Sex differences and the influence of sex hormones on fear extinction and exposure therapy across the lifespan: A systematic review of studies in rodents and humans

Abstract

Fear extinction is a laboratory model that informs the mechanisms of exposure therapy for anxiety disorders. Although knowledge on fear extinction is primarily based on males, converging research shows that fear extinction and exposure therapy are influenced by sex-specific variables, including sex hormones. This systematic review aimed to synthesise the research on sex differences in fear extinction, and the influences of sex hormones on fear extinction, across the lifespan in rodents and humans, as well as the impact of these variables on exposure therapy in clinical populations. Pubmed and Scopus were searched through to May 2024 for articles that compared fear extinction or exposure therapy outcomes (behavioural and neurobiological measures) between sexes or examined the influence of sex hormones (or related factors, e.g., hormonal contraception) on these outcomes. One hundred and fifty-seven articles met inclusion criteria. Across species and ages, sex differences in fear extinction were commonly reported although the nature and direction of these differences were inconsistent. When accounting for female hormonal status, studies showed strong evidence that oestradiol enhances fear extinction and exposure therapy; conversely, hormonal contraceptives may disrupt extinction and exposure therapy. Sex and sex hormones frequently moderated the effects of other variables (e.g., drugs, stress) on fear extinction. This evidence synthesis strongly suggests future work on fear extinction and exposure therapy should routinely include both sexes, conduct sex-disaggregated analyses, and consider hormonal status. Given the heightened prevalence of anxiety disorders in women, such practices will facilitate more valid, useful, and equitable scientific models of anxiety treatments.