The 50 most-cited articles in The Journal of Clinical Endocrinology & Metabolism, 2024

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and…

The gut microbiota (GM), comprising trillions of microorganisms in the gastrointestinal tract, is a key player in the development of obesity and related metabolic disorders, such as type 2 diabetes (T2D), metabolic syndrome (MS), and cardiovascular diseases. This mini-review delves into the intricate roles and mechanisms of the GM in these conditions, offering insights into potential therapeutic strategies targeting the microbiota. The review elucidates the diversity and development of the human GM, highlighting its pivotal functions in host physiology, including nutrient absorption, immune regulation, and energy metabolism. Studies show that GM dysbiosis is linked to increased energy extraction, altered metabolic pathways, and inflammation, contributing to obesity, MS, and T2D. The interplay between dietary habits and GM composition is explored, underscoring the influence of diet on microbial diversity and metabolic functions. Additionally, the review addresses the impact of common medications and therapeutic interventions like fecal microbiota transplantation on GM composition.…

CONTEXT: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps to limit postprandial glycemic excursions and reduce chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, eg, retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration or bowel obstruction. DATA ACQUISITION: We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. DATA SYNTHESIS: Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs but rarely are associated with pulmonary aspiration. Well-justified recommendations for the periprocedural management of GLP-1RAs (eg, whether to withhold these medications and for how long) are compromised by limited evidence. Important aspects to be considered are (1) their long half-lives, (2) the…

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint…

OBJECTIVE: Thresholds for overweight and obesity are currently defined by body mass index (BMI), a poor surrogate marker of actual adiposity (percent body fat [%BF]). Practical modern technologies provide estimates of %BF but medical providers need outcome-based %BF thresholds to guide patients. This analysis determines %BF thresholds based on key obesity-related comorbidities, exhibited as metabolic syndrome (MetSyn). These limits were compared to existing BMI thresholds of overweight and obesity. DESIGN: Correlational analysis of data from cross sectional sampling of 16 918 adults (8734 men and 8184 women) from the US population, accessed by the National Health and Nutrition Examination Survey public use datasets. RESULTS: Individuals measured by BMI as overweight (BMI > 25 kg/m2) and with obesity (BMI > 30 kg/m2) included 5% and 35% of individuals with MetSyn, respectively. For men, there were no cases of MetSyn below 18%BF, %BF equivalence to "overweight" (ie, 5% of MetSyn individuals) occurred at 25%BF, and "obesity" (ie, 35% of MetSyn individuals) corresponded to 30%BF. For…

CONTEXT: Low vitamin D status is common and is associated with various common medical conditions. OBJECTIVE: To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. METHODS: We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. RESULTS: Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with…

CONTEXT: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. OBJECTIVE: To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure. DESIGN/PARTICIPANTS: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. SETTING: 4 international centers. INTERVENTIONS/MAIN OUTCOME MEASURES: The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. RESULTS: There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended…

CONTEXT: The effect of testosterone on depressive symptoms in men with hypogonadism remains incompletely understood. OBJECTIVE: We assessed the effects of testosterone-replacement therapy (TRT) in improving depressive symptoms in hypogonadal men with and without depressive symptoms enrolled in the TRAVERSE cardiovascular safety trial. METHODS: A randomized, placebo-controlled, double-blind study was conducted at 316 trial sites. Participants included men, aged 45 to 80 years, with 2 fasting testosterone levels less than 300 ng/dL, 1 or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated 3 subgroups of participants: (1) men with rigorously defined, late-life-onset, low-grade persistent depressive disorder (LG-PDD, previously "dysthymia"); (2) all men with significant depressive symptoms (Patient Health Questionnaire-9 Score >4); and (3) all randomly assigned men. Intervention included 1.62% transdermal testosterone or placebo gel. Outcome measures included the proportions of participants (1) meeting criteria for LG-PDD or (2) with…

CONTEXT: Romosozumab, a monoclonal sclerostin antibody, is a recently approved highly potent antiosteoporotic agent with osteoanabolic properties. Clinical use of romosozumab is hindered by the fear of adverse cardiovascular (CV) events raised following the pivotal ARCH trial. OBJECTIVE: This work aimed to assess real-world CV safety of romosozumab vs alternative osteoanabolic therapies used for treatment of severe osteoporosis. METHODS: Data were obtained from TriNetX, a global federated health research network including real-time electronic medical records from 113 health care organizations with 136 460 930 patients across 16 countries at time of analysis. Inclusion criteria were age 40 years or older, a diagnosis of osteoporosis and prescription of romosozumab or a parathyroid hormone (PTH) analogue (teriparatide/abaloparatide) during August 2019 through August 2022. Propensity-score-matched cohorts were created 1:1 using demographic variables, comorbidities, and medications. Kaplan-Meier analysis was used to estimate the probability of the outcomes. Outcome measures included…

