No Causal Links Between Lifetime Estradiol Exposure and Female’s Brain and Mental Health – A Mendelian Randomization Study

Estradiol, the predominant sex steroid in females, has been implicated in the development of depression and Alzheimer’s disease – two disorders that disproportionately affect females. Yet, while some studies suggest protective effects of estradiol on brain health and mental health, results are inconsistent partly due to methodological challenges of observational studies such as confounding and reverse causation. In this preregistered study, we examined whether estradiol levels and factors related to lifetime estradiol exposure are causally linked to brain age gap (predicted brain age relative to chronological age), AD risk, and depression risk in females. The factors related to estradiol exposure included reproductive span, age at menarche, age at menopause, number of childbirths, oral contraceptive use, HRT use, history of hysterectomy, and history of oophorectomy. To overcome some challenges of observational studies, we tested for causal associations by conducting two-sample Mendelian randomization analyses using female-specific summary statistics from previously conducted and newly run genome-wide association studies (GWAS). This included running the first female-specific GWAS on brain age gap and a GWAS on estradiol levels. No significant causal associations were found between estradiol levels, or any factors related to lifetime estradiol exposure and brain age gap, AD, or depression. Therefore, the results do not support causal links of estradiol with mental and brain health in females. Future studies should assess other influencing factors, as well as implement sex-specific, causal frameworks to examine potential effects of hormonal fluctuations and periods of increased susceptibility to sex steroids such as the perimenopausal period.