The 50 most-cited articles in The Journal of Clinical Endocrinology & Metabolism, 2022

BACKGROUND AND AIMS: Metabolic-associated fatty liver disease (MAFLD) was proposed as a better definition of nonalcoholic fatty liver disease (NAFLD) to encompass the metabolic dysregulation associated with NAFLD. This redefinition challenges our understanding of the disease. Hence, this study sought to conduct an updated analysis of the prevalence, clinical characteristics, and associated factors of MAFLD, with a further sensitivity analysis done based on lean and nonobese MAFLD individuals. METHODS: Medline and Embase databases were searched to include articles on MAFLD. Meta-analysis of proportions was conducted using the generalized linear mix model. Associating factors were evaluated in conventional pairwise meta-analysis with sensitivity analysis on lean and nonobese MAFLD. RESULTS: From pooled analysis involving 3 320 108 individuals, the overall prevalence of MAFLD was 38.77% (95% CI 32.94% to 44.95%); 5.37% (95% CI 4.36% to 6.59%) and 29.78% (95% CI 26.06% to 33.79%) of lean and nonobese individuals, respectively, had MAFLD. Metabolic complications such as hypertension…

BACKGROUND: Adult patients with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. These patients are at increased risk for adverse clinical outcomes in the absence of defined approaches to glycemic management. OBJECTIVE: To review and update the 2012 Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline and to address emerging areas specific to the target population of noncritically ill hospitalized patients with diabetes or newly recognized or stress-induced hyperglycemia. METHODS: A multidisciplinary panel of clinician experts, together with a patient representative and experts in systematic reviews and guideline development, identified and prioritized 10 clinical questions related to inpatient management of patients with diabetes and/or hyperglycemia. The systematic reviews queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was…

CONTEXT: Although glycated hemoglobin A1c is currently the best parameter used clinically to assess risk for the development of diabetes complications, it does not provide insight into short-term fluctuations in glucose levels. This review summarizes the relationship between continuous glucose monitoring (CGM)-derived metrics of glycemic variability and diabetes-related complications. EVIDENCE ACQUISITION: PubMed and Embase databases were searched from January 1, 2010 to August 22, 2020, using the terms type 1 diabetes, type 2 diabetes, diabetes-related microvascular and macrovascular complications, and measures of glycaemic variability. Exclusion criteria were studies that did not use CGM and studies involving participants who were not diabetic, acutely unwell (post stroke, post surgery), pregnant, or using insulin pumps. EVIDENCE SYNTHESIS: A total of 1636 records were identified, and 1602 were excluded, leaving 34 publications in the final review. Of the 20 852 total participants, 663 had type 1 diabetes (T1D) and 19 909 had type 2 diabetes (T2D). Glycemic variability and low…

CONTEXT: Evaluation of the infertile female requires an understanding of ovulation and biomarkers of ovarian reserve. Antimüllerian hormone (AMH) correlates with growing follicles in a menstrual cycle. Increasingly, AMH has been used as a "fertility test." This narrative review describes how to integrate the use of AMH into diagnosis and treatment. METHODS: A PubMed search was conducted to find recent literature on measurements and use of serum AMH as a marker of ovarian reserve and in treatment of infertility. RESULTS: Serum AMH estimates ovarian reserve, helps determine dosing in ovarian stimulation, and predicts stimulation response. As such, AMH is a good marker of oocyte quantity but does not reflect oocyte health or chances for pregnancy. Screening of AMH before fertility treatment should be used to estimate expected response and not to withhold treatment. Low AMH levels may suggest a shortened reproductive window. AMH levels must be interpreted in the context of the endogenous endocrine environment where low follicle-stimulating hormone, due to hypogonadotropic hypogonadism…

Central diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurons in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse etiologies, although it typically develops due to neoplastic, traumatic, or autoimmune destruction of AVP-synthesizing/secreting neurons. This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as…

CONTEXT: Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. OBJECTIVE: To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. METHODS: A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the…

CONTEXT: The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. OBJECTIVE: This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. METHODS: Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. RESULTS: The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and…

