It has been shown that steroid hormones are able to influence the sympathoadrenal system activity. Therefore, we have investigated in a double blind cross-over study the effect of percutaneous estradiol administration (100 micrograms) on the sympathoadrenal and cardiovascular responses to mental arithmetic stress in 20 normal young males. The plasma estradiol level was 154 +/- 14 pmol/L during the estrogen session (ES) and 44 +/- 7 pmol/L during the placebo session (PL; P < 0.001). The mental stress induced a significant increase in systolic blood pressure during both the PL (F = 7.2; P < 0.001) and the ES (F = 4.8; P < 0.01); the peak obtained during PL was, however, higher than that during ES (128 +/- 2 vs. 122 +/- 3 mm Hg; P < 0.02). A significant increase in pulse rate was observed during PL (F = 4.2; P < 0.002), but not during ES (F = 2.6; P = 0.47), with the peak pulse rate being higher during mental stress in the PL than the ES (78 +/- 2 vs. 74 +/- 2 beats/min; P < 0.03). In response to the mental stress, plasma epinephrine increased significantly during PL (F = 3.2; P < 0.03), but not during ES (F = 1.1; P = 0.3). The stress-induced peak in plasma epinephrine during PL was higher than that during ES when expressed as the absolute value or the incremental peak (513 +/- 103 vs. 125 +/- 32 pmol/L; P < 0.005). The incremental peak in plasma norepinephrine obtained during PL was higher than that during ES (0.78 +/- 0.1 vs. 0.27 +/- 0.07 nmol/L; P < 0.02). Plasma free fatty acid, acetoacetate, and 3-hydroxybutyrate increased significantly from basal values during PL, but not during ES. These data show that mildly elevated levels of estradiol are able to influence the response of the adrenal medulla to mental stress in men.