The 50 most-cited articles in The Journal of Clinical Endocrinology & Metabolism, 2018

Objective: To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. Participants: The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach 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 facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions: We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low…

Objective: To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency clinical practice guideline

Context: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. Objective: To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D. Design: Phase 3a, double-blind, placebo-controlled, 30-week trial. Setting: This study included 90 sites in five countries. Patients: We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin. Interventions: Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo. Main Outcome Measures: Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30. Results: At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1%…

Context: A majority of women with polycystic ovary syndrome (PCOS) have metabolic abnormalities that result in an increased risk of developing type 2 diabetes and heart disease. Correlative studies have shown an association between changes in the gut microbiome and metabolic disorders. Two recent studies reported a decrease in α diversity of the gut microbiome in women with PCOS compared with healthy women. Objective: We investigated whether changes in the gut microbiome correlated with specific clinical parameters in women with PCOS compared with healthy women. We also investigated whether there were changes in the gut microbiome in women with polycystic ovarian morphology (PCOM) who lacked the other diagnostic criteria of PCOS. Participants: Subjects were recruited at the Poznan University of Medical Sciences. Fecal microbial diversity profiles of healthy women (n = 48), women with PCOM (n = 42), and women diagnosed with PCOS using the Rotterdam criteria (n = 73) were analyzed using 16S ribosomal RNA gene sequencing. Results: Lower α diversity was observed in women with PCOS…

Objective: To update the "Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2008. Participants: The participants include an Endocrine Society-appointed task force of seven medical experts and a methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion: Wesuggest testing for elevated androgen levels in allwomenwith an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic…

Context: Globally, one in five men aged >50 years is predicted to experience an osteoporotic fracture. Because of the treatment gap in osteoporosis and the paucity of bone-forming agents for men, new osteoporosis treatments are needed. Objective: To evaluate the safety and efficacy of romosozumab in men with osteoporosis. Design: Phase III randomized BRIDGE study (placebo-controlled double-blind study evaluating the efficacy and safety of romosozumab in treating men with osteoporosis; ClinicalTrials.gov identifier, NCT02186171) for 12 months. Setting: Thirty-one centers in Europe, Latin America, Japan, and North America. Patients: Men aged 55 to 90 years with a baseline bone mineral density (BMD) T-score at the lumbar spine (LS), total hip (TH), or femoral neck of ≤-2.5 or ≤-1.5 with a history of a fragility nonvertebral or vertebral fracture. Interventions: The subjects were randomized 2:1 to receive romosozumab 210 mg subcutaneously monthly or placebo for 12 months. Main Outcome Measures: The primary efficacy endpoint was percentage change from baseline in LS BMD at month 12.…

Context: The prevalence of thyroid nodules in the general population is increasingly high, and at least half of those biopsied prove to be benign. Sonographic risk-stratification systems are being proposed as "rule-out" tests that can identify nodules that do not require fine-needle aspiration (FNA) cytology. Objective: To comparatively assess the performances of five internationally endorsed sonographic classification systems [those of the American Thyroid Association, the American Association of Clinical Endocrinologists, the American College of Radiology (ACR), the European Thyroid Association, and the Korean Society of Thyroid Radiology] in identifying nodules whose FNAs can be safely deferred and to estimate their negative predictive values (NPVs). Design: Prospective study of thyroid nodules referred for FNA. Setting: Single academic referral center. Patients: Four hundred seventy-seven patients (358 females, 75.2%); mean (SD) age, 55.9 (13.9) years. Main Outcome Measures: Number of biopsies classified as unnecessary, false-negative rate (FNR), sensitivity, specificity,…

Background: Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women. The clinical presentation of PHPT has evolved over the past 40 years to include three distinct clinical phenotypes, each of which has been studied in detail and has led to evolving concepts about target organ involvement, natural history, and management. Methods: In the present review, I provide an evidence-based summary of this disorder as it has been studied worldwide, citing key concepts and data that have helped to shape our concepts about this disease. Results: PHPT is now recognized to include three clinical phenotypes: overt target organ involvement, mild asymptomatic hypercalcemia, and high PTH levels with persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is used, vitamin D deficiency is present, and whether parathyroid hormone levels are routinely measured…

