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Original Investigation |

Effects of Continuous Estrogen and Estrogen-Progestin Replacement Regimens on Cardiovascular Risk Markers in Postmenopausal Women FREE

Michael H. Davidson, MD; Kevin C. Maki, PhD; Phyllis Marx, MD; Ann C. Maki, MS, RD; Mary Sue Cyrowski, RD; Nayan Nanavati, MS; Joan-Carles Arce, MD
[+] Author Affiliations

From the Chicago Center for Clinical Research, Chicago, Ill (Drs Davidson, Maki, and Marx and Mss Maki and Cyrowski); and Novo Nordisk Pharmaceuticals, Inc, Princeton, NJ (Mr Nanavati and Dr Arce).


Arch Intern Med. 2000;160(21):3315-3325. doi:10.1001/archinte.160.21.3315.
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Published online

Objective  To evaluate the influence of 2 continuous combined estrogen-progestin replacement products, compared with unopposed estrogen and placebo, on cardiovascular risk markers in postmenopausal women in a randomized, double-blind, placebo-controlled trial.

Methods  Two hundred seventy healthy postmenopausal women were randomly assigned to 1 of 4 treatment groups: placebo, unopposed 17-β estradiol (1 mg), 1 mg of 17-β estradiol with 0.25 mg of norethindrone acetate, or 1 mg of 17-β estradiol with 0.5 mg of norethindrone acetate. The primary outcome variable was change from baseline in low-density lipoprotein cholesterol concentration. Additional outcome variables included changes in other serum lipid levels, hemostatic variables, and indicators of carbohydrate metabolism.

Results  The low-density lipoprotein cholesterol level was reduced to a similar degree in all groups receiving active treatment (10%-14% from baseline; P = .001 for17-β estradiol with 0.5 mg of norethindrone acetate, P = .004 for 17-β estradiol with 0.25 mg of norethindrone acetate, and P = .001 for 1 mg of 17-β estradiol vs placebo). Compared with unopposed 17-β estradiol, 17-β estradiol with 0.5 mg of norethindrone acetate enhanced the reductions in total cholesterol and apolipoprotein B levels (P<.01 vs 17-β estradiol). 17-β Estradiol plus norethindrone blunted or reversed the increases in levels of high-density lipoprotein cholesterol, apolipoprotein A-I, and triglycerides produced by 17-β estradiol alone. Effects of 17-β estradiol plus norethindrone on hemostatic variables were similar to those of 17-β estradiol except for factor VII activity, which was significantly reduced with 17-β estradiol combined with 0.25 mg (P<.01) and 0.5 mg (P<.05%) of norethindrone acetate. 17-β Estradiol plus norethindrone appeared to blunt reductions in C-peptide and insulin levels produced by unopposed 17-β estradiol but did not elevate these values compared with placebo.

Conclusions  17-β Estradiol plus norethindrone produced favorable changes in most cardiovascular risk markers evaluated and has a profile distinct from that of unopposed 17-β estradiol. The impact of these differences on cardiovascular events warrants investigation.

Figures in this Article

THE BENEFICIAL effects of estrogen use in postmenopausal women for management of estrogen deficiency symptoms and prevention of bone loss have been widely documented.1,2 The addition of a progestin, especially in a continuous manner, has been shown to reduce the risk of endometrial cancer associated with unopposed estrogen use in women with an intact uterus.35

As cardiovascular disease is the most common cause of death in postmenopausal women, an important aspect to consider in the decision to use long-term postmenopausal estrogen replacement therapy (ERT) or estrogen-progestin replacement therapy (HRT) is its potential role in the prevention of coronary heart disease (CHD). A large number of epidemiological studies, including several meta-analyses, have shown a strong and consistent relationship between ERT or HRT use and reduced primary and secondary CHD risk.69 Nevertheless, limited data are available from randomized clinical trials assessing the influence of these therapies on CHD events.

In the first randomized, secondary prevention trial with HRT, the Heart and Estrogen-Progestin Replacement Study, no overall differences were found in the incidence of nonfatal myocardial infarction or CHD between groups treated with HRT (conjugated equine estrogens plus medroxyprogesterone acetate) and placebo.10 More CHD events were observed in the HRT group than with placebo in year 1 of treatment and fewer events in years 4 and 5 of treatment.10 Given the large body of epidemiological and animal data suggesting that ERT provides cardiovascular protection, the results of this trial highlight the need to identify the effects of progestins on cardiovascular health.

