Contributions of Estradiol and Hormonal Contraceptive Use to Sex Differences During Fear Extinction Recall

Rachel Zsido, Harvard College ‘14


Data from rodent and human studies have identified a network of brain regions involved in conditioned fear extinction. Recently, studies have emerged examining sex differences in the acquisition and expression of fear memories and their subsequent extinction, and in the functional activation of the fear extinction network. There is, however, inconsistency in the literature on whether or not sex differences exist in the functional activation of this network. We have previously reported that estrogen enhances the consolidation of fear extinction memories and increases the activation of the fear extinction network in women. My work aims to extend these efforts by examining whether or not estrogen, and hormonal contraceptives (HC) use, contributes to the presence or absence of sex differences in this network. To achieve this, I have analyzed a sample of 37 men and 47 women who underwent a 2-day fear conditioning and extinction paradigm while in a functional magnetic resonance imaging (fMRI) scanner. The sample included women that underwent extinction learning in a high estradiol (HE) state, low estradiol (LE) state, or while using HCs. Skin conductance response (SCR) was collected as the index of fear extinction. For SCR analysis, we observed no significant sex differences in the SCR differentials during conditioning or extinction but did during the extinction recall test in males compared to the entire female cohort, as well as increased functional activation in the ventromedial prefrontal cortex (vmPFC) in the men relative to women during recall. After dividing the women into the three cohorts, we still observed no significant differences in SCR during conditioning and extinction; during recall, however, men and HE women displayed comparable extinction retention levels, both of which were significantly higher than LE women and women using HCs. Although LE women and HC users did not statistically differ, there is a trend showing that HC users performed the worst during extinction recall. Differences in BOLD-signal changes in fMRI were much more robust after taking into consideration hormonal status: both men and the LE group exhibited higher activation in the vmPFC compared to HC users, whereas the HE group exhibited higher activation in the amygdala and hippocampus compared to the HC users. Overall, these results indicate that certain sex differences are masked when disregarding variation in estrogen levels and HCs use of the women; these differences became much more robust when differentiating the women by hormonal state. These findings not only highlight the importance of considering women’s hormonal state when responding to emotionally salient stimuli, but also raise questions surrounding the potential consequences of using HCs.

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