A study led by the Institut de Neurociències of the Universitat Autònoma de Barcelona suggests that assessing the relationship between two hormones present in both men and women, estradiol and progesterone, could help better understand how memory works

Assessing the relationship between a person’s progesterone and estradiol levels at a given moment could help determine when they are in a biologically optimal state for learning and memory. This is the conclusion of a study led by ICREA researcher Raül Andero at the Institut de Neurociències of the Universitat Autònoma de Barcelona (INc-UAB), which found that the ratio between these two sex hormones measured in saliva can predict participants’ performance in a learning and memory task.

The findings provide new evidence for the role of sex hormones in memory regulation, with implications for both everyday activities that rely on memory and clinical applications. In particular, the study identifies biological markers with strong therapeutic potential for conditions such as post-traumatic stress disorder (PTSD), phobias, and panic attacks.

The study, published in Neurobiology of Stress, also involved researchers from the Hospital del Mar Research Institute in Barcelona (HMRIB).

Fear Memory Experiment

The research was conducted in both mice and healthy human participants using a fear extinction paradigm following a negative experience. On the first day, the human participants (men, naturally cycling women, and women taking oral contraceptives) and mice learned to associate a neutral stimulus with a mild but unpleasant electric shock (fear acquisition). The following day, researchers assessed their ability to stop fearing the stimulus once it was no longer paired with the shock (fear extinction). This type of fear-conditioning task allows scientists to study the same memory processes in humans and animals, facilitating cross-species comparisons.

The team used advanced analytical techniques to measure hormone levels in saliva (for human participants) and blood (for mice), and applied a machine-learning model to identify the factors that best predicted successful fear extinction.

“The results showed that while individual hormone levels had some influence, the most important factor was their combination. Specifically, a higher progesterone-to-estradiol ratio before the second experimental session predicted better fear extinction in both humans and mice”, explains Raül Andero.

“Assessing the relationship between progesterone and estradiol levels can help us identify when an individual is most biologically prepared to perform a memory-related task, such as studying for an exam. If we know we have the hormonal balance that predisposes us to learn more effectively, we could take advantage of it”, says Jaime F. Nabás, researcher at INc-UAB and first author of the paper. “This could also help optimize treatments for anxiety- and trauma-related disorders, for example by identifying the most suitable moments to carry out psychological therapy”, adds Raül Andero.

When the researchers analyzed the data according to the menstrual-cycle phase of female participants, they found results supporting the idea that fear-extinction memory is most effective at the end of the follicular phase, just before ovulation. This would therefore be the period during which the hormonal environment is most conducive to forming new memories and modifying previously learned patterns.

“It is important to note that the predictive value of the progesterone-to-estradiol ratio applies to both men and women, since both sexes produce these hormones, although women generally have higher levels”, says Óscar Pozo, researcher at HMRIB and co-author of the study.
The next steps will be to validate these findings in larger and more diverse cohorts, and to investigate whether this hormonal relationship remains relevant in clinical settings and across other types of memory. In the long term, this knowledge could contribute to the development of tools for more personalized psychological and pharmacological interventions for fear- and anxiety-related disorders.