Hum. Reprod. Advance Access originally published online on January 5, 2006
Human Reproduction 2006 21(4):994-1001; doi:10.1093/humrep/dei439
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Estrogen receptor 
promoter polymorphism: stronger estrogen action is coupled with lower sperm count
1 Department of Clinical Physiopathology, Andrology Unit, 2 Endocrinology Unit, University of Florence, Florence and 3 Division of Endocrinology, Institute of Internal Medicine Polytechnic University of Marche, Ancona, Italy
4 To whom correspondence should be addressed at: Andrology Unit, Viale Pieraccini 6, Florence 50139, Italy. E-mail: c.krausz{at}dfc.unifi.it
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Abstract |
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BACKGROUND: Although the importance of estrogens in male reproduction is indisputable, little attention has been paid to the role of estrogen receptor (ER) gene mutations in male infertility. Significant correlation between (TA)n repeat allelic variants and lumbar bone mineral density was previously observed in the promoter region of the ER
gene, indicating that allelic combinations with higher number of (TA)n repeats are functionally more active genetic variants. METHODS: We studied the (TA)n repeat polymorphism situated in the promoter region of the ER gene in a large group of infertile and normospermic men (n = 347). RESULTS: Although the (TA)n polymorphism failed to show a significant association with male infertility, we found a significant effect of this polymorphism on sperm count. In the group of infertile men, the mean TA repeat number and sperm concentration (P = 0.022) and total sperm number (P = 0.043) were inversely correlated, showing an association between higher TA repeat number (genotype A) and lower sperm production. In line with this observation, normospermic subjects with genotype A had a significantly lower mean sperm concentration with respect to men bearing genotype B with shorter TA alleles (P < 0.05) and a lower total sperm count (P < 0.01). CONCLUSIONS: Our data indicate that specific allelic combinations of the ER, which confer a stronger estrogen effect, may negatively influence human spermatogenesis.
Key words: estrogen receptor/genetics/male infertility/polymorphism/spermatogenesis
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Introduction |
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Thanks to the large-scale availability of molecular genetic tools and to the identification of an increasing number of candidate genes, the field of genetics of male infertility is rapidly evolving. The crucial role of androgens, gonadotropins and estrogens in the endocrine regulation of spermatogenesis is well known; thus genes of their receptors represent a logical target for mutational analysis in the infertile male. The androgen receptor gene has been the object of a large quantity of publications, and both mutation screenings of the entire coding sequence and the analysis of polymorphic regions in exon 1 have been reported (Tut et al., 1997
; Dowsing et al., 1999; von Eckardstein et al., 2001; Rajpert-De Meyts et al., 2002; Foresta et al., 2005). On the contrary, although human and animal models evidenced an association between estrogen insufficiency and abnormal spermatogenesis, little attention has been paid to the role of estrogen receptor (ER) gene mutations or polymorphisms in male infertility.
The physiological responses to estrogens are known to be mediated by at least two functional isoforms of ER, namely ER and ER
, encoded by two different genes in different chromosomes (6q25 and 14q23-24, respectively). Both receptors share the common structure of steroid/thyroid hormone nuclear receptor, differing in the C-terminal ligand-binding domain and in the N-terminal trans-activation domain (O’Donnell et al., 2001). Besides these two isoforms, a third membrane receptor has been reported in different cellular models including human spermatozoa (Luconi et al., 2002 and references therein). This membrane receptor is probably involved in the stimulatory effect on sperm capacitation, acrosome reaction and fertilizing ability of 17-estradiol (E2) and environmental estrogens observed in the mouse spermatozoa (Adeoya-Osiguwa and Fraser, 2004).
The physiological role of estrogens in spermatogenesis is not clearly defined; however recent studies suggest a role as ‘survival factor’ for this hormone (Pentikainen et al., 2000). According to this concept, knockout models removing the ER (ERKO) or the aromatase genes (ArKO) showed an impairment of spermatogenesis (Korach, 1994; Robertson et al., 1999). The absence of ER leads to reduced epididymal sperm content, reduced sperm motility and fertilizing ability (Eddy et al., 1996; Ogawa et al., 1997). Infertility in ERKO mice is probably related to the defective fluid resorption by the efferent ductules, which would lead to a secondary damage of the germinal epithelium (Hess et al., 1997). On the contrary, ERKO mice are fertile and do not show abnormal testis histology.
