Fellinger, Paul; Beiglböck, Hannes; Semmler, Georg; Pfleger, Lorenz; Smajis, Sabina; Baumgartner, Clemens; Gajdosik, Martin; Marculescu, Rodrig; Vila, Greisa; Winhofer, Yvonne; Scherer, Thomas; Trauner, Michael; Kautzky-Willer, Alexandra; Krssak, Martin; Krebs, Michael; Wolf, Peter
ContextNon-alcoholic fatty liver disease (NAFLD) is a leading causes of liver-related morbidity and mortality. While data on acromegaly, a state of chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess, suggest an inverse relationship with intrahepatic lipid (IHL) content, less is known about the impact of the GH/IGF-I axis on IHL, lipid composition, and phosphor metabolites in individuals without disorders of GH secretion.ObjectiveThe aim was to investigate the relation between activity of the GH/IGF-I axis and IHL content and phosphor metabolism.MethodsWe performed a cross-sectional study in 59 otherwise metabolically healthy individuals (30 females), of which 16 met the criteria of NAFLD with IHL of ≥5.6%. The GH/IGF-I axis was evaluated in a fasting state and during an oral glucose tolerance test (OGTT). Insulin sensitivity was estimated by validated indices. IHL, lipid composition (unsaturation index), and phosphate metabolites were analyzed by using 1H/31P magnetic resonance spectroscopy.ResultsIn the overall cohort (40.6 ± 15 years; body mass index: 24.5 ± 3 kg/m2; IGF-I: 68.0 ± 17% upper limit of normal), fasting GH (R = −0.31; P = .02), GH during oral glucose tolerance test (R = −0.51; P < .01), and IGF-I (R = −0.28; P = .03) inversely correlated with IHL. GH levels during OGTT were significantly lower in NAFLD than in controls (47.7 [22; 143] ng/mL/min vs 16.8 [7; 32] ng/mL/min; P = .003). GH/IGF-I axis activity correlated with lipid composition and with phosphor metabolites. In multiple regression analysis, the GH/IGF-I axis activity was a strong predictor for IHL and lipid composition independent from insulin sensitivity.ConclusionGH/IGF-I axis activity impacts hepatic lipid and phosphate metabolism in individuals without disorders in GH secretion. Lower GH axis activity is associated with higher IHL and an unfavorable lipid composition, probably mediated by changes in hepatic energy metabolism.
ContextAlthough iodine-induced hyperthyroidism is a potential consequence of iodinated radiologic contrast administration, its association with long-term cardiovascular outcomes has not been previously studied.ObjectiveTo investigate the relationships between hyperthyroidism observed after iodine contrast administration and incident atrial fibrillation/flutter.MethodsRetrospective cohort study of the U.S. Veterans Health Administration (1998-2021) of patients age ≥18 years with a normal baseline serum thyrotropin (TSH) concentration, subsequent TSH <1 year, and receipt of iodine contrast <60 days before the subsequent TSH. Cox proportional hazards regression was employed to ascertain the adjusted hazard ratio (HR) with 95% CI of incident atrial fibrillation/flutter following iodine-induced hyperthyroidism, compared with iodine-induced euthyroidism.ResultsIodine-induced hyperthyroidism was observed in 2500 (5.6%) of 44 607 Veterans (mean ± SD age, 60.9 ± 14.1 years; 88% men) and atrial fibrillation/flutter in 10.4% over a median follow-up of 3.7 years (interquartile range 1.9-7.4). Adjusted for sociodemographic and cardiovascular risk factors, iodine-induced hyperthyroidism was associated with an increased risk of atrial fibrillation/flutter compared with those who remained euthyroid after iodine exposure (adjusted HR 1.19, 95% CI 1.06-1.33). Females were at greater risk for incident atrial fibrillation/flutter than males (females, HR 1.81, 95% CI 1.12-2.92; males, HR 1.15, 95% CI 1.03-1.30; P for interaction = .04).ConclusionHyperthyroidism following a high iodine load was associated with an increased risk of incident atrial fibrillation/flutter, particularly among females. The observed sex-based differences should be confirmed in a more sex-diverse study sample, and the cost–benefit analysis of long-term monitoring for cardiac arrhythmias following iodine-induced hyperthyroidism should be evaluated.
ContextA healthy sleep pattern has been related to a lower risk of type 2 diabetes mellitus (T2DM).ObjectiveWe aimed to identify the metabolomic signature for the healthy sleep pattern and assess its potential causality with T2DM.MethodsThis study included 78 659 participants with complete phenotypic data (sleep information and metabolomic measurements) from the UK Biobank study. Elastic net regularized regression was applied to calculate a metabolomic signature reflecting overall sleep patterns. We also performed genome-wide association analysis of the metabolomic signature and one-sample mendelian randomization (MR) with T2DM risk.ResultsDuring a median of 8.8 years of follow-up, we documented 1489 incident T2DM cases. Compared with individuals who had an unhealthy sleep pattern, those with a healthy sleep pattern had a 49% lower risk of T2DM (multivariable-adjusted hazard ratio [HR], 0.51; 95% CI, 0.40-0.63). We further constructed a metabolomic signature using elastic net regularized regressions that comprised 153 metabolites, and robustly correlated with sleep pattern (r = 0.19; P = 3×10−325). In multivariable Cox regressions, the metabolomic signature showed a statistically significant inverse association with T2DM risk (HR per SD increment in the signature, 0.56; 95% CI, 0.52-0.60). Additionally, MR analyses indicated a significant causal relation between the genetically predicted metabolomic signature and incident T2DM (P for trend < .001).ConclusionIn this large prospective study, we identified a metabolomic signature for the healthy sleep pattern, and such a signature showed a potential causality with T2DM risk independent of traditional risk factors.
ContextThe phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood.ObjectiveThis study investigates potential crosstalk between FGF23 and glucose homeostasis.MethodsFirst, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI > 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI.ResultsAfter glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β = .13 [.03-.23]; P = .01), insulin (β = .10 [.03-.17]; P < .001), and proinsulin (β = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI.ConclusionGlucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.