CONTEXT: Cardiovascular benefits of empagliflozin in patients with type 2 diabetes mellitus (T2DM) have been reported; however, the underlying mechanism remains unknown. OBJECTIVE: We hypothesized that the cardiovascular benefits of empagliflozin are associated with altered gut microbiota and plasma metabolites, and that empagliflozin may be used as an initial treatment for patients with T2DM at risk of cardiovascular diseases (CVDs). METHODS: This randomized, open-label, 3-month, 2-arm clinical trial included 76 treatment-naïve patients with T2DM and risk factors for CVD who were treated with either empagliflozin (10 mg/d, n = 40) or metformin (1700 mg/d, n = 36). We investigated changes in clinical parameters related to glucose metabolism and CVD risk factors, gut microbiota using 16S rRNA gene sequencing, and plasma metabolites using LC-MS. RESULTS: We found significant and similar reduction in HbA1c levels and alleviation of glucose metabolism in both groups. However, only empagliflozin improved CVD risk factors. Empagliflozin significantly reshaped the gut microbiota after 1…

BACKGROUND: Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. OBJECTIVE: To develop guidelines for the treatment of adults with HCM. METHODS: A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and…

CONTEXT: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. METHODS: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. RESULTS: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the…

CONTEXT: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. OBJECTIVE: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. METHODS: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks' open-label osilodrostat). RESULTS: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received…

CONTEXT: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are used off-label in the management of type 1 diabetes mellitus (T1DM) in real-world practice as adjuvant therapies to insulin. There are few real-world data regarding efficacy and safety of this practice. OBJECTIVE: This work aimed to determine the efficacy and safety of GLP-1RAs and sodium-glucose SGLT2is in the management of T1DM in real-world practice. METHODS: A retrospective chart review was performed of all instances of GLP-1RA and/or SGLT2i use greater than 90 days in adult patients with T1DM at a single academic center. We report the clinical and safety outcomes over the duration of use. RESULTS: We identified 104 patients with T1DM who ever used a GLP-1RA (76 patients) or SGLT2i (39 patients) for more than 90 days. After 1 year of therapy, GLP-1RA users had statistically significant reductions in weight (90.5 kg to 85.4 kg; P < .001), glycated hemoglobin A1c (HbA1c) (7.7% to 7.3%; P = .007), and total daily dose of insulin (61.8 units to 41.9 units; P <…

Patients with obesity have a high prevalence of nonalcoholic fatty liver disease (NAFLD), representing a spectrum of simple steatosis to nonalcoholic steatohepatitis (NASH), without and with fibrosis. Understanding the etiology of NAFLD is clinically relevant since NAFLD is an independent risk factor for diabetes and cardiovascular disease. In addition, NASH predisposes patients to the development of cirrhosis and hepatocellular carcinoma, and NASH cirrhosis represents the fastest growing indication for liver transplantation in the United States. It is appreciated that multiple factors are involved in the development and progression of NAFLD. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) regulate metabolic, immune, and hepatic stellate cell function, and alterations in the production and function of GH is associated with obesity and NAFLD/NASH. Therefore, this review will focus on the potential role of GH and IGF1 in the regulation of hepatic steatosis, inflammation, and fibrosis.

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of…

OBJECTIVE: We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS). METHODS: The protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies. RESULTS: SMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths…

CONTEXT: Thyroid hormones are important regulators of glucose metabolism, and studies investigating the association between thyroid function and type 2 diabetes incidence have shown conflicting results. OBJECTIVE: We aimed to combine the evidence from prospective studies addressing the association between thyroid function and type 2 diabetes risk. METHODS: We systematically searched in Embase, Medline (Ovid), Web of Science, Cochrane, and Google Scholar for prospective studies assessing the association of thyroid function and incident type 2 diabetes. Data extraction was performed using a standardized protocol by 2 independent reviewers. We assessed study quality using the Newcastle-Ottawa Scale and pooled hazard ratios (HRs) and 95% CI using random-effects models. RESULTS: From the 4574 publications identified, 7 met our inclusion criteria and were included in the qualitative synthesis. Six publications were included in the meta-analysis. Studies assessed hypothyroidism (6 studies), hyperthyroidism (5 studies), thyrotropin (TSH) in the reference range (4 studies), and free…

