Dataset Information

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

ABSTRACT:

Background

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.

Objectives

We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.

Data sources

Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE.

Study eligibility criteria

Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men.

Methods

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.

Results

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.

Conclusions

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.

SUBMITTER: Brand JS

PROVIDER: S-EPMC4096400 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

Brand Judith S JS Rovers Maroeska M MM Yeap Bu B BB Schneider Harald J HJ Tuomainen Tomi-Pekka TP Haring Robin R Corona Giovanni G Onat Altan A Maggio Marcello M Bouchard Claude C Tong Peter C Y PC Chen Richard Y T RY Akishita Masahiro M Gietema Jourik A JA Gannagé-Yared Marie-Hélène MH Undén Anna-Lena AL Hautanen Aarno A Goncharov Nicolai P NP Kumanov Philip P Chubb S A Paul SA Almeida Osvaldo P OP Wittchen Hans-Ulrich HU Klotsche Jens J Wallaschofski Henri H Völzke Henry H Kauhanen Jussi J Salonen Jukka T JT Ferrucci Luigi L van der Schouw Yvonne T YT

PloS one 20140714 7

<h4>Background</h4>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.<h4>Objectives</h4>We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.<h4>Data sources</h4>Two previously published meta-analyses including an updated systematic search i ...[more]

PMID: 25019163

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Project description:The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone-binding globulin (SHBG) is independently associated with the risk of metabolic syndrome.Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography-tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components.SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men.

Project description:Context:Testosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men. Objective:To confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T. Design Patients:Groups differing in general and reproductive parameters: young men (n = 540; 19.3 ± 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 ± 6.0 years), and male partners of pregnant women (n = 324; 31.9 ± 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia. Main Outcome Measures:Genetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele/genotype distribution comparisons. Results:Associations with serum SHBG levels were robust for SHBG -68 G>A [rs1799941; meta-analysis: P = 3.7 × 10-14; allelic effect (standard error) = 4.67 (0.62) nmol/L], SHBG +1091 C>T [rs727428; P = 7.3 × 10-11; -3.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 × 10-4, -12.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 × 10-4; -2.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P < 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 × 10-5; -1.66 (0.57) IU/L] and follicle-stimulating hormone [P = 3.4 × 10-3; -2.48 (1.23) IU/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927. Conclusions:Claims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy.

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Dataset Information

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

Background

Objectives

Data sources

Study eligibility criteria

Methods

Results

Conclusions

Publications

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

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