AimTo investigate the association of early peripheral sensory dysfunction (EPSD) identified through quantitative sensory testing (QST) with factors related to a dysmetabolic status in individuals with and without type 2 diabetes (T2DM) without peripheral neuropathy (PN), and the impact of those factors on PN development.MethodsA total of 225 individuals (117 and 108 without and with T2DM, respectively) without PN based on clinical and electrophysiological criteria were analyzed. Comparative analysis was conducted between those identified as “healthy” and those with EPSD based on a standardized QST protocol. A total of 196 were followed-up over a mean of 2.64 years for PN occurrence.ResultsAmong those without T2DM, apart from male sex, height, and higher fat and lower lean mass, only higher insulin resistance (IR; homeostatic model assessment for IR: odds ratio [OR], 1.70; P = .009; McAuley index OR, 0.62, P = .008), was independently associated with EPSD. In T2DM, metabolic syndrome (OR, 18.32; P < .001) and skin advanced glycation end-products (AGEs; OR, 5.66; P = .003) were independent predictors of EPSD. In longitudinal analysis, T2DM (hazard ratio [HR], 3.32 vs no diabetes mellitus; P < .001), EPSD (adjusted HR, 1.88 vs healthy; P = .049 adjusted for diabetes mellitus and sex), higher IR and AGEs predicted PN development. Among the 3 EPSD-associated sensory phenotypes, “sensory loss” was most strongly associated with PN development (adjusted HR, 4.35; P = .011).ConclusionWe demonstrate for the first time the utility of a standardized QST-based approach in identifying early sensory deficits in individuals with and without T2DM. These are associated with a dysmetabolic status signified by IR markers, metabolic syndrome, and higher AGEs, which in turn are shown to influence PN development.
ContextWe have recently shown that the secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is upregulated in human obesity and that overexpression of scEMC10 promotes, whereas antibody neutralization of circulating scEMC10 prevents diet-induced obesity in mice.ObjectiveTo explore associations of serum scEMC10 with body mass index (BMI), resting metabolism rate (RMR), and age in humans.DesignA cross-sectional study.Setting and PatientsA total of 833 participants from a Chinese physical examination cohort and 191 participants from the Leipzig Obesity Biobank cohort.Main Outcome MeasuresSerum scEMC10 concentrations are measured using chemiluminescent immunoassay. RMR is calculated based on measurements from indirect calorimetry with an open-circuit ventilated-hood system.ResultsIn the Chinese physical examination cohort, a J-shaped nonlinear correlation between BMI and serum scEMC10 was identified in participants where underweight, overweight, and obese people all presented higher serum scEMC10 levels than normal weight people. Participants younger than age 30 years old exhibited significantly higher serum scEMC10 levels than those older than 50 years of age. In addition, participants aged 30 to 40 years also had significantly higher serum scEMC10 levels than those aged 50 to 60 years. In the Leipzig Obesity Biobank cohort, we observed a significantly negative correlation between serum scEMC10 and resting energy expenditure after adjusting for BMI. Participants in the highest quartile of serum scEMC10 levels had significantly lower RMR than those in the first quartile. RMR had an independently inverse association with serum scEMC10.ConclusionsSerum scEMC10 levels are negatively associated with age and RMR in humans.
ContextN3 sleep (i.e., slow-wave sleep), a marker of deep restorative sleep, is implicated in hormonal and blood pressure regulation and may impact cardiometabolic health.ObjectiveWe conducted cross-sectional and prospective analyses to test whether a higher proportion and longer duration of N3 sleep are associated with reduced type 2 diabetes risk.MethodsA subsample of participants from the Multi-Ethnic Study of Atherosclerosis completed 1-night polysomnography at Exam 5 (2010-2013) and were prospectively followed until Exam 6 (2016-2018). We used modified Poisson regression to examine the cross-sectional associations of N3 proportion and duration with prevalent diabetes and Cox proportional hazards models to estimate risk of diabetes according to N3 measures.ResultsIn cross-sectional analyses (n = 2026, mean age: 69 years), diabetes prevalence was 28% (n = 572). Compared with the first quartile (Q1) of the N3 proportion (<2.0%), participants in Q4 (≥15.4%) were 29% (95% CI 0.58, 0.87) less likely to have prevalent diabetes (P trend = .0016). The association attenuated after adjustment for demographics, lifestyles, and sleep-related factors (P trend = .3322). In prospective analyses of 1251 participants and 129 incident cases over 6346 person-years of follow-up, a curvilinear relationship was observed between N3 proportion and incident diabetes risk. In the fully adjusted model, the hazard ratio (95% CI) of developing diabetes vs Q1 was 0.47 (0.26, 0.87) for Q2, 0.34 (0.15, 0.77) for Q3, and 0.32 (0.10, 0.97) for Q4 (P nonlinearity = .0213). The results were similar for N3 duration.ConclusionHigher N3 proportion and longer N3 duration were prospectively associated with lower type 2 diabetes risk in a nonlinear fashion among older American adults.
ContextHyponatremia is associated with increased risk for osteoporosis. Preclinical studies in untreated hyponatremia suggest osteoclast upregulation, whereas a clinical study showed improved osteoblast function after hyponatremia normalization in hospitalized patients with syndrome of inappropriate antidiuresis (SIAD).ObjectiveThis work aimed to investigate the effect of an increase in sodium on bone turnover, that is, the ratio of the osteoblast marker procollagen type 1 N-terminal propeptide (P1NP) to the osteoclast marker cross-linked C-terminal telopeptide of type 1 collagen (CTX), in outpatients with chronic SIAD.MethodsA predefined secondary analysis was conducted of the 2-month double-blind, crossover, placebo-controlled SANDx Trial (NCT03202667) performed from December 2017 to August 2021. Participants included 11 outpatients with chronic SIAD: 6 women, median age 73 years, who received a 4-week treatment with 25-mg empagliflozin or placebo. Main outcome measures included the relationship between the change in bone formation index (BFI), defined as P1NP/CTX, and the change in plasma sodium levels.ResultsChanges in sodium were positively correlated with changes in BFI and P1NP (BFI: ρ=.55; P < .001; P1NP: ρ=.45; P = .004) but not with CTX (P = .184) and osteocalcin (P = .149). A sodium increase of 1 mmol/l was associated with an increase of 5.21 in BFI (95% CI, 1.41-9.00; P = .013) and with an increase of 1.48 µg/l in P1NP (95% CI, .26-2.62; P = .03). The effect of sodium change on bone markers was independent of the study medication empagliflozin.ConclusionAn increase in plasma sodium levels in outpatients with chronic hyponatremia due to SIAD, even when mild, was associated with an increase in bone formation index (P1NP/CTX) triggered by an increase in P1NP, a surrogate marker of osteoblast function.
Ewert, Annika; Rehberg, Mirko; Schlingmann, Karl Peter; Hiort, Olaf; John-Kroegel, Ulrike; Metzing, Oliver; Wühl, Elke; Schaefer, Franz; Kemper, Markus J; Derichs, Ute; Richter-Unruh, Annette; Patzer, Ludwig; Albers, Norbert; Dunstheimer, Desiree; Haberland, Holger; Heger, Sabine; Schröder, Carmen; Jorch, Norbert; Schmid, Elmar; Staude, Hagen; Weitz, Marcus; Freiberg, Clemens; Leifheit-Nestler, Maren; Zivicnjak, Miroslav; Schnabel, Dirk; Haffner, Dieter
ContextBurosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking.ObjectiveTo assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH.DesignProspective national registry.SettingHospital clinics.PatientsA total of 93 patients with XLH (65 children, 28 adolescents).Main Outcome MeasuresZ scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months.ResultsAt baseline, patients showed hypophosphatemia (−4.4 SD), reduced TmP/GFR (−6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01).ConclusionsIn this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.
