Timing and route of menopausal hormone therapy critically shape structural brain outcomes: A systematic review of MRI evidence.

Menopausal hormone therapy (MHT) has long been hypothesized to support women's brain health through estrogen-related neurotrophic and metabolic mechanisms. However, structural MRI studies examining MHT-associated brain changes have produced strikingly inconsistent findings, ranging from apparent neuroprotection to accelerated structural decline. To clarify the sources of this heterogeneity, we conducted a systematic review of 24 structural MRI studies identified from PubMed, Web of Science, and EBSCO (search through June 2025), synthesizing evidence across global morphometric analyses, region-of-interest investigations, and brain structure-specific metrics. Across whole-brain analyses, most studies reported larger gray matter volumes in frontal and temporal regions among MHT users. In contrast, region-specific and metric-based studies yielded mixed results. Importantly, negative structural outcomes-such as reduced hippocampal volume or increased white matter hyperintensities-were consistently confined to studies in which MHT was initiated long after menopause or administered as oral conjugated equine estrogens. In studies that explicitly accounted for initiation timing or examined transdermal estradiol, structural findings were predominantly neutral or regionally specific and positive, rather than globally adverse. These converging patterns suggest that the apparent inconsistency in the literature does not reflect a uniform lack of MHT effects on the brain, but rather systematic modulation by two underappreciated factors: the neurobiological timing of intervention and the pharmacokinetic properties of hormone delivery. In addition, the widespread reliance on conventional structural MRI measures-particularly hippocampal volume-may limit sensitivity to subtle, early estrogen-related neural changes. We propose that future research prioritize longitudinal randomized controlled designs, integrate timing- and formulation-specific analyses, and adopt more sensitive neuroimaging markers, including cortical thickness, entorhinal cortex metrics, and multimodal MRI approaches. Such efforts are essential for resolving longstanding controversies and for determining whether, and under what conditions, MHT may support brain health across the menopausal transition.