Dissecting the role of estradiol in mediating gender-specific anxiolytic and prosocial effects of oxytocin

• Applicants: Professor René Hurlemann, Ph.D.; Professor Dr. Dirk Scheele
• Subject Area: Biological Psychiatry ; Human Cognitive and Systems Neuroscience
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398029128

• Final Report Year: 2023

Final Report Abstract

Accumulating evidence indicates that the hypothalamic peptide oxytocin can have opposing effects in women and men. In this project, we tested the hypothesis that sex-specific effects of oxytocin may result from interactions with the steroid hormone estradiol. We first examined whether sex-specific effects of oxytocin on amygdala reactivity can be explained as a byproduct of different dose-response functions in women and men. A decrease in amygdala responses to fearful faces was most pronounced for a dose of 24 IU in men, but the opposite effect was evident across three doses (6 IU, 12 IU, and 24 IU) of oxytocin in women. Furthermore, we conducted two randomized double-blind studies in which we combined the exogenous administration of oxytocin (24 IU) and estradiol (2 mg) in healthy women and men. In both studies we found evidence for sexspecific effects and antagonistic interactions of the hormones. In a study with functional magnetic resonance imaging (fMRI), we observed that women showed a significantly better recognition memory and increased hippocampal responses to subsequently remembered items compared to men under placebo. 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. Likewise, the effects of single treatments on fMRI resting state functional connectivity were no longer significant in the combined treatment group. Furthermore, in a behavioral study we found that elevated estradiol levels before oxytocin administration were associated with increased acceptance of fairly framed economic proposals in men, while estradiol had the opposite effect in women. Importantly, we could replicate a previously observed effect that 24 IU of oxytocin facilitate the extinction of fear memories in men. However, this effect was not significant in estradiol-treated men and in women. Finally, we conducted a proof-of-concept study to probe the efficacy of oxytocin as an adjunct to a short-term modular-based group intervention for individuals suffering from high trait-like loneliness. Oxytocin had no significant effect on trait-like loneliness, but the peptide significantly facilitated the decrease in state loneliness within sessions and significantly improved positive bonding between the group members. Interestingly, oxytocin significantly enhanced intervention effects on social anxiety only in men, while the other treatment effects were evident in both sexes. Thus, sexspecific effects of oxytocin are not domain-general, but vary between amygdala-related fear processing and bonding-related reward processing in women and men. Taken together, our findings support the increasingly recognized notion that it is vital to consider sex differences and hormonal interactions in pharmacological clinical trials.

Publications

• Kinetics of oxytocin effects on amygdala and striatal reactivity vary between women and men. Neuropsychopharmacology, 45(7), 1134-1140.
  Lieberz, Jana; Scheele, Dirk; Spengler, Franny B.; Matheisen, Tatjana; Schneider, Lìa; Stoffel-Wagner, Birgit; Kinfe, Thomas M. & Hurlemann, René
  
• Treatment-Resistant Depression and Ketamine Response in a Patient With Bilateral Amygdala Damage. American Journal of Psychiatry, 176(12), 982-986.
  Scheele, Dirk; Zimbal, Sophia; Feinstein, Justin S.; Delis, Achilles; Neumann, Claudia; Mielacher, Clemens; Philipsen, Alexandra & Hurlemann, René
  
• Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research. Molecular Psychiatry, 26(1), 80-91.
  Quintana, Daniel S.; Lischke, Alexander; Grace, Sally; Scheele, Dirk; Ma, Yina & Becker, Benjamin
  
• Sex differences in economic decision-making: Exogenous estradiol has opposing effects on fairness framing in women and men. European Neuropsychopharmacology, 50, 46-54.
  Coenjaerts, Marie; Pape, Frederike; Santoso, Virginia; Grau, Franziska; Stoffel-Wagner, Birgit; Philipsen, Alexandra; Schultz, Johannes; Hurlemann, René & Scheele, Dirk
  
• Exogenous estradiol and oxytocin modulate sex differences in hippocampal reactivity during the encoding of episodic memories. NeuroImage, 264, 119689.
  Coenjaerts, Marie; Trimborn, Isabelle; Adrovic, Berina; Stoffel-Wagner, Birgit; Cahill, Larry; Philipsen, Alexandra; Hurlemann, René & Scheele, Dirk
  
• Effects of exogenous oxytocin and estradiol on resting-state functional connectivity in women and men. Scientific Reports, 13(1).
  Coenjaerts, Marie; Adrovic, Berina; Trimborn, Isabelle; Philipsen, Alexandra; Hurlemann, René & Scheele, Dirk
  
• Oxytocin-augmented modular-based group intervention for loneliness: A proof-of-concept randomized-controlled trial. Cold Spring Harbor Laboratory.
  Berger, Ruben; Hurlemann, Rene; Shamay-Tsoory, Simone G.; Kantermann, Alisa; Brauser, Maura; Gorni, Jessica; Luhmann, Maike; Schramm, Elisabeth; Schultz, Johannes; Philipsen, Alexandra; Lieberz, Jana & Scheele, Dirk