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

OBJECTIVE 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. DESIGN Community-based, cross-sectional study of 3369 men aged 40-79 years. METHODS 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. RESULTS 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. CONCLUSION 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.

[1]  J. Janowsky,et al.  Cognition is not modified by large but temporary changes in sex hormones in men. , 2009, The Journal of clinical endocrinology and metabolism.

[2]  A. Silman,et al.  The association between different cognitive domains and age in a multi‐centre study of middle‐aged and older European men , 2009, International journal of geriatric psychiatry.

[3]  N. Pendleton,et al.  Activational effects of sex hormones on cognition in men , 2009, Clinical endocrinology.

[4]  A. Silman,et al.  The European Male Ageing Study (EMAS): design, methods and recruitment. , 2009, International journal of andrology.

[5]  O. Wolkowitz,et al.  Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) , 2009, Frontiers in Neuroendocrinology.

[6]  D. V. von Mühlen,et al.  Effects of Dehydroepiandrosterone Supplementation on Cognitive Function and Quality of Life: The DHEA and Well‐Ness (DAWN) Trial , 2008, Journal of the American Geriatrics Society.

[7]  A. Silman,et al.  Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. , 2008, The Journal of clinical endocrinology and metabolism.

[8]  G. Hankey,et al.  Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not. The Health In Men Study , 2008, Clinical endocrinology.

[9]  F. Huppert,et al.  Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial. , 2008, The Journal of clinical endocrinology and metabolism.

[10]  W. Bremner,et al.  Advances in male contraception. , 2008, Endocrine reviews.

[11]  Matthew T. Haren,et al.  Testosterone and cognitive function in ageing men: data from the Florey Adelaide Male Ageing Study (FAMAS). , 2007, Maturitas.

[12]  N. Goldman,et al.  Sex differences in the relationship between DHEAS and health , 2007, Experimental Gerontology.

[13]  C. Brayne,et al.  The burden of diseases on disability-free life expectancy in later life. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[14]  H. Raff,et al.  Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. , 2007, The Journal of clinical endocrinology and metabolism.

[15]  A. Herlitz,et al.  Negative Association of Testosterone on Spatial Visualization in 35 to 80 Year Old Men , 2006, Cortex.

[16]  M. Arroyo,et al.  Testosterone: Activation or organization of spatial cognition? , 2006, Biological Psychology.

[17]  P. Bélanger,et al.  Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women , 2006, The Journal of Steroid Biochemistry and Molecular Biology.

[18]  S. MacDonald,et al.  The association between endogenous free testosterone and cognitive performance: A population-based study in 35 to 90 year-oldmen and women , 2006, Psychoneuroendocrinology.

[19]  C. Blair.  How similar are fluid cognition and general intelligence? A developmental neuroscience perspective on fluid cognition as an aspect of human cognitive ability , 2006, Behavioral and Brain Sciences.

[20]  P A Wolf,et al.  Association of sex steroid hormones with brain morphology and cognition in healthy elderly men , 2005, Neurology.

[21]  J. Kaufman,et al.  The decline of androgen levels in elderly men and its clinical and therapeutic implications. , 2005, Endocrine reviews.

[22]  S. Asthana,et al.  Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment , 2005, Neurology.

[23]  E. D. de Haan,et al.  Endogenous sex hormone levels and cognitive function in aging men , 2005, Neurology.

[24]  Stephanie J. Fonda,et al.  Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[25]  Rozmin Halari,et al.  Sex differences and individual differences in cognitive performance and their relationship to endogenous gonadal hormones and gonadotropins. , 2005, Behavioral neuroscience.

[26]  D. Bennett,et al.  Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. , 2004, Archives of neurology.

[27]  J. Gabrieli,et al.  Insights into the ageing mind: a view from cognitive neuroscience , 2004, Nature Reviews Neuroscience.

[28]  Kristine Yaffe,et al.  Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men , 2003, Biological Psychiatry.

[29]  Michael Zitzmann,et al.  The CAG repeat polymorphism within the androgen receptor gene and maleness. , 2003, International journal of andrology.

[30]  Arthur F Kramer,et al.  Achieving and maintaining cognitive vitality with aging. , 2002, Mayo Clinic proceedings.

[31]  Oliver T. Wolf,et al.  Endogenous Estradiol and Testosterone Levels Are Associated with Cognitive Performance in Older Women and Men , 2002, Hormones and Behavior.

[32]  Kristine Yaffe,et al.  Sex Hormones and Cognitive Function in Older Men , 2002, Journal of the American Geriatrics Society.

[33]  A. Araujo,et al.  Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. , 2002, The Journal of clinical endocrinology and metabolism.

[34]  W. Morton Hair,et al.  Activational effects of testosterone on cognitive function in men , 2001, Neuropsychologia.

[35]  A. Araujo,et al.  Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men , 2001, Biological Psychiatry.

[36]  S. Asthana,et al.  Testosterone supplementation improves spatial and verbal memory in healthy older men , 2001, Neurology.

[37]  E. Metter,et al.  Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. , 2001, The Journal of clinical endocrinology and metabolism.

[38]  Yong Gu,et al.  Visual Responses of Neurons in the Pretectal Nucleus lentiformis mesencephali to Moving Patterns Within and Beyond Receptive Fields in Pigeons , 2001, Brain, Behavior and Evolution.

[39]  Christian E Elger,et al.  Androgen receptor mRNA expression in the human hippocampus , 2000, Neuroscience Letters.

[40]  S. Resnick,et al.  The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. , 2000, Archives of internal medicine.

[41]  David A. Bennett,et al.  Decline of language among women and men with Alzheimer's disease , 2000, Neurobiology of Aging.

[42]  M. Albert,et al.  Change in cognitive function in older persons from a community population: relation to age and Alzheimer disease. , 1999, Archives of neurology.

[43]  A. Vermeulen,et al.  A critical evaluation of simple methods for the estimation of free testosterone in serum. , 1999, The Journal of clinical endocrinology and metabolism.

[44]  E. Barrett-Connor,et al.  Endogenous sex hormones and cognitive function in older men. , 1999, The Journal of clinical endocrinology and metabolism.

[45]  P J Garry,et al.  Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. , 1997, Metabolism: clinical and experimental.

[46]  E. Wilson,et al.  Reduced androgen receptor gene expression with first exon CAG repeat expansion. , 1996, Molecular endocrinology.

[47]  Mitsuhiro Kawata,et al.  Roles of steroid hormones and their receptors in structural organization in the nervous system , 1995, Neuroscience Research.

[48]  R. Zec,et al.  The neuropsychology of aging , 1995, Experimental Gerontology.

[49]  E. Barrett-Connor,et al.  A Prospective Study of Dehydroepiandrosterone Sulfate and Cognitive Function in an Older Population: The Rancho Bernardo Study , 1994, Journal of the American Geriatrics Society.

[50]  M. Meaney,et al.  Androgen binding sites in human temporal cortex. , 1990, Neuroendocrinology.

[51]  W. Cleveland.  Robust Locally Weighted Regression and Smoothing Scatterplots , 1979 .

[52]  A. Silman,et al.  Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. , 2009, The Journal of clinical endocrinology and metabolism.

[53]  E. Ford,et al.  Cognitive functioning as a predictor of functional disability in later life. , 2006, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[54]  A. Drewnowski,et al.  Journals of Gerontology , 2001 .

[55]  D. Tulsky,et al.  WAIS-III WMS-III Technical manual , 1977 .

[56]  P. Osterrieth.  Le test de copie d'une figure complexe , 1944 .