The 50 most-cited articles in The Journal of Clinical Endocrinology & Metabolism, 2019

OBJECTIVE: The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. CONCLUSIONS: Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal…

OBJECTIVE: The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults. CONCLUSIONS: Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.

OBJECTIVE: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. PARTICIPANTS: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. EVIDENCE: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. CONSENSUS PROCESS: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the…

BACKGROUND: Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. RESULTS: We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with…

CONTEXT: Use of continuous glucose monitoring (CGM) is increasing for insulin-requiring patients with diabetes. Although data on glycemic profiles of healthy, nondiabetic individuals exist for older sensors, assessment of glycemic metrics with new-generation CGM devices is lacking. OBJECTIVE: To establish reference sensor glucose ranges in healthy, nondiabetic individuals across different age groups using a current generation CGM sensor. DESIGN: Multicenter, prospective study. SETTING: Twelve centers within the T1D Exchange Clinic Network. PATIENTS OR PARTICIPANTS: Nonpregnant, healthy, nondiabetic children and adults (age ≥6 years) with nonobese body mass index. INTERVENTION: Each participant wore a blinded Dexcom G6 CGM, with once-daily calibration, for up to 10 days. MAIN OUTCOME MEASURES: CGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability. RESULTS: A total of 153 participants (age 7 to 80 years) were included in the analyses. Mean average glucose was 98 to 99 mg/dL (5.4 to 5.5 mmol/L) for all age groups except those over 60 years, in whom mean…

This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynecologists.

CONTEXT: Saturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms. OBJECTIVE: To investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans. DESIGN: Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction. SETTING: General community. PARTICIPANTS: Men and women who are overweight or have obesity (n = 61). INTERVENTION: Muffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet. MAIN OUTCOME MEASURES: Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots. RESULTS: By design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or…

Abstract Context The lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations. Objective To establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3). Design LC-MS/MS method development and construction of estrogen reference ranges. Settings Population-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas. Participants Healthy participants aged 3 months to 61 years (n = 1838). Results An isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from Conclusion Reference ranges of…

BACKGROUND: Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival (OS) in MPP patients. PATIENTS AND METHODS: Retrospective multicenter study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. RESULTS: One hundred sixty-nine patients from 18 European centers were included. Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases. Metastatic sites included bone (64%), lymph node (40%), lung (29%), and liver (26%); mean time between initial and malignancy diagnosis was 43 months (range, 0 to 614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines less…

CONTEXT: Signs and symptoms of Cushing's syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. OBJECTIVE: The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. DATA SOURCES: A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. STUDY SELECTION: Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. DATA EXTRACTION: Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were…

CONTEXT: Modern management of differentiated thyroid cancer requires individualized care plans that tailor the intensity of therapy and follow-up to the estimated risks of recurrence and disease-specific mortality. DESIGN: This summary is based on the authors' knowledge and extensive clinical experience, supplemented by review of published review articles, thyroid cancer management guidelines, published staging systems, and original articles identified through a PubMed search, which included terms such as risk stratification, staging, clinical outcomes, and differentiated thyroid cancer. MAIN OUTCOME MEASURES: In the past, risk stratification in differentiated thyroid cancer usually referred to a static estimate of disease-specific mortality that was based on a small set of clinicopathological features available within a few weeks of completing initial therapy (thyroidectomy, with or without radioactive iodine). Today, risk stratification is a dynamic, active process used to predict the appropriateness for minimalistic initial therapy, disease-specific mortality, risk of recurrence,…

PURPOSE: Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. METHODS: Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7-36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and…

CONTEXT: No universal waist circumference (WC) percentile cutoffs used have been proposed for screening central obesity in children and adolescents. OBJECTIVE: To develop international WC percentile cutoffs for children and adolescents with normal weight based on data from 8 countries in different global regions and to examine the relation with cardiovascular risk. DESIGN AND SETTING: We used pooled data on WC in 113,453 children and adolescents (males 50.2%) aged 4 to 20 years from 8 countries in different regions (Bulgaria, China, Iran, Korea, Malaysia, Poland, Seychelles, and Switzerland). We calculated WC percentile cutoffs in samples including or excluding children with obesity, overweight, or underweight. WC percentiles were generated using the general additive model for location, scale, and shape (GAMLSS). We also estimated the predictive power of the WC 90th percentile cutoffs to predict cardiovascular risk using receiver operator characteristics curve analysis based on data from 3 countries that had available data (China, Iran, and Korea). We also examined which WC…