CONTEXT: Over the past several decades, there have been indications of potential shifts in the diagnostic strategies, treatment, and monitoring of patients with Graves disease (GD). OBJECTIVE: To evaluate current practices in managing GD and compare them to previous surveys. METHODS: We used a global online survey of endocrinologists to assess shifts in the diagnosis, monitoring, and treatment in a typical patient with GD, as well as treatment variation in 5 different clinical scenarios. RESULTS: A total of 1252 respondents from 85 countries completed the survey. Methods used to diagnose an uncomplicated GD case have changed over the past decade, reflecting increased use of thyrotropin receptor antibody (TRAb) and reciprocal decreases in nuclear medicine studies. The preferred mode of therapy for uncomplicated GD was antithyroid drugs (ATDs) by 91.5% of respondents, radioactive iodine (RAI) therapy by 7%, and thyroidectomy by 1.5%. Compared with previous surveys, the use of RAI as a first-line choice decreased in all geographic regions. The United States had the sharpest decline in…

CONTEXT: Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. OBJECTIVE: Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. DESIGN: Phase 3 trial with a 26-week, double-blind, placebo-controlled period followed by a 156-week, open-label extension (OLE). SETTING: Twenty-one sites across North America and Europe. PARTICIPANTS: A total of 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. INTERVENTION(S): All OLE participants received TransCon PTH administered once daily. MAIN OUTCOME MEASURE(S): Multicomponent efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes and bone mineral density. Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events.…

CONTEXT: Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs). METHODS: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had IGF-I ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0× ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary score, and maintenance of mean 5-sample GH <1.0 ng/mL. RESULTS: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0× ULN (odds ratio, 126.53; 95% CI, 13.73->999.99; P < .0001). Paltusotine was…

A long-held precept is that vitamin D supplementation primarily, if not exclusively, benefits individuals with low circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline. However, the most appropriate 25(OH)D threshold to distinguish unacceptably low vs reliably adequate concentrations remains controversial. Such threshold proposals have largely been based on observational studies, which provide less robust evidence compared to randomized clinical trials (RCTs). Since the Endocrine Society's first vitamin D-related guideline was published in 2011, several large vitamin D-related RCTs have been published, and a newly commissioned guideline development panel (GDP) prioritized 4 clinical questions related to the benefits and harms of vitamin D supplementation in generally healthy individuals with 25(OH)D levels below a threshold. The GDP determined that available clinical trial evidence does not permit the establishment of 25(OH)D thresholds that specifically predict meaningful benefit with vitamin D supplementation. The panel noted important limitations in the available…

CONTEXT: A Body Shape Index (ABSI) has been reported to have associations with cardiovascular risk factors. However, there is no information on the association between ABSI and incidence of cardiovascular events. METHODS: We investigated the associations between ABSI and first major cardiovascular events (death from cardiovascular disease, nonfatal acute coronary syndrome, and nonfatal stroke) in 1857 subjects from the database of Flow-Mediated Dilation Japan registry and from Hiroshima University Vascular Function registry. RESULTS: The areas under the curves of ABSI to predict the first major cardiovascular events were superior to BMI (men: P = .032, women: P = .015) and waist circumference in women (men: P = .078, women: P = .002). The subjects were divided into 2 groups based on the cutoff value of ABSI for predicting first major cardiovascular events: a low ABSI group (<0.0822 in men and <0.0814 in women) and a high ABSI group (≥0.0822 in men and ≥0.0814 in women). During a median follow-up period of 41.6 months, 56 subjects died (23 from cardiovascular causes), 16 had nonfatal…

