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, par allel-group clinical trial. Setting.-Outpatients at 65 centers. Patien ts.-Asymptomatic or mildly symptomatic women aged 40 years or older wh o had undergone the onset of spontaneous menopause within the last 5 y ears and who had an intact uterus. Interventions.-Patients were equall y 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 m u 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 Mea sures.-Bone mineral density (BMD) measured by quantitative computed to mography, serum lipids, and endometrial effects as assessed by rate of hyperplasia and proliferative status. Results.-Twelve hundred sixty-f ive patients entered the study, Bone mineral density increased signifi cantly 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 th e unopposed EE(2) groups, only the 10-mu g group had increased BMD abo ve baseline, but also was accompanied by an unacceptably high rate of endometrial hyperplasia. The NA-EE(2) treatment groups had a significa nt linear dose-response trend for increasing BMD. Increased endometria l proliferation and hyperplasia occurred with increasing unopposed est rogen doses, The combination of NA and EE(2) effectively protected the endometrium against hyperplasia. The percentage of change in the rati o of high-density lipoprotein cholesterol to low-density lipoprotein c holesterol was positive for all treatment groups; The increase in trig lyceride levels associated with EE(2) was attenuated with NA-EE(2) tre atment. Conclusions.-Daily treatment with NA-EE(2) was well tolerated and protected the endometrium from EE(2)-induced proliferation and hyp erplasia, The NA-EE(2) treatments produced a dose-related significant increase in BMD that was not present with unopposed EE(2)treatment. Th e overall effect of NA-EE(2) treatments on lipid measures was favorabl e.