Estrogen receptor polymorphism predicts the onset of natural and surgical menopause

Age at menopause and risk of hysterectomy have strong genetic components, b ut the genes involved remain ill defined. We investigated whether genetic v ariation at the estrogen receptor (ER) gene contributes to the variability in the onset of menopause in 900 post-menopausal women, aged 55-80 yr, of t he Rotterdam Study, a population-based cohort study in The Netherlands. Gyn ecological information was obtained, and if women reported surgical menopau se, validation of type and indication of surgery was accomplished by checki ng medical records. The ER genotypes (PP, Pp, and pp) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1 -yr (P < 0.02) earlier onset of menopause. Furthermore, an allele dose effe ct was observed, corresponding to a 0.5-yr (P < 0.02) earlier onset of meno pause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5-3.8) times higher for women carrying the PP genot ype compared to those in the pp group, with the most prominent effect in wo men who underwent hysterectomy due to fibroids or menorrhagia. We conclude that genetic variations of the ER gene are related to the onset of natural menopause and the risk of surgical menopause, especially hyster ectomy.