. Autoantibodies were measured and candidate genes (CaSR, AIRE, GATA3, and 22q11-deletion) were sequenced for classification of etiology. RESULTS: We identified 522 patients (511 alive) and estimated overall prevalence at 102 per million divided among postsurgical HP (64 per million), nonsurgical HP (30 per million), and pseudo-HP (8 per million). Nonsurgical HP comprised autosomal dominant hypocalcemia (21%), autoimmune polyendocrine syndrome type 1 (17%), DiGeorge/22q11 deletion syndrome (15%), idiopathic HP (44%), and others (4%). Among the 283 respondents (median age, 53 years [range, 9-89], 75%…

CONTEXT: Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as 25-50% due to delays in diagnosis and inadequate treatment. Congenital HI has been described since the birth of the JCEM under various terms, including "idiopathic hypoglycemia of infancy," "leucine-sensitive hypoglycemia," or "nesidioblastosis." EVIDENCE ACQUISITION: In the past 20 years, it has become apparent that HI is caused by genetic defects in the pathways that regulate pancreatic β-cell insulin secretion. EVIDENCE SYNTHESIS: There are now 11 genes associated with monogenic forms of HI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1), as well as several syndromic genetic forms of HI (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). HI is also the cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as birth asphyxia, small for gestational age birthweight, infant of diabetic mother).…

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…

CONTEXT: Although response to therapy assessment is a validated tool for dynamic risk stratification in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TT) and radioactive iodine therapy (RAI), it has not been well studied in patients treated with lobectomy or TT without RAI. Because these responses to therapy definitions are heavily dependent on serum thyroglobulin (Tg) levels, modifications of the original definitions were needed to appropriately classify patients treated without RAI. OBJECTIVE: This study aimed to validate the response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI. DESIGN AND SETTING: This was a retrospective study, which took place at a referral center. PATIENTS: A total of 507 adults with DTC were treated with lobectomy (n = 187) or TT (n = 320) without RAI. They had a median age of 43.7 y, 88% were female, 85.4% had low risk, and 14.6% intermediate risk. MAIN OUTCOME MEASURE: Main outcome measured was recurrent/persistent structural evidence of disease (SED) during a median followup…

BACKGROUND: Nonalcoholic fatty liver disease is very frequent in type 2 diabetes, with increased risk of further development of liver fibrosis. Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis. However, data in humans are scarce. OBJECTIVE: To study the effect of liraglutide 1.2 mg/d on liver fat content (LFC) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC. DESIGN, SETTING, PARTICIPANTS: LFC was measured by proton magnetic resonance spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus. INTERVENTION: Liraglutide 1.2 mg/d. OUTCOME MEASURE: Change in LFC. RESULTS: Treatment with liraglutide was associated with a significant decrease in body weight, HbA1C, and a marked relative reduction in LFC of 31% (P < 0.0001). No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin. The reduction in LFC and…

CONTEXT AND OBJECTIVE: There has been increased attention to the issue of fertility preservation (FP). We aimed to investigate the long-term safety of FP via controlled ovarian stimulation with letrozole supplementation (COSTLES) prior to breast cancer treatment. DESIGN, SETTING, AND PARTICIPANTS: This is a prospective, nonrandomized, controlled study conducted between the years 2002 and 2014. A total of 337 women diagnosed with stage 3 or less invasive breast cancer were enrolled during a FP consultation before chemotherapy. Of those, 120 elected to undergo COSTLES for FP prior to chemotherapy (FP group). The remaining 217 patients did not undergo any FP procedure and served as the controls. MAIN OUTCOME MEASURE: The primary end point was cancer recurrence defined as the detection of locoregional tumor (chest wall, regional nodal disease), distant metastases, or contralateral invasive breast cancer. RESULTS: The baseline characteristics at enrollment were similar between the FP and control groups except for the less frequent lymph node involvement (P = .02) in the former. The mean…

CONTEXT: Lifestyle approaches for preventing gestational diabetes mellitus (GDM) have produced mixed results. OBJECTIVE: The aim of the present study was to compare the effectiveness of 3 lifestyle interventions [healthy eating (HE), physical activity (PA), and both HE and PA (HE+PA)] with usual care (UC) in reducing GDM risk. DESIGN: The present study was a multicenter randomized controlled trial conducted from 2012 to 2014 [the DALI (vitamin D and lifestyle intervention for GDM prevention) lifestyle study]. SETTING: The study occurred at antenatal clinics across 11 centers in 9 European countries. PATIENTS: Consecutive pregnant women at <20 weeks of gestation with a body mass index (BMI) of ≥29 kg/m2 and without GDM using the International Association of Diabetes and Pregnancy Study Group criteria (n = 436). For the intervention, women were randomized, stratified by site, to UC, HE, PA, or HE+PA. The women received 5 face-to-face and ≤4 telephone coaching sessions using the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. The coaches…