CONTEXT: The comparative effectiveness of drugs and surgical therapy for women with obesity and polycystic ovary syndrome (PCOS) has not been systematically compared. OBJECTIVE: We aimed to determine the difference in efficacy between drug and bariatric surgery therapy for women with obesity and PCOS. METHODS: This prospective nonrandomized trial enrolled 90 women aged 18 to 40 years with body mass index (BMI) ≥ 27.5 kg/m2 and waist circumference ≥ 85 cm and fulfilling the 2011 Chinese diagnostic criteria for PCOS; 81 subjects completed the study. In the drug group, patients were administered metformin and an oral contraceptive containing ethinyl-estradiol and cyproterone acetate for the first 6 months, and metformin alone for the second 6 months. In the surgical group, patients underwent laparoscopic sleeve gastrectomies. The follow-up period was 12 months. The main outcome was the complete remission of PCOS, requiring 6 consecutive regular menstruation cycles or spontaneous pregnancy. RESULTS: Median BMI at endpoint was 30.1 kg/m2 in the drug group and 23.7 kg/m2 in the surgical…

OBJECTIVE: Obesity is a global public health challenge and strongly associated with type 2 diabetes (T2D), but its burden and effects are not well understood in people with type 1 diabetes (T1D). Particularly, the link between obesity and chronic kidney disease (CKD) in T1D is poorly characterized. RESEARCH DESIGN AND METHODS: We included all T1D and, for comparison, T2D in the Geisinger Health System from 2004 to 2018. We evaluated trends in obesity (body mass index ≥ 30 kg/m2), low estimated glomerular filtration rate (eGFR) (≤60 mL/min/1.73m2), and albuminuria (urine albumin-to-creatinine ratio ≥ 30 mg/g). We used multivariable logistic regression to evaluate the independent association of obesity with CKD in 2018. RESULTS: People with T1D were younger than T2D (median age 39 vs 62 years). Obesity increased in T1D over time (32.6% in 2004 to 36.8% in 2018), while obesity in T2D was stable at ~60%. The crude prevalence of low eGFR was higher in T2D than in T1D in all years (eg, 30.6% vs 16.1% in 2018), but after adjusting for age differences, prevalence was higher in T1D than T2D…

INTRODUCTION: Concerns about future regret and treatment discontinuation have led to restricted access to gender-affirming medical treatment for transgender and gender-diverse (TGD) minors in some jurisdictions. However, these concerns are merely speculative because few studies have examined gender-affirming hormone continuation rates among TGD individuals. METHODS: We performed a secondary analysis of 2009 to 2018 medical and pharmacy records from the US Military Healthcare System. We identified TGD patients who were children and spouses of active-duty, retired, or deceased military members using International Classification of Diseases-9/10 codes. We assessed initiation and continuation of gender-affirming hormones using pharmacy records. Kaplan-Meier and Cox proportional hazard analyses estimated continuation rates. RESULTS: The study sample included 627 transmasculine and 325 transfeminine individuals with an average age of 19.2 ± 5.3 years. The 4-year gender-affirming hormone continuation rate was 70.2% (95% CI, 63.9-76.5). Transfeminine individuals had a higher continuation…

CONTEXT: Low-risk differentiated thyroid cancer (DTC) is overdiagnosed, but true incidence has increased as well. Owing to its excellent prognosis with low morbidity and mortality, balancing treatment risks with risks of disease progression can be challenging, leading to several areas of controversy. EVIDENCE ACQUISITION: This mini-review is an overview of controversies and difficult decisions around the management of all stages of low-risk DTC, from diagnosis through treatment and follow-up. In particular, overdiagnosis, active surveillance vs surgery, extent of surgery, radioactive iodine (RAI) treatment, thyrotropin suppression, and postoperative surveillance are discussed. EVIDENCE SYNTHESIS: Recommendations regarding the diagnosis of DTC, the extent of treatment for low-risk DTC patients, and the intensity of posttreatment follow-up have all changed substantially in the past decade. While overdiagnosis remains a problem, there has been a true increase in incidence as well. Treatment options range from active surveillance of small tumors to total thyroidectomy followed by RAI in…

CONTEXT: Time-restricted eating (TRE), which restricts food intake to a limited duration of the day, is a key regimen of intermittent fasting. OBJECTIVE: The aim of our study was to provide an up-to-date meta-analysis and systematic review to evaluate the efficacy of TRE on weight loss and other metabolic-related parameters in adults. METHODS: We searched PubMed, EMBASE, and the Cochrane Library for relevant studies published before February 26, 2022. Study duration of TRE was at least 4 weeks. Body weight and other metabolic-related continuous parameters were described as weighted mean difference (WMD) with 95% CI. RESULTS: Seventeen randomized controlled trials involving 899 participants were analyzed. The pooled meta-analysis has shown that TRE contributed to a significant decrease in body weight with a WMD of -1.60 kg (95% CI -2.27 to -0.93) and fat mass with WMD -1.48 kg (95% CI -1.59 to -1.38). Subgroup analysis showed that TRE could reduce body weight and fat mass especially in overweight participants with WMD -1.43 kg (95% CI -2.05 to -0.81) and -1.56 kg (95% CI -1.67 to…

