The activity of the sympathetic nervous system shows gender-specific differences with lower sympathoneural activity to the muscle vascular bed in women compared with men, with this difference vanishing after menopause. The present study tested the hypothesis that estrogen exerts regulatory influence on the autonomic nervous system in postmenopausal women. Eleven healthy postmenopausal women (age, 58.5 +/- 1.0 yr; mean +/- SEM) were studied in a randomized double-blind crossover protocol with transdermal administration of 100 microgram/day estradiol (E(2)) or placebo (P) for 2 days. Muscle sympathetic activity (MSA), blood pressure, and heart rate were recorded at rest and during sympathoexcitatory maneuvers (apnea, cold pressor test). E(2) administration significantly increased serum E(2) to physiological levels (E(2), 469.5 +/- 51.5; P, 34.8 +/- 2.2 pmol/L; P < 0.05) and significantly lowered MSA (E(2), 30.1 +/- 3.0 vs. P 37.7 +/- 3.1 bursts/min; P < 0.05). At the same time, blood pressure and heart rate were not affected. MSA was significantly enhanced during apnea and the cold pressure test, and this physiological response to the maneuvers was not changed after estrogen supplementation. In conclusion, elevation of low postmenopausal estrogen levels to physiological premenopausal levels by transdermal E(2) administration supresses MSA. This effect is most likely the consequence of a direct E(2) effect on central nervous autonomic centers, which could explain the gender-specific differences in sympathetic outflow to the muscle vascular bed. The sympathoinhibitory estrogen effects could be important for beneficial cardiovascular effects of estrogen replacement therapy in postmenopausal women.