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the…

CONTEXT: Ultrasound (US) risk stratification systems (RSSs) have been developed to reduce the number of unnecessary fine-needle aspiration procedures (FNA) in patients with thyroid nodules. OBJECTIVE: We conducted a systematic review and meta-analysis evaluating the ability of the 5 most common US RSSs for the appropriate selection of thyroid nodules for FNA. DATA SOURCES: This systematic review and meta-analysis was registered on PROSPERO (CRD42019131771). PubMed, CENTRAL, Scopus, and Web of Science were searched until March 2019. STUDY SELECTION: Original articles reporting data on the performance of AACE/ACE/AME, ACR TI-RADS, ATA, EU-TIRADS, and K-TIRADS were included. DATA EXTRACTION: The number of nodules classified as true negative, true positive, false negative, and false positive was extracted. Summary operating points were estimated using a random-effects model. Interobserver agreement was also assessed. DATA SYNTHESIS: Twelve studies evaluating 18 750 thyroid nodules were included. Participants were adult outpatients with thyroid nodules submitted to either FNA or…

CONTEXT: The dramatic rise in the incidence of thyroid cancer over the last 30 years is largely attributable to the increasing diagnosis of papillary microcarcinomas (mPTCs). Current guidelines endorse an observational management approach in properly selected cases. OBJECTIVE: To evaluate the feasibility of active surveillance in mPTC in Italy, its impact on real life, and to identify risk factors of progression. DESIGN AND SETTING: In 2014 we started a prospective-observational study of active surveillance in mPTC patients. PATIENTS: Included patients demonstrated a single Thy4 or Thy5 thyroid nodule, with largest diameter ≤1.3 cm, and no suspicious laterocervical lymph nodes by neck ultrasonography. Of 185 eligible subjects, 50.3% (93/185) enrolled in the observational management protocol while the others opted for surgery and were excluded from this analysis. INTERVENTION: Enrolled patients were followed with neck ultrasound at 6- to 12-month intervals. Disease progression was defined as the appearance of abnormal lymph nodes or nodule enlargement during follow-up. In these…

CONTEXT: Patients with type 1 diabetes (T1D) have lower microbiota diversity and distinct gut microbial profiles that have been linked to changes in intestinal permeability. Prebiotics are nondigestible carbohydrates that alter gut microbiota and could potentially improve glycemic control and reduce intestinal permeability and thereby insulin sensitivity. OBJECTIVE: To determine the effect of prebiotics on glycemic control, gut microbiota, and intestinal permeability in children with T1D. DESIGN: A randomized, placebo-controlled trial in children 8 to 17 years of age with T1D using placebo or prebiotic oligofructose-enriched inulin for 12 weeks. Baseline, 3-month, and 6-month assessments included HbA1c, C-peptide, gut microbiota, intestinal permeability, frequency of diabetic ketoacidosis (DKA), and severe hypoglycemia. RESULTS: Forty-three subjects were randomized and 38 completed the study. The groups were similar at baseline: prebiotic (N = 17), age 12.5 years (SD of 2.8), HbA1c 8.02% (SD of 0.82); placebo (N = 21), age 12.0 years (SD of 2.6), HbA1c 8.08% (SD of 0.91). No…

CONTEXT: The thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs). OBJECTIVE: To evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs. DESIGN: Twelve-week, double-blind, randomized, placebo-controlled study. SETTING: Eight Belgian centers from September 2015 to October 2016. PARTICIPANTS: Generally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs. INTERVENTIONS: Subjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks. MAIN OUTCOME MEASURES: Subjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were…

