Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a randomized open-label study.

Objectives: To establish whether transdermal continuous hormone replacement therapy (HRT) with estrogen/progestogen provides adequate long-term endometrial protection in postmenopausal women over a period of 96 weeks.

Methods: This multicenter, randomized, open-label, parallel-group study evaluated the endometrial effects and overall safety and tolerability of a transdermal matrix patch delivering estradiol (E2) 50 microg/day and norethisterone acetate (NETA) 140 microg/day (Estalis; patches applied twice weekly without intermediate breaks) and a once-daily oral comparator (Kliogest; one tablet containing E2 2 mg/NETA 1 mg) in postmenopausal women. A total of 406 women with an intact uterus, aged 44-69 years, were randomized in the 48-week core phase of the study, and 239 continued into the 48-week extension phase. Subjects were randomized in the ratio 3 : 1 to transdermal or oral E2/NETA treatment.

Results: No cases of endometrial hyperplasia or endometrial cancer were reported with either treatment during the core or extension phase. Both treatments were generally well tolerated, with most adverse events (>90%) being mild to moderate, although minor differences in the tolerability profile were observed between treatments.

Conclusions: Continuous combined transdermal HRT with E2/NETA shows no evidence of an increased endometrial hyperplasia or endometrial cancer risk over a 96-week period.