ContextThe American Diabetes Association (ADA) recommends a 3-day preparatory diet prior to a diagnostic oral glucose tolerance test (OGTT), a test often recommended in postpartum individuals with a history of gestational diabetes (GDM).ObjectiveEvaluate the relationship between carbohydrate intake and OGTT glucose in 2 cohorts of postpartum individuals.MethodsWe performed analyses of postpartum individuals from 2 prospective studies with recent GDM (Balance after Baby Intervention, BABI, n = 177) or risk factors for GDM (Study of Pregnancy Regulation of INsulin and Glucose, SPRING, n = 104) .We measured carbohydrate intake using 24-hour dietary recalls (SPRING) or Food Frequency Questionnaire (BABI) and performed 2-hour 75-g OGTTs. The main outcome measure was 120-minute post-OGTT glucose.ResultsThere was no relationship between carbohydrate intake and 120-minute post-OGTT glucose level in either study population (SPRING: β = 0.03, [−5.5, 5.5] mg/dL, P = .99; BABI: β = −3.1, [−9.5, 3.4] mg/dL, P = .35). Adding breastfeeding status to the model did not change results (SPRING β = −0.14, [−5.7, 5.5] mg/dL, P = .95; BABI β = −3.9, [−10.4, 2.7] mg/dL, P = .25). There was, however, an inverse relationship between glycemic index and 120-minute post OGTT glucose (BABI: β = −1.1, [−2.2, −0.03] mg/dL, P = .04).ConclusionCarbohydrate intake is not associated with post-OGTT glucose levels among postpartum individuals. Dietary preparation prior to the OGTT may not be necessary in this population.
Meier, Christian; Eastell, Richard; Pierroz, Dominique D; Lane, Nancy E; Al-Daghri, Nasser; Suzuki, Atsushi; Napoli, Nicola; Mithal, Ambrish; Chakhtoura, Marlene; Fuleihan, Ghada El-Hajj; Ferrari, Serge
ContextThe risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context.ObjectiveThis review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes.MethodsA group of experts from the International Osteoporosis Foundation and European Calcified Tissue Society reviewed the literature focusing on biochemical markers, diabetes, diabetes treatments, and bone in adults.ResultsAlthough bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers (BTMs) in diabetics similarly to nondiabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with bone mineral density and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, glycated hemoglobin A1c (HbA1c) and advanced glycation end products, inflammatory markers, and adipokines, as well as insulin-like growth factor-1 and calciotropic hormones.ConclusionSeveral biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while BTMs could be used to monitor the effects of antiosteoporosis therapy.
ContextChildhood hyperphosphatasemia is usually transient and may be associated with infections. It remains less well known how hyperphosphatasemia is related to growth and bone mineralization.ObjectiveWe explored alkaline phosphatase (ALP) concentrations and prevalence of hyperphosphatasemia, and their association with vitamin D, growth, infections, and bone parameters in healthy children.MethodsThe study was a secondary analysis of a vitamin D intervention trial. Participants received vitamin D3 10 or 30 µg daily from age 2 weeks to 2 years. Children with data on ALP at 12 and/or 24 months (n = 813, girls 51.9%) were included. Anthropometrics and bone parameters were measured at 12 and 24 months. Infections were recorded prospectively by the parents.ResultsBoys had higher ALP than girls at 12 months (median [IQR] 287 [241-345] U/L vs 266 [218-341] U/L; P = .02). At 24 months concentrations were lower than at 12 months (240 [202-284]; P < .001) but without sex difference. The prevalence of hyperphosphatasemia (ALP > 1000 U/L) at 12 months was 5.3% and at 24 months 0.6%. Body size, growth rate, and bone mineral content associated positively with ALP, while vitamin D intervention had no effect. Infants with hyperphosphatasemia were smaller than infants with ALP ≤ 1000 U/L. Hyperphosphatasemia was not associated with previous infections.ConclusionApproximately 5% of infants had hyperphosphatasemia at 12 months, but <1% at 24 months. ALP concentrations and hyperphosphatasemia were associated with sex, anthropometry, and bone mineralization. Infections did not contribute to hyperphosphatasemia.
ContextThe functional status of organs, such as the liver, involved in IGF-1 signaling pathways influences circulating levels of IGF-1 and hence its relationship to risk of chronic disease and mortality, yet this has received limited attention.ObjectiveTo examine the relationship between IGF-1 and risk of morbidity and mortality from cancer, cardiovascular diseases (CVD), and all causes, accounting for liver function.MethodsThis study was a case-cohort design nested within EPIC-Heidelberg. IGF-1 was measured in 7461 stored serum samples collected from 1994 to 1998. Median follow-up for incident mortality events was 17.5 years. The case-cohort included a subcohort of 1810 men and 1890 women, in addition to 1668 incident cases of cancer (623 breast, 577 prostate, 202 lung, and 268 colorectal), and 1428 cases of CVD (707 myocardial infarctions and 723 strokes) and 2441 cases of death.ResultsHigher IGF-1 levels showed direct associations with risks of breast (1.25; 95% CI [1.06-1.47]) and prostate (1.31; [1.09-1.57]) cancers. Restricted cubic splines plots and models including IGF-1 as quintiles revealed a U-shaped relationship between the biomarker and mortality. Participants with the lowest and the highest levels of IGF-1 experienced higher hazards of mortality from cancer, CVD, and all causes. The U-shaped form of the relationship persisted but was attenuated in analyses including only participants without any indications of liver dysfunction.ConclusionThis large population-based prospective study showed that both individuals with lowest and highest levels of circulating IGF-1 were at increased risk of deaths from cancer, CVD, and all causes. For individuals with low IGF-1, the excess risks of death were more pronounced among individuals with liver cancer and cirrhosis but were also present among individuals without elevated liver enzymes.
