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Hum. Reprod. Advance Access originally published online on March 27, 2008
Human Reproduction 2008 23(6):1466-1471; doi:10.1093/humrep/den098
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias

Susumu Ban1,4, Fumihiro Sata1, Norie Kurahashi1, Setsuko Kasai1, Kimihiko Moriya2, Hidehiro Kakizaki2,3, Katsuya Nonomura2 and Reiko Kishi1

1 Department of Public Health, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan 2 Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan 3 Department of Urology, Asahikawa Medical College, Asahikawa 078-8510, Japan

4 Correspondence address. Tel: +81-11-706-5068; Fax: +81 11-706-7805; E-mail: sban{at}med.hokudai.ac.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
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 Discussion
 Authors' roles
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 Acknowledgements
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BACKGROUND: The etiology of hypospadias is regarded as a complex disorder with both genetic and environmental contributions. Although alterations in androgen activity have been associated with hypospadias, few associations with estrogen activity have been documented. Here, we assessed genetic polymorphisms in estrogen receptor genes and their association with hypospadias.

METHODS: Using a case–control study of 59 cases with hypospadias and 286 controls, we examined the association of hypospadias with the following polymorphisms: PvuII and XbaI in ESR1, and 2681-4A>G in ESR2.

RESULTS: For the cases, we found a negative association with the G allele containing variants of ESR1 XbaI (OR = 0.52, P < 0.05), and a negative association with the G allele containing variants of ESR2 2681-4A>G (OR = 0.59, P < 0.05). For the cases, we also identified a negative association with the CG haplotype, and a positive association with the CA haplotype, defined by ESR1 PvuII and XbaI (P < 0.05).

CONCLUSIONS: These findings suggest that the G allele containing variants of ESR1 XbaI and the G allele containing variants of ESR2 2681-4A>G may decrease the risk of hypospadias, whereas the ESR1 C-A haplotype may increase its risk.

Key words: estrogen/hypospadias/polymorphism/ESR1/ESR2


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Authors' roles
 Funding
 Acknowledgements
 References
 
Hypospadias, in which the urethral orifice is located along the ventral side of the penis, is one of the most common congenital anomalies in males. The prevalence of hypospadias varies widely between countries and populations, ranging from 0.37 to 41 per 10 000 infants (Kallen et al., 1986Go); the prevalence in Hokkaido, Japan, e.g. is 3.9 per 10 000 infants (Kurahashi et al., 2004Go). Although the etiology is unclear in most cases, hypospadias is regarded as a complex disorder having both genetic and environmental causes (Manson and Carr, 2003Go).

Because development of the urethra and external genitalia in the male fetus is androgen dependent, abnormalities in the synthesis and metabolism of androgens can result in abnormal genital morphogenesis. In steroid metabolism, associations of gene polymorphisms with hypospadias have been well studied for the genes encoding the androgen receptor (AR) and 5{alpha}-reductase (SRD5A2). Increases in polymorphic GGN trinucleotide repeats in AR (Aschim et al., 2004Go) and the less active Leu variant of the SRD5A2 V89L polymorphism (Thai et al., 2005Go) are both associated with hypospadias.

ESR1 and ESR2 encode the estrogen receptor {alpha} (ER{alpha}) and ERβ, respectively. ESR1 is on chromosome 6, whereas ESR2 is on chromosome 14 (Menasce et al., 1993Go; Enmark et al., 1997Go). Estrogens binding to either ER{alpha} or ERβ activate estrogen-responsive genes and stimulate ER-positive cell lines. These receptors are expressed in most cells of the male urethra (Dietrich et al., 2004Go). Four studies have investigated the association of polymorphisms of ESR1 and ESR2 with hypospadias. Watanabe et al. (2007)Go showed a strong association of the ‘AGAGA’ haplotype [SNPs 10–14 (rs926779, rs3020364, rs6932902, rs3020371 and rs3020375)] of ESR1 with hypospadias. Beleza-Meireles et al. (2006Go, 2007Go) showed that prolonged CA repeats and the heterozygous genotype of 2681-4A>G of ESR2 increase the risk of hypospadias, whereas Aschim showed no association between hypospadias and two (RsaI and AluI) polymorphisms of ESR2 in a Norwegian population (Aschim et al., 2005Go). Thus, several studies suggest that both ESR1 and ESR2 polymorphisms may be related to hypospadias.