OBJECTIVE: Metabolic signatures have emerged as valuable signaling molecules in the biochemical process of type 2 diabetes (T2D). To summarize and identify metabolic biomarkers in T2D, we performed a systematic review and meta-analysis of the associations between metabolites and T2D using high-throughput metabolomics techniques. METHODS: We searched relevant studies from MEDLINE (PubMed), Embase, Web of Science, and Cochrane Library as well as Chinese databases (Wanfang, Vip, and CNKI) inception through 31 December 2018. Meta-analysis was conducted using STATA 14.0 under random effect. Besides, bioinformatic analysis was performed to explore molecule mechanism by MetaboAnalyst and R 3.5.2. RESULTS: Finally, 46 articles were included in this review on metabolites involved amino acids, acylcarnitines, lipids, carbohydrates, organic acids, and others. Results of meta-analysis in prospective studies indicated that isoleucine, leucine, valine, tyrosine, phenylalanine, glutamate, alanine, valerylcarnitine (C5), palmitoylcarnitine (C16), palmitic acid, and linoleic acid were associated…

CONTEXT: The effects of maternal subclinical hypothyroidism on pregnancy outcomes are not clear. OBJECTIVE: We aimed to assess potential associations between maternal thyrotropin (thyroid-stimulating hormone [TSH]) levels in pregnancy and obstetric and perinatal outcomes. DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. PATIENTS: Women aged ≥18 years with a singleton gestation and no known thyroid disease seen for prenatal care at Boston Medical Center from January 1, 2003 through May 22, 2014, and their fetuses and infants were included. MAIN OUTCOME MEASURES: Risk ratios of adverse obstetric and perinatal outcomes. RESULTS: A total of 8,413 pregnant women (mean age 29.1 years, 15% white, 60% black, 13% Hispanic) and their fetuses and infants (mean gestational age at birth 38.5 weeks, 52% male, mean birth weight 3.2 kg) were included in the analyses. The median (interquartile range) TSH level was 1.06(0.62-1.60) mIU/L, and 130 women (1.6%) had TSH > 4 mIU/L. Maternal TSH levels > 4 mIU/L were associated with increased risks of prematurity (risk ratio…

CONTEXT: We have summarized key studies assessing the epidemiology, mechanisms, and consequences of cognitive dysfunction (CD) in type 1 diabetes. EVIDENCE SYNTHESIS: In a number of studies, the severity of CD in type 1 diabetes was affected by the age of onset and duration, and the presence of proliferative retinopathy and autonomic neuropathy. Diabetes-related CD has been observed, not only in adults, but also in children and adolescents. Most neuroimaging studies of patients with type 1 diabetes did not show any differences in whole brain volumes; however, they did reveal selective deficits in gray matter volume or density within the frontal, posterior, and temporal cortex and subcortical gray matter. Studies of middle-age adults with long-standing type 1 diabetes using diffusion tensor imaging have demonstrated partial lesions in the white matter and decreased fractional anisotropy in posterior brain regions. The mechanisms underlying diabetes-related CD are very complex and include factors related to diabetes per se and to diabetes-related cardiovascular disease and…

CONTEXT: The improved remission and complication rates of current transsphenoidal surgery warrant reappraisal of the position of surgery as a viable alternative to dopamine agonists in the treatment algorithm of prolactinomas. OBJECTIVE: To compare clinical outcomes after dopamine agonist withdrawal and transsphenoidal surgery in prolactinoma patients. METHODS: Eight databases were searched up to July 13, 2018. Primary outcome was disease remission after drug withdrawal or surgery. Secondary outcomes were biochemical control and side effects during dopamine agonist treatment and postoperative complications. Fixed- or random-effects meta-analysis was performed to estimate pooled proportions. Robustness of results was assessed by sensitivity analyses. RESULTS: A total of 1469 articles were screened: 55 (10 low risk of bias) on medical treatment (n = 3564 patients) and 25 (12 low risk of bias) on transsphenoidal surgery (n = 1836 patients). Long-term disease remission after dopamine agonist withdrawal was 34% (95% confidence interval [CI], 26-46) and 67% (95% CI, 60-74) after surgery.…