CONTEXT: Normal weight polycystic ovary syndrome (PCOS) women may have altered adipose structure-function underlying metabolic dysfunction. OBJECTIVE: This study examines whether adipose structure-functional changes exist in normal weight PCOS women and correlate with hyperandrogenism and/or hyperinsulinemia. DESIGN: This is a prospective cohort study. SETTING: The setting was an academic medical center. PATIENTS: Six normal weight PCOS women and 14 age- and body mass index-matched normoandrogenic ovulatory (NL) women were included. INTERVENTION(S): All women underwent circulating hormone and metabolic measurements; frequently sampled intravenous glucose tolerance testing; total body dual-energy x-ray absorptiometry; abdominal magnetic resonance imaging; and SC abdominal fat biopsy. MAIN OUTCOME MEASURE(S): Circulating hormones and metabolites, body fat and its distribution, and adipocyte size were compared between PCOS and NL women, and were correlated with each other in all women. RESULTS: Circulating LH and androgen levels were significantly greater in PCOS than NL women, as were…

Abstract Context: Type 2 diabetes mellitus is associated with gastrointestinal dysbiosis involving both compositional and functional changes in the gut microbiome. Changes in diet and supplementation with probiotics and prebiotics (ie, fermentable fibers) can induce favorable changes in gut bacterial species and improve glucose homeostasis. Objective: This paper will review the data supporting several potential mechanisms whereby gut dysbiosis contributes to metabolic dysfunction, including microbiota driven increases in systemic lipopolysaccharide concentrations, changes in bile acid metabolism, alterations in short chain fatty acid production, alterations in gut hormone secretion, and changes in circulating branched-chain amino acids. Methods: Data for this review were identified by searching English language references from PubMed and relevant articles. Conclusions: Understanding the mechanisms linking the gut microbiome to glucose metabolism, and the relevant compositional and functional characteristics of the gut microbiome, will help direct future research to develop more…

CONTEXT: Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism. EVIDENCE ACQUISITION: Contributing authors reviewed the literature regarding physiology, pathophysiology, and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized. EVIDENCE SYNTHESIS: Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence…

Context: Common concerns when using low-calorie diets as a treatment for obesity are the reduction in fat-free mass, mostly muscular mass, that occurs together with the fat mass (FM) loss, and determining the best methodologies to evaluate body composition changes. Objective: This study aimed to evaluate the very-low-calorie ketogenic (VLCK) diet-induced changes in body composition of obese patients and to compare 3 different methodologies used to evaluate those changes. Design: Twenty obese patients followed a VLCK diet for 4 months. Body composition assessment was performed by dual-energy X-ray absorptiometry (DXA), multifrequency bioelectrical impedance (MF-BIA), and air displacement plethysmography (ADP) techniques. Muscular strength was also assessed. Measurements were performed at 4 points matched with the ketotic phases (basal, maximum ketosis, ketosis declining, and out of ketosis). Results: After 4 months the VLCK diet induced a -20.2 ± 4.5 kg weight loss, at expenses of reductions in fat mass (FM) of -16.5 ± 5.1 kg (DXA), -18.2 ± 5.8 kg (MF-BIA), and -17.7 ± 9.9 kg (ADP).…

CONTEXT: Recently, two patients with primary ovarian insufficiency (POI) delivered healthy babies after in vitro activation (IVA) treatment followed by auto-transplantation of frozen-thawed ovarian tissues. OBJECTIVE: This study sought to report the first case of live birth after IVA treatment following fresh ovarian tissue grafting in patients with POI, together with monitoring of follicle development and serum hormonal changes. DESIGN: This was a prospective observational cohort study. SETTING: We performed IVA treatment in 14 patients with POI with mean age of 29 years, mean duration since last menses of 3.8 years, and average basal FSH level of 94.5 mIU/mL. INTERVENTIONS: Prior to IVA treatment, all patients received routine hormonal treatments with no follicle development. We removed one ovary from patients with POI and treated them with Akt stimulators. We improved upon early procedures by grafting back fresh tissues using a simplified protocol. MAIN OUTCOME MEASURES: In six of the 14 patients (43%), a total of 15 follicle development waves were detected, and four patients had…

