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Follicle-Stimulating Hormone Receptor Gene Haplotype Distribution in Normozoospermic and Azoospermic Men

From the Institute of Reproductive Medicine, Münster University Hospital, Münster, Germany.

Correspondence to: Prof Dr E. Nieschlag, Institute of Reproductive Medicine of the University, Domagkstr. 11, D - 48129 Münster, Germany (e-mail: eberhard.nieschlag{at}ukmuenster.de).

Received for publication December 13, 2004; accepted for publication February 4, 2005.

	Abstract

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The human follicle-stimulating hormone (FSH) receptor (FSHR) gene possesses single nucleotide polymorphisms (SNP) in exon 10, which influence serum FSH levels in women, but not in men. In the present study we extend our previous investigation and for the first time analyze a novel, common SNP at position -29 of the FSHR core promoter in men. The SNP in codon 680 was analyzed in 438 men with nonobstructive azoospermia and in 304 controls. The SNP in codon 307 and at position -29 was analyzed in 345 men with nonobstructive azoospermia and 186 controls. SNPs were determined by allelic discrimination. No significant difference in the frequency of the polymorphism at position 680 and serum FSH levels was found. At position -29 (A/G) the A^-29 allele was less frequent than the G^-29 allele both in controls (25% vs 75%) and in patients (30% vs 70%) (P not signficant). Together the three SNPs form four discrete haplotypes (A-Thr-Asn, G-Thr-Asn, A-Ala-Ser, and G-Ala-Ser) occurring in 10 combinations. A statistically significant difference in the allelic distribution between controls and azoospermic men was found (P < .05 by ² test). The A-Ala-Ser allele was more frequent in patients (9.1%) than in controls (5.4%), whereas the G-Thr-Asn allele was less frequent in patients (33.1%) than in controls (40.6%) (P < .01 by Fisher's exact test). No significant correlation between serum FSH levels and FSHR allele was found. We conclude that the FSHR haplotype does not associate with different serum FSH levels but it is differently distributed in normal and azoospermic men. The A-Ala-Ser and the G-Thr-Asn allele might represent genetic factors contributing to phenotypic expression of severe spermatogenetic impairment.

     Key words: Male infertility, polymorphism, SNP, testis, azoospermia

Mutation screening of the FSHR gene revealed various single nucleotide polymorphisms (SNPs) both in the core promoter and in the coding region. In particular, we found a common SNP in the core promoter of the human FSHR gene at nucleotide position -29 (Simoni et al, 2002). This SNP at position -29 results in a GA exchange in a potential GGAA binding domain for an E-twenty-six specific transcription factor and occurs in about 30% of the subjects (Simoni et al, 2002). In exon 10 two SNPs are found at nucleotide positions 919 and 2039 (numbered according to the translation start codon with ATG as "1") corresponding to amino acid positions 307 and 680 of the mature protein (Simoni et al, 1999). Polymorphisms within exon 10 result in two major, almost equally common allelic variants in the Caucasian population: Thr³⁰⁷-Asn⁶⁸⁰ and Ala³⁰⁷-Ser⁶⁸⁰ (Simoni et al, 1999, 2002). Investigations on the distribution of these two variants produced varying results. Some studies in normal and infertile men and women revealed no difference (Liu et al, 1998; Conway et al, 1999; Simoni et al, 1999), whereas other investigations found significant differences in the distribution of allelic variants between patients and controls (Sudo et al, 2002; Laven et al, 2003), suggesting that ethnic differences could be involved.

The FSHR polymorphism at position 680 in exon 10 influences serum FSH levels and the sensitivity of the FSHR to FSH stimulation in vivo. In women with normal ovarian function undergoing controlled ovarian hyperstimulation for in vitro fertilization/intracytoplasmic sperm injection, we and others showed that basal FSH levels and the amount of FSH for ovarian stimulation depended on FSHR genotype. Women homozygous for Ser at position 680 had higher FSH levels and needed more FSH compared to women with homozygous Asn⁶⁸⁰ (Perez-Mayorga et al, 2000; de Castro et al, 2003). However, the FSHR polymorphism at position 680 showed no effect on serum FSH levels and other clinical parameters in men (Simoni et al, 1999; Asatiani et al, 2002). This discrepancy between the two genders remains unexplained. Possible limitations of the previous study could be low numbers and the heterogeneity of the infertile men analyzed. In addition, the possible clinical impact of the SNP at position -29, alone or in combination with the SNPs in exon 10, has not been considered so far.