OBJECTIVE: To determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female pattern hair loss (FPHL), a common form of hair loss in women that is characterized by the reduction of hair density in the central area of the scalp, whereas the frontal hairline is generally well conserved. PARTICIPANTS: An expert task force appointed by the Androgen Excess and PCOS Society, which included specialists from dermatology, endocrinology, and reproductive endocrinology. DESIGN: Levels of evidence were assessed and graded from A to D. Peer-reviewed studies evaluating FPHL published through December 2017 were reviewed. Criteria for inclusion/exclusion of the published papers were agreed on by at least two reviewers in each area and arbitrated by a third when necessary. CONCLUSIONS: (i) The term "female pattern hair loss" should be used, avoiding the previous terms of alopecia or androgenetic alopecia. (ii) The two typical patterns of hair loss in FPHL are centrifugal expansion in the mid scalp, and a frontal…

CONTEXT: Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. CASE SERIES DESCRIPTION: Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti-programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti-PD-1-based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L…

CONTEXT: The increased use of opioids has resulted in an unprecedented opioid epidemic. Chronic opioid use causes hypogonadism, but its frequency, as well as the effects of opioids on other hypothalamo-pituitary-end organ hormone axes, remains unclear. OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the effects of opioid use on pituitary function. METHODS: Eight electronic databases were searched for articles published up to May 8, 2018. Fixed or random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals (CI). This study is reported following the PRISMA and MOOSE guidelines. DATA SYNTHESIS: 52 studies (22 low risk of bias) were included describing 18 428 subjects, consisting of patients with chronic pain (n = 21 studies) or on maintenance treatment for opioid addiction (n = 9) and healthy volunteers (n = 4). The most frequently used opioid was methadone (n = 13 studies), followed by morphine (n = 12). Prevalence of hypogonadism was 63% (95% CI: 55%-70%, 15 studies, 3250 patients, 99.5% males). Prevalence of…

CONTEXT: Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. EVIDENCE ACQUISITION: The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. EVIDENCE SYNTHESIS: Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in…

CONTEXT: Powerful demographic trends toward reproductive aging of human populations, older age at first childbirth, and lower birth rates will profoundly influence the health, vitality, and economies of human societies and deserve greater attention in health policy and research. EVIDENCE ACQUISITION: Information on birth rates, fertility rates, and outcomes of assisted reproductive technologies were obtained from databases of government agencies (census data, Centers for Disease Control and Prevention). EVIDENCE SYNTHESIS: Fecundity declines with advancing age, especially in women >35 years and men >50 years. Advanced parental age adversely affects pregnancy outcomes for the mother and the offspring and increases the offspring's risk of chromosomal disorders, neurodegenerative diseases, and birth defects. Because of increased life expectancy, today people will spend a major portion of life in a period of reproductive senescence; diseases associated with reproductive senescence will influence the health and well-being of middle-aged and older adults. Inversion of the population age…

CONTEXT: Radiofrequency ablation (RFA) of benign thyroid nodules has been gaining consensus. However, no solid information on its long-term efficacy is available. OBJECTIVE: To analyze the long-term results of single-session RFA. DESIGN: Retrospective longitudinal observational study. SETTING: Primary care center. PATIENTS OR OTHER PARTICIPANTS: Adult outpatients who underwent a single-session RFA and posttreatment follow-up of least 3 years. INTERVENTION: Ultrasound-guided RFA was performed after local anesthesia by "moving-shot" technique. RFA was performed with a median power of 55W and a median time of 14 minutes with an internally cooled 18-gauge electrode with an active 10-mm tip. MAIN OUTCOME MEASURES: Objective (trend of nodule volume) and subjective (compressive and cosmetic concerns) response to RFA were evaluated. Continuous variables were analyzed by the Wilcoxon and ANOVA test and their correlations by using the Spearman test. Categorical variables were compared by Pearson χ2 test. RESULTS: Two hundred and fifteen patients were included. An early significant reduction…

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia. RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term…