CONTEXT: Several long-acting growth hormone (LAGH) therapies have recently become available, but guidance on their usage in children with growth hormone (GH) deficiency is limited. METHODS: International experts in pediatric endocrinology were invited to join a consensus group based on their expertise in treating children with daily GH and LAGH. The group comprised 11 experts from 10 countries across the world. Online group meetings were held in February to March 2024 followed by a 1-day in-person meeting in May 2024 to finalize the consensus recommendations. A targeted literature search approach was used to identify and share evidence ahead of the meetings. Formulations considered were limited to those with international populations in phase III pivotal trials and regulatory approvals in multiple countries. EVIDENCE SYNTHESIS: Topics covered include patient selection and preference, dose adjustment, initiating and switching therapies, administration, adherence and missed doses, practical considerations, and knowledge gaps. LAGH formulations offer a potential advantage over daily GH…

BACKGROUND: After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. METHODS: We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. RESULTS: Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, P = 0.008). All…

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the…

CONTEXT: Continuous glucose monitor (CGM) companies are beginning to market these sensors to populations without diabetes, but the range of CGM values clinicians should expect to see for this population is unclear because there have been no large studies reporting these ranges. OBJECTIVE: This work aimed to report the physiological range of CGM time in range values observed across glycemic status, including individuals without diabetes, to serve as a reference for clinicians. METHODS: The Framingham Heart Study, a prospective cohort study, was conducted among community-dwelling adults with normoglycemia (n = 560), prediabetes (n = 463), and diabetes (n = 152). We conducted a cross-sectional investigation in participants who wore a Dexcom G6 Pro CGM (in blinded mode) for 7 or more complete days. Main outcome measures included CGM metrics including mean glucose and time spent in glucose ranges. RESULTS: Normoglycemic participants (mean age 58.5 years, 64.5% women, 93.3% non-Hispanic White) spent 87.0% time in the 70 to 140 mg/dL CGM range, and, on average, more than 15 minutes/day…

CONTEXT: Static measures of continuous glucose monitoring (CGM) data, such as time spent in specific glucose ranges (70-180 mg/dL or 70-140 mg/dL), do not fully capture the dynamic nature of blood glucose, particularly the subtle gradual deterioration of glycemic control over time in individuals with early-stage type 1 diabetes. OBJECTIVE: Develop a diabetes diagnostic tool based on 2 markers of CGM dynamics: CGM entropy rate (ER) and Poincaré plot (PP) ellipse area (S). METHODS: A total of 5754 daily CGM profiles from 843 individuals with type 1, type 2 diabetes, or healthy individuals with or without islet autoantibody status were used to compute 2 individual dynamic markers: ER (in bits per transition; BPT) of daily probability matrices describing CGM transitions between 8 glycemic states, and the area S (mg2/dL2) of individual CGM PP ellipses using standard PP descriptors. The Youden index was used to determine "optimal" cut-points for ER and S for health vs diabetes (case 1); type 1 vs type 2 (case 2); and low vs high type 1 immunological risk (case 3). The markers'…

CONTEXT: Hypoparathyroidism is a rare disorder characterized by a deficiency in PTH resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. Eneboparatide is an investigational peptide agonist of the PTH1 receptor for the treatment of chronic hypoparathyroidism (HP). OBJECTIVE: To evaluate the efficacy, safety, and tolerability of eneboparatide in HP patients. DESIGN: Open-label, phase 2 study. PARTICIPANTS: Twenty-eight patients (21 women, 7 men), mean age (range): 58 years (28-72), with HP were enrolled into 2 consecutive cohorts (C1, n = 12 and C2, n = 16). INTERVENTION: Following an optimization period, daily subcutaneous injections of eneboparatide were administered for 3 months at a 20 µg/day (C1) or 10 µg/day (C2) starting dose. Conventional therapy was progressively removed, and eneboparatide could be titrated up to 60 µg (C1) or 80 µg (C2). MAIN OUTCOMES: Proportion of patients achieving independence from conventional therapy, albumin-adjusted serum calcium (ADsCa), 24-h urine calcium (uCa), serum bone turnover markers (serum carboxy-terminal telopeptide of type I…