Haines, Melanie S; Kaur, Snimarjot; Scarff, Geetanjali; Lauze, Meghan; Gerweck, Anu; Slattery, Meghan; Oreskovic, Nicolas M; Ackerman, Kathryn E; Tenforde, Adam S; Popp, Kristin L; Bouxsein, Mary L; Miller, Karen K; Misra, Madhusmita
ContextFemale athletes, particularly runners, with insufficient caloric intake for their energy expenditure [low energy availability (EA) or relative energy deficiency] are at risk for impaired skeletal integrity. Data are lacking in male runners.ObjectiveTo determine whether male runners at risk for energy deficit have impaired bone mineral density (BMD), microarchitecture, and estimated strength.DesignCross-sectional.SettingClinical research center.Participants39 men (20 runners, 19 controls), ages 16–30 years.Main Outcome MeasuresAreal BMD (dual-energy x-ray absorptiometry); tibia and radius volumetric BMD and microarchitecture (high-resolution peripheral quantitative computed tomography); failure load (microfinite element analysis); serum testosterone, estradiol, leptin; energy availability.ResultsMean age (24.5 ± 3.8 y), lean mass, testosterone, and estradiol levels were similar; body mass index, percent fat mass, leptin, and lumbar spine BMD Z-score (−1.4 ± 0.8 vs −0.8 ± 0.8) lower (P < .05); and calcium intake and running mileage higher (P ≤ .01) in runners vs controls. Runners with EA <median had lower lumbar spine (−1.5 ± 0.7, P = .028), while runners with EA ≥median had higher hip (0.3 ± 0.7 vs −0.4 ± 0.5, P = .002), BMD Z-scores vs controls. After adjusting for calcium intake and running mileage, runners with EA <median had lower mean tibial total and trabecular volumetric BMD, trabecular bone volume fraction, cortical porosity, and apparent modulus vs controls (P < .05). Appendicular lean mass and serum estradiol (R ≥ 0.45, P ≤ .046), but not testosterone, were positively associated with tibial failure load among runners.ConclusionsDespite weight-bearing activity, skeletal integrity is impaired in male runners with lower caloric intake relative to exercise energy expenditure, which may increase bone stress injury risk. Lower estradiol and lean mass are associated with lower tibial strength in runners.
ContextCortisol-lowering drugs may not restore a normal cortisol secretion in Cushing disease (CD).ObjectiveThis work aimed to assess the long-term cortisol exposure in medically treated CD patients using hair-cortisol (HF) and hair-cortisone (HE) measurement.MethodsThis multicenter prospective study included 3 groups of female patients: CushMed = 16 treated with a stable cortisol-lowering drug dosage and normal urinary free cortisol (UFC); CushSurg = 13 cured by pituitary surgery; CushBla = 15 receiving stable recommended doses of hydrocortisone following bilateral adrenalectomy. Patients were evaluated for 3 months with their usual treatments. Two late-night saliva and 24-hour urine samples were collected monthly in CushMed, and at study end in CushSurg and CushBla patients. A 3-cm hair sample was collected at study end from all patients. Main outcome measures included clinical score and centralized measurement of UFC, late-night salivary cortisol (LNSF), late-night salivary cortisone (LNSE), HE, HF.ResultsDespite having almost all UFCs normalized, CushMed patients exhibited increased HE as compared to CushSurg controls (P = .003). CushMed patients also had increased clinical score (P = .001), UFC (P = .03), LNSF, LNSE (P = .0001), and variability in the latter parameters (P = .004). CushBla patients had increased HF and HE, contrasting with LNSEs similar to CushSurg patients. Six of 15 CushMed patients exhibited increased HE concentrations and had increased antihypertensive drug dosage compared to CushMed patients with normal HE (P = .05).ConclusionDespite normalized UFCs, a subset of medically treated CD patients displays an altered circadian rhythm of serum cortisol. A single HE measurement identifies chronic mild persistent hypercortisolism and could replace multiple saliva analyzes to monitor medical treatments in CD patients once UFC is normalized.
ContextPrevious studies, including our own, have demonstrated a highly variable incidence of primary hyperparathyroidism (PHPT) from year to year.ObjectiveWe planned to provide a current estimate of the incidence and prevalence of PHPT in a community-based study.MethodsA population-based retrospective follow-up study was conducted in Tayside (Scotland) from 2007 to 2018. Record-linkage technology (demography, biochemistry, prescribing, hospital admissions, radiology, and mortality data) was used to identify all patients. Cases of PHPT were defined as those with at least 2 raised serum corrected calcium concentration CCA (> 2.55 mmol/L) and/or hospital admissions with PHPT diagnoses and/or surgery records with parathyroidectomy during the follow-up period. The number of prevalent and incident cases of PHPT per calendar year by age and sex were estimated.ResultsA total of 2118 people (72.3% female, mean age 65 years) were identified with an incident case of PHPT. The overall prevalence of PHPT over the 12 years of the study was 0.84% (95% CI, 0.68%-1.02%), steadily increasing from 0.71% in 2007 to 1.02% in 2018. From 2008, the incidence of PHPT was relatively stable from 4 to 6 cases per 10 000 person-years, declining from 11.5 per 10 000 person-years in 2007. The incidence varied from 0.59 per 10 000 person-years (95% CI, 0.40%-0.77%) for those aged 20 to 29 years, to 12.4 per 10 000 person-years (95% CI, 11.2%-13.3%) in those aged 70 to 79 years. Incidence of PHPT was 2.5 times higher in women than in men.ConclusionThis study is the first showing a relatively steady annual incidence of PHPT at 4 to 6 per 10 000 person-years. This population-based study reports a PHPT prevalence of 0.84%.
ContextCongenital adrenal hyperplasia (CAH) is a genetic disorder that results in hormonal imbalances and decreased brain volumes in regions important for emotional processing.ObjectiveTo examine whether emotion perception differs between youth with CAH and control youth, and if these differences relate to brain volumes.MethodsIn this cross-sectional study of 27 youths with CAH (mean age = 12.63 years, 16 female) and 35 age- and sex-matched controls (mean age = 13.03 years, 20 female), each participant rated picture stimuli and completed a 3T structural brain scan. Valence and arousal ratings and reaction times of 61 affective images were assessed. Gray matter volumes were measured by MRI.ResultsYouth with CAH had lower valence ratings for negative (P = .007) and neutral (P = .019) images. Controls showed differences in reaction times and arousal ratings across stimuli conditions, but youth with CAH did not. Brain volumes of the right amygdala (P = .025) and left hippocampus (P = .002) were associated with valence ratings. Left rostral middle frontal (P < .001) and right medial orbitofrontal cortex (P = .002) volumes were negatively related to valence scores only in youth with CAH, whereas left medial orbitofrontal cortex (P < .001) volumes were associated with valence scores positively in youth with CAH and negatively in controls.ConclusionFindings suggest that youth with CAH perceive emotive stimuli as more unpleasant. Decreased brain volumes in the amygdala, hippocampus, and prefrontal cortex are associated with these measures of altered emotion perception in youth with CAH.
ContextPregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators.ObjectiveTo investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe.MethodsSections of placentas were collected and frozen at −80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA.ResultsThe placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA.ConclusionWe present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.
