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A Randomized Controlled Trial

Leon Speroff, MD; Jean Rowan, MBChB, MS; James Symons, MS, PhD; Harry Genant, MD; Walter Wilborn, PhD

JAMA. 1996;276(17):1397-1403.

Abstract
Objective.
—To compare the effect of continuous norethindrone acetate (NA)— ethinyl estradiol (EE₂) combinations with matching unopposed EE₂ or placebo.

Design.
—A 2-year, double-blind, placebo-controlled, parallel-group clinical trial.

Setting.
—Outpatients at 65 centers.

Patients.
—Asymptomatic or mildly symptomatic women aged 40 years or older who had undergone the onset of spontaneous menopause within the last 5 years and who had an intact uterus.

Interventions.
—Patients were equally randomized to placebo or 1 of 8 treatment groups: 0.2 mg of NA and 1 µg of EE₂; 0.5 mg of NA and 2.5 µg of EE₂; 1 mg of NA and 5 µg of EE₂; 1 mg of NA and 10 µg of EE₂; 1 µg of EE₂; 2.5 µg of EE₂; 5 µg of EE₂; or 10 µg of EE₂.

Primary Outcome Measures.
—Bone mineral density (BMD) measured by quantitative computed tomography, serum lipids, and endometrial effects as assessed by rate of hyperplasia and proliferative status.

Results.
—Twelve hundred sixty-five patients entered the study. Bone mineral density increased significantly from baseline (P<.001) in the 1 mg NA-5 µg EE₂ and the 1 mg NA-10 µg EE₂ treatment groups at each annual assessment. Among the unopposed EE₂ groups, only the 10-µg group had increased BMD above baseline, but also was accompanied by an unacceptably high rate of endometrial hyperplasia. The NA-EE₂ treatment groups had a significant linear dose-response trend for increasing BMD. Increased endometrial proliferation and hyperplasia occurred with increasing unopposed estrogen doses. The combination of NA and EE₂ effectively protected the endometrium against hyperplasia. The percentage of change in the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol was positive for all treatment groups. The increase in triglyceride levels associated with EE₂ was attenuated with NA-EE₂ treatment.

Conclusions.
—Daily treatment with NA-EE2 was well tolerated and protected the endometrium from EE₂-induced proliferation and hyperplasia. The NA-EE₂ treatments produced a dose-related significant increase in BMD that was not present with unopposed EE₂treatment. The overall effect of NA-EE₂ treatments on lipid measures was favorable.

Author Affiliations
for the CHART Study Group

From the Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland (Dr Speroff); Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Mich (Drs Rowan and Symons); Department of Radiology, University of California, San Francisco (Dr Genant); and the Structural Research Center, Mobile, Ala (Dr Wilborn).

Footnotes
Drs Rowan and Symons are employees of the Parke-Davis Pharmeceutical Research Division and own stock in the company. Dr Speroff received salary support from Parke-Davis. Drs Genant and Wilborn are paid consultants for Parke-Davis.

A complete list of the CHART Study Investigators appears at the end of this article.

Reprints: Jean Rowan, MBChB, MS, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd, Ann Arbor, MI 48105.

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