Effect of Estrogen on Adrenal Catecholamine Secretion and Synthesis

Both human and experimental animal studies have demonstrated that stress-induced increases in plasma catecholamine levels are lower in females than in age-matched males. In post-menopausal women, estrogen replacement therapy suppresses stress-evoked catecholamine responses, suggesting that this sex steroid can affect adrenal medullary function. To date, support for this concept has been limited to in vitro studies showing that short-term exposure to non-physiological concentrations of estrogen can suppress agonist-induced catecholamine secretion. In the present study, a combination of in vivo and in vitro experimental approaches will be used to determine whether physiological levels of estrogen can modulate stress-evoked catecholamine responses, and whether this involves both rapid onset (non-genomic) and longer-term (genomic) effects of estrogen on the adrenal medulla. In phase 1 of the study, catecholamine responses will be measured in conscious, chronically-instrumented rats in response to either tail shock or insulin-induced hypoglycemia. Stress-evoked increases in plasma catecholamines will be compared between estrogen-deficient (ovariectomized; OVX) rats and OVX rats in which plasma estrogen concentrations have been increased to levels achieved during specific phases of the normal rat estrous cycle. In the first study, responses will be measured within minutes of elevating plasma estrogen levels by intravenous infusion to preclude potential genomic effects. In the second study, responses will be measured after 4 days of continuous exposure to estrogen delivered by subcutaneous implant. In addition to measuring plasma levels, adrenal medullary catecholamine release will be measured by in vivo microdialysis, and splanchnic nerve activity will be recorded to determine whether estrogen treatment affects the principal input stimulus for catecholamine secretion. In phase 2, the specific site(s) and mechanism(s) of estrogen action will be examined in cultured rat adrenal chromaffin cells, using electrophysiological, fluorescence and molecular biological techniques. It is anticipated that these data will contribute to our overall understanding of the cardioprotective effects of estrogenic steroids, and to our understanding of the primary risk factors associated with the increased risk of cardiovascular disease that exists in post-menopausal women.