This study compares the pharmacokinetic performance of a matrix system for transdermal 17-beta-estradiol (E(2)) delivery using multiple consecutive dosing with a first application in postmenopausal women undergoing hormone replacement therapy. A clinical study (SI) was conducted over a treatment period of 11 days in 16 postmenopausal women receiving three consecutively applied matrix patches for the delivery of E(2). The first patch was worn for 4 days, the second for 3 days, and the third patch for 4 days. The E(2) plasma profiles determined during the third application were compared with results obtained by a published clinical study (SII) using the same patch in the same group of postmenopausal women without E(2) pretreatment. Additionally, the 24 h plasma profiles of E(2) and estrone were determined before and on day 4 during patch application of the third patch. Comparison of the mean pharmacokinetic parameters from the two studies showed no significant difference in E(2) plasma levels: AUC(0-->96h) [pg/mL h] SI: 4342 +/- 1513 and SII: 4512 +/- 1229; C(max)[pg/mL] SI: 51.3 +/- 28.8 and SII: 54.2 +/- 22.3; C(average) [pg/mL] SI: 45.0 +/- 13.2 and SII: 47.0 +/- 9.4; C(min) [pg/mL] SI: 31.4 +/- 5.9 and SII: 32.2 +/- 8.1. Over 96 h, fluctuation, f, defined as (C(max) - C(min)) / C(average), was 0.44 in SI and 0.47 in SII. Individual comparison of E(2)-C(max), -AUC, and -C(min) revealed that more than 87.5% of all patients showed a variation between SI and SII of less than 10%. The mean of the individual AUC(0-->96h) variation between the first and the third patch was only 4.7%. There was no significant drop in E(2) plasma values after patch removal and reapplication, and accumulation of E(2) did not occur after several patches were applied consecutively. Plasma E(2) showed a circadian rhythm that was lower in the morning and higher in the evening. No circadian rhythm was observed in untreated basal plasma E(2) in the group of postmenopausal women. The transdermal matrix system yielded sustained E(2) plasma levels in postmenopausal women in the initial application period. In long-term dosing there was no accumulation of E(2) in plasma and no significant drop after patch removal. It is presently not known why the circadian variation in the experimentally obtained E(2) plasma values exists.