CONTEXT: Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown. OBJECTIVE: This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH. METHODS: This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64. RESULTS: The LSMD in outcomes through 64 weeks on burosumab vs conventional…

CONTEXT: Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. OBJECTIVE: To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS. METHODS: This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage <2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety. RESULTS: Change in BMI SDS from baseline to…

CONTEXT: Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD). OBJECTIVE: To demonstrate efficacy and safety of somapacitan vs daily GH. METHODS: REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535). SETTING: Eighty-six sites across 20 countries. PATIENTS: 200 treatment-naïve patients were randomized and exposed. INTERVENTIONS: Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously. MAIN OUTCOME MEASURES: The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures. RESULTS: Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar…

CONTEXT: Serum neurofilament light chain (sNfL) levels are biomarkers of neuroaxonal injury in multiple neurological diseases. OBJECTIVE: Given the paucity of data on the distribution of sNfL levels in the general population, in the present study we identified predictors of sNfL levels in a community setting and investigated the association between diabetes and sNfL. METHODS: sNfL levels were measured in 2070 people aged 20 to 75 years from the general US population (275 with and 1795 without diabetes) that participated in the 2013-2014 cycle of the National Health and Nutrition Examination Survey. We evaluated the association between diabetes and sNfL levels after adjustment for age, sex, race-ethnicity, alcohol use, and kidney function using a multivariable linear regression model. Cognitive function was evaluated in a subset of participants aged 60 to 75 years using the Consortium to Establish a Registry for Alzheimer's Disease-Word Learning test, the Animal Fluency test, and the Digit Symbol Substitution test. RESULTS: The weighted prevalence of diabetes was 10.4% (95% CI,…

CONTEXT: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS). OBJECTIVE: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS. METHODS: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11). RESULTS: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P…

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, usually caused by small, benign, and slow-growing phosphaturic mesenchymal tumors. Clinically, TIO is characterized by renal phosphate leak, causing hypophosphatemia and osteomalacia. This review was performed to assess the clinical characteristics of TIO patients described worldwide so far. EVIDENCE ACQUISITION: On June 26, 2021, a systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library using the terms: "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia." There were no language restrictions. This review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. EVIDENCE RESULTS: Overall, 1725 TIO cases were collected. TIO was more frequent in adult men, who showed a higher incidence of fractures compared with TIO women. The TIO-causing neoplasms were identified in 1493 patients. The somatostatin receptor-based imaging modalities have the highest sensitivity for the identification of TIO-causing…

Recent data show that patients with a diagnosis of diabetes insipidus (DI) are coming to harm. Here we give the rationale for a name change to arginine vasopressin deficiency and resistance for central and nephrogenic DI, respectively.

CONTEXT: Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. EVIDENCE ACQUISITION: Pubmed literature search using combinations of "obesity," "breast cancer risk," "diet," "exercise," "weight gain," "weight loss," "adipose tissue inflammation," "crown-like structure," "immune markers," "metformin," "gliflozins," "SGLT-2i," "GLP1-RA," and related terms. EVIDENCE SYNTHESIS: Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor-positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis.…

CONTEXT: Individuals with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. Management of hyperglycemia in these patients is challenging. OBJECTIVE: To support development of the Endocrine Society Clinical Practice Guideline for management of hyperglycemia in adults hospitalized for noncritical illness or undergoing elective surgical procedures. METHODS: We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence. RESULTS: We included 94 studies reporting on 135 553 patients. Compared with capillary blood glucose, continuous glucose monitoring increased the number of patients identified with hypoglycemia and decreased mean daily blood glucose (BG) (very low certainty). Data on continuation of insulin pump therapy in hospitalized adults were sparse. In hospitalized patients receiving…

