Endogenous hormones, androgen receptor CAG repeat length and fluid cognition in middle-aged and older men: results from the European Male Ageing Study.
ABSTRACT Data remain divergent regarding the activational effects of endogenous hormones on adult cognitive function. We examined the association between cognition, hormones and androgen receptor (AR) CAG repeat length in a large cohort of men.
Community-based, cross-sectional study of 3369 men aged 40-79 years.
Cognition tests were the Rey-Osterrieth Complex Figure, Camden Topographical Recognition Memory and Digit-Symbol Substitution. A fluid cognition (FC) z-score was computed from the individual tests. Testosterone, oestradiol (OE(2)) and 5alpha-dihydrotestosterone were measured by gas chromatography-mass spectrometry; DHEAS, LH, FSH and sex hormone-binding globulin (SHBG) by electrochemiluminescence. Free testosterone and OE(2) were calculated from total hormone, SHBG and albumin. CAG repeat lengths were assayed by PCR genotyping.
Total testosterone and free testosterone were associated with higher FC z-scores, LH and FSH with lower FC z-scores in age-adjusted linear regressions. After adjusting for health, lifestyle and centre, a modest association was only observed between DHEAS and a lower FC z-score (beta=-0.011, P=0.02), although this was driven by subjects with DHEAS levels >10 micromol/l. Locally weighted plots revealed no threshold effects between hormones and FC. There was no association between CAG repeat length and FC z-score after adjustment for age and centre (beta=-0.007, P=0.06), nor any interaction effect between CAG repeat length and hormones.
Our results suggest that endogenous hormones are not associated with a vision-based measure of FC among healthy, community-dwelling men. Further studies are warranted to determine whether 'high' DHEAS levels are associated with poorer performance on a broader range of neuropsychological tests.
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ABSTRACT: Variation in polyglutamine repeat number in the androgen receptor (AR CAGn) is negatively correlated with the transcription of androgen-responsive genes and is associated with susceptibility to an extensive list of human disease. Only a small portion of the heritability for many of these diseases is explained by conventional SNP-based genome-wide association studies, and the forces shaping AR CAGn among humans remains largely unexplored. Here, we propose evolutionary models for understanding selection at the AR CAG locus, namely balancing selection, sexual conflict, accumulation-selection, and antagonistic pleiotropy. We evaluate these models by examining AR CAGn-linked susceptibility to eight extensively studied diseases representing the diverse physiological roles of androgens, and consider the costs of these diseases by their frequency and fitness effects. Five diseases could contribute to the distribution of AR CAGn observed among contemporary human populations. With support for disease susceptibilities associated with long and short AR CAGn, balancing selection provides a useful model for studying selection at this locus. Gender-specific differences AR CAGn health effects also support this locus as a candidate for sexual conflict over repeat number. Accompanied by the accumulation of AR CAGn in humans, these models help explain the distribution of repeat number in contemporary human populations.Evolutionary Applications 02/2013; 6(2):180-96. · 4.15 Impact Factor
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ABSTRACT: Testosterone was shown to organize brain and modulate cognitive functions. It is currently unknown whether mental rotation is also associated with prenatal testosterone exposure and testosterone-related genetic polymorphisms. The aim of our study was to analyze associations between mental rotation performance, the actual testosterone levels, the prenatal testosterone level (expressed as 2D:4D ratio) and the androgen receptor CAG repeat polymorphism in intellectually gifted boys. One hundred forty seven boys aged 10-18 years with IQ>130 were enrolled. Saliva samples were collected and used for ELISA of actual levels of salivary testosterone. The 2D:4D finger length ratio as an indicator of prenatal testosterone was measured on both hands and averaged. Amthauer mental rotation test was used for the assessment of this spatial ability. The CAG repeat polymorphism in the androgen receptor gene was analyzed using PCR and capillary electrophoresis. Linear regression revealed that 2D:4D finger length ratio and the number of CAG repeats in the androgen receptor gene were associated with mental rotation. Actual levels of testosterone did not correlate significantly with mental rotation. Multivariate analysis of covariance revealed that after adjustment of age as a confounding variable, only the effect of the genetic polymorphism was significant. The results are in line with our previous genetic analysis of intellectually gifted boys showing the importance of CAG repeat polymorphism in the androgen receptor gene. Details of the interactions between androgen signaling, testosterone levels and its metabolism especially during the prenatal development of brain function remain to be elucidated.Neuropsychologia 05/2013; · 3.48 Impact Factor
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ABSTRACT: Klinefelter syndrome (KS, 47,XXY) is associated with increased psychiatric morbidity and cognitive disabilities, although the neuropsychological phenotype shows great variability. Androgen receptor polymorphism (CAG repeat length), skewed X-chromosome inactivation and parent-of-origin of the extra X-chromosome have been suggested to influence cognitive function and psychological traits. These issues have not been clarified for KS patients. We studied X-chromosome inactivation pattern, CAG repeat length and parent-of-origin in relation to educational and cohabitation status, personality and autism traits, psychological distress, cognitive function and brain volumes in 73 KS patients and 73 controls. Grey matter (GM) volume of left insula was significantly decreased in KS patients with skewed X-inactivation (z = 5.78) and we observed a borderline significant difference in global brain matter volume where KS patients with skewed X-chromosome inactivation tended to have smaller brains. Skewed X-inactivation, CAG repeat length and parent-of-origin were not correlated with educational and marital status, personality traits, autism traits, and psychological distress, prevalence of depression and anxiety or cognitive function. Interestingly our results regarding brain volumes indicate that X-inactivation has an influence on GM volume in left insula and might also be related to global GM volume, indicating a possible effect of X-linked genes on the development of GM volume in KS patient. Skewed X-inactivation, CAG repeat length and parent-of-origin have no impact on the neuropsychological phenotype in KS (http://www.clinicaltrials.gov (Clinical trial NCT00999310)).Andrology 05/2014; · 3.37 Impact Factor