The expression pattern of the two receptors varies in different species. Both receptors are expressed in the epididymis and in the testis (O’Donnell et al., 2001). In the rat, Pelletier et al. (2000) found ER expressed in nuclei of Leydig cells as well as in round spermatocytes and spermatids, while ER was only detected in Sertoli-cell nuclei. In human testis, ER and ER were found in ejaculated spermatozoa (Durkee et al., 1998; Luconi et al., 1999; Lambard et al., 2004), in early meiotic spermatocytes and elongated spermatids (Pentikainen et al., 2000) and in immature germ cells (pre- and post-meiotic) (Lambard et al., 2004) in contrast with other studies (Makinen et al., 2001; Saunders et al., 2001). These data, although controversial, indicate a possible direct effect of estrogens through both receptors in male germ cells.
In apparent contradiction to the sperm-survival function of estrogens, excess of this hormone during the neonatal period or adulthood can impair sperm production and maturation (Atanassova et al., 2000).
The human ER gene encodes a protein of 595 amino acids with a molecular weigh of about 66 kDa. Genetic screening of the ER gene locus has revealed the existence of several polymorphic sites (Gennari et al., 2005 and references therein). The most widely studied are the PvuII (T397C) and XbaI restriction fragment length polymorphisms (RFLPs) in intron I and the (TA)n variable number of tandem repeats (VNTR) within the promoter region of the gene. In different studies, these polymorphisms have been associated with several pathologic conditions such as breast and prostate cancer, osteoporosis, Alzheimer’s and cardiovascular diseases (Brandi et al., 1999; Dunning et al., 1999; Massart et al., 2001; Tanaka et al., 2003; Tempfer et al., 2004).
Recently, a possible relation of ER polymorphisms with male infertility has been reported in Greek and Japanese populations (Kukuvitis et al., 2002; Suzuki et al., 2002). However, due to the relatively small populations in both studies, the interpretation of these data remains difficult.
In a recent study on the Italian population, Becherini et al. (2000) have reported a high degree of linkage disequilibrium between intron 1 PvuII and XbaI polymorphisms and the variable length of dinucleotide (TA)n repeats in the promoter region of the ER gene. A statistically significant correlation between (TA)n repeat allelic variants and lumbar bone mineral density (BMD) was observed, indicating a putative functional role for this polymorphism. Despite the observed linkage disequilibrium between the promoter polymorphism (TA)n and the two intronic polymorphisms, no significant relationship between intron I RFLPs and BMD was observed.
The aim of the present study was to get further insights into the role of ER in spermatogenesis. For this purpose, we analysed the functionally relevant (TA)n promoter polymorphism of ER in a large group of infertile and normospermic control men.
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Materials and methods |
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Subjects
A total of 347 subjects were analysed for the (TA)n polymorphism of the ER
. The study population consisted of (i) 191 patients seeking complete andrological work-up for couple infertility at the Andrology Unit and the Unit of Physiopathology of Reproduction of the University Hospital Careggi (Florence) and from the Endocrinology Unit of the University of Ancona and (ii) 156 men with normal sperm parameters. The 191 patients were selected from 360 consecutive infertile patients on the basis of a comprehensive andrological examination including medical history, semen analysis, scrotal ultrasound, hormone analysis, karyotype and Y-chromosome microdeletion screening. Patients with cryptorchidism, bilateral varicocele of grades 2 and 3, obstructive azoospermia, recurrent infections, iatrogen infertility, hypogonadotrophic hypogonadism, karyotype anomalies, Y-chromosome microdeletions and patients with no-Italian origin were excluded.
Sperm count revealed azoospermia (the complete absence of spermatozoa) in 35 patients, cryptozoospermia (<1 million spermatozoa/ml) in 17 patients, severe oligozoospermia (1–5 millions spermatozoa/ml) in 72 patients, moderate oligozoospermia (5–20 millions spermatozoa/ml) in 59 patients, asthenoteratozoospermia (total progressive motility <50% with total normal morphology <30%) in five patients and pure teratozoospermia in three patients. The mean values of the three principal sperm parameters in this group were as follows: sperm concentration 4.7±0.55 (SEM) millions/ml; total sperm count 14.6±2.8 (SEM); % progressive motility (a+b) 23.92±1.24 (SEM); % normal morphology 16.1±0.78 (SEM).
