Age at menopause and risk of hysterectomy have strong genetic components,
but the genes involved remain ill defined. We investigated whether genetic
variation at the estrogen receptor (ER) gene contributes to the
variability in the onset of menopause in 900 postmenopausal women, aged
55-80 yr, of the Rotterdam Study, a population-based cohort study in The
Netherlands. Gynecological information was obtained, and if women reported
surgical menopause, validation of type and indication of surgery was
accomplished by checking 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 effect was
observed, corresponding to a 0.5-yr (P < 0.02) earlier onset of menopause
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
genotype compared to those in the pp group, with the most prominent effect
in women 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
hysterectomy