Context: Gut microbiota play a major role in health and disease by influencing physiology, metabolism, nutrition, and immune function. Objective: To evaluate the composition of gut microbiota in women with polycystic ovary syndrome (PCOS), focusing on the influence of sex, sex hormones and obesity on the associations found. Design: Cross-sectional study. Setting: Academic hospital. Participants: We recruited 15 women with PCOS, 16 nonhyperandrogenic control women, and 15 control men. Participants were classified as nonobese (<30 kg/m2) or obese (≥30 kg/m2) according to their body mass index. Interventions: Standardization of diet for 3 consecutive days (at least 300 g of carbohydrates per day) followed by fecal sampling and a standard 75-g oral glucose tolerance test. Main Outcome Measures: Analysis of bacterial abundance and composition of gut microbiota by massive sequencing of 16S ribosomal DNA amplicons in a MiSeq platform (Illumina). Results: α Bacterial diversity was reduced in women compared with men, and β diversity was reduced particularly in obese patients with PCOS. Women…

Context: Vitamin D is classically recognized as a regulator of calcium and phosphorus metabolism. Recent advances in the measurement of vitamin D metabolites, diagnosis of vitamin D deficiency, and clinical observations have led to an appreciation that along with its role in skeletal metabolism, vitamin D may well have an important role in nonclassical settings. Measurement of the circulating form of vitamin D that best describes total body stores, namely 25-hydroxyvitamin D, can be unreliable despite many sophisticated methodologies that have been proposed and implemented. Likewise, evidence from clinical studies showing a beneficial role of vitamin D in different disease states has been controversial and at times speculative. Moreover, the target concentrations of 25-hydroxyvitamin D to address a number of putative links between vitamin D inadequacy and nonskeletal diseases are further areas of uncertainty. Setting: To address these issues, an international conference on "Controversies in Vitamin D" was held in Pisa, Italy, in June 2017. Three main topics were addressed: (i)…

CONTEXT: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN: This was a pilot trial that enrolled from June 2014 to January 2016. SETTING: Academic cancer center. PATIENTS: Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS: Twelve BRAF mutant…

Context: N6-methyladenosine (m6A) in mRNA is the most abundant and reversible modification. However, the mechanism behind the decrease in m6A in patients with type 2 diabetes (T2D) has not yet been thoroughly investigated. Objective: To clarify whether glucose is involved in the dynamic regulation of m6A in T2D and to identify a possible underlying mechanism. Methods: Liquid chromatography/electrospray ionization/tandem mass spectrometry and quantitative PCR were performed to determine the m6A content and the mRNA expression of target genes in 102 patients with T2D and 107 controls. An additional 12 patients with normal fasting blood glucose, emergency hyperglycemia, or emergency hypoglycemia, as well as HepG2 cells with high-glucose treatment and FTO knockout or overexpression were used to confirm the initial observations in patients. Results: In patients with T2D, the m6A content was decreased, and mRNA expression levels of FTO, METTL3, METTL14, and WTAP were increased. Interestingly, the m6A content was negatively associated with mRNA expression levels of METTL3, METTL14, and…

Context: Emerging evidence has related the gut microbiome and circulating metabolites to human obesity. Gut microbiota is responsible for several metabolic functions, and altered plasma metabolome might reflect differences in the gut microbiome. Objective: To identify a plasma metabolite profile associated with body mass index (BMI) in a general population and investigate whether such metabolite profile is associated with distinct composition of the gut microbiota. Design: Targeted profiling of 48 plasma metabolites was performed in a population of 920 Swedish adults (mean age, 39 years; 53% women) from the ongoing Malmö Offspring Study using targeted liquid chromatography-mass spectrometry. Gut microbiota was analyzed by sequencing the 16S ribosomal RNA gene (V1-V3 region) in fecal samples of 674 study participants. Results: BMI was associated with 19 metabolites (P < 0.001 for all), of which glutamate provided the strongest direct association (P = 5.2e-53). By orthogonal partial least squares regression, a metabolite principal component predictive of BMI was constructed (PCBMI).…