The present study was the first to determine the polymorphism of the FSHR core promoter at position -29, alone and in combination with the two common SNPs in exon 10. Since "infertile" men are a quite heterogeneous population and spermatogenesis can vary qualitatively and quantitatively in individual subjects, to increase the stringency of the study we selected only men with nonobstructive azoospermia and compared them to controls with normal spermatogenesis. We found that the SNPs in the promoter and in exon 10 of the FSHR gene give rise to four major haplotypes differently distributed in azoospermic and normozoospermic men.

	Materials and Methods

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Study Population

The study population consisted of 304 men with normal semen values according to World Health Organization (WHO) criteria (1999) and normal serum FSH levels (<7 IU/L), recruited for contraceptive trials through advertisement in the local newspaper, and 438 infertile men with nonobstructive azoospermia and elevated FSH levels (7 IU/L) attending our infertility clinic. In the patient group the median FSH concentration was 18.5 IU/L (range: 7.1–65.8 IU/L) Hypogonadotropic hypogonadism and genetic defects causing azoospermia (Klinefelter syndrome or deletions of the Y chromosome) were exclusion criteria. All subjects were of Caucasian origin. In 258 of the 304 control subjects and in 81 of the 438 azoospermic men the FSHR polymorphism at position 680 had been previously analyzed and reported (Simoni et al, 1999; Asatiani et al, 2002). For the present study we included 357 additional azoospermic patients and 46 additional controls. All subjects gave informed consent to participate in this study, which was approved by the Ethics Committee of the Medical Faculty and State Medical Board.

Analysis of the SNPs at Nucleotide Positions -29, 919 (codon 307), and 2039 (codon 680)

Genomic DNA was extracted from peripheral blood using FlexiGene DNA extraction kit (Qiagen, Hildesheim, Germany) according to the manufacturer's instruction. In the subjects reported previously, the polymorphism at position 2039 (codon 680) was analyzed by single stranded confirmation polymorphism and restriction fragment length polymorphism, as described in the original papers (Simoni et al, 1999; Gromoll et al, 2000; Asatiani et al, 2002). The SNPs at positions -29, 919 (codon 307), and 2039 (codon 680) of exon 10 additionally determined in the present study were analyzed by the Taqman® allelic discrimination assay, using the Taqman machine (ABI Prism 7000 sequence detection system; Applied Biosystems, Darmstadt, Germany). Using this method SNPs at positions -29 and 307 were determined in 186 control and 345 azoospermic men and the SNP at position 680 in 46 normal and 357 azoospermic men. Each polymerase chain reaction (PCR) (25 µL) contained 2 µL diethyl pyrocarbonate-treated water, 12.5 µL of Universal master mix, 0.25 µL of each probe, and 4.5 µL of each primer (5 pmol). The probes and primers that were used in the PCR reactions are listed in Tables 1 and 2, respectively.

Using the Taqman machine, PCR was performed in two steps: absolute quantification and allelic discrimination. For absolute quantification, the cycles are as follows: Stage 1: 50°C, 2 minutes (1 cycle) for probe binding; Stage 2: denaturation at 95°C, 10 minutes (1 cycle); and followed by 35 cycles at 95°C for 15 seconds, and 60°C for 1 minutes (Stage 3), whereas allelic discrimination assay took 1 minute at 60°C.

Statistical Analysis

Statistical analysis was performed by applying a commercially available software package (GraphPad Prism, GraphPad Software, San Diego, Calif). Data were analyzed for normal distribution. Data are presented as mean ± SEM. One-way analysis of variance (ANOVA), Kruskall-Wallis test, and ² test were used for the analysis of the data. P .05 was considered statistically significant. Fisher's exact test was used for a posteriori analysis of allelic frequency and, after Bonferroni's correction to increase the statistical power, P < .01 was considered statistically significant.

	Results

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SNPs at Amino Acid Position 680 (Exon 10)

The polymorphism at position 680 was determined in 304 normozoospermic and 438 azoospermic patients. The FSHR genotype at position 680 was 33.2% (Asn/Asn), 47% (Asn/Ser), and 19.8% (Ser/Ser) in controls and 28.8% (Asn/Asn), 49.3% (Asn/Ser), and 21.9% (Ser/Ser) in azoospermic men, respectively (P > .05, ² test). The serum FSH concentrations in controls were 3.0 ± 0.1 IU/L (Asn/Asn, n = 101), 3.1 ± 0.1 IU/L (Asn/Ser, n = 143), and 3.0 ± 0.2 IU/L (Ser/Ser, n = 60). In the azoospermic men serum FSH levels resulted in 19.9 ± 0.8 IU/L (Asn/Asn, n = 126), 20.1 ± 0.7 IU/L (Asn/Ser, n = 216), and 22.9 ± 1.3 IU/L (Ser/Ser, n = 96).Therefore, we confirm that the FSHR genotype does not result in different FSH levels both in men with normal spermatogenesis and with nonobstructive azoospermia (P > .05, Kruskal-Wallis test).

