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Considerable evidence supports sex differences in autobiographical and episodic memory which may translate to heightened vulnerability to stress- and trauma-related disorders in women. The hormones estradiol and oxytocin both affect episodic memory, but possible sex-specific effects and hormonal interactions have not been systemically tested in humans. We conducted a randomized, placebo-controlled, parallel-group functional magnetic resonance imaging (fMRI) study involving healthy women (n = 111) and men (n = 115). Participants were scanned under four experimental conditions: 1. estradiol gel (2 mg) and intranasal oxytocin (24 IU), 2. placebo gel and intranasal oxytocin, 3. estradiol gel and placebo spray, 4. placebo gel and placebo spray. During fMRI, participants viewed positive, neutral and negative scenes. A surprise recognition task three days later was used to classify encoding trials as remembered or forgotten. Under placebo, women showed a significantly better recognition memory and increased hippocampal responses to subsequently remembered items independent of the emotional valence compared to men. Separate treatments with either estradiol or oxytocin significantly diminished this mnemonic and hippocampal sex difference, whereas the combined treatment produced no significant effect. Collectively, our results suggest that estradiol and oxytocin play a crucial role in modulating sex differences in episodic memory. Furthermore, possible antagonistic interactions between estradiol and oxytocin could explain previously observed opposing hormonal effects in women and men.

Possible interactions of the neuropeptide oxytocin and the sex hormone estradiol may contribute to previously observed sex-specific effects of oxytocin on resting-state functional connectivity (rsFC) of the amygdala and hippocampus. Therefore, we used a placebo-controlled, randomized, parallel-group functional magnetic resonance imaging study design and measured amygdala and hippocampus rsFC in healthy men (n = 116) and free-cycling women (n = 111), who received estradiol gel (2 mg) or placebo before the intranasal administration of oxytocin (24 IU) or placebo. Our results reveal significant interaction effects of sex and treatments on rsFC of the amygdala and hippocampus in a seed-to-voxel analysis. In men, both oxytocin and estradiol significantly decreased rsFC between the left amygdala and the right and left lingual gyrus, the right calcarine fissure, and the right superior parietal gyrus compared to placebo, while the combined treatment produced a significant increase in rsFC. In women, the single treatments significantly increased the rsFC between the right hippocampus and the left anterior cingulate gyrus, whereas the combined treatment had the opposite effect. Collectively, our study indicates that exogenous oxytocin and estradiol have different region-specific effects on rsFC in women and men and that the combined treatment may produce antagonistic effects.

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