The PvuII and XbaI polymorphisms of ESR1, although only ~50 bp apart in intron 1, are in strong linkage disequilibrium (Castagnoli et al., 1987Go). Although it is not yet clear how these polymorphisms may affect ESR1 function, the presence of the dominant T allele of PvuII and the dominant A allele of XbaI polymorphisms can enhance ER{alpha} activity (Maruyama et al., 2000Go). These polymorphisms have been associated with several different pathological conditions, such as breast cancer, prostate cancer, osteoporosis, Alzheimer's disease and cardiovascular diseases (Brandi et al., 1999Go; Schubert et al., 1999Go; Tanaka et al., 2003Go; Tempfer et al., 2004Go). Table I shows the regions where PvuII and XbaI polymorphisms of ESR1 and the 2681-4A>G polymorphism of ESR2 locate, and their expected activities. Here, we investigate the association of the PvuII and XbaI polymorphisms of ESR1 and the 2681-4A>G polymorphism of ESR2 with hypospadias to determine whether these polymorphisms could be major susceptibility markers of this congenital anomaly.


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  		Table I. Gene polymorphisms examined and their expected estrogen activities.

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Authors' roles
 Funding
 Acknowledgements
 References
 
Patients
This case–control study was performed in Sapporo, Japan. Eligible cases were defined as male children who underwent surgery for hypospadias at the Department of Urology of Hokkaido University during the period 2000–2005. We obtained information about the severity of hypospadias, family history and any syndromes in each patient from hospital records. Five patients were excluded from this study because one patient had a brother with hypospadias and four patients had syndromes [Klippel–Trenaunay–Weber syndrome (n = 1), VATER syndrome (n = 1), mixed gonadal dysgenesis (n = 2)]. Hypospadias is classified as mild when the opening of the urethra is in the penile, coronal or glanular portion, and as severe when the opening is in the penoscrotal, scrotal or perineal portion. The urologists who operated on the patients determined the severity of hypospadias, classifying 40 cases as mild and 19 as severe. The controls were male children without any malformation who were born at 39 obstetrics departments in Hokkaido hospitals during 2003–2005. We studied 59 cases with hypospadias and 286 controls, all of whom were male children of Japanese ethnicity.

The study was conducted with the informed consent of the subjects' parents and was approved by the Institutional Ethical Board for Human Gene and Genome Studies of the Hokkaido University Graduate School of Medicine.

Genetic analysis
Peripheral blood was gathered from children with hypospadias during their corrective operations, and cord blood was gathered from control children. Genomic DNA was extracted from the peripheral blood and cord blood samples using a QIAamp or EZ1 DNA Blood kit (Qiagen GmbH, Hilden, Germany) according to the manufacturer's protocol.

The PvuII and XbaI sites in ESR1 (dbSNP: rs2234693, rs9340799) and the 2681-4A>G polymorphism in ESR2 (dbSNP: rs944050) were genotyped by allelic discrimination using fluorogenic probes and the 5' nuclease (TaqMan®) assay as described in the manufacturer's protocol. SNP genotyping products were used as probes (Applied Biosystems, Foster City, USA). PCR products were measured at 490/520 nm and 530/560 nm excitation/emission at 60°C for 1 min and genotyped using allelic discrimination with the Applied Biosystems 7500 Real-Time PCR System (Applied Biosystems) according to the manufacturer's instructions.

Statistical analysis
Odds ratios (ORs) and 95% confidence intervals (CIs) associated with the genotypes PvuII and XbaI in ESR1 and 2681-4A>G in ESR2 were calculated by unconditional logistic analysis using SPSS software for Windows version 11.0 (SPSS Inc., Chicago, USA). Association of haplotype defined by PvuII and XbaI polymorphisms in ESR1 with hypospadias was calculated by {chi}2 analysis. Hardy–Weinberg equilibrium analyses were performed to compare observed and expected genotypic frequencies using a {chi}2 test. The haplotype was analyzed using Haploview version 3.32 based on the expectation-maximization algorithm (Barrett et al., 2005Go), and linkage disequilibrium between loci was measured using Lewontin's D' (Hedrick, 1987Go).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Authors' roles
 Funding
 Acknowledgements
 References
 
The distributions of all genotypes in both cases and controls were in Hardy–Weinberg equilibrium ({chi}2 test, P > 0.05). First, we conducted single-marker analysis of the ESR1 PvuII and XbaI variants and the ESR2 2681-4 A>G polymorphism between the 59 cases with hypospadias and the 286 controls (Table II). The G allele and the G-containing genotype (AG+GG) of ESR1 XbaI were negatively associated with hypospadias (OR = 0.55, 95% CI = 0.31–0.99, P = 0.045; OR = 0.52, 95% CI = 0.27–0.99, P = 0.048, respectively). The AG genotype and the G-containing genotype (AG+GG) in the ESR2 2681-4A>G polymorphism were also significantly less frequent in hypospadias patients (OR = 0.43, 95% CI = 0.23–0.80, P = 0.008; OR = 0.50, 95% CI = 0.28–0.88, P = 0.045, respectively). However, no significant association was found between hypospadias and the ESR1 PvuII polymorphism.


