Hypophysial portal circulation levels of immunoreactive (ir) CRF, immunoreactive arginine vasopressin (ir-AVP), and systemic ir-ACTH and cortisol were determined in dexamethasone-infused (20 μg/h) ewes, both under basal conditions and in response to audiovisual and hypoglycemic stress. Glucocorticoid infusion lowered mean basal levels of ir-CRF (P < 0.05), ir-ACTH (P < 0.05), and cortisol (P < 0.05), but not of ir-AVP. Audiovisual stress led to coordinate release of ir-AVP and ir-CRF, and although the hypothalamic response to this stress was not altered in dexamethasone (DEX)-infused sheep, the pituitary-adrenal response was blocked, suggesting that glucocorticoids act on the pituitary rather than on higher centers to inhibit this response. In contrast, hypoglycemia led to preferential release of ir-AVP over ir-CRF, and DEX infusion delayed and inhibited both hypothalamic and pituitary responses. Ketamine injection also led to preferential release of ir-AVP, but neither the hypothalamic nor pituitary-adrenal responses were affected by DEX infusion. These results suggest that different stressors evoke different patterns of hypothalamic secretagogue release, and that glucocorticoids act in a site-specific fashion to regulate the hypothalamo-pituitary-adrenal responses to stress.