Endometrium Protection and Acceptability of Nasally Administered Continuously Combined Hormone Therapy: A Multicentre, Multinational, Double-Blind Trial in Postmenopausal Women Evaluating 3 Regimens of 17[beta]-Estradiol and Norethisterone When Compared With an Orally Administered 17[beta]-Estradiol Norethisterone Regimen

The results of the 'Women's Health Initiative' published in 2002 and several other large trials showed that long-lasting unopposed estrogen exposure can lead to endometrial hyperplasia, atypical hyperplasia, and eventually type-1 endometrial cancer. In the search for safer regimens, several investigators have studied different estrogens, progestins, routes of administration, or dosages. Recent studies have reported that intranasal estradiol/Norethisterone (E₂/NET) and other nonoral routes may be safer than oral therapy. The primary objective of this phase III multicenter, double-blind/double-dummy randomized controlled trial was to determine the specific daily dose of intranasal NET that should be used in combination with a fixed daily dose of intranasal E₂ to protect the endometrium. In a study population of 1741 postmenopausal women, a daily intranasal dose of 350 mcg 17 β-estradiol in combination with either 50, 175, or 550 mcg NET was compared with oral administration of 2 mg E₂ and 1 mg NET and a placebo over a 52-week period. Endometrial safety was assessed at selection, at various times during the 52-week treatment and at the end of study by measuring endometrial thickness and by endometrial histology.

As expected, most women (73%-86%) treated with an active regimen had an atrophic and/or inactive endometrium. There was a higher incidence of proliferative endometrium among women who had received lower doses of NET (1.4% for 550 mcg NET, 3.1% for 175 mcg NET, and 7.1% for 50 mcg NET, all comparisons P < 0.001). Of the women using the highest doses of NET during the last 4 months of the study, 88.1% had amenorrhea in comparison to 71.7% of those using the oral comparator in the last 4 months; the difference was 16.5%, with a 95% confidence interval of 10.9% to 22.0%, P < 0.001. Comparison of premature discontinuation rates among the groups showed a rate of 12% to 17% for the 3 nasal regimens, 22% for the oral comparator and 45% for the placebo group.

These findings show that the intranasal regimen using 550 mg NET combined with 350 mg E₂ is associated with the best histologic profile in relation to short-term endometrial safety and with less vaginal bleeding than an oral comparator using 2 mg E₂ and 1 mg NET.