CONTEXT: Patients with rare familial chylomicronemia syndrome (FCS) and relatively common multifactorial chylomicronemia syndrome (MCS) both express severe hypertriglyceridemia, defined as plasma triglyceride concentration ≥10 mmol/L (≥885 mg/dL). Clinically there can be confusion between the 2 conditions. OBJECTIVE: To compare clinical and biochemical phenotypes in patients with genotypically characterized FCS and MCS. METHODS: We performed targeted sequencing of DNA from 193 patients with severe hypertriglyceridemia, classified them as having either FCS or MCS, and compared clinical and biochemical characteristics. RESULTS: Patients with FCS were significantly younger than patients with MCS (31.4 ± 16.7 vs 51.0 ± 11.3 years; P = .003), with earlier age at symptom onset (15.0 ± 15.8 vs 37.8 ± 8.8 years; P = .00066), lower body mass index (23.3 ± 3.1 vs 30.7 ± 5.0 kg/m2; P = .000016), and higher prevalence of pancreatitis events (81.8% vs 35.2%; P = .003). Furthermore, patients with FCS had a higher ratio of triglyceride to total cholesterol (ie, 4.18 ± 0.92 vs 1.08 ± 0.51; P <…

CONTEXT: The association between magnesium status and metabolic syndrome (MetS) remains unclear. OBJECTIVE: This study aimed to examine the relationship between kidney reabsorption-related magnesium depletion score (MDS) and MetS among US adults. METHODS: We analyzed data from 15 565 adults participating in the National Health and Nutrition Examination Survey (NHANES) 2003 to 2018. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report. The MDS is a scoring system developed to predict the status of magnesium deficiency that fully considers the pathophysiological factors influencing the kidneys' reabsorption capability. Weighted univariate and multivariable logistic regression were used to assess the association between MDS and MetS. Restricted cubic spline (RCS) analysis was conducted to characterize dose-response relationships. Stratified analyses by sociodemographic and lifestyle factors were also performed. RESULTS: In both univariate and multivariable analyses, higher MDS was significantly associated with increased odds of…

Inappropriate aldosterone excess plays a key role in the pathophysiology of various cardiovascular, endocrine, and renal diseases. Mineralocorticoid receptor antagonists (MRAs) such as spironolactone block of the harmful effects of aldosterone and are recommended treatment in these various conditions. However, the sexual adverse effects of spironolactone from its lack of specificity for the mineralocorticoid receptor and the risk of hyperkalemia in patients with decreased renal function, limit its use. While eplerenone is a more selective MRA, it is less potent than spironolactone. Newer nonsteroidal MRAs, though promising, are either unavailable globally or still under development. Moreover, aldosterone exerts both genomic and nongenomic effects, the latter not fully blocked by MRAs. Aldosterone synthase inhibitors (ASIs) have thus emerged as potential alternatives to MRAs, though the development of selective ASIs has been challenging. This is due to the close homology between the final step of aldosterone synthesis, mediated by CYP11B2 in the zona glomerulosa of the adrenal…

CONTEXT: Adrenarche marks the timepoint of human adrenal development when the cortex starts secreting androgens in increasing amounts, in healthy children at age 8-9 years, with premature adrenarche (PA) earlier. Because the molecular regulation and significance of adrenarche are unknown, this prepubertal event is characterized descriptively, and PA is a diagnosis by exclusion with unclear long-term consequences. EVIDENCE ACQUISITION: We searched the literature of the past 5 years, including original articles, reviews, and meta-analyses from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms adrenarche, pubarche, DHEAS, steroidogenesis, adrenal, and zona reticularis. EVIDENCE SYNTHESIS: Numerous studies addressed different topics of adrenarche and PA. Although basic studies on human adrenal development, zonation, and zona reticularis function enhanced our knowledge, the exact mechanism leading to adrenarche remains unsolved. Many regulators seem involved. A promising marker of adrenarche (11-ketotestosterone) was found in the 11-oxy androgen pathway. By…

CONTEXT: Surrogate measures of childhood and adolescent obesity have impaired the understanding of the relationship of body composition with insulin resistance in the young population. OBJECTIVE: We aim to examine the longitudinal associations of directly measured total fat mass, trunk fat mass, and lean mass with the risk of hyperglycemia, hyperinsulinemia, and insulin resistance from ages 15 to 24 years, the mediation path through which lipids and inflammation influence insulin resistance, and whether increased fat mass temporally precede insulin resistance. METHODS: We studied 3160 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, who had complete dual-energy x-ray absorptiometry measure and fasting blood samples at age 15 years and repeated measures at ages 17- and 24-years clinic visit. Fasting glucose greater than 6.1 mmol/L, insulin greater than 11.78 mU/L, and homeostatic model assessment for insulin resistance (HOMA-IR) greater than or equal to the 75th percentile were categorized as hyperglycemia, hyperinsulinemia, and high…

