Male infertility is a major contributor to couple infertility, however in most cases it remains “idiopathic” and putative treatment regimens are lacking. This leads to a scenario in which intra-cytoplasmic spermatozoa injection (ICSI) is widely used in idiopathic male infertility, though the treatment burden is high for the couple and it entails considerable costs and risks. Given the crucial role of the Follicle-stimulating hormone (FSH) for spermatogenesis, FSH has been used empirically to improve semen parameters, but the response to FSH varied strongly among treated infertile men. Single nucleotide polymorphisms (SNPs) within FSH ligand/receptor genes ( FSHB/FSHR ), significantly influencing reproductive parameters in men, represent promising candidates to serve as pharmacogenetic markers to improve prediction of response to FSH. Consequently, several FSH-based pharmacogenetic studies have been conducted within the last years with unfortunately wide divergence concerning selection criteria, treatment and primary endpoints. In this review we therefore outline the current knowledge on single nucleotide polymorphisms (SNPs) in the FSH and FSH receptor genes and their putative functional effects. We compile and critically assess the previously performed pharmacogenetic studies in the male and propose a putative strategy that might allow identifying patients who could benefit from FSH treatment.
Background A genetic variant within the FSHB gene can deviate FSH action on spermatogenesis. The c.‐211G>T FSHB single nucleotide polymorphism impacts FSHB transcription and biosynthesis due to interference with the LHX3 transcription factor binding. This SNP was previously shown to be strongly associated with lowered testicular volume, reduced sperm counts, and decreased FSH levels in patients carrying one or two T‐alleles. Objective To determine the impact of the SNP FSHB c.‐211G>T on Sertoli cell (SC) number, Sertoli cell workload (SCWL) and thereby spermatogenic potential. Material and methods Testicular biopsies of 31 azoospermic, homozygous T patients (26 non‐obstructive azoospermia (NOA), and five obstructive azoospermia (OA)) were matched to patients with GG genotype. Marker proteins for SC (SOX9), spermatogonia (MAGE A4), and round spermatids (CREM) were used for semi‐automatical quantification by immunofluorescence. SCWL (number of germ cells served by one SC) was determined and an unbiased clustering on the patient groups performed. Results Quantification of SC number in NOA patients did not yield significant differences when stratified by FSHB genotype. SC numbers are also not significantly different between FSHB genotypes for the OA patient group and between NOA and OA groups. SCWL in the NOA patient cohort is significantly reduced when compared to the OA control patients; however, in neither group an effect of the genotype could be observed. The cluster analysis of the whole study cohort yielded two groups only, namely NOA and OA, and no clustering according to the FSHB genotype. Discussion and conclusion The FSHB c.‐211G>T polymorphism does not affect SC numbers or SCWL, thereby in principle maintaining the spermatogenic potential. The previously observed clinical phenotype for the FSHB genotype might therefore be caused by a hypo‐stimulated spermatogenesis and not due to a decreased SC number.
Purpose Around 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic. Follicle stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single nucleotide polymorphisms (SNP) (i.e. FSHB c.-211G>T, FSHR c.2039A>G) are associated with FSH, testicular volume and spermatogenesis. It is unknown to which extent other variants are associated with FSH levels and therewith resemble causative factors for infertility. Methods We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n=760) a Genome wide association study (GWAS) was performed (Infinium PsychArrays®) with association to FSH values (Illumina®GenomeStudiov2.0). Minor allele frequencies (MAFs) were analyzed for the discovery – and an independent normozoospermic cohort. In the validation study (n=1140) TaqMan SNP-PCR was conducted for rs10031005 and rs10835638 with association to andrological parameters. Results Imputation revealed nine SNPs in high linkage disequilibrium, with genome-wide significance (p <4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The nine SNPs accounted for up to 4.65% variance in FSH level. In the oligozoospermic subgroup this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation significant association for rs110031005/rs10835638 with FSH (p=4.71e-06/5.55e-07) and FSH/LH ratio (p=2.08e-12/6.4e-12) was evident. Conclusions This GWAS delineates the polymorphic FSHB genomic region as main determinant for FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNPs, that cause lowered FSH and therewith decreased spermatogenesis, could resolve the idiopathic/unexplained origin by this etiologic factor.
Study question Which single nucleotide polymorphisms (SNPs) are associated with Follicle stimulating hormone (FSH) levels in men with unexplained infertility and can affect FSH action and spermatogenesis? Summary answer We identified a genomic region at chromosome 11p.14.1, including nine SNPs, that are significantly associated with FSH levels in men with unexplained infertility. What is known already FSH action is essential for the initiation and maintenance of human spermatogenesis. One well-studied SNP, FSHB c.-211G>T (rs10835638), is associated with FSHB mRNA transcription and directly affects FSH serum levels, testicular volume and spermatogenesis. Carriers of a T-allele in this promoter are diagnosed with functional secondary hypogonadism with isolated FSH deficiency. Other genetic variants, for example at the FSHR have been shown to slightly modulate FSH action, however the clinical impact in these variants seems to be low. The so far identified FSH-associated SNPs revealed an impact of up to 2.3 % on FSH serum level variance. Study design, size, duration A Genome wide association study (GWAS) was performed on a clinically well characterized cohort of 742 men with unexplained infertility (discovery study). Of the nine identified SNPs, validation was performed for rs11031005 and the already described rs10835638 in an independent cohort of 1123 men with unexplained infertility (validation study). Participants/materials, setting, methods Patients were retrospectively selected from our CeRA database Androbase® applying strict selection criteria; DNA was isolated from stored EDTA-blood samples. Informative genetic variants were identified using Illumina PsychArray v1.3. Illumina®GenomeStudio v2.0, PLINK v1.90 and R 3.6.3 were used to perform quantitative association analysis based on normalized FSH values. The validation study was performed using TaqMan PCR for SNP detection and R 3.6.3 for quantitative association to analyze the impact of each SNP on FSH level. Main results and the role of chance Imputation of the GWAS data revealed 94 SNPs with suggestive significance (p < 8.56e-06) and nine SNPs (including rs10835638) with genome-wide significance (p < 4.28e-07). The nine SNPs are all located at the FSHB locus on Chromosome 11p.14.1 and are in high linkage disequilibrium (LD). The validation study of 1123 patients with unexplained infertility for the SNPs rs11003005 and rs10835638 revealed a significant association with FSH (p = 4.71e-06 and p = 5.55e-07) and FSH/LH ratio (p = 2.08e-12 and p = 6.4e-12).The nine significant SNPs accounted for 3.60 –4.65 % variance in FSH serum level each in the entire discovery cohort. In an oligozoospermic subgroup (n = 249) this effect was increased to 4.89 – 6.95 %. This the first GWAS in men with unexplained infertility. This study shows that not one single SNP, but rather a genomic region has an impact on FSH serum level in men with unexplained male infertility. This effect is even more pronounced in the more severe phenotype of oligozoospermic men. Limitations, reasons for caution The study is restricted to men with unexplained infertility, which might cause a selection bias. Validation and functional evaluation of the eight newly identified SNPs in independent cohorts would emphasize the results more. The sample size of 742 limits detection of loci with smaller effect on FSH levels. Wider implications of the findings The determination of one of the nine SNPs can improve diagnostic precision in identifying men with secondary functional hypogonadism with isolated FSH deficiency. An oligozoospermic subgroup of these men would putatively benefit from FSH treatment and has to be proven in randomized controlled trials. Trial registration number German Research Foundation CRU326
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