The control population consisted of 156 volunteers recruited by the same institutions from the same geographic area. All presented normozoospermia. Ninety-six men fathered at least one child spontaneously or had normal fertilization after IVF for pure tubal factor infertility, while the remaining 60 men were students from the local university. The mean values of the three principal sperm parameters in this group were as follows: sperm concentration 98.7±5.2 (SEM) millions/ml; total sperm count 320.4±17.2 (SEM); % progressive motility (a+b) 64±0.74 (SEM); % normal morphology 36.3±0.54 (SEM).
All subjects gave an informed consent for molecular analysis of their blood samples, and the study was performed according to the policy of the local ethical committee.
Semen analysis
Semen samples were obtained by masturbation. In order to minimize the variability of semen analysis results, the duration of ejaculation abstinence was minimum 3 and maximum 5 days. Semen analysis has been performed according to the World Health Organization guidelines (World Health Organization, 1999) at the Andrology Laboratory of the University Hospital of Careggi (Florence). Sperm morphology assessment was scored by determining percentage of normal and abnormal forms after Diff–Quik staining, with a reference value of normal morphology of >30% according to the third edition of the WHO manual (World Health Organization, 1992).
Molecular analysis
DNA source
The DNA has been extracted from peripheral lymphocytes in the infertile group, whereas DNA from normospermic controls was isolated either from peripheral lymphocytes or from frozen semen.
TA repeat length analysis
The TA repeat region in the promoter element of the ER gene was amplified by PCR. The sequence of primers was: forward 5"-GACG CATGATATACTTCACC-3" and reverse 5"-GCAGAATCAAATATC CAGATG-3". PCR conditions were as follows: denaturation at 94°C for 30 s, annealing at 55°C for 45 s and extension at 72°C for 60 s for 35 cycles and final extension at 72°C for 7 min.
The TA repeat length analysis has been performed by using an automated sequencer (ABI PRISM 310, Applied Biosystems, Foster City, CA, USA) The size of the PCR products was determined by GeneScan software. Each PCR product was subjected to direct sequencing on the autosequencer for the definition of the correct TA repeat length; an example of electropherogram is shown in Figure 1. The number of TA repeats was calculated comparing the detected PCR fragment by GeneScan software to the sequenced fragments.
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Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences software (SPSS, Evanston, IL, USA). Genotype and allele frequencies were analysed by c2 test. Owing to nonparametric distribution, group comparisons were performed by Mann–Whitney U-test for unpaired data. Correlation between two variables was ascertained by linear regression analysis and Pearson correlation coefficient calculation for parametrically distributed variables. Spearman’s correlation test was used for nonparametrically distributed variables. A P-value <0.05 was considered statistically significant. Results are expressed as median and range unless otherwise stated.
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Results |
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The (TA)n allele and genotype distribution in infertile patients and normospermic controls
We analysed a total of 694 alleles. The allelic frequency in the two study populations is reported in Figure 2 and shows a similar pattern to that observed in other studies dealing with populations from Europe (Gennari et al., 2005). The median number of the TA repeat was 14 (10–26) and 14 (9–27) for the infertile and control group, respectively.
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The distribution pattern of TA alleles in our study population shows two major peaks at 13–15 and 20–24 repeats and a lower distribution of intermediate 16–19 repeat alleles. According to a previous study (Becherini et al., 2000), we established three allele groups: (i) group H including alleles with a high number of TA repeats (TA
20); (ii) group M including alleles with a medium number of TA repeats (15<TA< 20); and (iii) group L including low TA alleles (TA
15).
The combination of these alleles gave rise to six different genotypes (HH, HM, HL, MM, LM and LL). Since genotypes HH and HM showed the highest BMD with respect to the other allelic combinations (Becherini et al., 2000), we considered them as the functionally more active genetic variant. Consequently, we grouped the six possible allelic combinations into two major groups: ‘genotype A’ (including HH and HM genotypes) and ‘genotype B’ (including genotypes HL, MM, LM and LL).
