Authors
Jaime F Nabás, Eric R Velasco, David Fabregat-Safont, Élida Alechaga, Alex Gomez-Gomez, Marta Torrent, Mariana G Fronza, Victoria Mueller, Mohammed R Milad, Rafael Torrubia, Miquel A Fullana, Katharina Schultebraucks, Oscar Pozo, Raul Andero
Published in
Neurobiology of stress. Volume 43. Pages 100823. Epub May 22, 2026.
Abstract
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.
PMID:
42318369
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.
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