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Variations in the Hypothalamic-Pituitary-Adrenal Response to Stress during the Estrous Cycle in the Rat

Developmental Neuroendocrinology Laboratory, Douglas Hospital-McGill University Research Institute, Departments of Psychiatry, and Neurology and Neurosurgery, Faculty of Medecine, McGill University Montreal, Canada H4H 1R3

Address all correspondence and requests for reprints to: Michael J. Meaney, Douglas Hospital Research Centre, 6875 Boulevard LaSalle, Montreal (Quebec) H4H 1R3, Canada.

Abstract

To investigate the role of gonadal steroids in the hypothalamic-pituitary-adrenal (HPA) response to stress, we studied adrenocorticotrophin (ACTH) and corticosterone (B) responses to 20-min restraint stress in cycling female rats, and in ovariectomized (OVX) rats replaced with physiological levels of estradiol (E2) and progesterone (P). In cycling rats, we found significantly higher peak ACTH (P < 0.01) and B (P > 0.05) responses to stress during proestrus compared to the estrous and diestrous phases. No differences were found in either basal ACTH and B levels across the cycle phases. In a separate study, OVX rats were maintained on low, physiological levels of E2 and P with silastic implants for 3 days, and injected either with oil (0'), 10 µg of E₂ (E') 24 h before stress testing, or with E2 and 500 µg P 24 and 4 h, respectively, prior to stress (EP'). These treatments mimicked endogenous profiles of E₂ and P occuring during diestrous, proestrous, and late proestrous-early estrous phases, respectively. In response to stress, ACTH levels were higher (P < 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P < 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P < 0.05 and P < 0.01, respectively) compared to the EP' and O' group. /3-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P < 0.05) and O' (P < 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E₂ injection in the E' group were comparable to O' animals. There was no effect of E₂ on ACTH clearance, whereas B clearance was enhanced in E' treated animals us. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity. (Endocrinology 129: 2503–2511, 1991)

Received January 4, 1991.

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