Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.
OBJECTIVE
We investigated the effects of 2-year transdermal continuous combined estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) (Estragest TTS) on bleeding and on the endometrium.


METHODS
This double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years past menopause with intact uteri. Patients received a transdermal patch delivering either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo. Of the 266 women initially included, 135 (96 Estragest TTS, 39 placebo) completed a second year open follow-up, where all women had the estradiol/norethisterone patch. Endometrial biopsies were performed at weeks 0, 48 (n = 171), and 96 (n =109). Effects on endometrial morphology and uterine bleeding were studied.


RESULTS
The overall incidence of endometrial hyperplasia after treatment with the estradiol/norethisterone acetate patch for one year was 0.8% with only one case of atypical hyperplasia. There were no clinically significant changes in endometrial thickness in either treatment group. The proportion of bleed-free patients with the estradiol/norethisterone acetate transdermal system increased from 55% in cycles 1-3 to 83% in cycles 10-12. By the 12th cycle, 92% of patients receiving estradiol/norethisterone acetate patches were bleed-free. No additional hyperplasia was seen during the second year follow-up.


CONCLUSIONS
A continuous combined transdermal patch delivering 0.025 mg estradiol/day and 0.125 mg norethisterone acetate/day provided good endometrial protection. The dose maintained a consistently high rate of amenorrhea in postmenopausal women.
Brynhildsen
Jan
J
Division of Obstetrics & Gynaecology, Department of Health and Environment, Faculty of Health Sciences, Linköping University, Linköping, Sweden. jan.brynhildsen@lio.se
Hammar
Mats
M
D000279:Administration, Cutaneous; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects* / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D008875:Middle Aged; D009426:Netherlands; D009640:Norethindrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077563:Norethindrone Acetate; D017698:Postmenopause; D013548:Sweden; D014592:Uterine Hemorrhage
D004958:Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone