title: The FSHB -211G>T variant attenuates serum FSH levels in the supraphysiological gonadotropin setting of Klinefelter syndrome.
abstract: Klinefelter syndrome (47, XXY) is the most frequent genetic cause of male infertility and individuals share the endocrine hallmark of hypergonadotropic hypogonadism. Single-nucleotide polymorphisms located within the FSHB/FSHR gene were recently shown to impact serum follicle-stimulating hormone (FSH) levels and other reproductive parameters in men. The objective of this study was to analyse the effect of FSHB-211G>T (c.-280G>T, rs10835638) as well as FSHR c.2039G>A (rs6166) and FSHR c.-29G>A (rs1394205) on endocrine and reproductive parameters in untreated and testosterone-treated Klinefelter patients. Patients were retrospectively selected from the clientele attending a university-based andrology centre. A total of 309 non-mosaic Klinefelter individuals between 18 and 65 years were included and genotyped for the variants by TaqMan assays. The untreated group comprised 248 men, in which the FSHB -211G>T allele was significantly associated with the reduced serum follicle-stimulating hormone levels (-6.5 U/l per T allele, P=1.3 × 10(-3)). Testosterone treatment (n=150) abolished the observed association. When analysing patients before and under testosterone treatment (n=89), gonadotropin levels were similarly suppressed independently of the FSHB genotype. The FSHR polymorphisms did not exhibit any significant influence in any group, neither on the endocrine nor reproductive parameters. In conclusion, a hypergonadotropic setting such as Klinefelter syndrome does not mask the FSHB -211G>T genotype effects on the follicle-stimulating hormone serum levels. The impact was indeed more pronounced compared with normal or infertile men, whereas gonadotropin suppression under testosterone treatment seems to be independent of the genotype. Thus, the FSHB -211G>T genotype is a key determinant in the regulation of gonadotropins in different reproductive-endocrine pathopyhsiologies.
authors: Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors: Alexander S
authors: AS
authors: Busch
authors: Institute of Human Genetics, University of Münster, Münster, Germany.
authors: Frank
authors: F
authors: Tüttelmann
authors: Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors: Michael
authors: M
authors: Zitzmann
authors: Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors: Sabine
authors: S
authors: Kliesch
authors: Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors: Jörg
authors: J
authors: Gromoll
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D005640:Follicle Stimulating Hormone / Q000097:blood*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D005838:Genotype; D006062:Gonadotropins / Q000378:metabolism*; D006801:Humans; D007713:Klinefelter Syndrome / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D037201:Follicle Stimulating Hormone, beta Subunit; D006062:Gonadotropins; D005640:Follicle Stimulating Hormone