The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males
Michael Zitzmann, Maik Brune, Britta Kornmann, Jörg Gromoll, Ralf Junker,
Eberhard Nieschlag,
Ralf Junker
Institute of Clinical Chemistry and Laboratory Medicine and Institute of Arteriosclerosis Research of the University, D-48129 Münster, Germany
Search for more papers by this authorMichael Zitzmann, Maik Brune, Britta Kornmann, Jörg Gromoll, Ralf Junker,
Eberhard Nieschlag,
Ralf Junker
Institute of Clinical Chemistry and Laboratory Medicine and Institute of Arteriosclerosis Research of the University, D-48129 Münster, Germany
Search for more papers by this author Prof. Dr E. Nieschlag, FRCP, Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48129 Münster, Germany. Tel.: +49 251 83 56097; Fax: +49 251 83 56093; E-mail: [email protected]
Abstract
OBJECTIVE Bone metabolism and bone density (BD) are influenced by sex hormones. Testosterone (T) action is exerted through the androgen receptor (AR). We investigated the potential impact of the CAG repeat (CAGR) polymorphism within the AR gene on BD and bone metabolism in healthy younger males.
PATIENTS AND MEASUREMENTS The number of CAGRs in 110 healthy men aged 20–50 years was determined by sequence analysis. We assessed BD by the radiation-free method of quantitative ultrasound (QUS) of the phalanges. Serum levels of bone-specific alkaline phosphatase (BAP) and urine secretion of free deoxypyridinoline (DPD, corrected for creatinine), serum levels of sex hormones, body fat content and lifestyle factors were determined.
RESULTS In stepwise multiple regression models controlling for age, body fat content and lifestyle factors, the number of CAGRs was an independent negative predictor of BD (partial r = − 0·286, P = 0·001), whereas it was positively associated with markers of bone turnover (for BAP: partial r = 0·32, P = 0·001; for DPD: partial r = 0·241, P = 0·013). Levels of free T and oestradiol showed an independent and positive association with BD; age contributed significantly to lower BD. Age and free T were negatively associated with markers of bone turnover, whereas oestradiol showed a positive correlation with BAP and DPD. anova in groups according to age and the CAGR length suggested an increased age-dependent bone loss in subjects with a CAGR length of 22–31 compared with 14–21 CAGRs (overall P < 0·01).
CONCLUSIONS A high number of CAG repeats within the androgen receptor gene attenuates testosterone effects on bone density and bone metabolism. This seems to be associated with accelerated age-dependent bone loss.
References
- Albagha, O.M., McGuigan, F.E., Reid, D.M., Ralston, S.H. (2001) Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. Journal of Bone Mineral Research, 16 128–134.
- Alenfeld, F.E., Wüster, C., Funck, C., Pereira-Lima, J.F., Fritz, T., Meeder, P.J., Ziegler, R. (1998) Ultrasound measurements at the proximal phalanges in healthy women and patients with hip fractures. Osteoporosis International, 8 393–398.DOI: 10.1007/s001980050081
- Becherini, L., Gennari, L., Masi, L., Mansani, R., Massart, F., Morelli, A., Falchetti, A., Gonnelli, S., Fiorelli, G., Tanini, A., Brandi, M.L. (2000) Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women. Human Molecular Genetics, 9 2043–2050.DOI: 10.1093/hmg/9.13.2043
- Behre, H.M., Kliesch, S., Leifke, E., Link, T.M., Nieschlag, E. (1997) Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. Journal of Clinical Endocrinology and Metabolism, 82 2386–2390.
- Beilin, J., Ball, E.M., Favaloro, J.M., Zajac, J.D. (2000) Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. Journal of Molecular Endocrinology, 25 85–96.
- Bellido, T., Jilka, R.L., Boyce, B.F., Girasole, G., Broxmeyer, H., Dalrymple, S.A., Murray, R., Manolagas, S.C. (1995) Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. Journal of Clinical Investigation, 95 2886–2895.
- Belsham, D.D., Yee, W.C., Greenberg, C.R., Wrogemann, K. (1992) Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy. Journal of the Neurological Sciences, 112 133–138.
- Bertelloni, S., Baroncelli, G.I., Federico, G., Cappa, M., Lala, R., Saggese, G. (1998) Altered bone mineral density in patients with complete androgen insensitivity syndrome. Hormone Research, 50 309–314.
- Chamberlain, N.L., Driver, E.D., Miesfeld, R.L. (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Progress in Nucleic Acid Research and Molecular Biology, 22 3181–3186.
- Damien, E., Price, J.S., Lanyon, L.E. (2000) Mechanical strain stimulates osteoblast proliferation through the estrogen receptor in males as well as females. Journal of Bone and Mineral Research, 15 2169–2177.