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  		Table II. Associations of gene polymorphisms of ESR1 PvuII, ESR1 XbaI and ESR2 2681-4A>G with all cases of hypospadias.

 
We also investigated the associations of the ESR1 PvuII and XbaI haplotypes with hypospadias (Table III). We observed a high degree of linkage disequilibrium between the ESR1 PvuII and XbaI polymorphisms (D' = 0.983), meaning that they were inherited together as a haplotype. The C-A haplotype was over-represented in patients (P = 0.024), and the C-G haplotype was over-represented in controls (P = 0.048). Further analysis showed that the risk of the CC/AA genotypic combination (PvuII/XbaI) for hypospadias was significantly higher (OR = 3.07, 95% CI = 1.16–8.17, P = 0.024) compared with any other genotypic combination.


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  		Table III. Associations of the ESR1 haplotype and diplotype with all cases of hypospadias.

 
We further investigated the association of the genetic polymorphisms within the subgroups of mild or severe hypospadias. The CC genotype in ESR1 PvuII was positively associated with mild hypospadias (OR = 2.13, 95% CI = 1.01–4.47, P = 0.047). For the ESR1 XbaI polymorphism, the G allele and the G-containing genotype (AG+GG) in ESR1 XbaI were negatively associated with mild hypospadias with borderline significance (P = 0.085 and P = 0.070, respectively). The ORs for mild hypospadias with the AG genotype and the G-containing genotype in the ESR2 2681-4 A>G polymorphism were significantly lower (OR = 0.37, 95% CI = 0.17–0.77, P = 0.008; and OR = 0.41, 95% CI = 0.21–0.80, P = 0.009, respectively), and the G allele was negatively associated with mild hypospadias with borderline significance (P = 0.052). However, no significant association of the ESR1 PvuII and XbaI polymorphisms, or of the ESR2 2681-4A>G allele, was found with severe hypospadias (Table IV).


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  		Table IV. Associations of gene polymorphisms of ESR1 PvuII, ESR1 XbaI, and ESR2 2681-4A>G with mild and severe of hypospadias.

 
For the ESR1 PvuII–XbaI haplotype, the C-A haplotype was over-represented in mild hypospadias (P = 0.002) but not in severe hypospadias. The risk of the CC/AA genotypic combination (PvuII/XbaI) for mild hypospadias was significantly higher (OR = 4.84, 95% CI = 1.78–13.16, P = 0.002) compared with any other genotype combination (Table V A and B). However, the CC/AA genotypic combination was not found in severe hypospadias.


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  		Table V. Associations of ESR1 haplotype and diplotype with mild and severe hypospadias.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Authors' roles
 Funding
 Acknowledgements
 References
 
In recent years, it has been hypothesized that prenatal exposure of the male fetus to environmental xenoestrogens having estrogen activity may be responsible for hypospadias through the ER (Steinhardt, 2004Go; Vidaeff and Sever, 2005Go). The present study presents evidence suggesting that the ESR1 haplotype (PvuII–XbaI) and ESR2 2681-4A>G polymorphisms may be associated with hypospadias. Only a few studies have reported associations of ESR polymorphisms with hypospadias. For ESR1 polymorphisms, Watanabe et al. (2007)Go showed a strong association of the ‘AGAGA’ haplotype [SNPs 10-14 (rs926779, rs3020364, rs6932902, rs3020371 and rs3020375)] with hypospadias. For the ESR2 polymorphism, Beleza-Meireles et al. (2006Go, 2007Go) showed that prolonged CA repeats and the heterozygous genotype of 2681-4A>G increased the risk of hypospadias. These studies may suggest that both ESR1 and ESR2 influence the genetic susceptibility for hypospadias.