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common female cardiometabolic-reproductive disorder. It is unclear whether the global obesity epidemic is impacting the high PCOS prevalence. OBJECTIVE: To determine the association between the prevalence of PCOS and obesity. MATERIALS AND METHODS: A systematic review was conducted to identify population studies on PCOS prevalence globally through July 2023. Linear regression and random-effect models were applied to examine the association of mean body mass index (BMI) or obesity prevalence with the prevalence of PCOS diagnosed by 1990 National Institutes of Health (NIH), 2003 Rotterdam (Rotterdam), and 2006 Androgen Excess-PCOS (AE-PCOS) criteria. Subgroup analyses were also conducted for recruitment methods and study quality. RESULTS: Fifty-eight studies with 85 956 adults from 24 countries were included. Considering all available data, a borderline association was observed between PCOS and obesity prevalence when using the AE-PCOS but not the NIH or Rotterdam criteria. Alternatively, subgroup analysis of studies with better…

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with disordered eating/eating disorders, but prior meta-analyses are limited by small numbers. OBJECTIVE: To inform the 2023 International PCOS Guideline, we performed a systematic review and meta-analysis evaluating the prevalence of disordered eating/eating disorders among women with and without PCOS. METHODS: Ovid MEDLINE, EMBASE, PsycInfo, and All EMB were searched from inception through February 1, 2024, for studies that compared prevalences of eating disordered/disordered eating in adolescent or adult women. Random effects meta-analyses were used to estimate the pooled odds ratios (OR) or standardized mean differences (SMD) of outcomes in women with PCOS compared to controls. Methodological quality was assessed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system, and included studies were assessed for risk of bias. RESULTS: Of 1352 articles identified, 20 were included, with a total of 28 922 women with PCOS and 258 619 controls. Individuals with PCOS had higher odds of any eating…

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR)…

CONTEXT: Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS). OBJECTIVE: This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes. METHODS: Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of…

CONTEXT: Diabetes mellitus is associated with morbid complications such as diabetic foot ulcers (DFUs) that may lead to amputations or mortality if not managed adequately. OBJECTIVE: New adjunctive interventions to treat diabetic wounds include topical biologics and growth factors. This study aims to evaluate their efficacy in improving wound-healing outcomes and safety. METHODS: Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2022. Three independent researchers selected the studies. Randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to other biologics or standard of care (SOC) were included. This review followed PRISMA guidelines. Risk of bias analysis was performed using the Jadad scale. Network meta-analysis was performed. Treatments were grouped into common nodes based on the type of biologic agent. Primary outcomes of interest were healing rate and time to wound closure. Secondary outcomes included wound infection, serious adverse events (AEs), and…

CONTEXT: Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. OBJECTIVE: We aimed to investigate the effects of denosumab on bone mineral density (BMD), spinal morphometry, and safety in children with OI compared with zoledronic acid. METHODS: In this prospective study, 84 children or adolescents with OI were randomized to receive denosumab subcutaneous injection every 6 months or zoledronic acid intravenous infusion once. Changes of BMD and its Z-score, vertebral shape, serum levels of calcium and bone turnover biomarkers were assessed during the 1-year treatment. RESULTS: After 12 months of treatment, BMD at the lumbar spine, femoral neck, and total hip significantly increased by 29.3%, 27.8%, and 30.2% in the denosumab group, and by 32.2%, 47.1%, and 41.1% in the zoledronic acid group (all P < .001 vs baseline). Vertebral height and projection area significantly increased after denosumab and zoledronic acid treatment. Rebound hypercalcemia was found to be a common and serious side effect of…

CONTEXT: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare genetic disorder. Incidence and prevalence are not well-studied. Epidemiological research is complicated by the rarity of FD/MAS, absence of registries, heterogeneous presentation, and possibly asymptomatic phenotype. FD/MAS may present with FGF23-mediated hypophosphatemia, of which the epidemiology is also unclear. OBJECTIVE: Evaluate incidence and prevalence of FD/MAS and FD/MAS-related hypophosphatemia. METHODS: This cohort study based on the nationwide Danish National Patient Registry from 1995-2018, included patients identified by ICD-10 codes M85.0 (monostotic FD [MFD]) and Q78.1 (polyostotic FD [PFD]/MAS). Incidence rates and prevalence were calculated and stratified by sex, age, calendar period, and diagnosis code. Cases were screened for FD-associated hypophosphatemia by diagnosis code E.83 (disorder of mineral metabolism) and dispatched vitamin D analogues. RESULTS: A total of 408 patients were identified, 269 with MFD (66%), 139 with PFD/MAS (34%), comparable between sexes. Incidence of FD/MAS…