CONTEXT: Skeletal deterioration, leading to an increased risk of fracture, is a known complication of type 2 diabetes mellitus (T2D). Yet plausible mechanisms to account for skeletal fragility in T2D have not been clearly established. OBJECTIVE: The objective of the study was to determine whether bone material properties, as measured by reference point indentation, and advanced glycation endproducts (AGEs), as determined by skin autofluorescence (SAF), are related in patients with T2D. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a tertiary medical center. PATIENTS: Sixteen postmenopausal women with T2D and 19 matched controls participated in the study. MAIN OUTCOME MEASURES: Bone material strength index (BMSi) by in vivo reference point indentation, AGE accumulation by SAF, and circulating bone turnover markers were measured. RESULTS: BMSi was reduced by 9.2% in T2D (P = .02) and was inversely associated with the duration of T2D (r = -0.68, P = .004). Increased SAF was associated with reduced BMSi (r = -0.65, P = .006) and lower bone formation…

CONTEXT: Although thyroid function is associated with several risk factors of nonalcoholic fatty liver disease (NAFLD), its role in NAFLD development remains unclear. OBJECTIVE: We aimed to prospectively investigate the association between variations in thyroid function and NAFLD. DESIGN AND SETTING: The Rotterdam Study, a large population-based, prospective cohort study. PARTICIPANTS AND MAIN OUTCOME MEASURES: Participants with thyroid function measurements at baseline and NAFLD data (ie, at baseline fatty liver index/at follow-up ultrasound) were eligible. Transient elastography was performed to assess the presence of fibrosis in patients with NAFLD, using the liver stiffness measurements more than or equal to 8 kPa as cutoff for clinically relevant fibrosis. The association between thyroid parameters and incident NAFLD was explored by using logistic regression models. RESULTS: A total of 9419 participants (mean age, 64.75 y) were included. The median follow-up time was 10.04 years (interquartile range, 5.70-10.88 y). After adjusting for age, sex, cohort, follow-up time, use of…

CONTEXT: Vitamin D deficiency is associated with insulin resistance and risk of future diabetes. OBJECTIVE: The objective of the study was to test whether supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes mellitus (T2DM). DESIGN: This was a randomized controlled trial performed in 2008 through 2015. SETTING: The study was conducted at the clinical research unit at a teaching hospital. PATIENTS: Five hundred eleven subjects (mean age 62 y, 314 males) with prediabetes diagnosed with an oral glucose tolerance test as part of the Tromsø Study 2007–2008 were included. A total of 256 were randomized to vitamin D and 255 to placebo. Twenty-nine subjects in the vitamin D and 24 in the placebo group withdrew because of adverse events. INTERVENTIONS: Interventions included vitamin D (cholecalciferol) 20 000 IU/wk vs placebo for 5 years. Annual oral glucose tolerance tests were performed. MAIN OUTCOME MEASURE: Progression to T2DM was the main outcome measure. Secondary outcomes were change in glucose levels, insulin resistance, serum…

CONTEXT: A growing body of evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to female reproductive disorders. OBJECTIVE: To calculate the associated combined health care and economic costs attributable to specific EDC exposures within the European Union (EU). DESIGN: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. Cost-of-illness estimation used multiple peer-reviewed sources. SETTING, PATIENTS AND PARTICIPANTS AND INTERVENTION: Cost estimation was carried out from a societal perspective, ie, including direct costs (eg, treatment costs) and indirect costs such as productivity loss. RESULTS: The most robust EDC-related data for female reproductive disorders exist for 1)…

CONTEXT: To date, there are few studies investigating the impact of body changes induced by cross-sex hormonal treatment (CHT) on psychobiological well-being in gender-dysphoric persons (GDs). OBJECTIVE: The objective of the study was to assess whether CHT-related body changes affect psychobiological well-being in GDs. METHODS: A consecutive series of 359 GDs was considered for a cross-sectional section of the study. In addition, 54 GDs were studied in a 2-year follow-up. A physical examination was performed, including body mass index, waist circumference, and hair distribution. We also evaluated breast development and testis volume in male to female subjects and clitoris length in female to male. Subjects were asked to complete several psychometric measures for the assessment of body uneasiness, GD, and psychopathology levels. The evaluation was repeated 2 years prospectively. RESULTS: The following results were found: 1) GDs undergoing CHT reported significantly lower subjective levels of GD, body uneasiness, and depressive symptoms as compared with those without; 2) CHT-induced…

