Estrogen receptor α gene polymorphisms are associated with idiopathic premature ovarian failure

Bretherick, Karla L.; Hanna, Courtney W.; Currie, Lauren M.; Fluker, Margo R.; Hammond, Geoffrey L.; Robinson, Wendy P.

doi:10.1016/j.fertnstert.2007.03.008

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Volume 89, Issue 2 , Pages 318-324, February 2008

Estrogen receptor α gene polymorphisms are associated with idiopathic premature ovarian failure

Karla L. Bretherick, B.Sc.
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Courtney W. Hanna, B.Sc.
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Lauren M. Currie, B.Sc.
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Margo R. Fluker, M.D.
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Women's Hospital and Health Centre, Vancouver, Canada
- Genesis Fertility Centre, Vancouver, Canada
Geoffrey L. Hammond, Ph.D.
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Women's Hospital and Health Centre, Vancouver, Canada
- Reproductive Health Research Program, Child and Family Research Institute, Vancouver, Canada
Wendy P. Robinson, Ph.D.
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
- Reproductive Health Research Program, Child and Family Research Institute, Vancouver, Canada
- Reprint requests: Wendy P. Robinson, Child and Family Research Institute, 950 W. 28th Avenue, Room 3096, Vancouver, BC, CANADA V5Z 4H4 (FAX: 604-875-3120).

Received 16 January 2007; received in revised form 2 March 2007; accepted 5 March 2007. published online 14 August 2007.

Objective

To assess the role of hormone receptor/binding protein variants in genetic predisposition to premature ovarian failure (POF).

Design

Case-control study.

Setting

Academic.

Patient(s)

Fifty-five POF patients, 107 control women from the general population, and 27 control women who had proven fertility after age 37.

Intervention(s)

None.

Main Outcome Measure(s)

Allele distributions in cases and controls were assessed for genetic association.

Result(s)

Allele distributions of polymorphisms at the androgen receptor (AR) gene, estrogen receptor β (ESR2) gene, sex hormone-binding globulin (SHBG) gene, and FSH receptor (FSHR) gene did not differ between patients and controls. At a repeat in a promoter of the estrogen receptor α (ESR1) gene, POF patients had fewer (<18) short repeat alleles than did controls (P=.004 vs. combined controls). Genotypes consisting of two short alleles were found in 36.4% of control women but only 5.5% of POF patients (P<.0001 vs. combined controls). The ESR1 repeat may confer risk for POF in a simple dominant manner in which carriers of a long repeat have a relative risk of 9.7 (95% CI = 2.6 – 35.6).

Conclusion(s)

Polymorphisms at the ESR1 gene are associated with POF in this patient population, while those in AR, ESR2, SHBG, and FSHR showed no association. Further studies are necessary to confirm these findings in larger patient samples and to identify the specific predisposing lesion.

Key Words: ESR1, estrogen receptor, infertility, menopause, POF