CONTEXT: Elevated serum remnant cholesterol independently predicts risks of cardiovascular diseases. However, the association between remnant cholesterol and metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. OBJECTIVE: This study aimed to explore the association of remnant cholesterol with MAFLD and its long-term mortality. METHODS: We extracted data from the NHANES III, 1988 to1994 and the linked mortality data until December 31, 2015. The association between remnant cholesterol and MAFLD was analyzed by multivariable logistic regression. Cox proportional hazards regression was performed to assess whether elevated remnant cholesterol increased all-cause and cause-specific mortalities in MAFLD patients. RESULTS: At baseline, 28.6% (1474/5156) of participants had MAFLD. In multivariable logistic regression, the fourth quartile of remnant cholesterol was associated with an increased risk of MAFLD compared with the first quartile (odds ratio [OR]: 1.714; 95% CI, 1.586-1.971; P < .001). In participants with normal levels of triglycerides, low-density…

CONTEXT: The male hypothalamic-pituitary-gonadal (HPG) axis is transiently active during the first months of life with surging serum concentrations of reproductive hormones. This period, termed minipuberty, appears to be essential for priming testicular function. Despite the central role for male reproductive function, longitudinal data on HPG axis activation in infancy is sparse. OBJECTIVE: To explore the dynamics of HPG hormone activity in healthy male infants, to assess the association of HPG axis activity and testicular volume, and to establish reference curves for serum levels of reproductive hormones. DESIGN: Prospective, longitudinal birth cohort (the COPENHAGEN Minipuberty Study, 2016-2018, 1-year follow-up). SETTING: Population-based. PATIENTS OR OTHER PARTICIPANTS: Healthy, male, term, singleton newborns were followed from birth on with repeated clinical examinations including blood sampling during a 1-year follow-up. A total of 128 boys contributed to this study, while 119 participated in the postnatal follow-up. MAIN OUTCOME MEASURES: Serum reproductive hormone…

CONTEXT: Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown. OBJECTIVE: Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD. DESIGN: Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR. SETTING: University ambulatory care practice. PARTICIPANTS: A total of 483 participants with T2D. INTERVENTION: Screening for steatosis and fibrosis with elastography. MAIN OUTCOME MEASURES: Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18). RESULTS: Clinically significant liver fibrosis (stage F ≥ 2 =…

Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat. This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines, and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized. Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (hypoxia-inducible factor 2 alpha [HIF2α] inhibitors, tumor vaccination together with checkpoint…

CONTEXT: Polycystic ovary syndrome (PCOS) is accompanied by chronic inflammation and metabolic disorders. Whether metabolic abnormalities affect inflammation in PCOS or not, the underlying mechanism remains to be clarified. OBJECTIVE: We aimed to investigate changes in fatty acids and their effects on inflammatory response in the follicular niche of PCOS patients. METHODS: This study recruited 50 PCOS patients and 50 age-matched controls for follicular fluids and ovarian mural granulosa cells collection. The human ovarian granulosa cell line KGN was used for evaluating the effect of oleic acid (OA) stimulation. The levels of follicular fatty acids were measured by liquid chromatography-tandem mass spectrometry. The concentrations of inflammatory cytokines were detected by electrochemiluminescence and enzyme-linked immunosorbent assays. The regulation of inflammation-related genes was confirmed by quantitative polymerase chain reaction and Western blotting after OA stimuli. RESULTS: Three saturated fatty acids and 8 unsaturated fatty acids were significantly elevated in follicular…

CONTEXT: Observational studies have suggested associations between adipokines and cardiovascular disease (CVD), but the roles of certain adipokines remain controversial, and these associations have not yet been ascertained causally. OBJECTIVE: To investigate whether circulating adipokines causally affect the risk of CVD using 2-sample Mendelian randomization (MR). METHODS: Independent genetic variants strongly associated with adiponectin, resistin, chemerin, and retinol binding protein 4 (RBP4) were selected from public genome-wide association studies. Summary-level statistics for CVD, including coronary artery disease (CAD), myocardial infarction, atrial fibrillation (AF), heart failure (HF), and stroke and its subtypes were collected. The inverse-variance weighted and Wald ratio methods were used for the MR estimates. The MR pleiotropy residual sum and outlier, weighted median, MR-Egger, leave-one-out analysis, MR Steiger, and colocalization analyses were used in the sensitivity analysis. RESULTS: Genetically predicted resistin levels were positively associated with AF risk (odds…

