Long-term effects of bilateral oophorectomy on brain aging: Unanswered questions from the Mayo Clinic cohorts study of oophorectomy and aging

In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who had both ovaries removed before reaching natural menopause experienced a long-term increased risk of parkinsonism, cognitive impairment or dementia, and depressive and anxiety symptoms. Here, we discuss five possible mechanistic interpretations of the observed associations; first, the associations may be non-causal because they result from the confounding effect of genetic variants or of other risk factors; second, the associations may be mediated by an abrupt reduction in levels of circulating estrogen; third, the associations may be mediated by an abrupt reduction in levels of circulating progesterone or testosterone; fourth, the associations may be mediated by an increased release of gonadotropins by the pituitary gland; and fifth, genetic variants may modify the hormonal effects of bilateral oophorectomy through simple or more complex interactions. Results from other studies are cited as evidence for or against each possible mechanism. These putative causal mechanisms are probably intertwined, and their clarification is a research priority.