Context: Hypoglycemia, occurring after bariatric and other forms of upper gastrointestinal surgery, is increasingly encountered by clinical endocrinologists. The true frequency of this condition remains uncertain, due, in part, to differences in the diagnostic criteria and in the affected populations, as well as relative lack of patient and physician awareness and understanding of this condition. Postbariatric hypoglycemia can be severe and disabling for some patients, with neuroglycopenia (altered cognition, seizures, and loss of consciousness) leading to falls, motor vehicle accidents, and job and income loss. Moreover, repeated episodes of hypoglycemia can result in hypoglycemia unawareness, further impairing safety and requiring the assistance of others to treat hypoglycemia. Objective: In this review, we summarize and integrate data from studies of patients affected by hypoglycemia after Roux-en-Y gastric bypass (RYGB) surgery, obtained from PubMed searches (1990 to 2017) and reference searches of relevant retrieved articles. Whereas hypoglycemia can also be observed after…

Context: Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases. Evidence Acquisition: Systematic search of four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) using the search terms "diabetes" or "ketoacidosis" and "pembrolizumab," "nivolumab," "PD-1 inhibitor," or "immunotherapy." Included were articles published in English between 1 January 2012 and 1 January 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers. Evidence Synthesis: We provide an overview of all published cases (n = 42) of PD-1 inhibitor-induced type 1 diabetes mellitus to date, including a well-characterized case of islet cell antibody and…

Objective: To formulate clinical practice guidelines for the endocrine treatment of hypothalamic-pituitary and growth disorders in survivors of childhood cancer. Participants: An Endocrine Society-appointed guideline writing committee of six medical experts and a methodologist. Conclusions: Due to remarkable improvements in childhood cancer treatment and supportive care during the past several decades, 5-year survival rates for childhood cancer currently are >80%. However, by virtue of their disease and its treatments, childhood cancer survivors are at increased risk for a wide range of serious health conditions, including disorders of the endocrine system. Recent data indicate that 40% to 50% of survivors will develop an endocrine disorder during their lifetime. Risk factors for endocrine complications include both host (e.g., age, sex) and treatment factors (e.g., radiation). Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid, and gonads) places cancer survivors at the highest risk of developing an endocrine abnormality over time; these…

Purpose: In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods: Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results: Five hundred fifty-eight women from ACTIVE's ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan-Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during…

CONTEXT: Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. EVIDENCE ACQUISITION: A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. EVIDENCE SYNTHESIS: The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence…

Context: Metformin is used in pregnancy in women with gestational diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity. Metformin passes the placenta. Objective: To explore the effects of metformin use in PCOS pregnancies on offspring growth to 4 years of age. Design: Follow-up study of two randomized, double-blind, placebo-controlled trials. Setting: Secondary care centers. Eleven public hospitals in Norway. Participants: One hundred eighty-two children of mothers with PCOS who participated in two randomized controlled trials. Intervention: Metformin 1700 or 2000 mg/d or placebo from first trimester to delivery in the original studies. No intervention in the current study. Main Outcome Measures: Height, weight, body mass index (BMI), and overweight/obesity at 4 years of age and head circumference at 1 year of age, converted to z scores. Results: The difference in height z score means between the groups at 4 years of age was nonsignificant (0.07 [95% confidence interval (CI): -0.22 to 0.36]; P = 0.651). At 4 years of age, the metformin group had higher weight z score…

Context: Randomized controlled trials evaluating real-time continuous glucose monitoring (RT-CGM) patients with type 1 diabetes (T1D) show improved glycemic control, but limited data are available on real-world use. Objective: To assess impact of RT-CGM in real-world settings on glycemic control, hospital admissions, work absenteeism, and quality of life (QOL). Design: Prospective, observational, multicenter, cohort study. Participants: A total of 515 adults with T1D on continuous subcutaneous insulin infusion (CSII) therapy starting in the Belgian RT-CGM reimbursement program. Intervention: Initiation of RT-CGM reimbursement. Main Outcome Measure: Hemoglobin A1c (HbA1c) evolution from baseline to 12 months. Results: Between September 1, 2014, and December 31, 2016, 515 adults entered the reimbursement system. Over this period, 417 (81%) patients used RT-CGM for at least 12 months. Baseline HbA1c was 7.7 ± 0.9% (61 ± 9.8 mmol/mol) and decreased to 7.4 ± 0.8% (57 ± 8.7 mmol/mol) at 12 months (P < 0.0001). Subjects who started RT-CGM because of insufficient glycemic control showed…

