General Obstetrics and Gynecology Gynecology
A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone,☆☆

https://doi.org/10.1067/mob.2003.91Get rights and content

Abstract

Objective: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. Study design: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. Results: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P < .004; 12 months: P < .001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P < .02). Conclusion: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects. (Am J Obstet Gynecol 2003;188:334-42.)

Section snippets

Subjects

In total, 945 postmenopausal women were assigned randomly to receive treatment at 57 investigation centers. All centers obtained Institutional Review Board approval of the protocol and amendments, and written informed consent was obtained from each subject before enrollment in the study.

Inclusion and exclusion criteria

Women were eligible for treatment if they were ≥40 years old with an intact uterus, had undergone the onset of spontaneous or surgical menopause within 5 years of study enrollment, had been amenorrheic for at

Subject disposition and baseline patient characteristics

A total of 945 subjects were randomized to either the placebo group or one of the seven active treatment groups (Fig 1). No differences were observed in baseline demographics across the treatment groups (Table I).

. Baseline patient characteristics

CharacteristicPlacebo5 EE0.25/5 NA/EE1/5 NA/EE10 EE0.5/10 NA/EE1/10 NA/EECEE/MPAOverall
Randomized to treatment (No.)117115115121119120120119945
Age (y)51.3 ± 3.951.5 ± 3.851.1 ± 4.351.6 ± 4.251.4 ± 4.251.4 ± 3.551.5 ± 3.851.4 ± 3.851.4 ± 3.9
Months since

Comment

Treatment with all NA/EE dose combinations that were evaluated in this study effectively prevented estrogen-induced endometrial hyperplasia. One case of hyperplasia occurred in the NA/EE treatment groups (0.25/5 NA/EE), and 1 case occurred in the placebo group. In addition, there was no change in endometrial proliferative status from baseline in postmenopausal women with an intact uterus. Biopsy severity scores for each NA/EE combination treatment group were significantly lower than in the

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    Supported by Pfizer Global Research and Development.

    ☆☆

    Reprint requests: David Portman, MD, Columbus Center for Women's Health Research, 5965 East Broad St, Suite 110, Columbus, OH 43213. E-mail: [email protected]

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