Sixty years after the landmark publication by O'Sullivan and Mahan, the current paper seeks to review and place into context the importance of gestational diabetes (GDM) both as a marker of increased risk of adverse maternal and fetal pregnancy outcomes and as an indicator of future maternal and infant health risks. We review the evolution of GDM as a diagnosis, the ongoing debate regarding diagnostic approaches, the underlying pathophysiology, and the epidemiology and the importance of GDM in the context of the global epidemics of diabetes and obesity. Focusing on clinical management, we review lifestyle-based therapy and pharmacotherapy for GDM, consider obstetric management, and outline the short-term and lifelong health risks posed by a GDM diagnosis.

CONTEXT: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE: This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. METHODS: A 28-week double-blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15 mg, semaglutide 1 mg, and placebo. Main outcome measures included glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < .01). Incremental glucose AUC did not differ significantly…

CONTEXT: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and β-cell function to a greater extent than comparators. OBJECTIVE: Explore changes in biomarkers of β-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. DESIGN: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). SETTING: Post hoc analysis of 128 sites in 8 countries. PARTICIPANTS: A total of 1879 participants with type 2 diabetes. INTERVENTIONS: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. MAIN OUTCOMES MEASURES: Change in homeostatic model assessment indices for pancreatic β-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin. RESULTS: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg…

CONTEXT: Medical treatment of acromegaly is currently performed through a trial-and-error approach using first-generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. OBJECTIVE: Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS: This was a prospective trial (21 university hospitals) comparing the effectiveness and time-to-control of 2 treatment protocols during 12 months: (A) a personalized protocol in which the first options were fgSRLs as monotherapy or in combination with pegvisomant, or pegvisomant as monotherapy depending on the short acute octreotide test (sAOT) results, tumor T2 magnetic resonance (MRI) signal or immunostaining for E-cadherin; and (B) a control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45…

CONTEXT: Prolonged bisphosphonate (BP) treatment for osteoporosis prevents hip and other fractures but causes atypical femoral fractures (AFF). OBJECTIVE: To establish the relationship between patterns of BP use and the risk of AFF and hip fractures. Other potential risk factors for AFF were also examined. METHODS: This population-based case-cohort study utilized data from the Danish National Healthcare system, including longitudinal records of medication use, healthcare utilization, and x-ray images. Among all 1.9 million Danish adults ≥50, those with subtrochanteric or femoral shaft fractures between 2010 and 2015 (n = 4973) were identified and compared to a random sample (n = 37 021). Bisphosphonate use was collected from 1995-2015. Fracture radiographs (n = 4769) were reviewed by blinded study radiologists to identify AFFs (n = 189) using established criteria. Traditional hip fractures in the random sample (n = 691) were identified by ICD-10. RESULTS: Compared to <1 year of BP use, 5 to 7 years of use was associated with a 7-fold increase in AFF (adjusted HR = 7.29 [CI: 3.07,…

Glucagon-like peptide 1 receptor agonists (GLP1RAs) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the US Food and Drug Administration recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RAs and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data,…

CONTEXT: While some studies have suggested an association between metabolic syndrome and kidney stones, the quality and level of evidence in these studies vary. OBJECTIVE: Whether some individual characteristics and clustering of metabolic syndrome traits increase the risk of kidney stones has not been examined in a large-scale prospective cohort. MATERIALS: We conducted a retrospective analysis of data from a prospective cohort of 487 860 UK Biobank participants who were free from kidney stones at baseline. The presence of metabolic syndrome was based on 5 criteria: abdominal obesity, high triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, high blood pressure (HBP), and type 2 diabetes mellitus (T2DM). Cox proportional hazards regression models were used to evaluate the association between metabolic syndrome and risk of kidney stones. RESULTS: After an average follow-up period of 12.6 years, a total of 5213 of the 487 860 participants included in the UK Biobank study developed kidney stones. The partial traits of metabolic syndrome, including waist…

CONTEXT: Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. OBJECTIVE: To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. DESIGN: Retrospective study. SETTING: University hospitals. PATIENTS: Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation. RESULTS: Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92-.99] in the primary study and .99 [95% CI, .98-1.00] in the validation cohort). The addition of clinical,…