SNP at Nucleotide Position -29 (FSHR Promoter)

The SNP at position -29 of the FSHR was analyzed in 186 normozoospermic and 345 azoospermic men. In the control group the genotype was AA in 10, AG in 74, and GG in 102 subjects. A similar distribution was found in the azoospermic patients, where the genotype was AA in 27, AG in 153, and GG in 165 men. The A^-29 was less frequent than the G^-29 allele both in controls (25% vs 75%) and in patients (30% vs 70%) (P > .05 by ² test). To assess whether the polymorphism at -29 of the FSHR promoter influences FSH levels, we compared FSH concentrations among genotypes. The FSH levels in normal men resulted in 2.8 ± 0.3 IU/L, 3.0 ± 0.1 IU/L, and 3.1 ± 0.1 IU/L for AA, AG, and GG, respectively, whereas in the azoospermic men the FSH values were 21.1 ± 1.6 IU/L, 20.3 ± 0.8 IU/L, and 20.5 ± 0.8 IU/L for AA, AG, and GG, respectively. The FSH levels were not significantly different between the genotypes both in the control group and in the azoospermic men (P > .05, ANOVA). Therefore, the common SNP at position -29 of the FSHR promoter is similarly distributed both in men with normal spermatogenesis and nonobstructive azoospermia and does not influence serum FSH levels when considered alone.

FSHR Haplotypes

We then analyzed the haplotypes determined by the three SNPs of the FSHR gene. Analysis of the SNPs in exon 10 in 186 control and 345 azoospermic men confirmed an almost complete linkage dysequilibrium between positions 680 and 307 except for four patients. Considering the polymorphisms in the promoter as well, our results show that the FSHR exists in four most common haplotypes at the nucleotide level, that is, A^-29-A⁹¹⁹-A²⁰³⁹ (A-Thr-Asn), G^-29-A⁹¹⁹-A²⁰³⁹ (G-Thr-Asn), A^-29-G⁹¹⁹-G²⁰³⁹ (A-Ala-Ser), and G^-29-G⁹¹⁹-G²⁰³⁹ (G-Ala-Ser). These four haplotypes account for over 99% of FSHR alleles in the Caucasian population and are combined into the 10 major combinations shown in Tables 3 and 4, in which nine groups are presented since the two possible allelic combinations of group 5 (double heterozygous) cannot be distinguished and are considered together. The genotype distribution between controls and azoospermic men was not significantly different (P > .05, ² test). No significant differences in the FSH levels among the FSHR genotypes in both patients and controls were found (Tables 3 and 4). Serum inhibin B levels were available only for 33 controls (median value 159.9 pmol/mL) and 79 patients (median value 16.9 pmol/mL) and could not be correlated with the genotype. Testis histology was available for 68 patients. In most cases histology showed a complete Sertoli-cell-only picture (n = 46), or a spermatogenic arrest (n = 11), suggesting that the selected patients represent a relatively homogeneous group. We then calculated the overall frequency of the four FSHR haplotypes in control and azoospermic men. As shown in Table 5, a statistically significant difference between the groups was found (P < .05, ² test). By a posteriori Fisher's exact test, the two allelic variants A-Ala-Ser and G-Thr-Asn showed a statistically significant different distribution between controls and men with nonobstructive azoospermia (P < .01).

View this table: [in this window] [in a new window]   Table 5. Allelic frequency in men with normozoospermia (n = 186) and nonobstructive azoospermia (n = 341) (P < .05 by 2 test)

