Purpose of Review Anxiety symptoms increase during the peri-menstrual phase of the menstrual cycle in people with anxiety disorders. Whether this reflects a heightened variant of normal menstrual-related changes in psychological states experienced by healthy (i.e. non-anxious) people is unknown. Moreover, menstrual-related change in anxiety symptoms is a poorly understood phenomenon, highlighting a need for pre-clinical models to aid mechanistic discovery. Here, we review recent evidence for menstrual effects on anxiety-like features in healthy humans as a counterpart to recent reviews that have focused on clinically anxious populations. We appraise the utility of rodent models to identify mechanisms of menstrual effects on anxiety and offer suggestions to harmonise methodological practices across species to advance knowledge in this field. Recent Findings Consistent with reports in clinical populations, some evidence indicates anxiety symptoms increase during the peri-menstrual period in healthy people, although null results have been reported, and these effects are heterogeneous across studies and individuals. Studies in rats show robust increases in anxiety during analogous phases of the oestrous cycle. Summary Studies in female rats are useful to identify the evolutionarily conserved biological mechanisms of menstrual-related changes in anxiety. Future experimental approaches in rats should model the heterogeneity observed in human studies to increase alignment across species and advance understanding of the individual factors that increase the propensity to experience menstrual-related changes in anxiety.

Reproductive experience leads to long-lasting changes in anxiety-like behaviour and fear extinction, the laboratory model of exposure therapy for anxiety disorders. For example, fear extinction is influenced by estrous cycle in nulliparous (no reproductive experience) female rats, but this effect is abolished in primiparous (one reproductive experience) females. It is unclear whether such changes are driven by pregnancy, maternal experience of caring for offspring during the postpartum period, or a combination of both experiences. The present study sought to determine the influence of maternal experience (i.e., exposure to pups and mother-pup interactions) on fear extinction in primiparous rats. In Experiment 1, we tested whether pup exposure is necessary to mitigate estrous effects on fear extinction in primiparous rats. Age-matched nulliparous rats, primiparous rats, and primiparous rats who experienced pregnancy but not pup exposure, underwent fear conditioning on day 1 (2 months post-parturition), extinction training during proestrus (high sex hormones) or metestrus (low sex hormones) on day 2, and extinction recall on day 3. Replicating past research, nulliparous rats showed impaired extinction recall when they were extinguished during metestrus compared to proestrus. In contrast, primiparous rats with and without pup exposure showed comparable extinction recall irrespective of estrous phase. In Experiment 2, we assessed whether naturally-occurring variation in mother-pup interactions predict future fear extinction performance and anxiety-like behaviour. During the first week of lactation, primiparous rats were measured for maternal behaviours toward pups. Primiparous rats were then tested on the light-dark box and elevated plus maze to measure anxiety-like behaviour and underwent a fear extinction protocol 1 month post-weaning. We found no significant correlations between maternal behaviour and fear extinction outcomes or anxiety-like behaviour. Our findings suggest that pregnancy, not maternal experience, mitigates the impact of estrous cycle on fear extinction. In addition, natural variation in maternal experience does not appear to contribute to variability in future fear extinction outcomes or anxiety-like behaviour in primiparous rats.

Fluctuations in ovarian steroids across the estrous and menstrual cycle in female rats and women, respectively, are associated with changes in anxiety. Pregnancy causes long-term changes to ovarian hormone release, yet research on estrous- and menstrual-related changes in anxiety has focused on reproductively inexperienced females. Therefore, this study assessed whether the impact of estrous and menstrual cycles on anxiety differs pre- versus post-motherhood in female rats (n = 32) and a community sample of women (n = 63). Estrous cycle phase altered anxiety-like behavior in virgin rats, but had no effect in age-matched mother rats tested 1-month post-weaning. In humans, menstrual cycle phase was associated with ecological momentary assessed anxiety and mood in non-mothers, but not mothers; although, the menstrual cycle × reproductive status interaction for anxiety, but not mood, was rendered non-significant with age and cycle length as covariates. These findings suggest that changes in anxiety coincident with cycling hormones is an evolutionarily conserved feature of the estrous and menstrual cycle in rats and women, which is mitigated following motherhood in both species. We identified several potential mechanisms for the observed dissociation in estrous cycle effects on anxiety. Compared to virgin rats, mother rats had a lower peak and blunted decline in circulating allopregnanolone during proestrus, upregulated GABAA receptor subunit (α1, α2, α5, α4, ß2) mRNA in the ventral hippocampus, and altered corticotropin-releasing hormone mRNA across the estrous cycle in the basolateral amygdala. Together, these findings suggest that the mechanisms underlying anxiety regulation undergo fundamental transformation following pregnancy in female rats and humans.

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