Hum. Reprod. Advance Access published online on April 7, 2009
Human Reproduction, doi:10.1093/humrep/dep067
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Endometrium protection and acceptability of nasally administered continuously combined hormone therapy: a multicentre, multinational, double-blind trial in post-menopausal women evaluating three regimens of 17β-estradiol and norethisterone when compared with an orally administered 17β-estradiol norethisterone regimen
1 Department of Obstetrics and Gynaecology, CHU St Pierre, Rue Haute 290, 1000 Brussels, Belgium 2 Brussels Menopause Center, Brussels, Belgium 3 Department of Obstetrics and Gynaecology, UZ Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium 4 Instituto Palacios, Salud y Medicina de la Mujer, Madrid, Spain 5 Nordic Bioscience A/S, Herlev, Denmark
6 Correspondence address. E-mail: serge.rozenberg{at}skynet.be, sergerozenberg{at}stpierre-bru.be
BACKGROUND: To determine the optimal daily dose of intranasal hormone therapy (HT) in order to achieve adequate endometrial protection.
METHODS: Multicentre, double-blind/double-dummy randomized controlled trial (Phase III) was conducted in 1741 women to compare a daily intranasal dose of 350 µg 17β-estradiol (E2) together with 50, 175 or 550 µg norethisterone (NET) with the oral administration of 2 mg E2 and 1 mg NET, over a period of 52 weeks. An endometrial biopsy was performed at the end of HT use.
RESULTS: Most women (73–86%) had an ‘atrophic and/or inactive’ endometrium. Lower doses of NET were associated with a higher incidence of ‘proliferative’ endometrium. The incidence of vaginal bleeding decreased with time. During the last 4 months of the study, 88.1% of women using the highest dose of NET were in amenorrhoea when compared with 71.7% using the oral comparator (difference 16.5%; 95% confidence interval: 10.9–22.0%) (P < 0.001). Premature discontinuation rates were in the range of 12–17% for the three nasal regimens and 22% for the oral comparator.
CONCLUSIONS: HT using a fixed intranasal dose of 350 µg E2 combined with 550 µg NET is a safe regimen, in relation to 1 year endometrial safety. This regimen is associated with less vaginal bleeding when compared with an oral comparator using 2 mg E2 and 1 mg NET.
Key words: hormone therapy/menopause/intranasal/estradiol/norethisterone
Submitted on October 1, 2008; resubmitted on December 28, 2008; accepted on January 13, 2009.