CONTEXT: Observational studies indicated obesity and glutamatergic dysfunction as potential risk factors of depression, and reported disturbance of glutamine metabolism in obese state. However, it remains unclear whether the interrelationships between obesity, glutamine, and depression are causal. OBJECTIVE: We conducted 2-sample bidirectional mendelian randomization (MR) analyses to explore the causalities between circulating glutamine levels, specific depressive symptoms, major depressive disorder (MDD), and body mass index (BMI). METHODS: Univariable MR, multivariable MR (MVMR), and linkage disequilibrium score regression (LDSR) analyses were performed. RESULTS: Genetic downregulation of glutamine was causally associated with MDD, anhedonia, tiredness, and depressed mood at the false discovery rate (FDR)-controlled significance level (estimate, -0.036 ∼ -0.013; P = .005 to P = .050). Elevated BMI was causally linked to lower glutamine level (estimate, -0.103; P = .037), as well as more severe depressed mood, tiredness, and anhedonia (estimate, 0.017 ∼ 0.050; P < .001 to P =…

Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal glands. Hirsutism, in other words, increased terminal hair growth in androgen-dependent areas of the body, is considered the most effective measure of hyperandrogenism in women. Other symptoms can be acne and androgenic alopecia or the development of virilization, including clitoromegaly. Postmenopausal hyperandrogenism may also be associated with metabolic disorders such as abdominal obesity, insulin resistance, and type 2 diabetes. Mild hyperandrogenic symptoms can be due to relative androgen excess associated with menopausal transition or polycystic ovary syndrome, which is likely the most common cause of postmenopausal hyperandrogenism. Virilizing symptoms, on the other hand, can be caused by ovarian hyperthecosis or an androgen-producing ovarian or adrenal tumor that could be malignant. Determination of serum testosterone, preferably by tandem mass spectrometry, is the first step in the endocrine evaluation, providing important…

CONTEXT: The plasma aldosterone concentration (PAC), renin, and aldosterone-to-renin ratio (ARR) are used to screen for primary aldosteronism (PA). Substantial intra-individual variability of PAC and ARR using plasma renin activity in the context of usual antihypertensive therapy has been described, but there is no data on ARR variability calculated using direct renin concentration (DRC). OBJECTIVE: To describe the intra-individual variability of PAC, DRC, and ARR in the absence of interfering medications in patients with and without PA. DESIGN: Retrospective cohort study. PATIENTS: Hypertensive patients referred for investigation of PA, with at least 2 ARR measurements while off interfering medications. SETTING: Endocrine hypertension service of a tertiary center, from May 2017 to July 2021. MAIN OUTCOME MEASURES: PAC, DRC, and ARR variability was calculated as coefficient of variation (CV) and percent difference (PD). RESULTS: Analysis of 223 patients (55% female, median age 52 years), including 162 with confirmed PA, demonstrated high variability with a sample CV of 22-25% in the…

CONTEXT: Calorie restriction plus dietary advice is suggested as a preventive strategy for individuals with obesity and prediabetes; however, optimal diet is still debatable. We aimed to compare the effects of Mediterranean diet (MD) and Chinese diets high or low in plants on body weight and glucose homeostasis among high-risk Chinese. SUBJECTS AND METHODS: In this parallel-arm randomized controlled trial, 253 Chinese adults aged 25 to 60 years with a body mass index ≥ 24.0 kg/m2 and fasting blood glucose ≥ 5.6 mmol/L were randomly assigned to 3 isocaloric-restricted diets: MD (n = 84), a traditional Jiangnan diet high in plants (TJD, n = 85), or a control diet low in plants (CD, n = 84). During the 6-month trial, a 5-weekday full-feeding regimen was followed, along with mobile app-based monitoring. Abdominal fat measurement (magnetic resonance imaging), oral glucose tolerance test (OGTT), and continuous glucose monitoring (CGM) were conducted at baseline and 3 and 6 months. RESULTS: With a 25% calorie restriction for 6 months, weight deduction was 5.72 kg (95% confidence interval,…