In order to evaluate whether genotype A or B of the ER (TA)n polymorphism associates with male infertility, we compared the frequency of the two genotypes between the two study groups.
The distribution of genotypes A and B was similar in the controls and in the infertile group, showing a higher frequency of genotype B in both groups (76.3 versus 74.9%, respectively).
Effect of (TA)n repeats polymorphism on sperm parameters
Although the genotype distribution between controls and patients did not identify an ‘at-risk’ genotype for male infertility, we further evaluated whether (TA)n repeats may affect spermatogenesis. First, we performed an analysis of correlation between the mean number of (TA)n repeats with the four principal sperm parameters (sperm concentration, total number, motility and morphology) in each study population. The second approach was the comparison of sperm parameters among patients bearing different ER genotypes.
Analysis of correlation between (TA)n repeats and sperm parameters
The mean number of TA repeats and sperm concentration and total sperm number in the group of infertile men were inversely correlated. Such a correlation, though weak (Rho coefficient = –0.166 and =–0.169 for sperm concentration and total sperm count, respectively), was statistically significant (P = 0.022 and P = 0.043, respectively). Therefore, higher (TA) repeat numbers seem to negatively affect spermatogenesis. We observed a similar trend in the control group although not significant.
Comparison of sperm parameters between controls with different ER genotypes
In order to assess whether different ER genotypes are able to influence spermatogenesis, we compared the mean values of the four sperm parameters (concentration/ml, total sperm count, morphology and motility) between normospermic controls bearing genotype A versus genotype B (HH, HM versus HL, MM, ML and LL).
We found a significant difference between the mean values of sperm concentration and the total sperm count. Subjects with HH or HM (genotype A; n = 39) have a significantly lower mean sperm concentration 65 million/ml (21–195) versus 92.5 million/ml (24–400) (P < 0.05) and a lower total sperm count 220 millions (71–544) versus 307 millions (42–1364) (P < 0.01) with respect to men bearing genotype B (n = 117) (Figure 3). Motility and morphology were not affected by the genotype, with median values comparable between the two groups: 66 (50–78) versus 65 (50–85) and 35 (30–48) versus 34 (30–66), for motility and morphology, respectively (Figure 3).
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Comparison of sperm parameters between patients with different ER genotypes
In the group of infertile patients, we compared the mean values of the four sperm parameters (concentration/ml, total sperm count, morphology and motility) among patients bearing the two genotype groups A (n = 49) and B (n = 142): 3 million/ml (0.38–19) versus 3 million/ml (0.4–63) for sperm concentration; 9.9 millions (0.9–38) versus 10 millions (0.68–282) for total sperm count; 23 (3–45) versus 20 (0–65) for motility; and 13 (4–26) versus 12 (1–46) for morphology. No statistical difference was found for any of the above parameters (Figure 3).
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Discussion |
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The analysis of polymorphisms in genes involved in spermatogenesis represents one of the most exciting area of research in genetics of male infertility. Some of these genetic variants are considered as genetic risk factors, and they are also present in control fertile or normospermic men, although at a significantly lower prevalence. It is likely that polymorphisms only in association with a specific genetic background or with environmental factors lead to testicular dysfunction (Krausz et al., 2001
, 2004a; and references therein; Giachini et al., 2005).
An important role for estrogens in male reproduction has been suggested by both animal models and the phenotype of men bearing mutations in the ER and aromatase gene (O’Donnel et al., 2001). Consequently, ER and aromatase became candidate infertility genes in humans.
To date, only one patient with an inactivating mutation in the ER gene (Smith et al., 1994) and five patients with aromatase deficiency have been reported (Morishima et al., 1995; Carani et al., 1997; Deladoey et al., 1999; Herrmann et al., 2002; Maffei et al., 2004). The phenotypes of these patients are rather heterogeneous, ranging from normal sperm concentration but reduced sperm viability in case of the ER mutation to oligozoospermia and bilateral cryptorchidism in case of aromatase deficiency (Carani et al., 1997; Herrmann et al., 2002; Maffei et al., 2004).