Context: Somatic mutations have been identified in more than half of aldosterone-producing adenomas (APAs) through mutation hotspot sequencing. The underlying pathogenesis of inappropriate aldosterone synthesis in the remaining population is still unknown. Objective: To investigate the prevalence and spectrum of somatic mutations in APAs using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)‒guided next-generation sequencing (NGS) approach. Methods: Formalin-fixed paraffin-embedded adrenal tissue from white American patients with primary aldosteronism who underwent adrenalectomy at the University of Michigan was used. Genomic DNA was isolated from 75 APAs (identified by CYP11B2 IHC). NGS was performed to identify somatic mutations by sequencing the entire coding region of a panel of genes mutated in APAs. Results: Somatic mutations were identified in 66 of 75 APAs (88%). Of the APAs with somatic mutations, six were smaller than coexisting CYP11B2-negative adrenocortical adenomas. The most frequently mutated gene was KCNJ5 (43%), followed by CACNA1D (21%), ATP1A1 (17%),…

BACKGROUND: Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern. OBJECTIVE: To investigate the relationship between PFC exposure and male reproductive health. DESIGN: This study was performed within a screening protocol to evaluate male reproductive health in high schools. PATIENTS: This is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 nonexposed controls. MAIN OUTCOME MEASURES: Anthropometrics, seminal parameters, and sex hormones were measured in young males from exposed areas compared with age-matched controls. We also performed biochemical studies in established experimental…

CONTEXT: Modern pheochromocytomas (PHEOs) are often discovered by incidental finding on cross-sectional imaging or mutation-based genetic case detection testing. Little is known about how these PHEOs behave. OBJECTIVE: To describe the characteristics and behavior of PHEOs discovered incidentally on imaging or through mutation-based genetic case detection testing. DESIGN: Retrospective study. SETTING: Referral center. PATIENTS: Consecutive patients with pathology-confirmed PHEOs, treated from 2005 to 2016. MAIN OUTCOME MEASURE(S): Tumor size, plasma/urine fractionated metanephrines and catecholamines, and preoperative management. RESULTS: Two hundred seventy-one patients (52% women, median age 52.0 years) presented with 296 PHEOs. Discovery method was most often incidental finding on cross-section imaging (61%) rather than PHEO-related symptoms (27%) or mutation-based case detection testing (12%). Patients with incidentally discovered PHEOs were older than symptomatic and mutation-based case detection testing patients (median age 56.6 vs 43 vs 35 years, P < 0.0001). Mutation-based…

Context: Despite evidence on the association between hypovitaminosis D and adverse pregnancy outcomes and the positive impact of vitamin D supplementation, no evidence exists supporting a universal screening program in pregnancy as part of routine prenatal care. Objective: We sought to determine the effectiveness of a prenatal screening program on optimizing 25-hydroxyvitamin D [25(OH)D] levels and preventing pregnancy complications. Also, to identify a safe regimen, we compared several regimens in a subgroup of vitamin D-deficient pregnant women. Design: Two cities of Masjed-Soleyman and Shushtar from Khuzestan province, Iran, were selected as the screening and nonscreening arms, respectively. Within the screening arm, a randomized controlled trial was conducted on 800 pregnant women. Setting: Health centers of Masjed-Soleyman and Shushtar cities. Patients or Participants: Pregnant women aged 18 to 40 years. Intervention: Women with moderate [25(OH)D, 10 to 20 ng/mL] and severe [25(OH)D, <10 ng/mL] deficiency were randomly divided into four subgroups and received vitamin D3 (D3)…

