Exogenous estradiol and oxytocin modulate sex differences in hippocampal reactivity during the encoding of episodic memories.

Considerable evidence supports sex differences in episodic memory. The hormones estradiol and oxytocin both affect episodic memory and may contribute to these sex differences, but possible underlying hormonal interactions have not been tested in a sample involving both sexes. To this end, we conducted a randomized, placebo-controlled, parallel-group functional magnetic resonance imaging (fMRI) study including healthy free-cycling women (n = 111) and men (n = 115). The fMRI session was conducted under four experimental conditions: 1. transdermal estradiol (2 mg) and intranasal oxytocin (24 IU), 2. transdermal placebo and intranasal oxytocin, 3. transdermal estradiol and intranasal placebo, 4. transdermal placebo and intranasal placebo. Participants were scanned during the encoding of positive, neutral, and negative scenes. Recognition memory was tested three days following the scanning sessions without additional treatments. 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. The separate treatments with either hormone significantly diminished this mnemonic sex difference and reversed the hippocampal activation pattern. However, the combined treatments produced no significant effect. Collectively, the results suggest that both hormones 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.