	Discussion

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In women with normal ovarian function the polymorphism at codon 680 of the FSHR is an important determinant of ovarian sensitivity to FSH (Perez-Mayorga et al, 2000; Sudo et al, 2002; de Castro et al, 2003, 2004). In particular, the Ser⁶⁸⁰ receptor variant seems to be less "sensitive" to FSH stimulation and women homozygous for this variant have significantly higher serum FSH levels in the follicular phase of the menstrual cycle than women with the Asn⁶⁸⁰ isoform. In addition, we recently demonstrated that the SNP at codon 680 is a major determinant of menstrual cycle length and hormonal dynamics (Greb et al, personal communication) and that FSH-dependent estradiol production is different in women undergoing controlled ovarian hyperstimulation depending on this SNP (Behre et al, personal communication). Such different responsiveness to FSH is not evident in men, both with normal or impaired spermatogenesis (Simoni et al, 1999; Asatiani et al, 2002; this study). This sex-related difference is striking and it is difficult to understand why no functional consequence of the exon 10 SNP is observed in men. Our studies in women show that inhibin A, which is not present in men, is a major factor in the feedback control of serum FSH, whereas inhibin B is rather a marker of the number of developing follicles: higher inhibin B levels in women with the Ser⁶⁸⁰ FSHR genotype are not effective in suppressing serum FSH, which is constantly higher in these women compared to those with the Asn⁶⁸⁰ genotype (Greb et al, personal communication). These data suggest that inhibin A, together with estradiol and progesterone in the luteal phase, could be the factor responsible for the difference in FSH levels correlated with the FSHR exon 10 polymorphism observed in women. This dual system based on two inhibins, A and B, does not exist in men. In the male, FSH secretion is not cyclic and the feedback regulation of FSH is controlled by testosterone/estradiol and by inhibin B, the latter being a "global" marker both of Sertoli cell function and spermatogenesis (Meacham et al, 2001), probably dependent on spermatogonia proliferation (Foppiani et al, 1999). Although available only for a limited number of patients, the very low levels of inhibin B and testicular histology suggest that the patient group was relatively homogeneous and consisted of men with important spermatogenic damage. We conclude that both in the presence (control subjects) and in the absence (azoospermic men) of the negative feedback on FSH secretion exerted by the spermatogenetic process and inhibin B, the FSHR polymorphism at codon 680 does not result in differences in serum FSH levels in men.

In this study we completed the SNP characterization of the most common FSHR gene allelic variants by analyzing the FSHR promoter. The SNP at position -29 is quite common. The combination of the SNP at position -29 and in exon 10 gives rise to four haplotypes most common in the population studied. The observation that these alleles show a statistically significant different distribution in azoospermic compared to control subjects is novel and suggests that two alleles, possibly the A-Ala-Ser and the G-Thr-Asn alleles, might represent a risk factor and a protective factor, respectively, for male infertility. The significance of this association needs now to be verified by further studies in other populations, possibly of different ethnic origin. Several studies have suggested associations between gene polymorphisms and male infertility with possible ethnic differences, for instance for the androgen receptor gene (reviewed by Yong et al, 2003), for the DAZL gene (Teng et al, 2002; Becherini et al, 2004; Tschanter et al, 2004), for the POLG gene (Rovio et al, 2001; Jensen et al, 2004; Krausz et al, 2004), and for gr/gr deletions of the Y chromosome (Repping et al, 2003; de Llanos et al, 2005; Hucklenbroich et al, 2005). We suggest that the FSHR haplotype should be considered among the gene polymorphisms that, alone or in combination, might influence spermatogenesis.

The mechanism by which the FSHR haplotype effects spermatogenesis remains to be determined. Although not the FSHR haplotype itself but another, still unrecognized, linked gene could be the significant factor, the transcriptional activity of the FSHR promoter might be influenced by the SNP at position -29 in such a way that FSH becomes less "efficient" when the Ala³⁰⁷-Ser⁶⁸⁰ receptor isoform is expressed and more "efficient" in the presence of the Thr³⁰⁷-Asn⁶⁸⁰ isoform. For instance, a common genetic variant of the luteinizing hormone (LH) ß-subunit gene results in a gonadotropin with higher in vitro bioactivity, whereas a polymorphism in the LH ß promoter leads to reduced expression, contributing to the differences in the pituitary–gonadal function in subjects with the LH ß variants (Jiang et al, 1999). In expression studies using the -29 SNP and a reporter gene in vitro we could not demonstrate major changes in the transcriptional activity induced by this polymorphism (Wunsch et al, 2005), but this does not exclude that subtle functional effects, not evident in the system used, might become relevant when considered in combination with the SNPs in exon 10 or upon stimulation with FSH. Therefore, it is possible that the A-Ala-Ser FSHR or the G-Asn-Thr variant (or both), without playing an exclusive pathogenetic role, might represent one of many genetic factors contributing to phenotypic expression of spermatogenetic failure.

In conclusion, our data demonstrate that the four most common FSHR haplotypes, resulting from the SNPs in the promoter and in the coding region of the FSHR gene, are not correlated with serum FSH levels in normal and azoospermic men, but are differently distributed, identifying an additional genetic factor possibly contributing to the multigenic origin of male infertility. It is tempting to speculate that patients with idiopathic infertility and normal FSH levels might respond differently to FSH administration depending on the FSHR haplotype they carry, a hypothesis that needs to be verified in future studies.

	Acknowledgments

 
The skillful technical assistance of N. Terwort and the language editing of S. Nieschlag, MA, are gratefully acknowledged.

	Footnotes

 
Supported by grant SI-526/1-1 from the Deutsche Forschungsgemeinschaft. Y. Ahda and K. Asatiani are recipients of fellowships from the German Academic Exchange Service (DAAD). A. Wunsch is a recipient of a fellowship from the Ernst Schering Research Foundation.

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