Context: Thyroid cancer incidence increased with the greatest change in adults aged ≥65 years. Objective: To determine the relationship between area-level use of imaging and thyroid cancer incidence over time. Design, Setting and Participants: Longitudinal imaging patterns in Medicare patients aged ≥65 years residing in Surveillance, Epidemiology, and End Results (SEER) regions were assessed in relationship to differentiated thyroid cancer diagnosis in patients aged ≥65 years included in SEER-Medicare. Linear mixed-effects modeling was used to determine factors associated with thyroid cancer incidence over time. Multivariable logistic regression was used to determine patient characteristics associated with receipt of thyroid ultrasound as initial imaging. Main Outcome Measure: Thyroid cancer incidence. Results: Between 2002 and 2013, thyroid ultrasound use as initial imaging increased (P < 0.001). Controlling for time and demographics, use of thyroid ultrasound was associated with thyroid cancer incidence (P < 0.001). Findings persisted when cohort was restricted to papillary…

Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. Case: A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Molecular Evaluation: Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide…

Context: Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT). Objective: The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA. Participants and Methods: With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years). Results: In reference population girls,…

Context: Acromegaly has been associated with increased risk of cancer morbidity and mortality, but research findings remain conflicting and population-based data are scarce. We therefore examined whether patients with acromegaly are at higher risk of cancer. Design: A nationwide cohort study (1978 to 2010) including 529 acromegaly cases was performed. Incident cancer diagnoses and mortality were compared with national rates estimating standardized incidence ratios (SIRs). A meta-analysis of cancer SIRs from 23 studies (including the present one) was performed. Results: The cohort study identified 81 cases of cancer after exclusion of cases diagnosed within the first year [SIR 1.1; 95% confidence interval (CI), 0.9 to 1.4]. SIRs were 1.4 (95% CI, 0.7 to 2.6) for colorectal cancer, 1.1 (95% CI, 0.5 to 2.1) for breast cancer, and 1.4 (95% CI, 0.6 to 2.6) for prostate cancer. Whereas overall mortality was elevated in acromegaly (SIR 1.3; 95% CI, 1.1 to 1.6), cancer-specific mortality was not. The meta-analysis yielded an SIR of overall cancer of 1.5 (95% CI, 1.2 to 1.8). SIRs were…

Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied. Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty. Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement.…

Context: The early activation of the hypothalamic-pituitary-gonadal axis during infancy can be used in the evaluation of infants suspected of disorders of sex development (DSD). However, few data exist on sex-specific reference ranges for these hormones during early life. Objective: To evaluate sex differences in reproductive hormone concentrations in serum from healthy infants to define sex-specific cutoff values and to apply these in infants with DSD. Design: A cross-sectional study. Setting: A tertiary center for pediatric endocrinology at the University Hospital of Copenhagen. Patients or Other Participants: Healthy infants (1840) and patients with DSD (27), aged 2 to 5 months. Main Outcome Measures: Serum concentrations of LH, FSH, testosterone (T), estradiol, sex hormone-binding globulin (SHBG), inhibin B, anti-Müllerian hormone (AMH), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and LH/FSH ratio. Results: LH and FSH concentrations showed overlap between sexes, with LH being highest in boys and FSH being highest in…

CONTEXT: The efficacy and safety of testosterone replacement therapy (TRT) in hypogonadal men remain incompletely understood. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized clinical trials (RCT) to determine the effects of TRT on patient-important outcomes and adverse events in hypogonadal men. DATA SOURCES: We searched Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus from inception to March 2th, 2017. STUDY SELECTION: RCTs that assessed the efficacy and adverse events of TRT of at least 12 weeks compared with placebo in adult men with hypogonadism, defined by morning testosterone ≤300 ng/dL and at least one symptom or sign of hypogonadism. DATA EXTRACTION: Reviewers working independently and in duplicate assessed the quality of the trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: We found 11 publications, reporting on 4 eligible trials (including 1,779 patients) at low risk of bias. Compared to placebo, TRT was…

Context: Primary adrenal insufficiency is an important clinical manifestation of X-linked adrenoleukodystrophy (ALD). Other manifestations include spinal cord disease and/or inflammatory demyelinating cerebral disease. Implementation of newborn screening requires natural history data to develop follow-up recommendations. Objective: To delineate the natural history of adrenal insufficiency in male patients with ALD and to assess associations between the risk for developing adrenal insufficiency, spinal cord disease, or cerebral disease and plasma C26:0/C22:0 and C24:0/C22:0 ratios, which are diagnostic biomarkers for ALD. Design: Retrospective review of medical records. Setting: Two international tertiary referral centers of expertise for ALD. Patients: Male patients with ALD followed at the centers between 2002 and 2016. Main Outcome Measures: The primary endpoint was adrenal insufficiency; secondary endpoints were spinal cord and cerebral disease. Results: Data on 159 male patients was available. The probability of developing adrenal insufficiency was described with survival…

