Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle

Abstract

Although ovarian hormones are thought to have a potential role in the well-known sex difference in mood and anxiety disorders, the mechanisms through which ovarian hormone changes contribute to stress regulation are not well understood. One mechanism by which ovarian hormones might impact mood regulation is by mediating the effect of psychosocial stress, which often precedes depressive episodes and may have mood consequences that are particularly relevant in women. In the current study, brain activity and mood response to psychosocial stress was examined in healthy, normally cycling women at either the high or low estradiol phase of the menstrual cycle. Twenty eight women were exposed to the Montreal Imaging Stress Task (MIST), with brain activity determined through functional magnetic resonance imaging, and behavioral response assessed with subjective mood and stress measures. Brain activity responses to psychosocial stress differed between women in the low versus high estrogen phase of the menstrual cycle: women with high estradiol levels showed significantly less deactivation in limbic regions during psychosocial stress compared to women with low estradiol levels. Additionally, women with higher estradiol levels also had less subjective distress in response to the MIST than women with lower estradiol levels. The results of this study suggest that, in normally cycling premenopausal women, high estradiol levels attenuate the brain activation changes and negative mood response to psychosocial stress. Normal ovarian hormone fluctuations may alter the impact of psychosocially stressful events by presenting periods of increased vulnerability to psychosocial stress during low estradiol phases of the menstrual cycle. This menstrual cycle-related fluctuation in stress vulnerability may be relevant to the greater risk for affective disorder or post-traumatic stress disorder in women.

Keywords: Estradiol; Menstrual cycle; Psychosocial stress; fMRI.

Figure 1

Psychosocial Stress Effect fMRI Stress Condition – Control Condition: All participants (n = 28). Greater deactivation in limbic regions during the stress condition compared to the control condition (corrected to p < 0.001).

Figure 2

Estradiol Effects fMRI Stress Condition – Control Condition: High estradiol (n = 10) – Low estradiol (n = 10). Greater activity in left hippocampus during the stress condition in the High estradiol group than the Low estradiol group (cluster-level corrected to p < 0.005).

Figure 3

Subjective Distress Effects fMRI Stress Condition – Control Condition: High Distress (n = 14) – Low Distress (n = 14). Greater activity in bilateral hippocampus and less subgenual cingulate activation during the stress condition in the Low Distress group than the High Distress group (cluster-level corrected to p < 0.001).

Figure 4

Estradiol and Progesterone Levels for Group Analyses Low estradiol group (n =10) estradiol mean = 24.91 pg/mL, SD = 9.17, high estradiol group (n = 10) estradiol mean = 103.52 pg. mL, SD = 34.09 (t (18) = 7.04, p < 0.001). Low estradiol group progesterone mean = 48.90 pg/mL, SD = 36.10, high estradiol group progesterone mean = 50.54 pg/mL, SD = 36.91 (t (18) = 0.099, p = 0.92). Low distress group (n =14) estradiol mean = 74.49 pg/mL, SD = 40.93, high distress group (n = 14) mean = 43.47 pg/mL, SD = 35.26, (t (26) = 2.15, p < 0.05). Low distress progesterone mean = 41.04 pg/mL, SD = 35.49, high distress progesterone mean = 58.96 pg/mL, SD = 36.84 − (t (26) = −1.31, p = 0.20).