AimsPrevious work found poor reproducibility for measures of glycemia in individuals at risk for dysglycemia. Differences between youth and adults have not been assessed. Using youth and adults in the Restoring Insulin Secretion Study, we tested variability and classification concordance for hemoglobin A1C (HbA1c), fasting and 2-hour glucose from oral glucose tolerance tests (OGTTs).MethodsHbA1c and glucose on repeated samples obtained ∼6 weeks apart were compared in 66 youth (mean age 14.2 years) and 354 adults (52.7 years). Changes, coefficient of variation (CV), and concordance of diagnostic categories between the 2 visits were compared.ResultsMean difference between the 2 visits in HbA1c was higher in youth than adults (P < .001), while fasting glucose was similar and 2-hour glucose was lower in youth (P = .051). CV was smallest for HbA1c compared to fasting and 2-hour glucose. For HbA1c, youth had higher CV (P < .001); whereas CV for 2-hour glucose was lower for youth (P = .041). Classification concordance by HbA1c was lower in youth (P = .004). Using OGTT or HbA1c for classification, intervisit variability produced discordant classification in 20% of youth and 28% of adults. Using both fasting glucose and HbA1c, intervisit variability reduced discordant classification to 16% of adults while not improving classification in youth.ConclusionsPoor reproducibility and lack of classification concordance highlight the limitations of one-time testing, with important implications for assessing eligibility in clinical trials. Consideration should be given to using more than a single parameter for screening and diagnosis, especially when classification category is important.
ContextFew iodine balance studies have been conducted in school-age children.ObjectiveThis study aimed to conduct an iodine balance study in school-age children.MethodsWe measured daily iodine intake, excretion, and retention for 3 consecutive days without any dietary interventions in school-age children. Linear mixed-effects models were used to fit the relationship between total iodine intake and iodine retention.Results29 children aged 7-12 years (mean age 10.2 ± 1.4 years) with normal thyroid function and thyroid volume were recruited. The 0 balance value (iodine intake = iodine excretion, iodine retention = 0 μg/day) shifted with iodine intake in an iodine sufficient population. The 0 balance value for school-age children with an iodine intake of 235 (133, 401) μg/day is 164 μg/day. Children aged 7-12 years with iodine intake >400 μg/day were almost all in a positive iodine state.ConclusionAn iodine intake of 235 (133, 401) μg/day for children aged 7-10 years achieved a 0 balance value of 164 μg/day. Long-term iodine intake of >400 μg/day is not recommended.
ContextAndrogen deprivation therapy (ADT) forms the cornerstone in prostate cancer (PCa) treatment. However, ADT also lowers skeletal muscle mass.ObjectiveTo identify the impact of ADT with and without resistance exercise training on muscle fiber characteristics in PCa patients.MethodsTwenty-one PCa patients (72 ± 6 years) starting ADT were included. Tissue samples from the vastus lateralis muscle were assessed at baseline and after 20 weeks of usual care (n = 11) or resistance exercise training (n = 10). Type I and II muscle fiber distribution, fiber size, and myonuclear and capillary contents were determined by immunohistochemistry.ResultsSignificant decreases in type I (from 7401 ± 1183 to 6489 ± 1293 μm2, P < .05) and type II (from 6225 ± 1503 to 5014 ± 714 μm2, P < .05) muscle fiber size were observed in the usual care group. In addition, type I and type II individual capillary-to-fiber ratio (C/Fi) declined (−12% ± 12% and −20% ± 21%, respectively, P < .05). In contrast, significant increases in type I (from 6700 ± 1464 to 7772 ± 1319 μm2, P < .05) and type II (from 5248 ± 892 to 6302 ± 1385 μm2, P < .05) muscle fiber size were observed in the training group, accompanied by an increase in type I and type II muscle fiber myonuclear contents (+24% ± 33% and +21% ± 23%, respectively, P < .05) and type I C/Fi (+18% ± 14%, P < .05).ConclusionThe onset of ADT is followed by a decline in both type I and type II muscle fiber size and capillarization in PCa patients. Resistance exercise training offsets the negative impact of ADT and increases type I and II muscle fiber size and type I muscle fiber capillarization in these patients.
BackgroundStatin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue.ObjectivesIn a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption.MethodsAnthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR.ResultsSimvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202).ConclusionSimvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.
ContextLong COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors.ObjectiveDue to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization.MethodsLong COVID was defined according to NICE guidelines. Fifty long COVID and 50 non–long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge.ResultsWe observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16).ConclusionCOVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.
ContextGuidelines recommend the assessment of cortisol secretion in patients with adrenal incidentalomas (AI) using the overnight dexamethasone suppression test (ONDST). This requires attendance at a health care facility and venepuncture. Alternatively, the ONDST can be done by measuring salivary cortisol and cortisone, which can be collected at home.ObjectiveWe aimed to assess the utility of these measurements in patients with AI.MethodsA retrospective analysis of data from 173 patients with AI who underwent an ONDST and salivary cortisol/cortisone diurnal studies. Serum and salivary cortisol and salivary cortisone were collected at 09:00, late night, and at 09:00 the following morning after dexamethasone. Dexamethasone levels were measured in the postdexamethasone samples. Serum and salivary samples were analyzed with liquid chromatography–tandem mass spectrometry.ResultsWe identified a strong correlation between salivary cortisone and serum cortisol after 1 mg of dexamethasone (r = 0.95). Stepwise multivariate regression showed that postdexamethasone salivary cortisone, baseline serum cortisol, salivary cortisone suppression (predexamethasone/postdexamethasone ratio), and sex were the only significant or near-significant independent variables. Performance of predictive indices using these 4 parameters (sensitivity = 88.5%, specificity = 91.2%; kappa 0.80) and postdexamethasone salivary cortisone alone (sensitivity = 85.3%, specificity = 91.7%; kappa 0.77) were comparable when used to predict an ONDST serum cortisol of ≤50 nmol/L. No correlation was observed with any of the other measured parameters.ConclusionIn AI patients, after dexamethasone, salivary cortisone correlates very strongly with serum cortisol in the ONDST and could therefore be used as an alternative sampling method which does not require venepuncture or attendance at hospital.
