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The RsaI Polymorphism in the Estrogen Receptor-ß Gene Is Associated with Male Infertility

Department of Gynecology and Obstetrics (E.L.A., T.B.H.), Rikshospitalet University Hospital, 0027 Oslo, Norway; Faculty of Health Sciences (E.L.A., T.B.H.), Oslo University College, and Cancer Registry of Norway (T.G.), N-0130 Oslo, Norway; Institution of Clinical Sciences, Fertility Center, and Department of Urology (A.G., Y.L.G.), Malmö University Hospital, Lund University, 221 00 Malmö, Sweden; Department of Oncology (O.S., J.E., M.C.), Lund University Hospital, 221 85 Lund, Sweden; and Department of Molecular Medicine (A.N.), Karolinska Institutet, SE-171 77 Stockholm, Sweden

Address all correspondence and requests for reprints to: Elin L. Aschim, Faculty of Health Sciences, Oslo University College, P.O. Box 4, St. Olavs Plass, N-0130 Oslo, Norway. E-mail: elin.aschim{at}hf.hio.no; or Yvonne Giwercman, Malmö University Hospital, Entrance 46, Floor 4, SE 205 02 Malmö, Sweden.

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. ERß 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 10⁶ 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 10⁶ spermatozoa/ml served as controls.

Main Outcome Measures: ERß 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 ERß may have modulating effects on human spermatogenesis. The phenotype of TDS seems to be, at least partly, determined by the genotype.

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