Oestradiol modulates the brain age gap

The brain age gap (BAG) -- the difference between chronological and neuroimaging-based predicted brain age -- has emerged as a sensitive biomarker of brain health. A higher BAG, reflecting an older-appearing brain, has been linked to cognitive decline, neurodegenerative disease, and mental disorders. Whether such apparent aging can be mitigated by targeted interventions remains unclear. Oestradiol (E2), a sex hormone fluctuating across the menstrual cycle and known for its neuromodulatory and cognitive effects, may represent one such target intervention. To test this, we conducted a double-blind, randomized, placebo-controlled crossover study in 28 premenopausal females. Each participant was assessed twice during the follicular phase, with at least two cycles between sessions, and received either 12 mg E2-valerate or a placebo before undergoing a T1-weighted MRI scan. BAG was estimated using a pre-trained Simple Fully Convolutional Network model. Predicted brain age was significantly younger following E2 administration compared to placebo. Exploratory analyses indicated that this effect may be moderated by resilience factors for mental health: Higher self-esteem and use of greater social support seeking was nominally associated with lower BAG, whereas females applying more expressive suppression showed more apparent brain aging. These findings suggest that even short-term increases in E2, together with resilience factors, can influence brain age estimates. Thus, E2 interventions may provide a targeted approach to support both brain and mental health. These findings underscore the urgent need for further research into the impact of E2 on mental health across the female lifespan.