ContextPositive antithyroglobulin (TgAb) and/or antithyroid peroxidase antibodies (TPOAb) at baseline indicate a high risk of thyroid immune-related adverse events (irAEs) induced by antiprogrammed cell death-1 antibodies (anti-PD-1-Ab). However, whether the positivity patterns of both antibodies are associated with the risk of thyroid irAEs is unknown.ObjectiveThe aim of the present study was to clarify the association of the pattern of TgAb and TPOAb positivity at baseline with the risk of thyroid irAEs induced by anti-PD-1-Ab.MethodsPatients (n = 516) were evaluated for TgAb and TPOAb at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after initiating anti-PD-1-Ab.ResultsFifty-one (9.9%) patients developed thyroid irAEs (thyrotoxicosis in 34, hypothyroidism without prior thyrotoxicosis in 17). Twenty-five patients subsequently developed hypothyroidism following thyrotoxicosis. The cumulative incidence of thyroid irAEs differed among 4 groups classified by the presence of TgAb/TPOAb at baseline (group 1: TgAb-(−)/TPOAb-(−), 4.6% [19/415]; group 2: TgAb-(−)/TPOAb-(+), 15.8% [9/57]; group 3: TgAb-(+)/TPOAb-(−), 42.1% [8/19]; group 4: TgAb-(+)/TPOAb-(+), 60.0% [15/25]) as follows: groups 1 vs 2-4 (P ≤ .001) and groups 2 vs 3 (P = .008) and 4 (P < .001). There were different incidences of thyrotoxicosis (groups 1-4, 3.1%, 5.3%, 31.6%, 48.0%, respectively; P < .001) in groups 1 vs 3 and 4, and groups 2 vs 3 and 4, and of hypothyroidism (groups 1-4: 2.9%, 15.8%, 31.6%, 60.0%, respectively; P < .001) in groups 1 vs 2 to 4, and groups 2 vs 4.ConclusionThe risk of thyroid irAEs was affected by the pattern of TgAb and TPOAb positivity at baseline; there were high risks of thyrotoxicosis in patients with TgAb-(+) and of hypothyroidism in patients with TgAb-(+) and those with TPOAb-(+).
Batman, Adnan; Yazıcı, Dilek; Dikbaş, Oğuz; Ağbaht, Kemal; Saygılı, Emre Sedar; Demirci, İbrahim; Bursa, Nurbanu; Ayas, Görkem; Anıl, Cüneyd; Cesur, Mustafa; Korkmaz, Fatma Nur; Bahçecioglu, Adile Begüm; Çorapçıoğlu, Demet; Erdoğan, Murat Faik; Bostan, Hayri; Calapkulu, Murat; Hepşen, Sema; Uçan, Bekir; Çakal, Erman; Güler, Bağdagül Yüksel; Haymana, Cem; İpekçi, Süleyman Hilmi; Aydın, Selami; Sezer, Havva; Özışık, Seçil; Deyneli, Oğuzhan; Alagöl, Faruk; Tanakol, Refik; Eroğlu, Mustafa; Mutlu, Ümmü; Hacışahinoğulları, Hülya; Üzüm, Ayşe Kubat; Demir, Canan; Koç, Gönül; Fırat, Sevde Nur; Omma, Tülay; İnce, Nurcan; Polat, Şefika Burçak; Topaloğlu, Oya; Aydın, Cevdet; Çakır, Bekir; Bahadır, Çiğdem Tura; Güven, Mehmet; Sözen, Mehmet; Selek, Alev; Cantürk, Zeynep; Çetinarslan, Berrin; Aydemir, Mustafa; Taşkaldıran, Işılay; Bozkuş, Yusuf; İyidir, Özlem Turhan; Haydardedeoğlu, Filiz Ekşi; Basmaz, Seda Erem; Ünal, Mehmet Çağrı; Demir, Tevfik; Oğuz, Ayten; Çelik, Özlem; Yilmaz, Merve; Cimsir, Aykut; Kayıhan, Serdar; Uc, Ziynet Alphan; Tekin, Sakin; Topaloğlu, Ömercan; Saydam, Başak Özgen; Ünsal, Yasemin Aydoğan; Özer, Özge; Yorulmaz, Göknur; Uğur, Kader; Çakır, Sezin Doğan; Aşık, Mehmet; Unubol, Mustafa; Genc, Selin; Andac, Burak; Okur, Mine; Dogan, Ozlem; Karakiliç, Ersen; Kocabas, Gokcen Unal; Kirac, Cem Onur; Cansu, Güven Barış; Uygur, Meliha Melin; Pekkolay, Zafer; Öztürk, Sadettin; Güngüneş, Aşkın; Gürkan, Eren; Keskin, Lezzan; Çağlayan, Kenan; Günay, Yasemin Emur; İmre, Eren; Şener, Selcuk Yusuf; Kalkan, Ahmet Toygar; Gök, Deniz Engin; Şahin, Mustafa
ContextThe aims of the study are to compare characteristics of subacute thyroiditis (SAT) related to different etiologies, and to identify predictors of recurrence of SAT and incident hypothyroidism.MethodsThis nationwide, multicenter, retrospective cohort study included 53 endocrinology centers in Turkey. The study participants were divided into either COVID-19–related SAT (Cov-SAT), SARS-CoV-2 vaccine–related SAT (Vac-SAT), or control SAT (Cont-SAT) groups.ResultsOf the 811 patients, 258 (31.8%) were included in the Vac-SAT group, 98 (12.1%) in the Cov-SAT group, and 455 (56.1%) in the Cont-SAT group. No difference was found between the groups with regard to laboratory and imaging findings. SAT etiology was not an independent predictor of recurrence or hypothyroidism. In the entire cohort, steroid therapy requirement and younger age were statistically significant predictors for SAT recurrence. C-reactive protein measured during SAT onset, female sex, absence of antithyroid peroxidase (TPO) positivity, and absence of steroid therapy were statistically significant predictors of incident (early) hypothyroidism, irrespective of SAT etiology. On the other hand, probable predictors of established hypothyroidism differed from that of incident hypothyroidism.ConclusionSince there is no difference in terms of follow-up parameters and outcomes, COVID-19– and SARS-CoV-2 vaccine–related SAT can be treated and followed up like classic SATs. Recurrence was determined by younger age and steroid therapy requirement. Steroid therapy independently predicts incident hypothyroidism that may sometimes be transient in overall SAT and is also associated with a lower risk of established hypothyroidism.
Teede, Helena J; Tay, Chau Thien; Laven, Joop J E; Dokras, Anuja; Moran, Lisa J; Piltonen, Terhi T; Costello, Michael F; Boivin, Jacky; Redman, Leanne M; Boyle, Jacqueline A; Norman, Robert J; Mousa, Aya; Joham, Anju E
Study QuestionWhat is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference?Summary AnswerInternational evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS.What is Known AlreadyThe 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist.Study Design, Size, DurationThe 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout.Participants/Materials, Setting, MethodsThis summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC).Main Results and the Role of ChanceThe evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management.Limitations, Reasons for CautionOverall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided.Wider Implications of the FindingsThe 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program.Study Funding/Competing Interest(s)This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.