- Erben, R.G., Eberle, J., Stahr, K., Goldberg, M. (2000) Androgen deficiency induces high turnover osteopenia in aged male rats: a sequential histomorphometric study. Journal of Bone and Mineral Research, 15 1085–1098.
- Feltrin, G.P., Nardin, M., Marangon, A., Khadivi, Y., Calderone, M., De Conti, G. (2000) Quantitative ultrasound at the hand phalanges: comparison with quantitative computed tomography of the lumbar spine in postmenopausal women. European Journal of Radiology, 10 826–831.
-
Finkelstein, J.S. (1998) Androgens and bone metabolism. In: Testosterone: Action, Deficiency, Substitution
(eds E. Nieschlag &
H. M. Behre), pp. 187–208. Springer. Berlin, New York.
10.1007/978-3-642-72185-4_6 Google Scholar
- Fiore, C.E., Pennisi, P., Gibilaro, M., Di Fazzio, S., Impellizzieri, D., Ramirez, M.G. (1999) Correlation of quantitative ultrasound of bone with biochemical markers of bone resorption in women with osteoporotic fractures. Journal of Clinical Densitometry, 2 231–239.
- Fohr, B., Schulz, A., Battmann, A. (2000) Sex steroids and bone metabolism: comparison of in vitro effects of 17beta-estradiol and testosterone on human osteosarcoma cell lines of various gender and differentiation. Experimental and Clinical Endocrinology and Diabetes, 108 414–423.
- Fukuda, S. & Iida, H. (2000) Effects of orchidectomy on bone metabolism in beagle dogs. Journal of Veterinary Medical Science, 62 69–73.
- Gambacciani, M., Ciaponi, M., Cappagli, B., Benussi, C., Genazzani, A.R. (2000) Longitudinal evaluation of perimenopausal femoral bone loss: effects of a low-dose oral contraceptive preparation on bone mineral density and metabolism. Osteoporosis International, 11 544–548.DOI: 10.1007/s001980050012
- Goerres, G., Altermatt, M., Muller-Brand, J., Tyndall, A., Theiler, R. (1998) Bone ultrasound and diagnosis of osteoporosis: correlation of 2 quantitative ultrasound methods with bone density. Schweizerische Rundschau für Medizin-Praxis, 87 1089–1095.
- Gori, F., Hofbauer, L.C., Conover, C.A., Khosla, S. (1999) Effects of androgens on the insulin-like growth factor system in an androgen-responsive human osteoblastic cell line. Endocrinology, 140 5579–5586.
- Gudivaka, R., Schoeller, D.A., Kushner, R.F., Bolt, M.J. (1999) Single- and multifrequency models for bioelectrical impedance analysis of body water compartments. Journal of Applied Physiology, 87 1087–1096.
- Guglielmi, G., Cammisa, M., De Serio, A., Scillitani, A., Chiodini, I., Carnevale, V., Fusilli, S. (1999) Phalangeal US velocity discriminates between normal and vertebrally fractured subjects. European Journal of Radiology, 9 1632–1637.
- Hiort, O., Holterhus, P.M., Horter, T., Schulze, W., Kremke, B., Bals-Pratsch, M., Sinnecker, G.H., Kruse, K. (2000) Significance of mutations in the androgen receptor gene in males with idiopathic infertility. Journal of Clinical Endocrinology and Metabolism, 85 2810–2815.
- Ho, A.Y., Yeung, S.S., Kung, A.W. (2000) PvuII polymorphisms of the estrogen receptor alpha and bone mineral density in healthy southern Chinese women. Calcified Tissue International, 66 405–408.DOI: 10.1007/s002230010082
- Hsiao, P.W., Lin, D.L., Nakao, R., Chang, C. (1999) The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. Journal of Biological Chemistry, 274 20229–20234.
- Hsing, A.W., Gao, Y.T., Wu, G., Wang, X., Deng, J., Chen, Y.L., Sesterhenn, I.A., Mostofi, F.K., Benichou, J., Chang, C. (2000) Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Research, 60 5111–5116.
- Irvine, R.A., Ma, H., Yu, M.C., Ross, R.K., Stallcup, M.R., Coetzee, G.A. (2000) Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Human Molecular Genetics, 9 267–274.DOI: 10.1093/hmg/9.2.267
- Kushner, R.F. & Schoeller, D.A. (1986) Estimation of total body water by bioelectrical impedance analysis. American Journal of Clinical Nutrition, 44 417–424.
- Langdahl, B.L., Lokke, E., Carstens, M., Stenkjaer, L.L., Eriksen, E.F. (2000) A TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are not. Journal of Bone and Mineral Research, 15 2222–2230.
- Leifke, E., Korner, H.C., Link, T.M., Behre, H.M., Peters, P.E., Nieschlag, E. (1998) Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men. European Journal of Endocrinology, 138 51–58.
- Marcus, R., Leary, D., Schneider, D.L., Shane, E., Favus, M., Quigley, C.A. (2000) The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. Journal of Clinical Endocrinology and Metabolism, 85 1032–1037.
