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 (EE2) combinations with matching unopposed EE2 or placebo.


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


METHODS
Outpatients at 65 centers.


METHODS
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.


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


METHODS
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 microg EE2 and the 1 mg NA-10 microg EE2 treatment groups at each annual assessment. Among the unopposed EE2 groups, only the 10-microg 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 EE2 treatment. The overall effect of NA-EE2 treatments on lipid measures was favorable.
Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, USA.
L
L
Speroff
J
J
Rowan
J
J
Symons
H
H
Genant
W
W
Wilborn
D000328:Adult; D015519:Bone Density / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004714:Endometrial Hyperplasia / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000473:pathology*; D045166:Estradiol Congeners / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood*; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017698:Postmenopause; D045167:Progesterone Congeners / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013223:Statistics as Topic
D045166:Estradiol Congeners; D008055:Lipids; D045167:Progesterone Congeners; D004997:Ethinyl Estradiol; D009640:Norethindrone