Transdermal sequential and continuous hormone replacement regimens with estradiol and norethisterone acetate in postmenopausal women: effects on the endometrium.

Objective: To evaluate, in postmenopausal women, the endometrial safety and histologic effects of two doses of transdermal norethisterone acetate (NETA) administered in sequential and continuous treatment regimens added to continuous transdermal estradiol, against a reference regimen consisting of sequential oral progestogen and continuous transdermal estradiol.

Methods: A total of 774 postmenopausal women were enrolled in the open-label study of 13 treatment cycles of 28 days each and randomly assigned evenly to regimens consisting of transdermal estradiol, 50 micrograms/day and NETA, given sequentially (last 14 days of each treatment cycle) or continuously at two doses (170 and 350 micrograms/day). Estradiol and NETA were delivered from a transdermal system containing both hormones. The reference group received estradiol, 50 micrograms/day transdermally and either 1 mg/day NET or 20 mg/day dydrogesterone orally during the last 14 days of each treatment cycle. Endometrial biopsies were taken pre-study and at the end of the treatment, if treatment had lasted at least 3 months. Safety was to be assessed in terms of the incidence of hyperplasia. Endometrial biopsies were assigned to one of the following histological classes: proliferative (predominant estrogen effect), suppressed proliferation (slightly, moderately, strongly progestogenic effect), progestational atrophy (predominant progestogenic effect), hyperplastic, cancerous, or other.

Results: No case of hyperplasia was recorded in any of the treatment groups, each with > 150 subjects enrolled, after one year of treatment. One case of serous carcinoma was found in the LP-C group. Progestational atrophy was seen frequently in women receiving continuous transdermal HRT (84%, high-dose NETA, 66%, low-dose NETA); it was much rarer with the sequential regimens (i.e., between 32% and 38%). The proportion of estrogen-dominated endometria was low, 0.9% and 2.6% with the high- and low-dose NETA continuous regimens, respectively, 6.2% and 12.5% with the high- and low-dose NETA sequential regimens, respectively; and, 4.5% in the oral progestogen group.

Conclusions: Transdermal administration of either dose of NETA, whether given sequentially or continuously, prevents the emergence of hyperplasia expected with unopposed estradiol. Since differences in outcomes of endometrial histology between the two NETA doses were minor for both continuous and sequential regimens, use of the lower NETA dose is considered sufficient for a safe transdermal combination hormone replacement therapy.