Pituitary response to GnRH stimulation tests in different FSHB-211 G/T genotypes.

Sansone, Andrea; Schubert, Maria; Tüttelmann, Frank; Krallmann, Claudia; Zitzmann, Michael; Kliesch, Sabine; Gromoll, Jörg

Abstract

Study question: Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes? Summary answer: The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs. What is known already: The FSHB-211 G > T single nucleotide polymorphism (SNP) is known to affect pituitary FSH output by impairing the transcriptional activity of FSHB. Study design, size, duration: This was a cross-sectional, retrospective study on 67 male subjects (mean age: 24.6 ± 10.3 years) undergoing a GnRH stimulation test for diagnostic purposes in cases of secondary hypogonadism. Participants/materials, setting, methods: A GnRH stimulation test was performed by administering an i.v. bolus of 100 µg of the GnRH-analogue gonadorelin acetate to all patients, with blood samples drawn from the cubital vein immediately prior to injection (T0) and 30 (T1) and 45 minutes (T2) after. Clinical and genetic data were retrieved from a computerized database. Linear longitudinal mixed-effect models were used to assess the effects of SNP genotype on FSH and LH levels over time via additive and recessive models. Main results and the role of chance: An overall marked increase in serum FSH and LH following administration i.v. of 100 µg of an LHRH-analogue was found (P < 0.0001 for linear trend, both models). Peak levels of LH were significantly higher in TT carriers than in GT and GG carriers (P = 0.012); no significant between-groups difference was found concerning stimulated FSH levels. In both the additive and recessive model, the main effect of T allele(s) did not reach statistical significance concerning FSH levels (P = 0.9502 and P = 0.8576, respectively), yet interaction effects over time demonstrated an attenuated response in T-allele carriers compared to the GG-allele carriers (P = 0.0219 and P = 0.0276). Main and interaction effects for LH were significant in both the additive (P = 0.0022 and P = 0.0013, respectively) and recessive model (P = 0.0025 and P = 0.0016, respectively). Limitations, reasons for caution: Given the retrospective nature of the study and the small number of TT carriers, results should be interpreted with caution. Wider implications of the findings: The FSHB c.-211G>T polymorphism might result in an impaired response to endogenous, as well as exogenous, GnRH stimulation. This finding might contribute to the clinical phenotype of reduced testicular volume and sperm count for patients carrying one or two T alleles. Study funding/competing interest(s): Parts of the study were supported by the German Research Foundation (CRU326 Male Germ Cells). On behalf of all authors, the corresponding author states that there is no conflict of interest. Trial registration number: NA.