Context: Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status. Objective: To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status. Design, Setting, and Participants: Meta-analysis of individual participant data from 9036 mother-child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease. Main Outcomes: Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age. Results: FT4 <2.5th…

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with the radiolabeled somatostatin analogue [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) is widely applied for inoperable metastatic small intestinal and nonfunctioning pancreatic neuroendocrine tumors (pNETs). The aim of this study is to describe the safety and efficacy of the treatment of functioning pNETs. METHODS: Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gbq per cycle. Radiological (Response Evaluation Criteria in Solid Tumors 1.1), symptomatic, and biochemical response were analyzed retrospectively for all patients with a functioning pNET (insulinoma, gastrinoma, VIPoma, and glucagonoma) treated with 177Lu-DOTATATE. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module questionnaire. RESULTS: Thirty-four patients with a metastatic functioning pNET (European Neuroendocrine Tumor Society grade 1 or 2) were included: 14 insulinomas, 5 VIPomas, 7 gastrinomas, and 8 glucagonomas.…

Context: Many differentiated thyroid cancers (DTC) dedifferentiate and become radioactive iodine (RAI)-refractory (RAIR) with worse outcomes. Targeted therapy (TTx) may downregulate MAPK signaling and sensitize tumors to RAI. Objective: We describe patients with RAIR DTC receiving TTx with demonstrated RAI uptake allowing for iodine-131 (I131) administration. Design: Charts of patients with metastatic, progressive, RAIR DTC in whom TTx increased RAI uptake on a diagnostic whole-body scan (WBS), were reviewed. Results of WBS, I131 administration, thyroglobulin (TG) panels, and cross-sectional studies were recorded. Setting: Thirteen patients [median age (range), 56 (45 to 75) years; seven men] were included; 11 (85%) had DTC, two (15%) had poorly DTC. Nine (69%) had BRAF mutations, three (23%) had RAS mutations, and one (8%) was wild type. Selective BRAF or an MEK inhibitor TTx was continued for a median (range) of 14.3 (1 to 76.4) months before diagnostic WBS. Results: Nine (69%) patients were treated with I131 [median (range) activity, 204.4 (150 to 253) mCi], after which TTx was…

Context: Although mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce. Objective: To assess the efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors. Design and Setting: Multicenter cohort study of three German referral centers. Patients: One hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy. Outcome Measures: Response Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression. Results: Twenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P = 0.017); and initiation of mitotane at delayed…

Background: Up to 7% of all adrenal incidentalomas (AIs) are pheochromocytomas (PCCs). In the evaluation of AI, it is generally recommended that PCC be excluded by measurement of plasma-free or 24-hour urinary fractionated metanephrines. However, recent studies suggest that biochemical exclusion of PCC not be performed for lesions with CT characteristics of an adrenocortical adenoma (ACA). Aim: To determine the proportion of PCCs with ACA-like attenuation or contrast washout on CT. Methods: For this multicenter retrospective study, two central investigators independently analyzed the CT reports of 533 patients with 548 histologically confirmed PCCs. Data on tumor size, unenhanced Hounsfield units (HU), absolute percentage washout (APW), and relative percentage washout (RPW) were collected in addition to clinical parameters. Results: Among the 376 PCCs for which unenhanced attenuation data were available, 374 had an attenuation of >10 HU (99.5%). In the two exceptions (0.5%), unenhanced attenuation was exactly 10 HU, which lies just within the range of ≤10 HU that would suggest a…

