A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause

Objective: To determine whether a continuous estradiol-norethindrone acetat e transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone. Methods: Six hundred twenty-five postmenopausal women were assigned randoml y to one of four treatments, transdermal E2 50 mu g/day, or transdermal E2- norethindrone acetate with 50 mu g E2 and 140, 250, or 400 mu g/day of nore thindrone acetate. Follow-up visits to collect information on safety and ef ficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatme nt. Endometrial biopsy for histologic evaluation was done at baseline and u pon exit from the study (completion or withdrawal). Endometrial histology w as evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue us ing predetermined criteria. Results: Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 a lone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) i n the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectiv ely (P <.001). Uterine bleeding was less frequent in the E2-norethindrone a cetate 50-140 group than other treatments. The mean number of hot flushes p er day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone. Conclusion: Continuous transdermal delivery of E2 combined with norethindro ne acetate effectively prevented endometrial hyperplasia in healthy postmen opausal women. Continuous combined transdermal delivery systems provide inc reased dosing flexibility and might improve convenience and compliance with hormone replacement therapy. (Obstet Gynecol 1999;94:498-503. (C) 1999 by The American College Obstetricians and Gynecologists.).