Acromegaly is a chronic condition caused by the excessive production of growth hormone and is characterized by progressive morphological and systemic complications, as well as increased prevalence of psychopathologies, which markedly affect patients’ quality of life. The advancing multimodal therapies, while significantly improving the morbidity and mortality, have limited impact on psychopathologies, which often persist despite disease remission. The most common psychopathologies in acromegaly include depression, anxiety and affective disorders, together with sexual dysfunction, which may be considered as either a consequence or potentially even a contributory factor to these psychopathologies. Approximately one-third of patients with acromegaly manifest depression, whereas two-thirds of patients display anxiety, with both conditions tending to be more prevalent and severe in younger patients with shorter duration of disease. Apparently, a major impact of psychological discomfort in women compared with men appears to be the fact that women tend to internalize whereas men tend to externalize their distress. Personality disorders also commonly associated with acromegaly, especially due to body image suffering, are linked to sexual dysfunction, which seems to affect women more than men. In summary, psychopathology in acromegaly is a major determinant of the quality of life and a complex array of psychological abnormalities are associated with acromegaly.
ContextCongenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors.ObjectiveWe aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups.MethodsPatients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure.ResultsWe identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births.ConclusioncCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.
Pozza, Carlotta; Sesti, Franz; Tenuta, Marta; Spaziani, Matteo; Tarantino, Chiara; Carlomagno, Francesco; Minnetti, Marianna; Pofi, Riccardo; Paparella, Roberto; Lenzi, Andrea; Radicioni, Antonio; Isidori, Andrea M; Tarani, Luigi; Gianfrilli, Daniele
ObjectiveKlinefelter syndrome is the most common chromosomal disorder in males and the most common cause of hypergonadotropic hypogonadism. We describe the natural history of testicular dysfunction in patients with Klinefelter syndrome through the integration of clinical, hormonal, and quantitative ultrasound data in a life-course perspective.DesignProspective semilongitudinal study.MethodsWe included 155 subjects with 47,XXY karyotype (age range: 7 months-55 years) naïve to testosterone replacement therapy. Subjects were divided according to pubertal stage and age group (transition age and adults). Serial clinical, hormonal, and testicular ultrasound (US) assessments were performed.ResultsTesticular development progresses until Tanner stage 4, with subsequent regression, whereas Sertoli and germ cell impairment is not hormonally detected before Tanner stages 3-4, as reflected by normal inhibin B values until stage 4 and the fall in the inhibin B/follicle-stimulating hormone ratio thereafter. The testosterone/luteinizing hormone ratio peaks during Tanner stages 2-3 and declines from Tanner stage 4 onward, preceding the development of overt hypogonadism. US echotexture progressively worsens until transition age, reflecting ongoing gonadal compromise, whereas quantitative US echotexture measures and the presence of both hypoechoic lesions and microlithiasis independently and significantly predict a lower circulating testosterone level.ConclusionsThe findings from this large prospective study contribute to our understanding of the natural history of testicular dysfunction in Klinefelter syndrome, underlining the importance of quantitative testicular US in infancy and childhood, as well as during pubertal development and transition age, for the optimal care of Klinefelter syndrome patients.
ContextGlycemic variation had been demonstrated to be associated with several complications of diabetes.ObjectiveInvestigation of the association between visit to visit hemoglobin A1c (HbA1c) variation and the long-term risk of major adverse limb events (MALEs).MethodsRetrospective database study. Average real variability was used to represent glycemic variations with all the HbA1c measurements during the 4 following years after the initial diagnosis of type 2 diabetes. Participants were followed from the beginning of the fifth year until death or the end of the follow-up. The association between HbA1c variations and MALEs was evaluated after adjusting for mean HbA1c and baseline characteristics. Included were 56 872 patients at the referral center with a first diagnosis of type 2 diabetes, no lower extremity arterial disease, and at least 1 HbA1c measurement in each of the 4 following years were identified from a multicenter database. The main outcome measure was incidence of a MALE, which was defined as the composite of revascularization, foot ulcers, and lower limb amputations.ResultsThe average number of HbA1c measurements was 12.6. The mean follow-up time was 6.1 years. The cumulative incidence of MALEs was 9.25 per 1000 person-years. Visit to visit HbA1c variations were significantly associated with MALEs and lower limb amputation after multivariate adjustment. People in the highest quartile of variations had increased risks for MALEs (HR 1.25, 95% CI 1.10-1.41) and lower limb amputation (HR 3.05, 95% CI 1.97-4.74).ConclusionHbA1c variation was independently associated with a long-term risk of MALEs and lower limb amputations in patients with type 2 diabetes.
ContextHyperglycemia and autonomic dysfunction are bidirectionally related.ObjectiveWe investigated the association of longitudinal evolution of heart rate variability (HRV) with incident type 2 diabetes (T2D) among the general population.MethodsWe included 7630 participants (mean age 63.7 years, 58% women) from the population-based Rotterdam Study who had no history of T2D and atrial fibrillation at baseline and had repeated HRV assessments at baseline and during follow-up. We used joint models to assess the association between longitudinal evolution of heart rate and different HRV metrics (including the heart rate–corrected SD of the normal-to-normal RR intervals [SDNNc], and root mean square of successive RR-interval differences [RMSSDc]) with incident T2D. Models were adjusted for cardiovascular risk factors. Bidirectional Mendelian randomization (MR) using summary-level data was also performed.ResultsDuring a median follow-up of 8.6 years, 871 individuals developed incident T2D. One SD increase in heart rate (hazard ratio [HR] 1.20; 95% CI, 1.09-1.33), and log(RMSSDc) (HR 1.16; 95% CI, 1.01-1.33) were independently associated with incident T2D. The HRs were 1.54 (95% CI, 1.08-2.06) for participants younger than 62 years and 1.15 (95% CI, 1.01-1.31) for those older than 62 years for heart rate (P for interaction <.001). Results from bidirectional MR analyses suggested that HRV and T2D were not significantly related to each other.ConclusionAutonomic dysfunction precedes development of T2D, especially among younger individuals, while MR analysis suggests no causal relationship. More studies are needed to further validate our findings.
