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Causal associations between hormone replacement therapy and brain structure: Evidence from large-scale Mendelian
Xiao Zhu1, Youcai Liang1, Tao Tao2
1The Second Affiliated Hospital of Guangdong Medical University, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, China.
Progress in Neuro-Psychopharmacology & Biological Psychiatry
|August 10, 2026
Summary
This study reveals that hormone replacement therapy (HRT) timing and duration causally impact brain structure, affecting white matter, cortical thickness, and regional volumes. Findings suggest neurobiological relevance for brain aging and personalized interventions.
Area of Science:
- Neuroscience
- Genetics
- Endocrinology
Background:
- Hormone replacement therapy (HRT) is common for hormone deficiency, especially during menopause.
- Its causal impact on human brain structure is not fully understood, with observational studies showing varied results.
Purpose of the Study:
- To investigate the causal effects of HRT initiation timing, cessation timing, and lifetime use on human brain structure.
- To utilize a robust causal inference framework combining Mendelian Randomization (MR) and Double Machine Learning (DML).
Main Methods:
- Employed a two-sample MR and DML integrated causal framework.
- Analyzed genetic associations with 1366 brain imaging phenotypes from the UK Biobank.
- Validated MR causal estimates using non-parametric DML with cross-fitting.
Main Results:
- Later HRT initiation was linked to altered cerebellar white matter microarchitecture.
- Later HRT cessation correlated with changes in cortical thickness and white matter integrity.
- Ever-use of HRT was associated with increased volumes in specific brain regions like the inferior frontal gyrus.
- DML validated these associations, providing causally debiased estimates.
Conclusions:
- Provides genetically-informed and machine-learning-validated evidence for HRT's causal effects on brain structure.
- Highlights the neurobiological significance of sex steroid exposure timing and duration.
- Suggests implications for understanding brain aging and developing personalized hormone-based interventions.
