Increased levels of circulating insulin and cortisol, interpreted as part of aging process, have been associated with an increase risk of developing cardiovascular disease and diabetes mellitus. Because estrogens affect insulin balance, hypoestrogenism in menopausal women may lead to elevations in both insulin and cortisol. The purpose of the present study was to determine the effect of transdermal estradiol administration on the insulin-cortisol binomial. A prospective study was carried out in 30 menopausal women aged 48 to 55 yr, receiving transdermal estradiol 50 micrograms/day during three months. Ten healthy menopausal women (49 to 58 yr) were the control group. Serum levels of cortisol, insulin, lipoproteins, and leptin were quantified by specific assays before and after 3 months of transdermal estradiol therapy. Baseline cortisol levels decreased significantly from 143.4 +/- 10.6 ng/mL to 110.2 +/- 6.7 ng/mL (M +/- SE) (p < 0.001) after 3 months of transdermal estradiol. In parallel, augmented baseline insulin levels diminished significantly from 26.1 +/- 2.0 microlitersU/mL to 21.7 +/- 1.2; (M +/- SE) (p < 0.05). Glucose level were unaffected by this therapy, but it was restored to normal the augmented baseline levels of both triglycerides and low-density cholesterol. Total cholesterol and high-density-cholesterol as well as circulating leptin were unchanged. Transdermal estrogen induced-decrease in circulating cortisol, insulin, triglycerides, and low-density cholesterol to normal values may have a beneficial metabolic effect in menopausal women.