Critical illnesses are hallmarked by increased systemic cortisol availability, a vital part of the stress response. Acute stress may trigger a life-threatening adrenal crisis when a disease of the hypothalamic-pituitary-adrenal (HPA) axis is present and not adequately treated with stress doses of hydrocortisone. Stress doses of hydrocortisone are also used to reduce high vasopressor need in patients suffering from septic shock, in the absence of adrenal insufficiency. Research performed over the last 10 years focusing on the HPA axis during critical illness has led to the insight that neither of these conditions can be labeled "critical illness-induced corticosteroid insufficiency" or CIRCI. Instead, these data suggested using the term CIRCI for a condition that may develop in prolonged critically ill patients. Indeed, when patients remain dependent on vital organ support for weeks, they are at risk of acquiring central adrenal insufficiency. The sustained increase in systemic glucocorticoid availability, mainly brought about by suppressed circulating cortisol-binding proteins and…

CONTEXT: Thyroid eye disease (TED) is a complex autoimmune disease process. Orbital fibroblasts represent the central orbital immune target. Involvement of the TSH receptor (TSHR) in TED is not fully understood. IGF-I receptor (IGF-IR) is overexpressed in several cell types in TED, including fibrocytes and orbital fibroblasts. IGF-IR may form a physical and functional complex with TSHR. OBJECTIVE: Review literature relevant to autoantibody generation in TED and whether these induce orbital fibroblast responses directly through TSHR, IGF-IR, or both. EVIDENCE: IGF-IR has traditionally been considered a typical tyrosine kinase receptor in which tyrosine residues become phosphorylated following IGF-I binding. Evidence has emerged that IGF-IR possesses kinase-independent activities and can be considered a functional receptor tyrosine kinase/G-protein-coupled receptor hybrid, using the G-protein receptor kinase/β-arrestin system. Teprotumumab, a monoclonal IGF-IR antibody, effectively reduces TED disease activity, proptosis, and diplopia. In addition, the drug attenuates in vitro actions…

CONTEXT: Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that in patients with type 2 diabetes (T2D), SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists. OBJECTIVE: We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. METHODS: We pooled data from 15 081 T2D patients randomized to empagliflozin (n = 10 177) or placebo (n = 4904) from 20 phase I-IV trials, including the large cardiovascular outcome trial, EMPA-REG OUTCOME. Incident urinary tract stone events were captured using a predefined collection of MedRA terms. A sensitivity analysis using a narrower definition was also performed. Incidence rate ratios (IRR) and 95% CIs were calculated using the relative risk estimate, stratified by study. RESULTS: The median exposures to study drug were 543 days (placebo) and 549 days (empagliflozin); 183 patients experienced an incident urolithiasis during follow-up (placebo, 79; empagliflozin, 104),…

CONTEXT: The 2021 consensus report on the definition and interpretation of remission of type 2 diabetes (T2D) has been released. Although intermittent fasting diets (IF) are becoming very popular, no studies have investigated their benefit in diabetes remission. OBJECTIVE: The present study examined the effectiveness of IF in diabetes remission and potential remission durability. METHODS: Participants between ages 38 and 72 years with a duration of T2D of 1 to 11 years, a body mass index (BMI) of 19.1 to 30.4, 66.7% male, and antidiabetic agent use and/or insulin injection were randomly allocated at a ratio of 1:1 to the Chinese Medical Nutrition Therapy (CMNT) or control group. The primary outcome was diabetes remission, defined as a stable glycated hemoglobin A1c (HbA1c) level of less than 48 mmol/mol (< 6.5%) for at least 3 months after discontinuing all antidiabetic medications. The secondary outcomes included HbA1c level, fasting blood glucose level, blood pressure, weight, quality of life, and medication costs. We conducted a 12-month follow-up to assess the continuation of…

BACKGROUND AND AIMS: This review aims to summarize current and emerging therapies for treatment of thyroid eye disease (TED), in the light of novel understanding of pathogenetic mechanisms, leading to new treatment options and clinical trials. METHODS: We reviewed and analyzed peer-reviewed literature reporting recent translational studies and clinical trials in the treatment of TED. Searches were made at www.pubmed.gov with keywords "thyroid eye disease," "Graves' ophthalmopathy," "thyroid orbitopathy," and "Graves' orbitopathy." RESULTS: Surgery is reserved for rehabilitation in chronic TED or for emergent compressive optic neuropathy. Oral and intravenous glucocorticoid therapy has been used for decades with variable efficacy in acute TED, but results may be temporary and side effects significant. Nonsteroidal oral immunosuppressive agents offer modest benefit in TED. Several immunomodulatory monoclonal antibodies, including rituximab and tocilizumab, have shown efficacy for inactivating TED. Recently, teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) inhibitor, has…

