Date Published: March 29, 2013
Publisher: Blackwell Publishing Ltd
Author(s): M Grigorova, M Punab, O Poolamets, S Sõber, V Vihljajev, B Žilaitienė, J Erenpreiss, V Matulevičius, I Tsarev, M Laan.
Follicle-stimulating hormone receptor (FSHR) contains two common linked polymorphisms, Thr307Ala (rs6165) and Asn680Ser (rs6166), shown to modulate ovarian function in women. The effect on male fertility and reproductive parameters has been inconclusive. We studied FSHR Asn680Ser polymorphism in a large study group (n = 1790) from the Baltic countries. The population-based Baltic male cohort (Estonians, Latvians, Lithuanians; n = 1052) and Estonian oligo-/azoospermic (sperm concentration <20 × 106/mL) idiopathic infertile patients (n = 738) were genotyped for the FSHR Asn680Ser using PCR-RFLP. Genetic associations were tested using linear regression under additive model and results were combined in meta-analysis. No statistical difference was detected in allelic distribution of the FSHR Asn680Ser between the Baltic cohort and Estonian male infertility group. A consistent significant association was detected between the FSHR Ser680 allele and lower total testes volume in both, the Baltic cohort (p = 0.010, effect = −1.16 mL) and Estonian idiopathic infertility group (p = 0.007, effect = −1.77 mL). In meta-analysis, the statistical significance was enhanced (p = 0.000066, effect = −1.40 mL). Meta-analysis supported further associations with moderate effect between the FSHR Ser680 variant and higher serum FSH (p = 0.072), lower Inhibin B (p = 0.037) and total testosterone (p = 0.034). No statistically significant associations were identified with serum LH and estradiol, and sperm parameters. In conclusion, the study in 1790 Baltic men shows statistically highly significant association of the FSHR Asn680Ser with total testes volume and supportive association with serum reproductive hormone levels indicative to the functional effect of the alternative FSHR variants on male reproductive physiology.
Follicle-stimulating hormone (FSH) contributes profoundly to the regulation of human reproductive processes. In women, FSH binds to FSH receptor (FSHR) on the ovarian granulosa cells driving the hormonal and cellular events that control folliculogenesis and oocyte maturation (Edson et al., 2009). In men, FSHR is located on the testicular Sertoli cells that are critical for quantitatively and qualitatively normal spermatogenesis. Binding of FSH to FSHR activates proliferation of Sertoli cells in foetal, neonatal and pubertal development and promotes mitosis in spermatogonia (Nieschlag et al., 1999; Plant & Marshall, 2001; Ruwanpura et al., 2010). FSH receptor (FSHR) is coded by the FSHR gene (chr 2p21) consisting of 10 exons and encoding for 695 aa residues (Gromoll et al., 1996). FSHR exon 10 contains two common non-synonymous polymorphisms, Thr307Ala (c.919A > G; rs6165) and Asn680Ser (c.2139A > G; rs6166) that have been well characterized and extensively studied (Simoni et al., 1999). These two allelic variants are in near complete linkage disequilibrium and result in two discrete combinations of FSH receptor isoforms (Thr307-Asn680, Ala307-Ser680) (Simoni et al., 2002). FSHR isoforms are almost equally prevalent in studied European populations, whereas Asian and African populations exhibit slightly higher prevalence of the Thr307-Asn680 isoform (Kuijper et al., 2010; Lalioti, 2011). In women, Ala307-Ser680 variant has been associated with higher basal FSH levels during the follicular phase and a longer menstrual cycle (reviewed in Casarini et al., 2011; Lalioti, 2011). As the carriers of the FSHR Ala307-Ser680 isoform were consistently shown to require elevated FSH dosage in controlled ovarian hyperstimulation in in vitro fertilization (Perez et al., 2000; Behre et al., 2005), there is a potential for pharmacogenetic application in optimizing treatment (reviewed in Altmäe et al., 2011; Laan et al., 2012).
The Baltic male cohort (n = 1052; 20.1 ± 2.0 years; sperm concentration, 81.4 ± 74.0 mLn/mL; Table 1) and Estonian idiopathic infertile male patients (n = 738; 31.7 ± 6.1 years; sperm concentration, 7.0 ± 6.0 mLn/mL) were genotyped for the human FSHR polymorphism rs6166 (c.2139 A > G; Asn680Ser). No statistical difference was observed in FSHR rs6166 allele and genotype frequencies when comparing the Baltic cohort with Estonian infertility patients, as well as among the oligo- and azoospermia subgroups of infertile men (Fisher’s exact test, P-value >0.70) (Table 2).
There has been a shortage of conclusive evidence on the association of the two common FSHR isoforms (Thr307-Asn680, Ala307-Ser680) (Simoni et al., 2002) with male reproductive parameters. The present analysis of FSHR Asn680Ser polymorphism (rs6166) in 1790 Baltic men represents the largest conducted study addressing this issue. No difference was observed in the allele frequencies of FSHR Asn680Ser polymorphism between population-based Baltic control cohort and Estonian idiopathic infertility patient group. This supports a recent meta-analysis of over 1644 infertile patients and 1748 fertile controls indicating lack of association with male infertility (Wu et al., 2012).