The progesterone to estradiol ratio predicts fear extinction in mice and humans

Sex differences in fear memory are well documented, yet the role of menstrual cycle phases and ovarian hormone dynamics remains unclear. Here, we investigated the individual and combined effects of progesterone and estradiol on fear acquisition and within-session fear extinction in both humans and mice. Human participants included men, women using oral contraceptives, and naturally cycling women across three menstrual phases. Our animal experiment included males and naturally cycling females tested across all estrous stages. Results in humans show an association between high estradiol levels and enhanced within-session extinction, whereas progesterone shows no direct effect. To further explore the relationship between sex hormones and within-session fear extinction, a machine-learning approach (Histogram-based Gradient Boosting Regression Tree) was followed. This showed that the facilitating effect of estradiol on within-session fear extinction is potentiated by its interactions with progesterone. Specifically, a high progesterone to estradiol ratio measured before extinction predicted enhanced extinction in both humans and mice. These findings identify the progesterone to estradiol ratio as a potential translational biomarker of fear extinction, with relevance to sex-informed treatments for fear-related disorders, and uncover a key memory process shared across species.