Estrogen Receptor a Gene Polymorphisms Are Associated With Idiopathic Premature Ovarian Failure

About 1 in 100 women enter menopause before age 40; they are generally diagnosed as having premature ovarian failure (POF). The only gene that has consistently been associated with POF is FMR1 (Fragile X Mental Retardation 1), but the finding that only about 14% of women with familial POF carry an FMR1 premutation suggests that other genes may be associated with POF. This case-control study examined the role, if any, of hormone receptor or binding protein variants in genetic predisposition to POF. Fifty-five women diagnosed as having POF were compared with 107 control women from the general population and with 27 others who were proved fertile after age 37 years. Participants were from a predominantly Caucasian population in western Canada with significant Asian (mainly Chinese) admixture. Allele frequencies for repeat polymorphisms and single nucleotide polymorphisms were examined at several candidate gene sites. No significant differences were found between POF patients and control women in allele distributions of polymorphisms at the androgen receptor (AR) gene, estrogen receptor β (ESR2) gene, sex hormone-binding globulin (SHBG) gene, or follicle-stimulating hormone (FSH) receptor (FSHR) gene. In contrast, at a repeat in a promoter of the estrogen receptor a (ESR1) gene, women with POF had fewer (less than 18) short repeat alleles than control women (P = 0.004 versus the combined control groups). A genotype consisting of 2 short alleles was identified in 36.4% of control women but only 5.5% of those with POF (P < 0.0001 versus combined controls). Calculations showed that the ESR1 repeat may create a risk of POF in a simple dominant manner in which carriers of a long repeat have a relative risk of POF of 9.7, with a 95% confidence interval of 2.6-35.6.