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Sex steroids have a role in modulating responses that extends beyond reproduction. The current study investigated the influence of the sex steroid 17β-oestradiol on hypothalamic-pituitary-adrenal (HPA) and behavioural responses to acute or repeated restraint stress. Ovariectomized rats treated with 17β-oestradiol or peanut oil via a subcutaneous silastic capsule were subjected to daily handling (non stressed), acute (single, 1 h) or daily (10 days, 1 h/day) restraint stress. Blood collected at the end of stress revealed that 17β-oestradiol treatment augmented the corticosterone response to acute restraint. After daily exposure to restraint, the corticosterone response was noticeably diminished in untreated females but 17β-oestradiol-treated rats still showed an exaggerated response compared to castrated, untreated females. Brain tissue collected 3 h after the end of restraint was probed using isotopic in situ hybridization for corticotropin-releasing factor (CRF) and vasopressin gene expression in the paraventricular nucleus (PVN) of the hypothalamus. 17β-oestradiol treatment at the higher dose (120 μg/ml) decreased basal CRF mRNA. Stress caused an increase in CRF mRNA expression in 17β-oestradiol-treated rats but not in the vehicle group. Repeated restraint stress caused an increase in PVN parvocellular vasopressin gene expression, which was more pronounced in 17β-oestradiol-replaced rats. Animals were exposed to the elevated plus maze for 5 min as a test for anxiety. Non-stressed control rats with or without 17β-oestradiol replacement spent the same percentage amount of time exploring the open arms of the maze. Previous exposure to acute restraint stress caused a marked reduction in the time spent exploring the open arms, indicating an increase in anxiety levels in these rats; this effect was observed in both vehicle and 17β-oestradiol-treated rats. After repeated restraint stress, 17β-oestradiol-replaced rats spent as much time exploring the open arms of the maze as controls, indicating adaptation. By contrast, nonreplaced rats were still showing a significant reduction in open arm exploration after repeated restraint. The present study presents novel data showing that the HPA axis remains reactive to repeated stress in 17β-oestradiol-treated ovariectomized rats, but stress-induced anxiety behaviour is reduced.