Puglisi, Soraya; Calabrese, Anna; Ferraù, Francesco; Violi, Maria Antonia; Laganà, Marta; Grisanti, Salvatore; Ceccato, Filippo; Scaroni, Carla; Di Dalmazi, Guido; Stigliano, Antonio; Altieri, Barbara; Canu, Letizia; Loli, Paola; Pivonello, Rosario; Arvat, Emanuela; Morelli, Valentina; Perotti, Paola; Basile, Vittoria; Berchialla, Paola; Urru, Sara; Fiori, Cristian; Porpiglia, Francesco; Berruti, Alfredo; Pia, Anna; Reimondo, Giuseppe; Cannavò, Salvatore; Terzolo, Massimo
ContextBecause of the rarity of adrenocortical cancer (ACC), only a few population-based studies are available, and they reported limited details in the characterization of patients and their treatment.ObjectiveTo describe in a nationwide cohort the presentation of patients with ACC, treatment strategies, and potential prognostic factors.MethodsRetrospective analysis of 512 patients with ACC, diagnosed in 12 referral centers in Italy from January 1990 to June 2018.ResultsACC diagnosed as incidentalomas accounted for overall 38.1% of cases, with a frequency that increases with age and with less aggressive pathological features than symptomatic tumors. Women (60.2%) were younger than men and had smaller tumors, which more frequently secreted hormones. Surgery was mainly done with an open approach (72%), and after surgical resection, 62.7% of patients started adjuvant mitotane therapy. Recurrence after tumor resection occurred in 56.2% of patients. In patients with localized disease, cortisol secretion, ENSAT stage III, Ki67%, and Weiss score were associated with an increased risk of recurrence, whereas margin-free resection, open surgery, and adjuvant mitotane treatment were associated with reduced risk. Death occurred in 38.1% of patients and recurrence-free survival (RFS) predicted overall survival (OS). In localized disease, age, cortisol secretion, Ki67%, ENSAT stage III, and recurrence were associated with increased risk of mortality. ACCs presenting as adrenal incidentalomas showed prolonged RFS and OS.ConclusionOur study shows that ACC is a sex-related disease and demonstrates that an incidental presentation is associated with a better outcome. Given the correlation between RFS and OS, RFS may be used as a surrogate endpoint in clinical studies.
ContextNoninvasive assessment of proton density fat fraction (PDFF) by magnetic resonance imaging (MRI) may improve the prediction of fractures.ObjectiveThis work aimed to determine if an association exists between PDFF and fractures.MethodsA case-control study was conducted at Lille University Hospital, Lille, France, with 2 groups of postmenopausal women: one with recent osteoporotic fractures, and the other with no fractures. Lumbar spine and proximal femur (femoral head, neck, and diaphysis) PDFF were determined using chemical shift-based water-fat separation MRI (WFI) and dual-energy x-ray absorptiometry scans of the lumbar spine and hip. Our primary objective was to determine the relationship between lumbar spine PDFF and osteoporotic fractures in postmenopausal women. Analysis of covariance was used to compare PDFF measurements between patient cases (overall and according to the type of fracture) and controls, after adjusting for age, Charlson comorbidity index (CCI) and BMD.ResultsIn 199 participants, controls (n = 99) were significantly younger (P < .001) and had significantly higher BMD (P < 0.001 for all sites) than patient cases (n = 100). A total of 52 women with clinical vertebral fractures and 48 with nonvertebral fractures were included. When PDFFs in patient cases and controls were compared, after adjustment on age, CCI, and BMD, no statistically significant differences between the groups were found at the lumbar spine or proximal femur. When PDFFs in participants with clinical vertebral fractures (n = 52) and controls were compared, femoral neck PDFF and femoral diaphysis PDFF were detected to be lower in participants with clinical vertebral fractures than in controls (adjusted mean [SE] 79.3% [1.2] vs 83.0% [0.8]; P = 0.020, and 77.7% [1.4] vs 81.6% [0.9]; P = 0.029, respectively).ConclusionNo difference in lumbar spine PDFF was found between those with osteoporotic fractures and controls. However, imaging-based proximal femur PDFF may discriminate between postmenopausal women with and without clinical vertebral fractures, independently of age, CCI, and BMD.
ContextAdipose tissue (AT) inflammation predisposes to insulin resistance and metabolic syndrome in obesity.ObjectiveTo investigate the association between adipocyte size, AT inflammation, systemic inflammation, and metabolic and atherosclerotic complications of obesity in a sex-specific manner.DesignCross-sectional cohort study.SettingUniversity hospital in the Netherlands.ParticipantsA total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2.Main outcome measuresWe obtained subcutaneous abdominal fat biopsies and systematically assessed, in a sex-specific manner, associations of several parameters of AT inflammation (including adipocyte size, macrophage content, crown-like structures, and gene expression) to biomarkers of systemic inflammation, leukocyte number and function, and to the presence of metabolic syndrome, insulin resistance, and carotid atherosclerotic plaques, assessed with ultrasound.ResultsAdipocyte size was associated with metabolic syndrome and AT macrophage content with insulin resistance. In contrast, none of the AT parameters was associated with carotid atherosclerosis, although mRNA expression of the anti-inflammatory IL-37 was associated with a lower intima-media thickness. We revealed profound sex-specific differences, with an association between BMI and adipocyte size, and between adipocyte size and metabolic syndrome in men only. Also, only men showed an association between adipocyte size, AT expression of leptin and MCP-1, and AT macrophage numbers, and between AT inflammation (crown-like structure number) and several circulating inflammatory proteins, including high specificity C-reactive protein, and IL-6.ConclusionsInflammation in abdominal subcutaneous adipose tissue is more related to the metabolic than the atherosclerotic complications of obesity, and there are profound sex-specific differences in the association between BMI, adipocyte size, AT inflammation, and systemic inflammation, which are much stronger in men than women.
Masunaga, Yohei; Fujisawa, Yasuko; Massart, Francesco; Spinelli, Claudio; Kojima, Yoshiyuki; Mizuno, Kentaro; Hayashi, Yutaro; Sasagawa, Isoji; Yoshida, Rie; Kato, Fumiko; Fukami, Maki; Kamatani, Naoyuki; Saitsu, Hirotomo; Ogata, Tsutomu
ContextWe have previously reported that a specific “AGATC” haplotype in a >34 kb tight linkage disequilibrium (LD) block within ESR1 is strongly associated with cryptorchidism and hypospadias in Japanese boys.ObjectiveWe aimed to determine the true susceptibility factor for cryptorchidism and hypospadias linked to the “AGATC” haplotype.MethodsWe performed various molecular studies in hitherto unreported 230 Italian boys (80 with cryptorchidism and 150 with normal genitalia) and previously reported and newly recruited 415 Japanese boys (149 with cryptorchidism, 141 with hypospadias, and 125 with normal genitalia). We also performed ESR1 expression analyses using breast cancer–derived MCF-7 cells.ResultsHaplotype analysis revealed the LD block and positive association of the “AGATC” haplotype with cryptorchidism in Italian boys. Whole genome sequencing identified an identical 2249-bp microdeletion (ΔESR1) generated by a microhomology-mediated replication error in both Japanese and Italian boys with the specific haplotype. ΔESR1 was found to be strongly associated with cryptorchidism and hypospadias by Cochran-Armitage trend test and was revealed to show nearly absolute LD with the “AGATC” haplotype. ESR1 expression was upregulated in MCF-7 cells with a homozygous deletion encompassing ΔESR1 and those with a homozygous deletion involving a CTCF-binding site within ΔESR1.ConclusionThe results reveal that ΔESR1, which has been registered as “DEL_6_75504” in gnomAD SVs v2.1, is the true susceptibility factor for cryptorchidism and hypospadias. It appears that ΔESR1 was produced in a single ancestral founder of modern humans and has been maintained within the genome of multiple ethnic groups by selection.