In the present study, the C-A haplotype of ESR1 PvuII–XbaI in hypospadias subjects occurred more frequently than in controls. Indeed, the OR for all cases of hypospadias with the CC/AA genotypic combination was 3.07. It was reported that the enhancer activity of ER{alpha} differed among PvuII–XbaI haplotypes in an in vitro study, and that the highest activity was associated with the T-A haplotype (Maruyama et al., 2000Go). Therefore, we considered that the XbaI polymorphism may have a greater effect on hypospadias than the PvuII polymorphism. Indeed, the single-marker analysis in our present study showed that the A allele of XbaI in patients with hypospadias was more frequent than in controls, and no significant difference in the frequency of PvuII polymorphisms was found between cases and controls.

It remains unknown whether the ESR2 2681-4A>G polymorphism may influence properties of the ERβ. In this study, we showed the negative association of the heterozygous genotype (AG) and the hetero- and homozygous genotype (AG+GG) with the risk of hypospadias. These findings are contrary to the findings of the previous report that indicated that the heterozygous genotype of 2681-4A>G of ESR2 increased the risk of hypospadias (Beleza-Meireles et al., 2006Go). This difference in results may be explained by varying frequencies of alleles among different ethnic groups. The frequency of the G allele is found low in individuals of Swedish, Middle-Eastern, and Finnish origins as in the study of Beleza-Meireles et al., whereas a higher frequency was found in a Japanese population in our study. We may assume from these findings that the G allele of this polymorphism has slight estrogenic influences on male genital and reproductive development, resulting in hypospadias. However, the association of this polymorphism with estrogen activity remains unclear and requires further studies.

We also investigated the association of the severity of hypospadias with the ESR1 PvuII, XbaI, and ESR2 2681-4A>G polymorphisms. Our results also showed that the frequency of the C-A haplotype of ESR1 PvuII–XbaI in patients with mild hypospadias was higher than in controls. Furthermore, heterozygosity and homozygosity of the G allele in the ESR2 2681-4A>G polymorphism were strongly associated with mild hypospadias, whereas no association of this polymorphism with severe hypospadias was found. These results suggested that these genetic polymorphisms contribute to susceptibility to mild hypospadias. The previous studies suggested that the ER may play a role for the development of hypospadias (Steinhardt, 2004Go; Vidaeff and Sever, 2005Go). Thus, the ESR1 PvuII, XbaI and ESR2 2681-4A>G polymorphisms may contribute to individual susceptibility for hypospadias through an effect on ER activity.

There are several limitations to this study. First, we were unable to measure estrogen activities in this study because subjects were male newborns or infants. Also, other factors such as lifestyle, environmental exposure and occupational status were not considered. Thus, further studies are necessary to discuss the viewpoint that hypospadias is a complex disorder having both genetic and environmental causes.

In conclusion, the present study suggests the involvement of the ESR1 PvuII, ESR1 XbaI and ESR2 2681-4A>G polymorphisms in susceptibility to hypospadias.


   Authors' roles
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Authors' roles
Funding
 Acknowledgements
 References
 
Contributions to conception, design, acquisition of data, analysis and interpretation of data—S.B.

Contributions to conception, design, acquisition of data, analysis and interpretation of data—F.S.

Contributions to acquisition of data—N.K.

Contributions to acquisition of data—S.K.

Contributions to acquisition of data—K.M.

Contributions to acquisition of data—H.K.

Contributions to supervision—K.N.

Contributions to supervision, a principal investigator—R.K.


   Funding
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Authors' roles
 Funding
Acknowledgements
 References
 
This study was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and the Japan Ministry of Health, Labor and Welfare.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Authors' roles
 Funding
 Acknowledgements
References
 
We thank Dr Y. Tsuji of Chukyo Hospital, Dr M. Tada of Saitama Children's Medical Center and Drs Y. Kurokawa and M. Takahashi of Tokushima University Hospital for patient and sample management.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Authors' roles
 Funding
 Acknowledgements
 References
 
Aschim EL, Nordenskjold A, Giwercman A, Lundin KB, Ruhayel Y, Haugen TB, Grotmol T, Giwercman YL. Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J Clin Endocrinol Metab (2004) 89:5105–5109.[Abstract/Free Full Text]

Aschim EL, Giwercman A, Stahl O, Eberhard J, Cwikiel M, Nordenskjold A, Haugen TB, Grotmol T, Giwercman YL. The RsaI polymorphism in the estrogen receptor-β gene is associated with male infertility. J Clin Endocrinol Metab (2005) 90:5343–5348.[Abstract/Free Full Text]

Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (2005) 21:263–265.[Abstract/Free Full Text]

