Combined effects of the variants FSHB -211G>T and FSHR 2039A>G on male reproductive parameters

Institute of Human Genetics, University of Münster, Vesaliusweg 12-14, 48149 Münster, Germany. .
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 07/2012; 97(10):3639-47. DOI: 10.1210/jc.2012-1761
Source: PubMed


Context: A polymorphism in the FSHB promoter (-211G>T, rs10835638) was shown to influence male serum FSH levels, whereas a polymorphism in the FSH receptor gene (FSHR; 2039A>G, rs6166) was previously shown to be associated with FSH levels in women only. Objective: The objective of the study was to analyze the effects of both FSHB -211G>T and FSHR 2039A>G on male reproductive parameters. Design and Setting: A total of 1213 German men attending an infertility clinic were genotyped by TaqMan assay. Patients: Patients included male partners in infertile couples without known causes for male infertility. Main Outcome Measures: An association analysis of single and combined single-nucleotide polymorphism genotypes with clinical parameters was performed. Results: The FSHB -211G>T T-allele showed significant dosage effects for FSH (-0.51 U/liter per T-allele), LH (0.28 U/liter), and bitesticular volume (-3.2 ml). Statistical significance was enhanced severalfold after a meta-analysis comprising 3017 men. TT carriers were significantly more prevalent among men with lower sperm counts. The FSHR 2039A>G G-allele exhibited nonsignificant trends for associations with higher FSH and reduced testicular volumes. However, in the combined model, FSHR 2039A>G significantly modulated the more dominant effect of FSHB -211G>T on serum FSH and testicular volume among the T-allele carriers. Conclusions: By analyzing both single-nucleotide polymorphisms for the first time, we convincingly show that indeed FSHR 2039A>G has an effect also in males. In the proposed model of the combined effects, FSHB -211G>T acts strongly on male reproductive parameters, whereas the FSHR 2039A>G effects were approximately 2-3 times smaller. Clinically this is of importance because oligozoospermic patients carrying unfavorable variants affecting FSH action may benefit from FSH treatment.

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Available from: Frank Tüttelmann
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    • "Concerning primary end points, the future FSH pharmacogenetic studies should consider not only semen parameters but also pregnancy rates as primary endpoint. According to our previous power calculations , at least 160 couples need to be included in a proper RCT (assuming 50% treated/placebo, an increase in pregnancy rate from 20 to 40%, and power of 80%) (T€ uttelmann et al., 2012) – making it a multicenter effort. "
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    ABSTRACT: Male infertility contributes to a substantial share to couple infertility. Despite scientific efforts, most cases of male infertility remain 'idiopathic' and male-specific therapeutic options are sparse. Given the crucial role of the follicle-stimulating hormone (FSH) for spermatogenesis, FSH is used empirically to improve semen parameters. Furthermore, a recently updated Cochrane review points to a beneficial effect of FSH treatment in idiopathic infertile men on spontaneous pregnancy rates. However, since response to FSH varies strongly even in selected patients and given the lack of powerful evidence of FSH treatment regimens, 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 some risks. 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. However, there is an evident lack of information which patients should be treated and how many patients in an andrological outpatient clinic would be eligible for such a treatment, a crucial decision criterion for clinicians and also pharmaceutical industry to start such a pharmacogenetic intervention therapy. After screening our andrological patient cohort, we present a realistic scenario and a basis for further prospective studies using FSH in idiopathic infertile men.
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    ABSTRACT: Context:A polymorphism in the FSHB promoter (-211G→T, rs10835638) was found to be associated with decreased FSH, elevated LH, reduced testosterone, and oligozoospermia in males. Although FSH is pivotal for ovarian function, no data on consequences of FSHB -211G→T are available in females.Objective:We studied the effects of FSHB -211G→T on the hypothalamic-pituitary-ovarian axis in women.Design and Setting:In a university-based in vitro fertilization unit, women undergoing standardized diagnostics were genotyped and compared with a fertile control group.Patients:The study group consisted of 365 thoroughly characterized women with normal menstrual cycle intervals and proven ovulation, with predominantly male-factor infertility. The independently recruited control group included 438 women with proven fertility and no history of abortions.Main Outcome Measures:Distribution of alleles and genotypes were compared between the study group and controls. In the study group, associations of endocrine parameters with FSHB -211G→T were assessed.Results:Allele and genotype frequencies were not significantly different between the study population and controls (T-allele: 14.4 vs. 16.6%; TT-homozygotes: 2.5 vs. 3.2%). The FSHB -211G→T TT-genotype was strongly associated with elevated FSH (TT-homozygosity effect 2.05 U/liter, P = 0.003). LH increased with the number of T-alleles (1.30 U/liter per T-allele, P < 0.001). Additionally, FSHB -211G→T was associated with reduced progesterone (-1.96 ng/ml per T-allele, P = 0.047).Conclusions:This is a report on phenotypic consequences of FSHB -211G→T on the hypothalamic-pituitary-ovarian axis in women. The findings, partially contradictory to those in men, point to a gender-specific compensatory mechanism of gonadotropin secretion, probably involving progesterone.
    Full-text · Article · Nov 2012 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: FSH production is important for human gametogenesis. In addition to inactivating mutations in the FSHB gene, which result in infertility in both sexes, a G/T single nucleotide polymorphism (SNP) at -211 relative to the transcription start site of the 5' untranslated region of FSHB has been reported to be associated with reduced serum FSH levels in men. In this study, we sought to identify the potential mechanism by which the -211 SNP reduces FSH levels. While the SNP resides in a putative hormone response element, we showed that, unlike the murine gene, human FSHB was not induced by androgens or progestins in gonadotropes. On the other hand, we found that the LHX3 homeodomain transcription factor binds to an 11 bp element in the human FSHB promoter which includes the -211 nucleotide. Furthermore, we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared to the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared to the wild-type FSHB promoter. Altogether, our results suggest that decreased serum FSH levels in men with the SNP likely result from reduced LHX3 binding and induction of FSHB transcription.Precis:The -211 G/T SNP in the human FSHB promoter results in decreased LHX3 binding and FSHB transcription in gonadotropes.
    No preview · Article · Jun 2013 · Endocrinology
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