CONTEXT: Underlying mechanisms leading to gestational diabetes mellitus (GDM) are still under investigation, and it is unclear whether the placenta plays a role in triggering glucose intolerance or if its functions are modified in response to the hyperglycemia. Circulating miRNAs are involved in placental development and function and are encapsulated in extracellular vesicles (EVs). OBJECTIVE: To compare differential expression of miRNAs in circulating EVs in pregnancies complicated by GDM vs controls. METHODS: This was a case-control study nested in a prospective pregnancy cohort including 23 women with GDM and 46 matched controls. The presence of serum EVs in early pregnancy was validated by transmission electron microscopy. Placental dimensions were assessed at 11 to 13 weeks of gestation. Differential expression of 17 miRNAs encapsulated in EVs (miR‒122-5p, miR‒132-3p, miR-1323, miR‒182-3p, miR‒210-3p, miR‒29a-3p, miR‒29b-3p, miR‒342-3p, miR‒517-5p, miR‒517a-3p, miR‒518b, miR-520h, miR‒525-5p, miR‒136-5p, miR‒342-3p, miR‒376c-5p, and miR‒494-3p) was assessed using quantitative…

CONTEXT: Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. OBJECTIVE: To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability. DESIGN: Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively. SETTING: General community. PARTICIPANTS: 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease. MAIN OUTCOME MEASURE: Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age. RESULTS: There was a positive curvilinear association of urinary…

CONTEXT: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable. OBJECTIVE: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD. DESIGN, PATIENTS, AND METHODS: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality. RESULTS: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and…

CONTEXT: Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. OBJECTIVE: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. DESIGN AND INTERVENTION: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. SETTING: Academic medical center. PATIENTS: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3). MAIN OUTCOME MEASURE: Depressive symptoms (MADRS score). RESULTS: During the study, 90.0% of participants had varying…

CONTEXT: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is rapidly emerging as feasible therapy for patients with pancreatic neuroendocrine tumors (pNETs) in selected cases, as a result of its favorable safety profile. OBJECTIVE: To assess the feasibility, safety, and efficacy of EUS-RFA in a cohort of patients with functional and nonfunctional pNETs (NF-pNETs). DESIGN: Data on pNET patients treated with EUS-RFA between March 2017 and October 2018 at two tertiary centers was retrospectively analyzed. RESULTS: The cohort included 18 adults (eight women, 10 men), aged 60.4 ± 14.4 years (mean ± SD), seven insulinoma patients, and 11 patients with NF-pNETs. Twenty-seven lesions with a mean diameter of 14.3 ± 7.3 mm (range 4.5 to 30) were treated. Technical success defined as typical postablative changes on a surveillance imaging was achieved in 26 out of 27 lesions. Clinical response with normalization of glucose levels was observed in all (seven of seven) insulinoma cases within 24 hours of treatment. Overall, there were no major complications 48 hours postprocedure. No…

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are characterized by a strong genetic component, with up to 40% of patients carrying a germline mutation in a PPGL susceptibility gene. International guidelines recommend that genetic screening be proposed to all patients with PPGL. OBJECTIVE: Our objective was to evaluate how a positive genetic test impacts the management and outcome of patients with SDHx or VHL-related PPGL. DESIGN: We performed a multicentric retrospective study involving 221 propositi carrying an SDHB, SDHD, SDHC, or VHL germline mutation. Patients were divided into two groups: genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and historic patients, who only benefited from the genetic test several years after initial PPGL diagnosis. RESULTS: Genetic patients had better follow-up than historic patients, with a greater number of examinations and a reduced number of patients lost to follow-up (9.6% vs 72%, respectively). During follow-up, smaller (18.7 vs 27.6 mm; P = 0.0128) new PPGLs and metastases…