Context: Denosumab inhibits bone resorption, increases bone mineral density, and reduces fracture risk. Denosumab was approved for the treatment of osteoporosis and the prevention of bone loss in some oncological situations. Denosumab discontinuation is associated with a severe bone turnover rebound (BTR) and a rapid loss of bone mineral density. The clinical consequences of the BTR observed after denosumab discontinuation are not known. Cases Description: We report 9 women who presented 50 rebound-associated vertebral fractures (RAVFs) after denosumab discontinuation. A broad biological and radiological assessment excluded other causes than osteoporosis. These 9 cases are unusual and disturbing for several reasons. First, all vertebral fractures (VFs) were spontaneous, and most patients had a high number of VFs (mean = 5.5) in a short period of time. Second, the fracture risk was low for most of these women. Third, their VFs occurred rapidly after last denosumab injection (9-16 months). Fourth, vertebroplasty was associated with a high number of new VFs. All the observed VFs seem…

Context: Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers. Objective: Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures. Design, Setting, and Patients: This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjects Main Outcome Measures: One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers. Results: Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in…

Treatment options of Graves' hyperthyroidism should be tailored to the needs of individual patients, taken into account recurrence risk, co-morbidities, and personal preferences. This study aimed to construct a prediction model to calculate recurrence risk after a course of antithyroid drugs, based on clinical and genetic parameters prior to the start of treatment. Consecutive, untreated patients with a first episode of Graves' hyperthyroidism were included in a prospective, multicenter, observational study. Before starting antithyroid drugs, clinical parameters and blood samples were collected. Antithyroid drugs were withdrawn after 1 year, and patients were followed for a further 2 years. Clinical and genetic markers that are independently associated with recurrent hyperthyroidism, and a multimarker prediction model for recurrence. Thirty-seven percent of 178 patients had recurrent Graves' hyperthyroidism within 2 years after antithyroid drug withdrawal. In Cox regression, lower age, higher serum free T4, higher serum thyrotropin-binding inhibitor immunoglobulin, larger goiter…

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…

CONTEXT: Knowing the changes of cardiovascular risk factors (CRFs) in relation to weight loss would be helpful to advise overweight children and their parents and to decide whether drugs should be prescribed in addition to lifestyle intervention. OBJECTIVE: The objective of the study was to determine the body mass index (BMI)-SD score (SDS) reduction to improve CRFs in overweight children. DESIGN: This was a prospective observation study. SETTING: The study was conducted at a specialized outpatient obesity clinic. PATIENTS: A total of 1388 overweight children (mean BMI 27.9 ± 0.1 kg/m(2), mean age 11.4 ± 0.1 y, 43.8% male, 45.5% prepubertal) participated in the study. INTERVENTION: The study included a 1-year lifestyle intervention. MAIN OUTCOME MEASURES: We studied changes of blood pressure (BP), fasting high-density lipoprotein- and low-density lipoprotein-cholesterol, triglycerides, glucose, and homeostasis model assessment (HOMA) of insulin resistance index. Change of weight status was determined by δBMI-SDS based on the recommended percentiles of the International Task Force of…

CONTEXT: Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3-5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases. OBJECTIVE: We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target. DESIGN: Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry. SETTING: The study was conducted at the University of Colorado Hospital. PATIENTS: Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study. INTERVENTION: There were no interventions. MAIN…

Objective: We aimed at determining the relationship of the gut microbiota and short chain fatty acids with obesity and fat partitioning and at testing potential differences in the ability of gut microbiota to ferment equal amounts of carbohydrates (CHO) between lean and obese youth. Research Design and Methods: We analyzed the gut microbiota of 84 youth in whom body fat distribution was measured by fast-magnetic resonance imaging, de novo lipogenesis (DNL) quantitated using deuterated water, and the capability of gut flora to ferment CHO was assessed by 13C-fructose treatment in vitro. Results: A significant association was found between the Firmicutes to Bacteroidetes ratio, and the abundance of Bacteroidetes and Actinobacteria with body mass index, visceral and SC fat (all P < .05). Plasma acetate, propionate, and butyrate were associated with body mass index and visceral and SC fat (all P < .05) and with hepatic DNL (P = .01, P = .09, P = .04, respectively). Moreover, the rate of CHO fermentation from the gut flora was higher in obese than in lean subjects (P = .018).…

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. This study sought to determine the risk of dementia and cognitive decline associated with subclinical thyroid dysfunction among prospective cohorts. We searched in MEDLINE and EMBASE from inception until November 2014. Two physicians identified prospective cohorts that assessed thyroid function and cognitive outcomes (dementia; Mini-Mental State Examination [MMSE]). 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. 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…