In a recent study, the RsaI polymorphism in the ER gene appears to be associated with infertility, showing a three times higher frequency of the heterozygous RsaI AG-genotype in the infertile group compared with controls (Aschim et al., 2005).
Two intronic polymorphisms in the ER (recognized by the restriction endonucleases PvuII and XbaI) have been studied in a relatively small group of infertile and control men of Greek origin (Kukuvitis et al., 2002). The XbaI RFLP showed a significant association with infertility, whereas this association was not found for the PvuII polymorphism. Another study on 31 patients from Japan, dealing with an exonic polymorphism (exon 4 codon 325 C
G), has also reported a significantly different allelic distribution between controls and men affected by idiopathic nonobstructive azoospermia (Suzuki et al., 2002).
For the first time, we studied a polymorphism situated within the promoter region of the ER in a large group (n = 347) of infertile and normospermic control men of Italian origin.
The reason for choosing this polymorphism is related to a previous study in a large cohort of post-menopausal women of Italian origin in which a clear effect of (TA)n repeat polymorphism on lumbar BMD has been reported (Becherini et al., 2000). In this study, the highest number of TA repeats resulted in the highest bone density values, indicating a possible functional role for the (TA)n VNTR. This polymorphism is in linkage (at least in the Italian population) with two other intronic polymorphisms (XbaI and PvuII), i.e. the xx and pp genotypes are associated with lower number of TA repeats, whereas the XX and PP genotypes are associated with higher number of TA repeats. Despite this association with (TA)n, and a clear trend of a higher prevalence of the ppxx genotype in the osteoporotic group versus controls, these differences did not reach to statistical significance, and thus the two intronic polymorphisms do not appear to have clear functional consequences.
In order to determine the role of ER (TA)n dinucleotide repeat polymorphism as a risk factor for male infertility, we evaluated the distribution of TA genotypes in controls and infertile men. The prevalence of men bearing the more ‘active’ genotype ‘A’, characterized by high number of repeats on both alleles (HH) or medium number on the second allele (HM), was similar in the two study populations. Therefore, our result failed to confirm a significant association between male infertility and ER polymorphism (Kukuvitis et al., 2002; Suzuki et al., 2002), indicating that this genetic variant cannot be considered a risk factor in our population.
Discrepancies between association studies are rather frequent and can be related to different factors. Low sample size represents one of the most frequent causes for lack of replication in case–control studies dealing with polymorphisms. Contradictory studies dealing with the androgen receptor CAG repeat length polymorphism (Dowsing et al., 1999; Rajpert-De Meyts et al., 2002) and the CAG polymorphism of the POLG gene (Rovio et al., 2001; Krausz et al., 2004b) in male infertility are good examples of the critical value of the sample size. According to a meta-analysis by Joannidis et al. (2001), a minimum of 150 subjects (controls and cases) should be required for association studies. On the other hand, ethnic and geographic differences can also contribute to the lack of confirmation of results in different populations (Krausz et al., 2004a and references therein). The recently described DAZL gene polymorphism represents a remarkable example of ethnic differences (Teng et al., 2002; Becherini et al., 2004).
Concerning the ER polymorphism, major differences between our and the other two studies are: (i) the size (347 in the Italian, 173 in the Greek and 31 in the Japanese studies) and the composition (only azoospermic men included in the Japanese study) of the study populations; (ii) the type of polymorphism analysed; and (iii) ethnic and geographic differences. Although the type of polymorphisms analysed are different in the three studies, the previously observed linkage disequilibrium in the Italian population between (TA)n and XbaI suggests an unlikely association between the XbaI polymorphism and male infertility. It is also possible that a different degree of linkage disequilibrium may exist in different populations for these polymorphisms (random differences in (TA)n alleles between groups, or even a systematic difference due to allelic association). However, the most obvious reason for the lack of replication seems to be that the two previous studies did not reach the critical size required for association studies (Ioannidis et al., 2001).
Although (TA)n polymorphism failed to show a significant association with male infertility, we found a significant effect of this polymorphism on sperm output. The mean number of TA repeats showed a significant inverse correlation with sperm count in the infertile group and a similar, although not significant, trend in the normospermic group. The lack of statistical difference in the latter group may be due to the higher dispersion of values.