OBJECTIVE: To develop clinical practice guidelines for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM) in individuals at metabolic risk for developing these conditions. CONCLUSIONS: Health care providers should incorporate regular screening and identification of individuals at metabolic risk (at higher risk for ASCVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and blood glucose. Individuals identified at metabolic risk should undergo 10-year global risk assessment for ASCVD or coronary heart disease to determine targets of therapy for reduction of apolipoprotein B-containing lipoproteins. Hypertension should be treated to targets outlined in this guideline. Individuals with prediabetes should be tested at least annually for progression to diabetes and referred to intensive diet and physical activity behavioral counseling programs. For the primary prevention of ASCVD and T2DM, the Writing Committee recommends lifestyle management be the first priority. Behavioral programs should…

CONTEXT: Diabetic ketoacidosis (DKA) has been associated with the use of sodium glucose cotransporter 2 inhibitors (SGLT2is). OBJECTIVE: To determine the incidence, characteristics, and outcomes of DKA in SGLT2i users vs nonusers with type 2 diabetes. DESIGN: Retrospective, multicenter, controlled cohort study. SETTING: All public hospitals in Melbourne and Geelong (combined population of 5 million), Australia, from 1 September 2015 to 31 October 2017. PATIENTS: Consecutive cases of DKA that developed in the community, or during the course of hospital admission, in patients with type 2 diabetes. MAIN OUTCOME MEASURES: In SGLT2i users vs nonusers: (i) OR of DKA developing during hospital admission, and (ii) incidence of DKA. RESULTS: There were 162 cases of DKA (37 SGLT2i users and 125 non-SGLT2i users) with a physician-adjudicated diagnosis of type 2 diabetes. Of these, DKA developed during the course of inpatient admission in 14 (38%) SGLT2i users vs 2 (2%) non-SGLT2i users (OR, 37.4; 95% CI, 8.0 to 175.9; P < 0.0001). The incidence of DKA was 1.02 per 1000 (95% CI, 0.74 to 1.41…

CONTEXT: Long-acting GH (LAGH) preparations are currently being developed in an attempt to improve adherence. The profile of GH action following administration of LAGH raises practical questions about clinical monitoring and long-term safety and efficacy of these new therapeutic agents. METHODS: Recent literature and meeting proceedings regarding LAGH preparations are reviewed. RESULTS: Multiple LAGH preparations are currently at various stages of development, allowing for decreased GH injection frequency from daily to weekly, biweekly, or monthly. Following administration of LAGH, the serum peak and trough GH and IGF-I levels vary depending upon the mechanism used to prolong GH action. Randomized, controlled clinical trials of some LAGH preparations have reported non-inferiority compared with daily recombinant human GH (rhGH) for improved growth velocity and body composition in children and adults with GH deficiency (GHD), respectively. No significant LAGH-related adverse events have been reported during short-term therapy. CONCLUSION: Multiple LAGH preparations are proceeding…

CONTEXT: Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer. OBJECTIVE: To study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established. DESIGN: Human endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing. SETTING: Academic institution. PATIENTS: Endometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent. MAIN OUTCOME MEASURES: Organoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured. RESULTS: A method to generate…

CONTEXT: The impact of gender-affirming hormone therapy (HT) on cardiometabolic parameters is largely unknown. OBJECTIVE: The effects of 1 year of treatment with oral or transdermal administration of estrogen (plus cyproterone) and transdermal or IM application of testosterone on serum lipid levels and blood pressure (BP) were assessed in transgender persons. DESIGN AND METHODS: In this prospective, observational substudy of the European Network for the Investigation of Gender Incongruence, measurements were performed before and after 12 months of HT in 242 transwomen and 188 transmen from 2010 to 2017. RESULTS: Mean values are reported. In transmen, HT increased diastolic BP (2.5%; 95% CI, 0.6 to 4.4) and levels of total cholesterol (TC; 4.1%; 95% CI, 1.5 to 6.6), low-density lipoprotein-cholesterol (LDL-C; 13.0%; 95% CI, 9.2 to 16.8), and triglycerides (36.9%; 95% CI, 29.8 to 44.1); high-density lipoprotein-cholesterol levels decreased (HDL-C; 10.8%; 95% CI, -14.0 to -7.6). In transwomen, HT slightly decreased BP (systolic BP, -2.6%, 95% CI, -4.2 to -1.0; diastolic BP, -2.2%, 95%…

