568. the Long-term Effects of Reproductive Experience on Anxiety and Its Pharmacological Treatment: a Cross-species Approach in Rats and Humans
Year: 2025
Type: article
Abstract: Background Anxiety symptoms fluctuate across the menstrual cycle in humans, such that symptoms worsen during menstrual phases of declining or low levels of estrogens and progesterone. Conceptually consistent findings have been observed across the estrous cycle (rodent reproductive cycle) in female rats. Fluctuations in sex hormones across the estrous cycle also influences the dose responsivity to benzodiazepines, a common class of anti-anxiety medications. Together, these findings suggest a role for the menstrual cycle, and the ensuing fluctuations in sex hormones, in the maintenance of anxiety disorders and their treatment outcomes. Pregnancy causes long-term changes in sex hormonal fluctuations across the estrous/menstrual cycle, yet extant research has focused on reproductively inexperienced females. Aims & Objectives The study employed a cross-species approach to assess whether the impact of the reproductive cycle on anxiety differs pre- versus post-motherhood in rats and humans. In addition, a second experiment assessed whether the impact of the estrous cycle on the dose responsivity to diazepam (a benzodiazepine) differs pre- versus post-motherhood in rats. Method Naturally cycling virgin rats (n=14) and mother rats 1-month post-weaning (n=18) were tested twice on the open field maze, light-dark box, and elevated plus maze (EPM) to measure anxiety-like behaviour; during the metestrus (low sex hormones) and proestrus (high sex hormones) phase of the estrous cycle. In addition, a human community sample of naturally cycling non-mothers (n=35) and mothers (n=28) completed the Patient Health Questionnaire-4 at three timepoints across the menstrual cycle, during the early-follicular phase (low sex hormones), ovulation (high sex hormones), and mid-luteal phase (high sex hormones). In another experiment, virgin (n=47) and age-matched mother rats 1-month post-weaning (n=50), were injected with diazepam (1.3mg/kg or 1.7mg/kg) or vehicle, during the proestrus or metestrus, and 30 min later were tested on the EPM. Results Replicating past research, virgin rats showed higher anxiety-like behaviour during metestrus versus proestrus (ps<.05). In contrast, mother rats showed similar anxiety-like behaviour irrespective of estrous phase (ps>.05). Conceptually consistent findings were observed in humans. Replicating past research, non-mothers self-reported higher anxiety and depression during the early-follicular phase compared to other menstrual phases (ps<.05). In contrast, mothers self-reported similar anxiety and depression irrespective of menstrual phase (ps>.05). In addition, replicating past research, in virgin rats, the low dose of diazepam produced anxiolytic-like effects in proestrus, but only the high dose was anxiolytic in metestrus. In contrast, in mother rats, both doses of diazepam were anxiolytic irrespective of estrous phase. Discussion & Conclusions This study demonstrates that changes in anxiety coincident with cycling hormones is an evolutionary conserved feature of the estrous/menstrual cycle in rats and women, which may be mitigated post-motherhood in both species. In addition, this study demonstrates that reproductive experience may alter the impact of the estrous cycle on the dose responsivity to benzodiazepines. These findings highlight the importance of considering reproductive status in studies on anxiety in females. Doing so may lead to more effective evidence-based treatments that are specifically tailored towards women both with and without reproductive history.
Authors: J Pestana, B Graham
Institution: UNSW Sydney
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,693
OpenAlex ID: W4413284801