Context: With the aging of the population and projected increase in osteoporotic fractures coupled with the declining use of osteoporosis medications, there is a compelling need for new approaches to treat osteoporosis. Given that age-related osteoporosis generally coexists with multiple other comorbidities (e.g., atherosclerosis, diabetes, frailty) that share aging as the leading risk factor, there is growing interest in the "Geroscience Hypothesis," which posits that manipulation of fundamental aging mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share aging as the underlying risk factor. In this context, one fundamental aging mechanism that has received considerable attention recently as contributing to multiple age-related morbidities is cellular senescence. This mini-review provides an overview on cellular senescence with a focus on its role in mediating age-related bone loss. Methods: This summary is based on the authors' knowledge of the field supplemented by a PubMed search using the terms "senescence," "aging," and…

Context: Perfluoroalkyl and polyfluoroalkyl substances (PFASs), a group of ubiquitous environmental chemicals with properties of endocrine disruption, are often detectable in humans. Objective: The current study investigated the association between exposure to PFAS and primary ovarian insufficiency (POI). Design, Patients, Interventions, and Main Outcome Measures: Levels of plasma PFAS were measured in 120 Chinese women with overt POI and 120 healthy control subjects from 2013 to 2016. Associations between PFAS levels and odds of POI, as well as hormonal profiles, were evaluated using multiple logistic regression and multiple linear regression models. Results: Levels of perfluorooctanate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexanesulfonate (PFHxS) were positively associated with the risks of POI (highest vs. lowest tertile, PFOA: OR, 3.80; 95% CI, 1.92-7.49; PFOS: OR, 2.81; 95% CI, 1.46-5.41; PFHxS: OR, 6.63; 95% CI, 3.22-13.65). In patients with POI, levels of PFOS and PFHxS exposure were positively associated with FSH (PFOS: adjusted β, 0.26; 95% CI, 0.15 to…

Background: Females with congenital adrenal hyperplasia (CAH) and atypical genitalia often undergo complex surgeries; however, their outcomes remain largely uncertain. Methods: We searched several databases through 8 March 2016 for studies evaluating genital reconstructive surgery in females with CAH. Reviewers working independently and in duplicate selected and appraised the studies. Results: We included 29 observational studies (1178 patients, mean age at surgery, 2.7 ± 4.7 years; mostly classic CAH). After an average follow-up of 10.3 years, most patients who had undergone surgery had a female gender identity (88.7%) and were heterosexual (76.2%). Females who underwent surgery reported a sexual function score of 25.13 using the Female Sexual Function Index (maximum score, 36). Many patients continued to complain of substantial impairment of sensitivity in the clitoris, vaginal penetration difficulties, and low intercourse frequency. Most patients were sexually active, although only 48% reported comfortable intercourse. Most patients (79.4%) and treating health care professionals…

Context: Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death. Objective: The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated. Design, Settings, and Participants: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes. Results: Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and…

Context: Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular disease (CVD). Objective: To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women. Design: The Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years. Setting: General community. Participants: A total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age <40 or >62). Intervention: None. Main Outcomes and Measures: Linear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone-binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave…

Background: Individuals with congenital adrenal hyperplasia (CAH) require glucocorticoid therapy to replace cortisol and to control androgen excess. We sought to evaluate the effects of glucocorticoid therapy on cardiovascular and metabolic outcomes in individuals with CAH. Methods: We searched bibliographical databases through January 2016 for studies evaluating cardiovascular risk factors in individuals with CAH treated with glucocorticoids compared with controls without CAH. We used a random-effects model to synthesize quantitative data. Results: We included 20 observational studies (14 longitudinal, six cross-sectional) with a moderate to high risk of bias. The average dose of glucocorticoids (in hydrocortisone equivalents) was 9 to 26.5 mg/m2/d. In the meta-analysis (416 patients), compared with controls without CAH, individuals with CAH had increased systolic blood pressure [weighted mean difference (WMD), 4.44 mm Hg; 95% CI, 3.26 to 5.63 mm Hg], diastolic blood pressure (WMD, 2.35 mm Hg; 95% CI, 0.49 to 4.20 mm Hg), homeostatic model assessment of insulin resistance (WMD,…

