The influence of the estrous cycle in preclinical models that mimic key features of post-traumatic stress disorder: A systematic review.

Similar to other mood and anxiety conditions, post-traumatic stress disorder (PTSD) appears to be more prevalent and have a more protracted course in females. In the clinic, PTSD symptoms have been shown to worsen during phases of the menstrual cycle characterized by low estrogen and progesterone levels. Similarly, low estrogen levels have been associated with the development of fear and anxiety-like behaviour in preclinical models. Despite the commonly held belief that sex hormones influence fear and anxiety, the literature contains conflicting findings and remains controversial. To better understand the impact of the estrous cycle and sex hormones on preclinical models of PTSD-like behaviour, we conducted a systematic review of the literature. Both fear conditioning/extinction and alternative models of PTSD-like behaviour were considered. Of the 78 studies included in our review, 51% (n = 40) found no behavioural effect of the estrous cycle, ovariectomy (OVX), or hormone replacement. Conversely, 27% found an effect of hormones or the estrous cycle on fear behaviour, while 22% reported a significant effect in some metrics but not all tests. Of the articles that demonstrated a positive effect in at least one test, approximately 70% exhibited increased fear expression during phases characterized by low hormone levels (metestrus, diestrus, or OVX). In contrast, 22% reported increased fear behaviour during phases with high hormone levels (proestrus, estrus, or ovarian hormone administration), while 8% exhibited increased fear expression under both high- and low-hormone conditions. These inconsistent findings highlight the need for further research into the effect of the estrous cycle and sex hormone levels on preclinical models that mimic some of the core features of PTSD.