The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study) . a randomized controlled trial
Speroff, L.; Rowan, J.; Symons, J.; Genant, H.; Wilborn, W.
JAMA 276(17): 1397-1403
1996
ISSN/ISBN: 0098-7484 PMID: 8892713 Document Number: 465136
To assess the effects of hormone therapy on bone mineral density (BMD) in the spine and hip of postmenopausal women. A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial. A total of 875 healthy women aged 45 to 64 years recruited at 7 clinical centers. Treatments were (1) placebo; (2) conjugated equine estrogens (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus MPA, 2.5 mg/d daily; or (5) CEE, 0.625 mg/d plus micronized progesterone (MP), 200 mg/d for 12 d/mo. Bone mineral density at baseline, 12 months, and 36 months. Participants assigned to the placebo group lost an average of 1.8% of spine BMD and 1.7% of hip BMD by the 36-month visit, while those assigned to active regimens gained BMD at both sites, ranging from 3.5% to 5.0% mean total increases in spinal BMD and a mean total increase of 1.7% of BMD in the hip. Changes in BMD for women assigned to active regimens were significantly greater than those assigned to placebo. Women assigned to CEE plus continuous MPA had significantly greater increases in spinal BMD (increase of 5%) than those assigned to the other 3 active regimens (average increase, 3.8%). Findings were similar among those adhering to assigned therapy, although, among adherent participants, there were no significant differences in BMD changes among the 4 active treatment groups. Older women, women with low initial BMD, and those with no previous hormone use gained significantly more bone than younger women, women with higher initial BMD, and those who had used hormones previously. Postmenopausal women assigned to placebo demonstrated decreased BMD at the spine and hip, whereas women assigned to estrogen therapy increased BMD during a 36-month period. These findings demonstrate that estrogen replacement therapy increases BMD at clinically important sites. To compare the effect of continuous norethindrone acetate (NA)-ethinyl estradiol (EE2) combinations with matching unopposed EE2 or placebo. A 2-year, double-blind, placebo-controlled, parallel-group clinical trial. Outpatients at 65 centers. 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. 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. Bone mineral density (BMD) measured by quantitative computed tomography, serum lipids, and endometrial effects as assessed by rate of hyperplasia and proliferative status. 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. 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.