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 ace tate (NETA) administered in sequential and continuous treatment regime ns added to continuous transdermal estradiol, against a reference regi men consisting of sequential oral progestogen and continuous transderm al estradiol. Methods-A total of 774 postmenopausal women were enrolle d in this open label study of 13 treatment cycles of 28 days each and randomly assigned evenly to regimens consisting of transdermal estradi ol, 50 mu g/day and NETA, given sequentially (last 14 days of each tre atment cycle) or continuously at two doses (170 and 350 mu g/day). Est radiol and NETA were delivered from a transdermal system containing bo th hormones. The reference group received estradiol, 50 mu g/day trans dermally and either 1 mg/day NET or 20 mg/day dydrogesterone orally du ring the last 14 days of each treatment cycle. Endometrial biopsies we re taken pre-study and at the end of the treatment, ii treat ment had lasted at least 3 months. Safety was to be assessed in terms of the in cidence of hyperplasia. Endometrial biopsies were assigned to one of t he following histological classes: proliferative (predominant estrogen effect), suppressed proliferation (slightly, moderately, strongly pro gestogenic effect), progestational atrophy (predominant progestogenic effect), hyperplastic, cancerous, or other. Results-No case of hyperpl asia was recorded in any of the treatment groups, each with > 150 subj ects enrolled, after one year of treat ment. One case of serous carcin oma was found in the LP-C group. Progestational atrophy was seen frequ ently in women receiving continuous transdermal HRT (84%, high-dose NE TA; 66%, low-dose NETA); it was much rarer with the sequential regimen s (i.e., between 32% and 38%). The proportion of estrogen-dominated en dometria was low, 0.9% and 2.6% with the high- and low-dose NETA conti nuous regimens, respectively; 6.2% and 12.5% with the high and low-dos e NETA sequential regimens, respectively; and, 4.5% in the oral proges togen group. Conclusion-Transdermal administration of either dose of N ETA, whether given sequentially or continuously, prevents the emergenc e of hyperplasia expected with unopposed estradiol. Since differences in outcomes of endometrial histology between the two NETA doses were m inor for both continuous and sequential regimens, use of the lower NET A dose is considered sufficient for a safe transdermal combination hor mone replacement therapy.