Background: Single nucleotide polymorphisms (SNPs) related to genes encoding the FSHβ subunit and FSH receptor (FSHB/FSHR) affect FSH production (FSHB c.-211G>T) and receptor sensitivity/expression in vitro (FSHR c.2039A>G & FSHR c.-29G>A). FSHR c.2039A>G, but not FSHR c.-29G>A, is associated with increased FSH levels in adult women, while there are conflicting results on FSHB c.-211G>T. We previously revealed that FSHB c.-211G>T and FSHR c.-29G>A delay pubertal onset in girls.
Objective and hypotheses: This present study aims to investigate the impact of the three SNPs on hormonal as well as morphologic parameters in healthy girls.
Method: Participants were recruited as part of two population-based cohort studies of healthy children and adolescents: The COPENHAGEN Puberty Study (813 years) & The Mother-Child Cohort (915 years) (n=574). In a subgroup, ovarian transabdominal ultrasound) was performed (n=91). Subjects were genotyped for SNPs using KASP assays and grouped according to pubertal stages (Tanners classification: B1/B2+3/B4+5). We compiled genetic, hormone and morphologic data of which minor parts have previously been reported. We assessed associations of the genotypes with circulating hormone levels and ovarian morphology.
Results: When evaluated separately, FSHR c.2039A>G, but not FSHR c.-29G>A, affected FSH levels in B2+3: r=0.1, P=0.02 and B4+5: r=0.2, P=0.01. In a combined model, cumulative minor allele counts of both FSHR SNPs were associated with FSH levels (r=0.2, P=0.01). FSHB c.-211G>T did not affect FSH levels. AMH, inhibin-B and estradiol levels were not associated with the SNPs. In prepubertal girls (B1, n=11), cumulative minor allele counts of all three SNPs were negatively correlated with the number of large ovarian follicles (≧5 mm) (r=−0.8, P=0.004) and positively correlated with small vs. large follicles ratio (14 vs ≧5 mm) (r=0.7, P=0.02) (relative underrepresentation of large follicles).
Conclusion: FSHR variants were associated with FSH levels in healthy early- and late-pubertal girls. We further reveal a combined negative effect of FSHB/FSHR minor allelic variants on follicular growth in prepubertal girls. We hypothesize that this represents the morphologic parallel to the previously observed delay of pubertal onset in girls.
Funding: Danish Agency for Science, Technology and Innovation (09-067180), Danish Ministry of the Environment, CeHoS (MST-621-00065), Capital Region of Denmark (December 2011), Ministry of Higher Education and Science (DFF1331-00113).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology