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

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 beta (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 alpha (ESR1) gene, POF patients had fever (< 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.