Differential effects of estradiol on neural and emotional stress response in postmenopausal women with remitted Major Depressive Disorder

Highlights • Estradiol effects on subjective psychosocial stress differ by depression history • Estradiol effects on brain activity to stress differ by depression history • In women with no depression history estradiol reduces emotion regulation activity • In women with depression history estradiol reduces emotion perception activity Abstract Estrogen fluctuations throughout the lifespan may contribute to major depressive disorder (MDD) risk in women through effects on brain networks important in stress responding, and mood regulation. Although there is evidence to support ovarian hormone treatment for peri-menopausal depression, postmenopausal use has not been well examined. The objective of this study was to investigate whether estrogen modulation of the neural and emotional cognitive responses to stress differs between postmenopausal women with and without MDD history. 60 postmenopausal women completed an fMRI psychosocial stress task, after receiving no drug or 3 months of daily estradiol (E2). fMRI activity and subjective mood response were examined. In women without a history of MDD, E2 was associated with a more negative mood response to stress and less activity in emotional regulation regions. In women with a history of MDD, E2 was associated with a less negative mood response to stress and less activity in emotion perception regions. This study was limited by open-label estradiol administration and inclusion of participants using antidepressants. These results support a differential effect of estrogen on emotional and neural responses to psychosocial stress in postmenopausal women with MDD history and may reflect a shift in brain activity patterns related to emotion processing following menopause.