Male 41, XXY Mice as a Model for Klinefelter Syndrome: Hyperactivation of Leydig Cells

• Published in: Endocrinology (Philadelphia) 2010-06, Vol.151 (6), p.2898-2910
• Main Authors: Wistuba, Joachim, Luetjens, C. Marc, Stukenborg, Jan-Bernd, Poplinski, Andreas, Werler, Steffi, Dittmann, Matthias, Damm, Oliver S, Hämäläinen, Tuula, Simoni, Manuela, Gromoll, Jörg
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Biological and medical sciences; Cells, Cultured; Chorionic gonadotropin; Chorionic Gonadotropin - pharmacology; Chromosomes; Cognitive ability; Deactivation; Embedding; Female; Flow Cytometry; Follicle-stimulating hormone; Fundamental and applied biological sciences. Psychology; Gene expression; Gonadotropins; Humans; Hyperplasia; Hypogonadism; In Situ Hybridization, Fluorescence; Inactivation; Infertility; Klinefelter Syndrome - genetics; Klinefelter Syndrome - pathology; Klinefelter's syndrome; Leydig cells; Leydig Cells - drug effects; Leydig Cells - metabolism; Luteinizing hormone; Male; Males; Methylation; Mice; Mice, Inbred C57BL; Pituitary (anterior); Polymerase Chain Reaction; Receptors, LH - genetics; RNA, Messenger - genetics; Sex chromosomes; Supernumerary; Vertebrates: endocrinology; X Chromosome - genetics; X chromosomes; X-chromosome inactivation
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-1396

Sex chromosome imbalance in males is linked to a supernumerary X chromosome, a condition resulting in Klinefelter syndrome (KS; 47, XXY). KS patients suffer from infertility, hypergonadotropic hypogonadism, and cognitive impairments. Mechanisms of KS pathophysiology are poorly understood and require further exploration using animal models. Therefore, we phenotypically characterized 41, XXY* mice of different ages, evaluated observed germ cell loss, studied X-inactivation, and focused on the previously postulated impaired Leydig cell maturation and function as a possible cause of the underandrogenization seen in KS. Xist methylation analysis revealed normal X-chromosome inactivation similar to that seen in females. Germ cell loss was found to be complete and to occur during the peripubertal phase. Significantly elevated FSH and LH levels were persistent in 41, XXY* mice of different ages. Although Leydig cell hyperplasia was prominent, isolated XXY* Leydig cells showed a mature mRNA expression profile and a significantly higher transcriptional activity compared with controls. Stimulation of XXY* Leydig cells in vitro by human chorionic gonadotropin indicated a mature LH receptor whose maximal response exceeded that of control Leydig cells. The hyperactivity of Leydig cells seen in XXY* mice suggests that the changes in the endocrine milieu observed in KS is not due to impaired Leydig cell function. We suggest that the embedding of Leydig cells into the changed testicular environment in 41 XXY* males as such influences their endocrine function. In the 41, XXY* mouse model it is shown that inactivation of the supernumerary-chromosome is normal and that observed hypergonadotropic hypogonadism is not due to impaired Leydig cell function, but that a hyperactive adult Leydig cell type is present in XXY* mice.