Context: We compared the incidence of hypoglycemia after Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG). Design, Setting, and Main Outcome Measures: Randomized, open-label trial conducted at the outpatient obesity clinic in a university hospital in Rome, Italy. The primary aim was the incidence of reactive hypoglycemia (<3.1 mmol/L after 75-g oral glucose load) at 1 year after surgery. Secondary aims were hypoglycemia under everyday life conditions, insulin sensitivity, insulin secretion, and lipid profile. Results: Of 175 eligible patients, 120 were randomized 1:1 to RYGB or SG; 117 (93%) completed the 12-month follow-up. Reactive hypoglycemia was detected in 14% and 29% of SG and RYGB patients (P = 0.079), respectively, with the effect of treatment in multivariate analysis significant at P = 0.018. Daily hypoglycemic episodes during continuous glucose monitoring did not differ between groups (P = 0.75). Four of 59 RYGB subjects (6.8%) had 1 to 3 hospitalizations for symptomatic hypoglycemia vs 0 in SG. The static β-cell glucose sensitivity index increased after both…

Context: Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. Objective: In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients: Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected. Design: The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1. Results: Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during…

Context: Progestin-based therapy is the first-line treatment for managing endometriosis-associated pain. However, response to progestins is currently variable and unpredictable. Predictive markers for response to progestin-based therapy would allow for a personalized approach to endometriosis treatment. Objective: We hypothesize that progesterone receptor (PR) levels in endometriotic lesions determine response to progestin-based therapy. Design: Retrospective cohort study. Setting: Academic center. Patients: Fifty-two subjects with histologically confirmed endometriosis and a previous documented response to hormonal therapy were included. Interventions: Immunohistochemistry was performed on sections of endometriotic lesions using a rabbit polyclonal IgG for detection of PR-A/B. Main Outcome Measures: The Histo (H)-score was used for quantifying PR status. Response to progestin-based therapies was determined from review of the electronic medical record. Results: H-score was higher in responders compared with nonresponders. Subjects were categorized into three groups: high (H-score >…

Context: Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome. Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine. Design: In total, 117 tumor samples from 107 patients with ACC were analyzed. Targeted next-generation sequencing of 160 genes and pyrosequencing of 4 genes were applied to formalin-fixed, paraffin-embedded (FFPE) specimens to detect point mutations, copy number alterations, and promoter region methylation. Molecular results were combined with clinical/histopathological parameters (tumor stage, age, symptoms, resection status, and Ki-67) to predict progression-free survival (PFS). Results: In addition to known driver mutations, we detected recurrent alterations in genes not previously associated with ACC (e.g., NOTCH1, CIC, KDM6A, BRCA1, BRCA2). Best prediction…

BACKGROUND: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. METHODS: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. RESULTS: We identified three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such…

Context: Failure of plasma aldosterone suppression during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). Aldosterone is often higher upright than recumbent in PA; upright levels are used during FST. In a pilot study (24 patients with PA), seated saline suppression testing (SSST) was more sensitive than recumbent saline suppression testing (RSST). Objective, Design, and Patients: The current validation study involved 100 patients who underwent FST, RSST, and SSST, eight before and after unilateral adrenalectomy. Of the 108 FSTs, 73 confirmed and 18 excluded PA. Four patients with inconclusive FST lateralized on adrenal venous sampling, making a total of 77 with PA. Results: The area under the receiver operating characteristic (ROC) curve was greater for SSST than RSST (0.96 vs. 0.80; P < 0.01). ROC analysis predicted optimal cutoff aldosterone levels of 162 pmol/L for SSST and 106 pmol/L for RSST. At these cutoffs, SSST showed high sensitivity for PA (87%) that markedly exceeded that for RSST (38%; P < 0.001) but…

Purpose: The diagnosis of adult GH deficiency (AGHD) is challenging and often requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is considered the reference standard GHST but is labor intensive, can cause severe hypoglycemia, and is contraindicated for certain patients. Macimorelin, an orally active GH secretagogue, could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose. Materials and Methods: The present multicenter, open-label, randomized, two-way crossover trial was designed to validate the efficacy and safety of single-dose oral macimorelin for AGHD diagnosis compared with the ITT. Subjects with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for AGHD and healthy, matched controls (n = 25) were included in the efficacy analysis. Results: After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Using GH cutoff levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for ITTs, the negative agreement was 95.38% (95% CI, 87% to 99%), the positive agreement was 74.32% (95% CI, 63% to…