Context:
Measurement of IGF-I is a cornerstone in diagnosis and monitoring of GH-related diseases, but considerable discrepancies exist between analytical methods. A recent consensus conference ...defined criteria for validation of IGF-I assays and for establishment of normative data.
Objectives:
Our objectives were development and validation of a novel automated IGF-I immunoassay (iSYS; Immunodiagnostic Systems) according to international guidelines and establishment of method-specific age- and sex-adjusted reference intervals and analysis of their robustness.
Setting and Participants:
We conducted a multicenter study with samples from 12 cohorts from the United States, Canada, and Europe including 15 014 subjects (6697 males and 8317 females, 0–94 years of age).
Main Outcome Measures:
We measured concentrations of IGF-I as determined by the IDS iSYS IGF-I assay.
Results:
A new IGF-I assay calibrated against the recommended standard (02/254) and insensitive to the 6 high-affinity IGF binding proteins was developed and rigorously validated. Age- and sex-adjusted reference intervals derived from a uniquely large cohort reflect the age-related pattern of IGF-I secretion: a decline immediately after birth followed by an increase until a pubertal peak (at 15 years of age). Later in life, values decrease continuously. The impact of gender is small, although across the lifespan, women have lower mean IGF-I concentrations. Geographical region, sampling setting (community or hospital based), and rigor of exclusion criteria in our large cohort did not affect the reference intervals.
Conclusions:
Using large cohorts of well-characterized subjects from different centers allowed construction of robust reference ranges for a new automated IGF-I assay. The strict adherence to recent consensus criteria for IGF-I assays might facilitate clinical application of the results.
The aim of the present study was to investigate the association of serum gamma‐glutamyltransferase (GGT) levels with all‐cause mortality and to assess the impact of ultrasonographic findings of ...hepatic hyperechogenicity in that association. We used data from 4,160 subjects (2,044 men and 2,116 women) recruited for the population‐based Study of Health in Pomerania (SHIP) without baseline hepatitis B and C infections or liver cirrhosis. GGT was divided into age‐ and sex‐dependent quintiles to calculate overall and sex‐specific crude incidence mortality rates. Hepatic steatosis was defined by elevated GGT levels (>80%) and the presence of hyperechogenic liver ultrasound. We used multiple‐adjusted Cox proportional hazards regression models, first, to assess the direct effect of GGT on all‐cause mortality, second, to stratify according to the ultrasonographic finding, and third, to investigate potential mediating effects of cardiometabolic risk factors. During 29,810 person‐years (7.3 years, median) of follow‐up, 307 individuals (7.5%) died, resulting in a death rate of 0.86 deaths per 1000 person‐years. Elevated GGT levels were associated with increased risk of mortality in men (hazard ratio HR 1.49; 95% confidence interval CI, 1.08–2.05), but not in women (HR 1.30; 95% CI, 0.80–2.12). This association was even stronger in men with hepatic steatosis (HR 1.98; 95% CI, 1.21–3.27). Cause‐specific mortality analysis by cardiovascular disease deaths confirmed the sex‐specific association. Adjustment for cardiometabolic risk factors did not affect the estimates. Conclusion: In the case of increased GGT levels, liver ultrasound should be performed, not only for diagnosis, but also for further risk stratification. (HEPATOLOGY 2009.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality.
Examine the direction and causality of the relationship between body ...mass index (BMI) and serum testosterone.
Bi-directional Mendelian randomization (MR) analysis on prospective cohorts.
Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden).
7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs.
BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site.
1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42--0.09, p = 2.8*10-3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349).
Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies ...considerably.
We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.
Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE.
Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men.
We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied.
Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension.
Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context: To date, it is unclear which measure of obesity is the most appropriate for risk stratification.
Objective: The aim of the study was to compare the associations of various measures of ...obesity with incident cardiovascular events and mortality.
Design and Setting: We analyzed two German cohort studies, the DETECT study and SHIP, including primary care and general population.
Participants: A total of 6355 (mean follow-up, 3.3 yr) and 4297 (mean follow-up, 8.5 yr) individuals participated in DETECT and SHIP, respectively.
Interventions: We measured body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) and assessed cardiovascular and all-cause mortality and the composite endpoint of incident stroke, myocardial infarction, or cardiovascular death.
