The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study) - A randomized controlled trial

Objective.-To compare the effect of continuous norethindrone acetate (NA)-ethinyl estradiol (EE(2)) combinations with matching unopposed EE(2) 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 mu g of EE(2); 0.5 mg of NA and 2.5 mu g of EE(2); 1 mg of NA and 5 mu g of EE(2); 1 mg of NA and 10 mu g of EE(2); 1 mu g of EE(2); 2.5 mu g of EE(2); 5 mu g of EE(2); or 10 mu g of EE(2). 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 mu g EE(2) and the 1 mg NA-10 mu g EE(2) treatment groups at each annual assessment. Among the unopposed EE(2) groups, only the 10-mu g group had increased BMD above baseline, but also was accompanied by an unacceptably high rate of endometrial hyperplasia. The NA-EE(2) 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 EE(2) 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 EE(2) was attenuated with NA-EE(2) treatment. Conclusions.-Daily treatment with NA-EE(2) was well tolerated and protected the endometrium from EE(2)-induced proliferation and hyperplasia, The NA-EE(2) treatments produced a dose-related significant increase in BMD that was not present with unopposed EE(2)treatment. The overall effect of NA-EE(2) treatments on lipid measures was favorable.