Menopausal Hormone Therapy and Risk of Neuropsychiatric Disease: A Drug Target Mendelian Randomisation Study

The effects of menopausal hormone therapy (MHT) on neurological and psychiatric disease risk have shown conflicting results across epidemiological and clinical studies. Given the widespread propagation of MHT among females experiencing menopausal symptoms, clarifying causality and impact is critical for informed decision-making. Although randomised controlled trials can establish causal effects, they are associated with significant costs and often of limited duration. Here, we present the first study using Mendelian randomisation (MR) to estimate causal effects of MHT on key neuropsychiatric and brain structural outcomes. To mimic the effects of MHT on oestrogen receptors (ER) α and β, we leveraged genetic variations located in the ESR1 and ESR2 genes that were significantly associated with positive controls as instrumental variables. In two-sample MR analyses, we used GWAS data on late-onset Alzheimer's disease (AD), key brain structural endophenotypes (cortical grey matter volume, hippocampal volume, and white matter hyperintensity volume), as well as depression and anxiety as outcomes, adjusting the p-values for multiple comparisons using false discovery rate correction with an α level of 0.05. There was no evidence for an impact of genetically proxied perturbation of ERα (β = -0.08, 95% CI [-0.34, 0.20], p=0.69 and β = -0.005, 95% CI [-1.45, 1.44], p=1.00) and ERβ (β = 0.35, 95% CI [-0.77, 1.47], p=0.69) on AD risk. Similarly, we found no significant impact of genetically proxied perturbation of ERα and ERβ on associated brain structural outcomes. Genetically proxied perturbation of ERβ was significantly related to higher depression risk (β = -0.66, 95% CI [-0.99, -0.32], p=0.002), but not anxiety risk. Our study provides support for a causal impact of genetically predicted oestrogen receptor perturbation on increased risk of depression, highlighting the importance of considering the implications of targeting these proteins with MHT, for psychiatric outcomes in clinical contexts. However, there was no support for either a harmful or protective causal effect of MHT on AD risk.