BERKELEY, CA (UroToday.com) - The prevalence of hypospadias varies widely among different countries and populations, ranging from 0.37-41 per infants¹ and the prevalence in Hokkaido, Japan is 3.9 per 10,000 infants². The etiology of hypospadias is still unclear, but it is regarded as a complex disorder with both genetic and environmental contributions. 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. Although the associations of hypospadias with gene polymorphisms in androgen pathway were well studied, few studies for the ESR, which codes the estrogen receptor, have been documented^3,4,5.

Here, we investigated the association of hypospadias of the PvuII and XbaI polymorphisms of ESR1 and the 2681-4A>G polymorphism of ESR2 with hypospadias using a case-control study of 59 cases with hypospadias and 286 controls to determine whether these polymorphisms constitute major susceptible markers of hypospadias.

We genotyped these polymorphisms and found a negative association for the G allele-containing variants in XbaI polymorphism of ESR1(OR = 0.52, P < 0.05). We found negative associations of the G allele-containing variants in ESR2 2681-4A>G with whole (OR = 0.59, P< 0.05) and mild hypospadias (OR = 0.41, P < 0.01). We also identified negative associations with the whole (P < 0.05) and mild hypospadias (P < 0.01) of the C-A haplotype defined by PvuII-XbaI polymorphisms of ESR1. In recent years, it has been hypothesized that prenatal exposure of the male fetus to xenoestrogens having estrogen activity may be responsible for hypospadias^6,7. Thus, it is considered that the ESR1 PvuII, XbaI and ESR2 2681-4A>G polymorphisms contribute to the individual susceptibility fot hypospadias through influencing to the activity of estrogen receptors. Thus further studies are necessary to discuss the viewpoint that hypospadias is a complex disorder having both genetic and environmental causes.

We should note that there are several limitations in this study. First, we were unable to measure estrogen activities in this study because subjects were male newborns or infants. Next, other factors such as lifestyle, exposure and occupational status were not considered.

In conclusion, 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 may increase its risk.

1. Kallen B, Bertollini R, Castilla E, Czeizel A, Knudsen LB, Martinez-Frias ML, Mastroiacovo P and Mutchinick O (1986) A joint international study on the epidemiology of hypospadias. Acta Paediatr Scand Suppl. 324, 1-52.
2. Kurahashi N, Murakumo M, Kakizaki H, Nonomura K, Koyanagi K, Kasai S, Sata F and Kishi R (2004) The estimated prevalence of hypospadias in Hokkaido, Japan. J Epidemiol 14, 73-77.
3. Beleza-Meireles A, Omrani D, Kockum I, Frisén L, Lagerstedt K, and Nordenskjöld A (2006) Polymorphisms of estrogen receptor beta gene are associated with hypospadias. J Endocrinol Invest 29, 5-10.
4. Beleza-Meireles A, Kockum I, Lundberg F, Söderhäll C, and Nordenskjöld A (2007) Risk factors for hypospadias in the estrogen receptor 2 gene. J Clin Endocrinol Metab 92, 3712-3718.
5. Watanabe M, Yoshida R, Ueoka K, Aoki K, Sasagawa I, Hasegawa T, Sueoka K, Kamatani N, Yoshimura Y, Ogata T (2007) Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities. Hum Reprod 22; 1279-1284.
6. Steinhardt GF (2004) Endocrine disruption and hypospadias. Adv Exp Med Biol 545, 203-215.
7. Vidaeff AC and Sever LE (2005) In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence. Reprod Toxicol 20, 5-20.

Written by
Susumu Ban, MD, as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Genetic Polymorphisms of ESR1 and ESR2 that may Influence Estrogen Activity and the Risk of Hypospadias - Abstract

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