GENES CONTROL THE CESSATION OF A WOMANS REPRODUCTIVE LIFE - A TWIN STUDY OF HYSTERECTOMY AND AGE AT MENOPAUSE

A classical twin study was performed to assess the extent to which gen etic factors explain individual differences in age at menopause and (i ndications for) hysterectomy. It was further examined whether a geneti c effect on the timing of the menopause was mediated through a genetic effect on age at menarche. The subjects were 275 monozygotic and 353 dizygotic female twin pairs. Maximum likelihood model fitting was used to estimate genetic and environmental variance components, Kaplan-Mei er survival analysis was used to account for censored data, and the Co x proportional hazards model was used to adjust for potential confound ers. A model specifying additive genetic and unique environmental fact ors showed the best fit to the data, yielding a heritability (h(2)) fo r age at menopause of 63%. The significance of the genetic effect was confirmed by the survival analysis and was not affected by adjustment for confounders. Both early and late menopause were found to be signif icantly influenced by genetic factors. Hysterectomy also showed consid erable heritability (h(2) = 59%), as did its two main indications: fib roids (h(2) = 69%) and menorrhagia (h(2) = 55%). The genetic contribut ion to the variance in age at menarche was estimated to be 45%, with t he majority (37%) being due to dominant genetic effects. No correlatio n was found between age at menopause and age at menarche, suggesting d ifferent genetic mechanisms. This study provides convincing evidence f or the importance of genetic factors in determining natural and surgic al menopause. Understanding how genes control the timing of menopause and exploring whether these genes are indirectly associated with disea se are important areas for future study.