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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Limitations: This study was limited by open-label estradiol administration and inclusion of participants using antidepressants.

Conclusions: 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.

Keywords: depression; estrogen; fMRI; menopause; stress.

Figure 1.. Change in brain activity during experimentally induced stress with the MIST.

A) Positive activity (“Stress” > “Control”) in superior temporal and occipital regions. B) Negative activity (“Stress” < “Control”) in left middle frontal, bilateral caudate, and left angular regions.

Figure 2.. Effects of MDD History and E2 on change in brain activity with stress exposure during the MIST.

Interactive effect of major depression disorder history and estradiol administration in A) left inferior frontal region and B) angular activity change between the “stress” and “control” conditions of the Montreal Imaging Stress Task.

Figure 3.. Percent Signal Change “Stress” – “Control”: MDD History – E2 Interaction.

Interactive effect of major depression disorder history and estradiol administration in left inferior frontal region and angular percent signal change (PSC) between the “stress” and “control” conditions of the Montreal Imaging Stress Task.

Figure 4.. Correlation between Change in Activity during the MIST and Subjective Stress.

Brain areas including cingulate, temporal, and motor regions where activity change between the “stress” and “control” condition of the Montreal Imaging Stress Task (MIST) was negatively correlated with Stress-Arousal Checklist Stress score change across the stress task. Greater Activity in these areas during the “stress” condition of the MIST was associated with less subjective stress.

Figure 5.. Effects of MDD History and E2 on the correlation between Change in Activity during the MIST and Subjective Stress.

A) Women with a history of MDD who received estradiol showed a negative correlation between activity in the right inferior frontal region during the “stress” condition (compared to “rest”) of the Montreal Imaging Stress Task (MIST)and Stress-Arousal Checklist (SACL) Stress change score with less activity associated with greater subjective stress. B) Women with a history of MDD who did not receive estradiol showed a positive correlation between activity in the right temporal/ insula region during the “stress” condition of the MIST (compared to “rest) and SACL-Stress change score and also between activity change between the “control” and “stress” conditions and SACL-Stress change score with greater activity associated with greater subjective stress.