PURPOSE: Recently, a novel index [the triglyceride-glucose (TyG) index]) was considered a surrogate marker of insulin resistance (IR); in addition, it was estimated to be a better expression of IR than widely used tools. Few and heterogeneous data are available on the relationship between this index and mortality risk in non-Asian populations. Therefore, we estimated the predictive role of baseline TyG on the incidence of all-cause and cardiovascular (CV) mortality in a large sample of the general population. Moreover, in consideration of the well-recognized role of serum uric acid (SUA) on CV risk and the close correlation between SUA and IR, we also evaluated the combined effect of TyG and SUA on mortality risk. METHODS: The analysis included 16 649 participants from the URRAH cohort. The risk of all-cause and CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. RESULTS: During a median follow-up of 144 months, 2569 deaths occurred. We stratified the sample by the optimal cut-off point for all-cause (4.62) and CV mortality (4.53). In the…

CONTEXT: Few data exist about the clinical course of acromegaly, surgical and medical outcomes in patients with GH- and prolactin cosecreting pituitary adenomas (GH&PRL-PAs). Nevertheless, some series described a more aggressive clinic-radiological behavior than in growth hormone-secreting pituitary adenomas (GH-PAs). OBJECTIVE: This work aims to evaluate differences in clinical presentation and in surgical outcomes between GH-PAs and GH&PRL-PAs. METHODS: A multicenter retrospective study was conducted of 604 patients with acromegaly who underwent pituitary surgery. Patients were classified into 2 groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal (ULN) and IHC for GH and PRL was positive or PRL levels were greater than 100 ng/dL and PRL IHC was not available (n = 130) and b) GH-PA patients who did not meet the previously mentioned criteria (n = 474). RESULTS: GH&PRL-PAs represented 21.5% (n = 130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs…

CONTEXT: Type 2 diabetes (T2D) is the major contributor to chronic kidney disease and end-stage kidney disease (ESKD). The influence of trimethylamine N-oxide (TMAO) on kidney outcomes in T2D remains unclear. OBJECTIVE: To examine the association between fasting serum TMAO levels and adverse kidney outcomes in patients with T2D. METHODS: Between October 2016 and June 2020, patients with T2D were recruited and monitored every 3 months until December 2021. Serum TMAO levels were assessed using liquid chromatography-mass spectrometry. The primary kidney outcomes were doubling of serum creatinine levels or progression to ESKD necessitating dialysis; the secondary kidney outcome was a rapid 30% decline in estimated glomerular filtration rate within 2 years. All-cause mortality was also evaluated. RESULTS: Among the 440 enrolled patients with T2D, those in the highest serum TMAO tertile (≥0.88 μM) were older, had a longer diabetes duration, elevated blood urea nitrogen, and lower estimated glomerular filtration rate. Over a median follow-up period of 4 years, 26 patients (5.9%) had a…

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective therapy that improves lung disease in people with cystic fibrosis (pwCF), but its effect on glucose tolerance and insulin secretion is unclear. METHODS: PROMISE is a multicenter prospective, observational study of ETI in pwCF ≥12 years and at least one F508del allele. The PROMISE Endocrine substudy (PROMISE-ENDO) enrolled participants at 10 CF Centers where hemoglobin A1c (HbA1c) was collected and 3-hour oral glucose tolerance tests (OGTT) conducted to examine glucose tolerance, glucose excursions, and insulin secretory rates (deconvolution of C-peptide) and sensitivity (oral minimal model) prior to ETI and 12 to 18 months and 24-30 months following ETI initiation. Longitudinal mixed effects models were used to test within-subject ETI effects. RESULTS: At baseline, 79 participants completed OGTTs (39 [49%] male, median [IQR] age 19.6 [14.7, 27.3] years, BMI z-score 0.12 [-0.51, 0.65]). At 12-18 months n = 68 and at 24-30 months n = 58 completed OGTTs. At 24-30 months, fasting glucose (mg/dL) decreased (94 [92,…