In line with this observation, men in the normospermic group bearing genotype A, with high or high and medium number of TA alleles (HH or HM), have significantly lower sperm concentration and total sperm count than those with genotype B. It is worth to notice that the XbaI XX genotype (which is in linkage in the Italian population with the longer TA alleles) is more frequent in the group of idiopathic azoo-oligospermic men with respect to controls in the Greek study (Kukuvitis et al., 2002).
The molecular mechanism(s) by which the variation in the number of dinucleotide repeats may affect sperm count remains unclear. Previous observations on bone tissue indicate that long TA repeats would enhance estrogen action, whereas short TA repeats would cause the opposite (Becherini et al., 2000).
An in vitro study suggested that estrogens may be eventually considered sperm-survival factors (Pentikainen et al., 2000), and thus the absence or reduction of estrogen action should lead to impaired sperm production. Knockout models of ER (ERKO) associated with infertility further support the importance of this hormone in male reproduction. Surprisingly, our data suggesting an association between a more abundant (or more active) receptor (genotypes HH, HM or higher TA numbers) and lower sperm count are in apparent contradiction with the positive role of this hormone. However, exposure of male rats to high doses of exogenous E2 during fetal life induces reproductive disorders (Atanassova et al., 2000); therefore it is possible that a more efficient receptor transcription or a more active ER protein may negatively modulate sperm production through an overamplification of estrogen action. Although expression data on ER receptors are contradictory in human adult testis since both the presence and absence of the receptor have been described (Pentikainen et al., 2000; Saunders et al., 2001, Lambard et al., 2004), the expression of ER receptor in fetal or perinatal testis has not been assessed in humans.
Apart from E2, a number of other compounds with estrogen-like activity (xenoestrogens) may bind to ERs. Among these compounds, diethylstilbestrol, a potent synthetic estrogen, bisphenol-A, a monomer of polycarbonate plastics and OP, contained in detergents, paints and pesticides, seem to exert negative effects (Luconi et al., 2002 and references therein). It has been hypothesized that exposure to xenoestrogens during fetal or perinatal life may account for the reported decline in sperm count as well as for the increased incidence of other components of the testicular dysgenesis syndrome (hypospadias, cryptorchidism and testicular cancer) observed in the last 50 years (Sharpe and Skakkebaek, 1993; Toppari et al., 1996; Sharpe, 2003). Therefore, a second hypothesis to explain our finding can be that a higher level of expression (or activity) of the ER may lead to lower sperm count through the action of environmental xenoestrogens.
Despite the observed association between long TA stretch and lower sperm count, we did not find an overrepresentation of genotype A in the patient group; therefore ER TA polymorphism cannot be considered a genetic risk factor for male infertility. This apparent contradiction is not surprising since even a selected group of idiopathic patients represent a heterogeneous population in which many other (yet unknown) genetic anomalies may be causative for spermatogenic failure. Moreover, it is likely that the pathogenic consequence of the TA polymorphism is relatively mild and would lead to a severe reduction of the sperm count only in cases in which specific hormonal alterations or environmental factors are contemporarily present.
While the exact role of ERs in male reproduction is debated, our data indicate that specific allelic combinations of the ER, which confer a higher BMD and thus a stronger estrogen effect, may negatively influence human spermatogenesis. A plausible explanation would be that not only deficit of estrogens but also an exaggerated estrogen action related to this genetic variant (eventually combined with environmental factors) can be deleterious. Whether the observed negative effect is the expression of a disturbance in the early testis development or in the adult testis and whether it is related to xenoestrogens remain to be established. Our study represents a starting point for further research, especially on selected subjects with different grade of exposure to xenoestrogens and in vitro studies aimed to define the functional consequences of this polymorphism.
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Acknowledgements |
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We thank the medical staff of the Andrology Unit of the University of Florence for their clinical contribution: Prof M. Maggi, Dr A. Magini, Dr R. Mansani, Dr A. Cilotti, Dr L. Petrone and Dr G. Corona. The study was supported by a grant from the University of Florence.
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Submitted on September 9, 2005; resubmitted on October 29, 2005; accepted on November 17, 2005.
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