title: Male 41, XXY* mice as a model for klinefelter syndrome: hyperactivation of leydig cells.
abstract: 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, XX(Y)* 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, XX(Y)* mice of different ages. Although Leydig cell hyperplasia was prominent, isolated XX(Y)* Leydig cells showed a mature mRNA expression profile and a significantly higher transcriptional activity compared with controls. Stimulation of XX(Y)* 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 XX(Y)* 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 XX(Y)* males as such influences their endocrine function.
authors.affiliation: Centre of Reproductive Medicine and Andrology, University Clinics, Domagkstrasse 11, 48149 Muenster, Germany. joachim.wistuba@ukmuenster.de
authors.forename: Joachim
authors.initials: J
authors.lastname: Wistuba
authors.forename: C Marc
authors.initials: CM
authors.lastname: Luetjens
authors.forename: Jan-Bernd
authors.initials: JB
authors.lastname: Stukenborg
authors.forename: Andreas
authors.initials: A
authors.lastname: Poplinski
authors.forename: Steffi
authors.initials: S
authors.lastname: Werler
authors.forename: Matthias
authors.initials: M
authors.lastname: Dittmann
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Damm
authors.forename: Tuula
authors.initials: T
authors.lastname: Hämäläinen
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
authors.forename: Jörg
authors.initials: J
authors.lastname: Gromoll
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006965:Hyperplasia; D017404:In Situ Hybridization, Fluorescence; D007713:Klinefelter Syndrome / Q000235:genetics* / Q000473:pathology*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D011974:Receptors, LH / Q000235:genetics; D014960:X Chromosome / Q000235:genetics*
chemical_list: D006063:Chorionic Gonadotropin; D012333:RNA, Messenger; D011974:Receptors, LH