CONTEXT: Acromegaly, characterized by excessive GH and insulin-like growth factor-1 (IGF-1), impacts quality of life (QoL) and mortality. Standard of care (SoC; octreotide long-acting repeatable or lanreotide autogel) treatment typically requires healthcare provider administration. CAM2029, a novel subcutaneous octreotide depot with increased bioavailability using FluidCrystal technology, enables self-administration and room-temperature storage. OBJECTIVE: Assess superiority of CAM2029 vs placebo for biochemical control in patients with controlled acromegaly. DESIGN: 24-week, multinational, randomized, double-blind, phase 3 trial (NCT04076462). SETTING: 45 sites; 10 countries. PATIENTS: 72 patients on SoC with biochemical control at screening [IGF-1 ≤upper limit of normal (ULN); mean GH <2.5 μg/L]. INTERVENTIONS: Patients were randomized 2:1 to once-monthly CAM2029 (n = 48) or placebo (n = 24). MAIN OUTCOME MEASURES: The primary endpoint was proportion of patients with IGF-1 ≤ULN (week 22/24 mean), with dose-reduced patients classified as nonresponders; first key secondary endpoint…

BACKGROUND: Growth differentiation factor 15 (GDF15), a divergent member of the TGF-β superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer. METHODS: MBL949 was evaluated in multiple nonclinical species, and then in humans, in 2 randomized and placebo-controlled clinical trials. In the phase 1, first-in-human, single ascending dose trial, MBL949 or placebo was injected subcutaneously to overweight and obese healthy volunteers (n = 65) at doses ranging from 0.03 to 20 mg. In phase 2, MBL949 or placebo was administered subcutaneously every other week for a total of 8 doses to obese participants (n = 126) in 5 different dose regimens predicted to be efficacious based on data from the phase 1 trial. RESULTS: In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight in mice, rats,…

CONTEXT: Hyperglycemia in hospital inpatients without pre-existing diabetes is associated with increased mortality. However, the independent contribution of hyperglycemia to health care-associated infection (HAI), acute kidney injury (AKI), and stroke is unclear. OBJECTIVE: To investigate the relationship between hyperglycemia and adverse clinical outcomes in hospital for patients with and without diabetes. METHODS: Diabetes IN-hospital: Glucose and Outcomes (DINGO) was a 26-week (October 2019-March 2020) prospective cohort study. Clinical and glucose data were collected up to the 14th day of admission. Primary stratification was by hyperglycemia, defined as ≥2 random capillary blood glucose (BG) measurements ≥11.1 mmol/L (≥200 mg/dL). Propensity weighting for 9 clinical characteristics was performed to allow interrogation of causality. To maintain the positivity assumption, patients with HbA1c >12.0% were excluded and prehospital treatment not adjusted for. The setting was the Royal Melbourne Hospital, a quaternary referral hospital in Melbourne, Australia. Admissions with at least…

CONTEXT: The relationship between the genomic profile and prognosis of advanced thyroid carcinoma requiring drug therapy has not been reported. OBJECTIVE: To evaluate the treatment period and overall survival time for each genetic alteration in advanced thyroid carcinoma that requires drug therapy. METHODS: We conducted a retrospective observational study using a national database in Japan, which included 552 cases of thyroid carcinoma out of 53 543 patients in the database. RESULTS: The database included anaplastic thyroid carcinoma (23.6%), poorly differentiated thyroid carcinoma (10.0%), and differentiated thyroid carcinoma (66.4%). The most common genetic abnormalities were TERT promoter (66.3%), BRAF (56.7%), and TP53 (32.2%). The typical driver genes were BRAF V600E (55.0%), RAS (18.5%), RET fusion (4.7%), NTRK fusion (1.6%), and ALK fusion (0.4%). The most common regimen was lenvatinib, and the time to treatment failure was not different despite the presence of BRAF or RAS mutations. In differentiated thyroid carcinoma and poorly differentiated thyroid carcinoma, TP53…

OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close…

CONTEXT: Abnormal brain glucose metabolism may cause cognitive disease in type 2 diabetes, yet the relation between insulin resistance and brain glucose metabolism has not been systematically described. OBJECTIVE: We evaluated the impact of metabolic condition (fasting vs insulin stimulation, eg, from hyperinsulinemic clamp) on the association between insulin resistance of different etiologies and brain glucose metabolism. DATA SOURCES: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception until February 2022. STUDY SELECTION: Of 656 unique records, we deemed 31 eligible. Criteria were studies assessing brain glucose metabolism (uptake or metabolic rate) by 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography in individuals characterized by measures of or clinical proxies for insulin resistance (eg, type 2 diabetes and obesity). DATA EXTRACTION: Two independent investigators extracted data and assessed study quality. DATA SYNTHESIS: We applied random-effects models to pool Hedge's g standardized mean differences. Insulin resistance…