Beleza-Meireles A, Omrani D, Kockum I, Frisén L, Lagerstedt K, Nordenskjöld A. Polymorphisms of estrogen receptor beta gene are associated with hypospadias. J Endocrinol Invest (2006) 29:5–10.[Web of Science][Medline]

Beleza-Meireles A, Kockum I, Lundberg F, Söderhäll C, Nordenskjöld A. Risk factors for hypospadias in the estrogen receptor 2 gene. J Clin Endocrinol Metab (2007) 92:3712–3718.[Abstract/Free Full Text]

Brandi ML, Becherini L, Gennari L, Racchi M, Bianchetti A, Nacmias B, Sorbi S, Mecocci P, Senin U, Govoni S. Association of the estrogen receptor alpha gene polymorphisms with sporadic Alzheimer's disease. Biochem Biophys Res Commun (1999) 265:335–338.[CrossRef][Web of Science][Medline]

Castagnoli A, Maestri I, Bernardi F, Del Senno L. PvuII RFLP inside the human estrogen receptor gene. Nucleic Acids Res (1987) 15:866.[Free Full Text]

Dietrich W, Haitel A, Huber JC, Reiter WJ. Expression of estrogen receptors in human corpus cavernosum and male urethra. J Histochem Cytochem (2004) 52:355–360.[Abstract/Free Full Text]

Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson JA. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab (1997) 82:4258–4265.[Abstract/Free Full Text]

Hedrick PW. Gametic disequilibrium measures: proceed with caution. Genetics (1987) 117:331–341.[Abstract/Free Full Text]

Kallen B, Bertollini R, Castilla E, Czeizel A, Knudsen LB, Martinez-Frias ML, Mastroiacovo P, Mutchinick O. A joint international study on the epidemiology of hypospadias. Acta Paediatr Scand Suppl (1986) 324:1–52.[Medline]

Kurahashi N, Murakumo M, Kakizaki H, Nonomura K, Koyanagi K, Kasai S, Sata F, Kishi R. The estimated prevalence of hypospadias in Hokkaido, Japan. J Epidemiol (2004) 14:73–77.[CrossRef][Web of Science][Medline]

Manson JM, Carr MC. Molecular epidemiology of hypospadias: review of genetic and environmental risk factors. Birth Defects Res A Clin Mol Teratol (2003) 67:825–836.[CrossRef][Web of Science][Medline]

Maruyama H, Toji H, Harrington CR, Sasaki K, Izumi Y, Ohnuma T, Arai H, Yasuda M, Tanaka C, Emson PC, et al. Lack of an association of estrogen receptor alpha gene polymorphisms and transcriptional activity with Alzheimer disease. Arch Neurol (2000) 57:236–240.[Abstract/Free Full Text]

Menasce LP, White GR, Harrison CJ, Boyle JM. Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique. Genomics (1993) 17:263–265.[CrossRef][Web of Science][Medline]

Schubert EL, Lee MK, Newman B, King MC. Single nucleotide polymorphism (SNPs) in the estrogen receptor gene and breast cancer susceptibility. J Steroid Biochem Mol Biol (1999) 71:21–27.[CrossRef][Web of Science][Medline]

Steinhardt GF. Endocrine disruption and hypospadias. Adv Exp Med Biol (2004) 545:203–215.[Web of Science][Medline]

Tanaka Y, Sasaki M, Kaneuchi M, Shiina H, Igawa M, Dahiya R. Polymorphism of estrogen receptor alpha in prostate cancer. Mol Carcinog (2003) 37:202–208.[CrossRef][Web of Science][Medline]

Tempfer CB, Schneeberger C, Huber JC. Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology. Pharmacogenomics (2004) 5:57–65.[CrossRef][Web of Science][Medline]

Thai HT, Kalbasi M, Lagerstedt K, Frisen L, Kockum I, Nordenskjold A. The Valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. J. Clin Endocrinol Metab (2005) 90:6695–6698.[Abstract/Free Full Text]

Vidaeff AC, Sever LE. In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence. Reprod Toxicol (2005) 20:5–20.[CrossRef][Web of Science][Medline]

Watanabe M, Yoshida R, Ueoka K, Aoki K, Sasagawa I, Hasegawa T, Sueoka K, Kamatani N, Yoshimura Y, Ogata T. Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities. Hum Reprod (2007) 22:1279–1284.[Abstract/Free Full Text]

Submitted on November 16, 2007; resubmitted on February 12, 2008; accepted on February 28, 2008.


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