CONTEXT: The significance of thyroid peroxidase (TPOAb) and thyroglobulin antibody (TgAb) in the pathogenesis of thyroid immune-related adverse events (irAEs) is unknown. OBJECTIVE: To characterize the association of anti-thyroid antibodies with the development of thyroid immune related adverse events. METHODS: A retrospective cohort study was conducted of patients with melanoma receiving immune checkpoint inhibitor (ICI) treatment. TPOAb, TgAb, and interleukin-6 (IL-6) were measured retrospectively using tumor-banked samples at baseline and at time of diagnosis of a thyroid irAE. In euthyroid patients (without thyroid irAEs) measures were repeated 30 to 60 days after ICI commencement, which was similar to the median time to onset of thyroid irAEs in other patients. RESULTS: A total of 122 patients were included-31 remained euthyroid, 47 developed subclinical thyrotoxicosis, 37 developed overt thyrotoxicosis, and 7 developed overt hypothyroidism without preceding thyrotoxicosis. Baseline elevation of TPOAb or TgAb was present in 19 (16%) and 28 (23%) patients, respectively. Positive…

CONTEXT: Homocysteine (Hcy), a known risk factor for cardiovascular disease, has been reported to be linked with thyroid dysfunction. However, the association of thyroid hormones sensitivity with Hcy levels remains unknown. OBJECTIVE: We aimed to investigate the relationship between thyroid hormone sensitivity and elevated Hcy levels in the euthyroid population. METHODS: A total of 8957 euthyroid adults were included in this study. Free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), Hcy levels, and other clinical parameters were measured. Hyperhomocysteinemia (HHcy) was defined as serum Hcy level > 15 μmol/L. Thyroid hormone sensitivity indices were calculated by thyroid feedback quantile-based index (TFQI), Chinese-referenced parametric TFQI (PTFQI), TSH index (TSHI) and thyrotropin thyroxine resistance index (TT4RI). RESULTS: Subjects with decreased sensitivity to thyroid hormones had higher Hcy levels (P for trend < 0.001). Logistic regression analysis revealed the higher quartiles of TFQI, PTFQI, TSHI, and TT4RI were significantly associated with elevated Hcy…

CONTEXT: Novel fasting interventions have gained scientific and public attention. Periodic fasting has emerged as a dietary modification promoting beneficial effects on metabolic syndrome. OBJECTIVE: Assess whether periodic fasting reduces albuminuria and activates nephropathy-driven pathways. DESIGN/PARTICIPANTS: Proof-of-concept study where individuals with type 2 diabetes (n = 40) and increased albumin-to-creatinine ratio (ACR) were randomly assigned to receive a monthly fasting-mimicking diet (FMD) or a Mediterranean diet for 6 months with 3-month follow-up. MAIN OUTCOMES MEASURES: Change in ACR was assessed by analysis of covariance adjusted for age, sex, weight loss, and baseline value. Prespecified subgroup analysis for patients with micro- vs macroalbuminuria at baseline was performed. Change in homeostatic model assessment for insulin resistance (HOMA-IR), circulating markers of dicarbonyl detoxification (methylglyoxal-derived hydroimidazolone 1, glyoxalase-1, and hydroxyacetone), DNA-damage/repair (phosphorylated histone H2AX), lipid oxidation (acylcarnitines), and…

Copeptin derives from the same precursor peptide preprovasopressin as arginine vasopressin (AVP). The secretion of both peptides is stimulated by similar physiological processes, such as osmotic stimulation, hypovolemia, or stress. AVP is difficult to measure due to complex preanalytical requirements and due to technical difficulties. In the last years, copeptin was found to be a stable, sensitive, and simple to measure surrogate marker of AVP release. Different immunoassays exist to measure copeptin. The 2 assays which have most often be used in clinical studies are the original sandwich immunoluminometric assay and its automated immunofluorescent successor. In addition, various enzyme-linked immunosorbent assay have been developed. With the availability of the copeptin assay, the differential diagnosis of diabetes insipidus was recently revisited. The goal for this article is therefore to first review the physiology of copeptin, and second to describe its use as marker for the differential diagnosis of vasopressin-dependent fluid disorders, mainly diabetes insipidus but also…

Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical examination, laboratory investigations, genetic analysis (especially in the absence of a guiding family history), and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of…