This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zitzmann, M. Articles by Nieschlag, E. Search for Related Content PubMed PubMed Citation Articles by Zitzmann, M. Articles by Nieschlag, E.

X-Chromosome Inactivation Patterns and Androgen Receptor Functionality Influence Phenotype and Social Characteristics as Well as Pharmacogenetics of Testosterone Therapy in Klinefelter Patients

Institute of Reproductive Medicine, University of Munster, D-48129 Munster, Germany

Address all correspondence and requests for reprints to: Dr. E. Nieschlag, Institute of Reproductive Medicine, University of Munster, Domagkstrasse 11, D-48129 Munster, Germany. E-mail: nieschl{at}uni-muenster.de.

Klinefelter syndrome is characterized by a vast range of phenotypes related to androgen effects. Testosterone (T) acts via the X-linked androgen receptor gene carrying the CAG repeat (CAGn) polymorphism, the length of which is inversely associated with androgen action and might account for the marked variation in phenotypes. In 77 newly diagnosed and untreated Klinefelter patients with a 47,XXY karyotype we assessed phenotype and social traits in relation to X-weighted biallelic CAGn length using X-chromosome inactivation analysis after digestion of leukocyte DNA with methylation-sensitive HpaII. Forty-eight men were hypogonadal and received T substitution therapy; in these, pharmacogenetic effects were investigated. The shorter CAGn allele was preferentially inactive. CAGn length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to CAGn length. The presence of long CAGn was predictive for gynecomastia and smaller testes, whereas short CAGn were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer CAGn to be diagnosed earlier in life. Under T substitution, men with shorter CAGn exhibited a more profound suppression of LH levels, augmented prostate growth, and higher hemoglobin concentrations. A significant genotype-phenotype association exists in Klinefelter patients: androgen effects on appearance and social characteristics are modulated by the androgen receptor CAGn polymorphism. The effects of T substitution are pharmacogenetically modified. This finding is magnified by preferential inactivation of the more functional short CAGn allele.

This article has been cited by other articles:

				R D Stanworth, D Kapoor, K S Channer, and T H Jones Androgen receptor CAG repeat polymorphism is associated with serum testosterone levels, obesity and serum leptin in men with type 2 diabetes Eur. J. Endocrinol., December 1, 2008; 159(6): 739 - 746. [Abstract] [Full Text] [PDF]

				A. Balestrieri, L. Zirilli, B. Madeo, E. Pignatti, G. Rossi, C. Carani, and V. Rochira 21-Hydroxylase Deficiency and Klinefelter Syndrome in an Adult Man: Striking a Balance Between Androgen Excess and Insufficiency J Androl, November 1, 2008; 29(6): 605 - 609. [Full Text] [PDF]

				S. T. Page, J. K. Amory, and W. J. Bremner Advances in Male Contraception Endocr. Rev., June 1, 2008; 29(4): 465 - 493. [Abstract] [Full Text] [PDF]

				M. Zitzmann and E. Nieschlag Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3844 - 3853. [Abstract] [Full Text] [PDF]

				E. Vorona, M. Zitzmann, J. Gromoll, A. N. Schuring, and E. Nieschlag Clinical, Endocrinological, and Epigenetic Features of the 46,XX Male Syndrome, Compared with 47,XXY Klinefelter Patients J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3458 - 3465. [Abstract] [Full Text] [PDF]

				C. Wang, P. Christenson, and R. Swerdloff Clinical Relevance of Racial and Ethnic Differences in Sex Steroids J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2433 - 2435. [Full Text] [PDF]

				M. Zitzmann, S. Faber, and E. Nieschlag Association of Specific Symptoms and Metabolic Risks with Serum Testosterone in Older Men J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4335 - 4343. [Abstract] [Full Text] [PDF]

				E. Itti, I. T. Gaw Gonzalo, A. Pawlikowska-Haddal, K. B. Boone, A. Mlikotic, L. Itti, F. S. Mishkin, and R. S. Swerdloff The Structural Brain Correlates of Cognitive Deficits in Adults with Klinefelter's Syndrome J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1423 - 1427. [Abstract] [Full Text] [PDF]

				L. Aksglaede, A. M. Wikstrom, E. R.-D. Meyts, L. Dunkel, N. E. Skakkebaek, and A. Juul Natural history of seminiferous tubule degeneration in Klinefelter syndrome Hum. Reprod. Update, January 1, 2006; 12(1): 39 - 48. [Abstract] [Full Text] [PDF]

				A. R. Zinn, P. Ramos, F. F. Elder, K. Kowal, C. Samango-Sprouse, and J. L. Ross Androgen Receptor CAGn Repeat Length Influences Phenotype of 47,XXY (Klinefelter) Syndrome J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5041 - 5046. [Abstract] [Full Text] [PDF]

				Y. Lue, J. D. Jentsch, C. Wang, P. N. Rao, A. P. Sinha Hikim, W. Salameh, and R. S. Swerdloff XXY Mice Exhibit Gonadal and Behavioral Phenotypes Similar to Klinefelter Syndrome Endocrinology, September 1, 2005; 146(9): 4148 - 4154. [Abstract] [Full Text] [PDF]