- Mariotti, C., Castellotti, B., Pareyson, D., Testa, D., Eoli, M., Antozzi, C., Silani, V., Marconi, R., Tezzon, F., Siciliano, G., Marchini, C., Gellera, C., Donato, S.D. (2000) Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscular Disorders, 10 391–397.
- Mauras, N., O'Brien, K.O., Klein, K.O., Hayes, V. (2000) Estrogen suppression in males: metabolic effects. Journal of Clinical Endocrinology and Metabolism, 85 2370–2377.
- Medras, M., Jankowska, E.A., Rogucka, E. (2001) Effects of long-term testosterone substitutive therapy on bone mineral content in men with hypergonadotrophic hypogonadism. Andrologia, 33 47–52.DOI: 10.1046/j.1439-0272.2001.00417.x
- Pace, H.V. & Rathbun, E.N. (1945) Studies on body composition, body water and chemically combined nitrogen content in relation to fat content. Journal of Biological Chemistry, 158 685–691.
- Patel, M.S., Cole, D.E., Smith, J.D., Hawker, G.A., Wong, B., Trang, H., Vieth, R., Meltzer, P., Rubin, L.A. (2000) Alleles of the estrogen receptor alpha-gene and an estrogen receptor cotranscriptional activator gene, amplified in breast cancer-1 (AIB1), are associated with quantitative calcaneal ultrasound. Journal of Bone and Mineral Research, 15 2231–2239.
- Platz, E.A., Rimm, E.B., Willett, W.C., Kantoff, P.W., Giovannucci, E. (2000) Racial variation in prostate cancer incidence and in hormonal system markers among male health professionals. Journal of the National Cancer Institute, 92 2009–2017.DOI: 10.1093/jnci/92.24.2009
- Przedlacki, J., Pluskiewicz, W., Wieliczko, M., Drozdzowska, B., Matuszkiewicz-Rowinska, J., Bogdanska-Straszynska, B., Wlodarczyk, D., Ostrowski, K. (1999) Quantitative ultrasound of phalanges and dual-energy X-ray absorptiometry of forearm and hand in patients with end-stage renal failure treated with dialysis. Osteoporosis International, 10 1–6.DOI: 10.1007/s001980050186
- Rochira, V., Faustini-Fustini, M., Balestrieri, A., Carani, C. (2000) Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters. Journal of Clinical Endocrinology and Metabolism, 85 1841–1845.
- Sartor, O., Zheng, Q., Eastham, J.A. (1999) Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology, 53 378–380.DOI: 10.1016/s0090-4295(98)00481-6
- Scopacasa, F., Horowitz, M., Wishart, J.M., Morris, H.A., Chatterton, B.E., Need, A.G. (2000) The relation between bone density, free androgen index, and estradiol in men 60–70 years old. Bone, 27 145–149.DOI: 10.1016/s8756-3282(00)00299-4
- Snyder, P.J., Peachey, H., Hannoush, P., Berlin, J.A., Loh, L., Holmes, J.H., Dlewati, A., Staley, J., Santanna, J., Kapoor, S.C., Attie, M.F., Haddad, J.G., Strom, B.L. (1999) Effect of testosterone treatment on bone mineral density in men over 65 years of age. Journal of Clinical Endocrinology and Metabolism, 84 1966–1972.
- Sowers, M., Willing, M., Burns, T., Deschenes, S., Hollis, B., Crutchfield, M., Jannausch, M. (1999) Genetic markers, bone mineral density, and serum osteocalcin levels. Journal of Bone and Mineral Research, 14 1411–1419.
- Stepan, J.J., Lachman, M., Zverina, J., Pacovsky, V., Baylink, D.J. (1989) Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. Journal of Clinical Endocrinology and Metabolism, 69 523–527.
- Vermeulen, A., Verdonck, L., Kaufman, J.M. (1999) A critical evaluation of simple methods for the estimation of free testosterone in serum. Journal of Clinical Endocrinology and Metabolism, 84 3666–3672.
- Wüster, C., Heilmann, P., Pereira-Lima, J., Schlegel, J., Anstatt, K., Soballa, T. (1998) Quantitative ultrasonometry (QUS) for the evaluation of osteoporosis risk: reference data for various measurement sites, limitations and application possibilities. Experimental and Clinical Endocrinology and Diabetes, 106 277–288.
- Yong, E.L., Lim, L.S., Wang, Q., Mifsud, A., Lim, J., Ong, Y.C., Sim, K.S. (2000) Androgen receptor polymorphisms and mutations in male infertility. Journal of Endocrinological Investigation, 23 573–577.
- Ziegler, R. (1995) Der Knochen und seine Erkrankungen, Teil II. Deutsche Medizinische Wochenschrift, 120 571–572.
Citing Literature