CONTEXT: Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity. OBJECTIVE: To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects. DESIGN/SETTING: Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites. PATIENTS: Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs. INTERVENTION: Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2). MAIN OUTCOME MEASURES: Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0-4h]) post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2). RESULTS: Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant…

BACKGROUND: In addition to the controversy regarding the association of hyperuricemia with mortality, uncertainty also remains regarding the association between low serum uric acid (SUA) and mortality. We aimed to assess the relationship between SUA and all-cause and cause-specific mortality. METHODS: This cohort study included 9118 US adults from the National Health and Nutrition Examination Survey (1999-2002). Multivariable Cox proportional hazards models were used to evaluate the relationship between SUA and mortality. Our analysis included the use of a generalized additive model and smooth curve fitting (penalized spline method), and 2-piecewise Cox proportional hazards models, to address the nonlinearity between SUA and mortality. RESULTS: During a median follow-up of 5.83 years, 448 all-cause deaths occurred, with 100 cardiovascular disease (CVD) deaths, 118 cancer deaths, and 37 respiratory disease deaths. Compared with the reference group, there was an increased risk of all-cause, CVD, cancer, and respiratory disease mortality for participants in the first and third tertiles…

CONTEXT: Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab. OBJECTIVE: The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. DESIGN: Single-arm, multicenter, phase 2 clinical trial with two-stage design. SETTING: Comprehensive cancer center. PATIENTS: Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. INTERVENTION: Nivolumab (240 mg) IV every 2 weeks. RESULTS: Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse…

CONTEXT: There are few studies on patients transitioning from denosumab to bisphosphonates. OBJECTIVE: To investigate patient characteristics and changes in bone mineral density (BMD) after transitioning from denosumab to alendronate. DESIGN: Randomized, open-label, 2-year crossover Denosumab Adherence Preference Satisfaction (DAPS) study (NCT00518531). SETTING: 25 study centers in the US and Canada. PATIENTS: Treatment-naïve postmenopausal women with BMD T-scores from -2.0 to -4.0. INTERVENTIONS: This post hoc analysis evaluated women randomized to subcutaneous denosumab 60 mg every 6 months in year 1 followed by once-weekly oral alendronate 70 mg in year 2. MAIN OUTCOME MEASURE: A 3% BMD threshold identified participants who lost, maintained, or gained BMD in year 2 on alendronate. RESULTS: Of 126 participants randomized to denosumab, 115 (91%) transitioned to alendronate in year 2. BMD increased by 3% to 6% with denosumab in year 1 and by 0% to 1% with alendronate in year 2. After transitioning to alendronate, most participants maintained or increased BMD; 15.9%, 7.6%, and 21.7%…

CONTEXT: The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment. OBJECTIVE: To expand current knowledge of the MEN4 phenotype including assessment of penetrance. DESIGN: This is a case report and a brief review of previously published MEN4 cases. PATIENTS: We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene. MAIN OUTCOME/RESULT: The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning…

The last 2 decades have seen growing recognition of the need to appropriately identify and treat children with osteoporotic fractures. This focus stems from important advances in our understanding of the genetic basis of bone fragility, the natural history and predictors of fractures in chronic conditions, the use of bone-active medications in children, and the inclusion of bone health screening into clinical guidelines for high-risk populations. Given the historic focus on bone densitometry in this setting, the International Society for Clinical Densitometry published revised criteria in 2013 to define osteoporosis in the young, oriented towards prevention of overdiagnosis given the high frequency of extremity fractures during the growing years. This definition has been successful in avoiding an inappropriate diagnosis of osteoporosis in healthy children who sustain long bone fractures during play. However, its emphasis on the number of long bone fractures plus a concomitant bone mineral density (BMD) threshold ≤ -2.0, without consideration for long bone fracture characteristics…

