Endogenous hormones, androgen receptor CAG repeat length and fluid cognition in middle-aged and older men: Results from the European Male Ageing Study

arc Epidemiology Unit, Department of Medicine, Manchester Academic and Health Sciences Centre, Manchester Royal Infirmary, The University of Manchester, Grafton Street, Manchester, UK.
European Journal of Endocrinology (Impact Factor: 4.07). 03/2010; 162(6):1155-64. DOI: 10.1530/EJE-09-0970
Source: PubMed


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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    • "The association between cognitive function and CAG repeat length has been investigated in middle-aged and older men, with equivocal results. Lee et al. (2010) failed to detect any association between CAG repeat length and spatial awareness, memory and processing speed, investigating middleaged or old men, however, Yaffe et al. (2003) reported that a higher CAG repeat length was associated with lower cognitive function and processing speed in older men. To conclude, no association has been found between CAG repeat length and cognitive function in boys or adults (age < 60 years) neither in KS patients nor in men from the general population, indicating that it is unlikely that CAG repeat length contributes to the cognitive variation in KS patients. "
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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 ( (Clinical trial NCT00999310)).
    Andrology 05/2014; 2(4). DOI:10.1111/j.2047-2927.2014.00229.x · 2.30 Impact Factor
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    • "In the range of normal variation low number of CAG repeats cause higher transactivation activity of receptor and, thus, higher sensitivity to androgens (Greenland, Beilin, Castro, Varghese, & Zajac, 2004; Irvine et al., 2000). Lee with colleagues found no association between CAG repeat length and fluid intelligence in older men (Lee et al., 2010). Our previous study revealed significant lower number of CAG repeats in the AR gene in gifted boys comparing to controls, indicating stronger androgen signaling in this population. "
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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; 51(9). DOI:10.1016/j.neuropsychologia.2013.05.016 · 3.30 Impact Factor
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    • "), markers of bone density (Zitzmann et al., 2001a; Guadalupe-Grau et al., 2010b), body composition (Nielsen et al., 2010; Pausova et al., 2010), fat-free mass (Walsh et al., 2005), systolic blood pressure (Stanworth et al., 2008; Pausova et al., 2010) and metabolic parameters (Skjaerpe et al., 2010). On contrary, several other studies did not report any associations of CAG repeat length with lipid concentrations (Goutou et al., 2009), coronary atherosclerosis (Hersberger et al., 2005), lean body mass (Guadalupe-Grau et al., 2010a), bone metabolism (Van Pottelbergh et al., 2001), or cognitive function (Lee et al., 2010). In addition, the only previous longitudinal study reported that CAG repeat length was not predictive of 15-year changes in anthropometric parameters and lipid concentrations (Page et al., 2006). "
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    ABSTRACT: Previous studies reported correlations of CAG repeat length with sex hormone serum concentrations and cardiometabolic risk factors, but were limited by small cross-sectional samples. We used data of 1859 men aged 20-79 years from the population-based Study of Health in Pomerania (SHIP) to investigate the direct and modulating effects of CAG repeat length on androgen action and cardiometabolic risk factors. We performed cross-sectional and longitudinal linear and Poisson regression models adjusted for age, smoking, physical activity, alcohol consumption and body mass index. The CAG repeat length was categorized into quartiles and low total testosterone (TT) defined according to the age-specific (by decades) 10th percentile, respectively. Age-adjusted cross-sectional linear regression models showed a positive association between CAG repeat length and serum testosterone concentrations [β coefficient for TT, 0.099 (p = 0.028) and for free T, 0.002 (p = 0.001), respectively]. After a 5.0 year median follow-up period, men with CAG repeat length in the lowest quartile had an increased risk of incident low TT concentrations [relative risk (RR), 2.31; 95% confidence interval (CI), 1.18-4.55]. We found no direct association between CAG repeat length and cardiometabolic risk factors in cross-sectional and longitudinal multivariable linear regression analyses; whereas men with longer CAG repeat length and low TT concentrations showed the highest risk of incident MetS (RR, 1.51; 95% CI, 1.05-2.16). CAG repeat length is a risk factor of incident low TT concentrations and a contributing factor of testosterone-related cardiometabolic effects. The added clinical value of a combined assessment of CAG repeat length and serum TT concentrations merits further investigation.
    International Journal of Andrology 09/2011; 35(4):511-20. DOI:10.1111/j.1365-2605.2011.01220.x · 3.70 Impact Factor
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