The RsaI polymorphism in the estrogen receptor-beta gene is associated with male infertility.

CONTEXT: Hypospadias, cryptorchidism, testicular cancer, and low semen quality have been proposed as being parts of the testicular dysgenesis syndrome (TDS) hypothetically due to changes in the androgen-estrogen balance in utero. Estrogens and estrogen receptors (ERs) play a role in regulating testicular function. ERbeta contains two silent polymorphisms, RsaI (G1082A) and AluI (G1730A).

OBJECTIVE

We investigated the significance of these polymorphisms in the etiology of disorders being part of TDS.

SETTING

The patients were recruited consecutively through university hospital clinics.

PARTICIPANTS

Four groups of Caucasian patients were included: 106 men from infertile couples with a sperm concentration less than 5 x 10(6) spermatozoa/ml, 86 testicular cancer patients, 51 boys with hypospadias, and 23 cases with cryptorchidism. Military conscripts (n = 186) with sperm concentration higher than 5 x 10(6) spermatozoa/ml served as controls.

MAIN OUTCOME MEASURES: ERbeta polymorphisms RsaI and AluI were determined by allele-specific PCR. In addition, reproductive hormone analyses were performed in controls and infertile men.

RESULTS

Compared with the controls, the frequency of the heterozygous RsaI AG-genotype was three times higher in infertile men (13.2 vs. 4.3%; P = 0.01). The heterozygous RsaI AG genotype was associated with an approximately 20% reduction in LH concentration, compared with the wild-type RsaI GG genotype in both controls and infertile men. Subjects with testicular cancer, hypospadias, or cryptorchidism did not differ from controls regarding the frequency of any of the polymorphisms.

CONCLUSIONS

Polymorphisms in ERbeta may have modulating effects on human spermatogenesis. The phenotype of TDS seems to be, at least partly, determined by the genotype.