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,…

CONTEXT: During aging, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free T (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. OBJECTIVE: Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. METHODS: A total of 3334 community-dwelling men, aged 40-79 years, were included in this study. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/liter) and normal cFT (≥220 pmol/liter) with those who had normal TT/low cFT, low TT/normal cFT, and low TT/low cFT were assessed by regression models adjusted for age, center, body mass index, and comorbidities. RESULTS: A total of 2641 men had normal TT (18.4 ± 5.5 [mean ± SD] nmol/liter)/normal cFT (326 ± 74 pmol/liter), 277 men had normal TT (14.2 ± 3.7)/low cFT (194 ± 23), 96 men had low TT (9.6 ± 0.7)/normal cFT (247 ± 20), and 320 men had low TT (7.8 ± 2.5)/low cFT (160 ± 55). Men with…

CONTEXT: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Hyperandrogenism is the central feature of PCOS. Studies on isolated ovarian theca-interstitial cells suggest that resveratrol, a natural polyphenol, reduces androgen production. OBJECTIVE: This study was designed to evaluate endocrine and metabolic effects of resveratrol on PCOS. DESIGN AND SETTING: This was a randomized (1:1) double-blind, placebo-controlled trial that evaluated the effects of resveratrol over a period of 3 months in an academic hospital. PATIENTS AND OTHER PARTICIPANTS: Subjects with PCOS were identified according to the Rotterdam criteria. Thirty-four subjects were enrolled and 30 subjects completed the trial. Evaluations were performed at baseline and repeated after 3 months of treatment. INTERVENTION: Resveratrol (1,500 mg p.o.) or placebo were administered daily. MAIN OUTCOME MEASURE: Primary outcome was the change in the serum total T. RESULTS: Resveratrol treatment led to a significant decrease of total T by 23.1% (P = .01). In parallel,…

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…

CONTEXT: A substantial number of obese individuals are relatively insulin sensitive and the etiology for this variation remains unknown. OBJECTIVE: The primary objective was to detect factors in adipose tissue differentiating obese insulin-sensitive (OBIS) from obese insulin-resistant (OBIR) individuals and investigate whether adipose tissue hypoxia is a contributing factor in the pathogenesis of insulin resistance. DESIGN AND SETTING: This was a cross-sectional study in the general community. PARTICIPANTS: Subjects consisted of nondiabetic OBIS and OBIR subjects with similar body mass index, age, and total body fat but different insulin sensitivity index as well as lean insulin-sensitive subjects. INTERVENTIONS(S): There were no interventions. MAIN OUTCOME MEASURE(S): We examined adipocytokines and the expression of candidate genes regulating hypoxia, inflammation, and lipogenesis in adipose tissue and adipose tissue oxygenation. RESULTS: OBIS subjects had increased plasma adiponectin but similar plasma TNFα and leptin levels as compared with OBIR subjects. Genes regulating…

Phosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors. Our objective was to evaluate the use of 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO). This was a single-center prospective study of patients with TIO. The study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015. Eleven subjects (six females, five males) with TIO were included. Subjects underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxyglucose-PET/CT (18F FDG-PET/CT) scan. Localization of PMTs on the previously described imaging modalities were determined. The tumor was…

CONTEXT: Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD. OBJECTIVES: Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD. DESIGN: This study used a cross-sectional design. SETTING: The general community in the United States, United Kingdom, and The Gambia were included in this study. PARTICIPANTS: Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included. EXPOSURES: Total 25OHD concentration, race, and DBP (GC) genotype exposures were included. OUTCOME MEASURES: Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures. RESULTS: Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured…

CONTEXT: The Testosterone Trials are a coordinated set of seven trials to determine the efficacy of T in symptomatic men ≥65 years old with unequivocally low T levels. Initial results of the Sexual Function Trial showed that T improved sexual activity, sexual desire, and erectile function. OBJECTIVE: To assess the responsiveness of specific sexual activities to T treatment; to relate hormone changes to changes in sexual function; and to determine predictive baseline characteristics and T threshold for sexual outcomes. DESIGN: A placebo-controlled trial. SETTING: Twelve academic medical centers in the United States. PARTICIPANTS: A total of 470 men ≥65 years of age with low libido, average T <275 ng/dL, and a partner willing to have sexual intercourse at least twice a month. METHODS: Men were assigned to take T gel or placebo for 1 year. Sexual function was assessed by three questionnaires every 3 months: the Psychosexual Daily Questionnaire, the Derogatis Interview for Sexual Function, and the International Index of Erectile Function. RESULTS: Compared with placebo, T administration…