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Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats

Department of Reproductive Biology (I.T.H.), Imperial College London, Hammersmith Campus, W12 0NN London, United Kingdom; Arthritis Research Campaign Epidemiology Unit (S.R.P., K.L.L., W.T., T.W.O., S.L.J., J.D.F., A.J.S.), The University of Manchester, M13 9PT Manchester, United Kingdom; Centre for Integrated Genomic Medical Research (H.P., D.P.), The University of Manchester, M13 9PT Manchester, United Kingdom; Department of Physiology (M.J.), University of Turku, 20014 Turku, Finland; Leuven University Division of Geriatric Medicine (S.B.), Katholieke Universiteit Leuven, 3000 Louvain/Leuven, Belgium; Leuven University Center for Metabolic Bone Diseases (S.B., H.B., D.V.), and Division of Endocrinology (D.V.), Katholieke Universiteit Leuven, 3000 Louvain/Leuven, Belgium; Clinical Radiology (J.E.A., K.A.W.), Imaging Science and Biomedical Engineering, The University of Manchester, M13 9PT Manchester, United Kingdom; Department of Obstetrics, Gynaecology and Andrology (G.B.), Albert Szent-György Medical University, 6701 Szeged, Hungary; Department of Medicine (F.C.), Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago, Centro de Investigacion Biomedica en Red de Fisiopatología Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, 15701 Santiago de Compostela, Spain; Andrology Unit (G.F.), Department of Clinical Physiopathology, University of Florence, 50121 Florence, Italy; Scanian Andrology Centre (A.G.), Department of Urology, Malmö University Hospital, University of Lund, 221 00 Lund, Sweden; Department of Endocrinology (T.S.H.), Royal Free and University College Hospital Medical School, Royal Free Hospital, NW3 2PF Hampstead, United Kingdom; Department of Andrology and Reproductive Endocrinology (K.K.), Medical University of Lodz, 90 419 Lodz, Poland; Department of Human Nutrition (M.E.J.L.), University of Glasgow, G32 2ER Glasgow, Scotland; Clinical Gerontology (N.P.), The University of Manchester, Hope Hospital, M6 8HD Salford, United Kingdom; Andrology Unit (M.P.), United Laboratories of Tartu University Clinics, 50406 Tartu, Estonia; and Department of Endocrinology (F.C.W.W.), Manchester Royal Infirmary, The University of Manchester, M13 9WL Manchester, United Kingdom

Address all correspondence and requests for reprints to: Prof. Ilpo Huhtaniemi, Department of Reproductive Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: ilpo.huhtaniemi{at}imperial.ac.uk.

Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive.

Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length.

Design: We conducted a multinational prospective cohort observational study with cross-sectional baseline data.

Setting: This was a population survey of community-dwelling men.

Participants: Men (40–79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men.

Main Outcome Measures: We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action.

Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions.

Conclusions: The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

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