CONTEXT: Studies suggest that female reproductive hormones are under circadian regulation, although methodological differences have led to inconsistent findings. OBJECTIVE: To determine whether circulating levels of reproductive hormones exhibit circadian rhythms. DESIGN: Blood samples were collected across ∼90 consecutive hours, including 2 baseline days under a standard sleep-wake schedule and ∼50 hours of extended wake under constant routine (CR) conditions. SETTING: Intensive Physiological Monitoring Unit, Brigham and Women's Hospital. PARTICIPANTS: Seventeen healthy premenopausal women (22.8 ± 2.6 years; nine follicular; eight luteal). INTERVENTIONS: Fifty-hour CR. MAIN OUTCOME MEASURES: Plasma estradiol (E2), progesterone (P4), LH, FSH, SHBG, melatonin, and core body temperature. RESULTS: All hormones exhibited significant 24-hour rhythms under both standard sleep-wake and CR conditions during the follicular phase (P < 0.05). In contrast, only FSH and SHBG were significantly rhythmic during the luteal phase. Rhythm acrophases and amplitudes were similar between standard…

OBJECTIVE: Whether serum androgen levels can identify women with "androgen insufficiency" or "androgen excess" is unresolved; thus, what constitutes "normal" remains uncertain. We sought to determine whether androgens, including 11-oxygenated C19 steroids, vary with age, menstrual cycle, or body mass index (BMI), during the reproductive years. DESIGN AND SETTING: Cross-sectional study recruited from eastern Australian states. PARTICIPANTS: A total of 588 women, aged 18 to 39 years, who were not pregnant, lactating, or using systemic hormone therapy, with regular menstrual cycles and no previous diagnosis of polycystic ovarian syndrome. MAIN OUTCOME MEASURES: Sex steroids measured using liquid chromatography-tandem mass spectrometry. RESULTS: Testosterone and androstenedione concentrations were significantly higher during the menstrual cycle mid- and luteal phases than in the early follicular phase, with median values across the cycle of 0.34 nmol/L (range, 0.04 to 1.01) and 1.97 nmol/L (range, 0.53 to 7.89), respectively. No cyclical variations were found in dehydroepiandrosterone…

CONTEXT: The lifetime prevalence of anabolic androgenic steroid (AAS) use is estimated at 1% to 5% worldwide. AAS use occurs primarily male elite athletes and men who want a muscular appearance. The evidence for effective, safe management of AAS cessation and withdrawal is weak. DESIGN: Key studies were extracted from PubMed (1990-2018) and Google Scholar with reference searches from relevant retrieved articles. RESULTS: The proven adverse effects of AASs include suppression of the gonadal axis and infertility, hirsutism and defeminization in women, and erythrocytosis. Alkylated AASs that are taken orally may cause hepatopathy. There is an association between high-dosage AAS use and increased risk of cardiovascular disease. Clues for AAS use include very low serum high-density cholesterol and sex hormone-binding globulin concentrations and unexplained erythrocytosis. For elite athletes, the biological passport (monitoring of blood or urinary androgen and androgen precursor concentrations after determining the athlete's baseline) is useful for detecting AAS use. For nonelite…

Context: Bariatric surgery results in reduced muscle mass as weight is lost, but postoperative changes in muscle strength and performance are incompletely understood. Objective: To examine changes in body composition, strength, physical activity, and physical performance following Roux-en-Y gastric bypass (RYGB). Design, Participants, Outcomes: In a prospective cohort of 47 adults (37 women, 10 men) aged 45 ± 12 years (mean ± SD) with body mass index (BMI) 44 ± 8 kg/m2, we measured body composition by dual-energy X-ray absorptiometry, handgrip strength, physical activity, and physical performance (chair stand time, gait speed, 400-m walk time) before and 6 and 12 months after RYGB. Relative strength was calculated as absolute handgrip strength/BMI and as absolute strength/appendicular lean mass (ALM). Results: Participants experienced substantial 12-month decreases in weight (-37 ± 10 kg or 30% ± 7%), fat mass (-48% ± 12%), and total lean mass (-13% ± 6%). Mean absolute strength declined by 9% ± 17% (P < 0.01). In contrast, relative strength increased by 32% ± 25% (strength/BMI) and…