Results: In both studies, we found a positive association of the composite endpoint with WHtR but not with BMI. There was no heterogeneity among studies. The relative risks in the highest versus the lowest sex- and age-specific quartile of WHtR, WC, WHR, and BMI after adjustment for multiple confounders were as follows in the pooled data: cardiovascular mortality, 2.75 (95% confidence interval, 1.31–5.77), 1.74 (0.84–3.6), 1.71 (0.91–3.22), and 0.74 (0.35–1.57), respectively; all-cause mortality, 1.86 (1.25–2.76), 1.62 (1.22–2.38), 1.36 (0.93–1.69), and 0.77 (0.53–1.13), respectively; and composite endpoint, 2.16 (1.39–3.35), 1.59 (1.04–2.44), 1.49 (1.07–2.07), and 0.57 (0.37–0.89), respectively. Separate analyses of sex and age groups yielded comparable results. Receiver operating characteristics analysis yielded the highest areas under the curve for WHtR for predicting these endpoints.
Conclusions: WHtR represents the best predictor of cardiovascular risk and mortality, followed by WC and WHR. Our results discourage the use of the BMI.
Measures of abdominal obesity but not body mass index predict cardiovascular risk and mortality.
We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for ...associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Context:
Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio ...are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals.
Objective:
The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays.
Setting:
This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe.
Participants:
A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study.
Main Outcome Measures:
Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured.
Results:
Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males.
Conclusions:
We present an extensive set of assay-specific age- and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.
Associations between androgens and depressive symptoms were mostly reported from cross-sectional and patient-based studies.
Longitudinal data from 4,110 participants of the Study of Health in ...Pomerania were used to assess sex-specific associations of baseline total and free testosterone, androstenedione and sex hormone-binding globulin with incident depressive symptoms and cognitive status at 5- and 10-year follow-up.
Despite sex-specific differences in depressive symptoms prevalence at baseline (women: 17.4%, men: 8.1%), cross-sectional analyses showed no associations between sex hormones and depressive symptoms. In age-adjusted longitudinal analyses, total testosterone was associated with incident depressive symptoms (relative risk at 5-year follow-up: 0.73, 95% confidence interval: 0.58-0.92). Similarly, age-adjusted analyses showed a positive association between sex hormone-binding globulin and cognitive status in men (β-coefficient per standard deviation: 0.44, 95% confidence interval: 0.13-0.74). In women, age-adjusted associations of androstenedione with baseline depressive symptoms (relative risk: 0.88, 95% confidence interval: 0.77-0.99) were found. None of the observed associations remained after multivariable adjustment.
The present population-based, longitudinal study revealed inverse associations between sex hormones and depressive symptoms. However, the null finding after multivariable adjustment suggests, that the observed associations were not independent of relevant confounders including body mass index, smoking and physical inactivity. Furthermore, the low number of incident endpoints in our non-clinical population-based sample limited the statistical power and reduced the chance to detect a statistically significant effect.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to evaluate the association of sex hormones with anthropometry in a large population-based cohort, with liquid chromatography-mass spectrometry (LCMS)-based sex hormone ...measurements and imaging markers.
Cross-sectional data from 957 men and women from the population-based Study of Health in Pomerania (SHIP) were used. Associations of a comprehensive panel of LCMS-measured sex hormones with anthropometric parameters, laboratory, and imaging markers were analyzed in multivariable regression models for the full sample and stratified by sex. Sex hormone measures included total testosterone (TT), free testosterone (fT), estrone and estradiol, androstenedione (ASD), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Domains of anthropometry included physical measures (body-mass-index (BMI), waist circumference, waist-to-height-ratio, waist-to-hip-ratio, and hip circumference), laboratory measures of adipokines (leptin and vaspin), and magnet resonance imaging-based measures (visceral and subcutaneous adipose tissue).
In men, inverse associations between all considered anthropometric parameters with TT were found: BMI (β-coefficient, standard error (SE): -0.159, 0.037), waist-circumference (β-coefficient, SE: -0.892, 0.292), subcutaneous adipose tissue (β-coefficient, SE: -0.156, 0.023), and leptin (β-coefficient, SE: -0.046, 0.009). In women TT (β-coefficient, SE: 1.356, 0.615) and estrone (β-coefficient, SE: 0.014, 0.005) were positively associated with BMI. In analyses of variance, BMI and leptin were inversely associated with TT, ASD, and DHEAS in men, but positively associated with estrone. In women, BMI and leptin were positively associated with all sex hormones.
The present population-based study confirmed and extended previously reported sex-specific associations between sex hormones and various anthropometric markers of overweight and obesity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these ...associations are still unknown. Design The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed. Results Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase −0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta −0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found. Conclusions The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.
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