Previous clinical trials have shown that HRT affects several cardiovascular risk factors, such as lipoproteins, hemostatic variables, carbohydrate metabolism, and endothelial function.5,11,12 Various HRT products have differential effects on the metabolic cardiovascular risk profile, particularly with regard to the progestin used, underscoring the need for clinical trials to evaluate and compare HRT options. Norethindrone acetate is a 19-nortestosterone–derived progestin, with potent effects on minimizing estrogen-induced endometrial stimulation, even at very low doses.4 The available data from animal models suggest that norethindrone does not attenuate the antiatherosclerotic effects of estrogens.3,13 Most of the information from humans on the metabolic effects of norethindrone has been obtained with high doses of 1 to 10 mg14; thus, there is a need to further assess the impact of low doses of norethindrone on cardiovascular measures. The present study was designed to evaluate the influence of 24 weeks of continuous low doses of norethindrone acetate, 0.25 and 0.5 mg, given with 1 mg of 17-β estradiol, compared with placebo and unopposed 17-β estradiol, 1 mg, on a wide range of risk markers for CHD in postmenopausal women.

SUBJECTS

The subjects for this trial were apparently healthy postmenopausal women, 70 years of age or less, with onset of natural or surgical menopause at least 12 months before enrollment. Postmenopausal status was confirmed by the presence of a plasma estradiol concentration of 73 pmol/L (20 pg/mL) or less.

Exclusion criteria included use of hormone replacement or lipid-altering agents within 8 weeks of the baseline (week −4) visit, body mass index (calculated as weight in kilograms divided by the square of height in meters%) greater than 31.5 kg/m2, current use of more than 20 cigarettes per day, alcohol abuse (>14 alcoholic drinks per week), and other substance abuse. Women with uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg) or elevated triglyceride levels (>4.0 mmol/L [>350 mg/dL] at 2 consecutive visits) were excluded. Other medical conditions excluding participation were history of stroke, pancreatitis, gallbladder disease, thrombophlebitis, or thromboembolic disorders; myocardial infarction within 6 months; abnormal genital bleeding of unknown etiology; endometrial hyperplasia; an abnormal mammogram suggestive of malignant neoplasm; the presence of hepatic enzyme levels more than twice the upper limit of normal; diabetes mellitus or other endocrine disease (except hypothyroidism adequately treated with a stable dose of thyroid replacement); and notable psychiatric disorders. Women using β-adrenergic blockers, high doses of thiazide diuretics (>25 mg of hydrochlorothiazide per day or its equivalent), erythromycin, immunosuppressants, systemic corticosteroids, or anticoagulants, or who had participated in a clinical trial of another investigational agent within 30 days, were also not eligible to participate.

STUDY DESIGN

This randomized, double-blind, placebo-controlled trial with 4 parallel treatment arms was conducted at a single clinical research center (including a satellite location) in the Chicago, Ill, area. An institutional review board (Schulman Associates, Cincinnati, Ohio) approved the study protocol, and all subjects provided written informed consent. Subjects were recruited through advertisements and community outreach, were reimbursed for expenses, and received a monetary stipend for their participation.

Clinic visits were scheduled at 9 time points during the trial: weeks −4, −2, 0 (randomization), 3, 6, 12, 18, 23, and 24. At week 0, all eligible subjects were randomly assigned to 1 of 4 treatment groups: (1) placebo; (2) unopposed 17-β estradiol, 1 mg; (3) 17-β estradiol, 1 mg, combined with norethindrone acetate, 0.25 mg; or (4) 17-β estradiol, 1 mg, combined with norethindrone acetate, 0.5 mg (Activella; Novo Nordisk Pharmaceuticals, Inc, Princeton, NJ). The study medication and placebo were formulated in identical-appearing oral tablets and provided in 28-day, dial blister packs. Subjects were instructed to take 1 tablet with water each day at bedtime. Compliance was assessed by pill counts and subject interviews performed at each postrandomization clinic visit. A subject was considered noncompliant if she missed study medication for 6 or more days within any 28-day period.

ASSESSMENTS

All biochemical assays were completed at a central facility (Quest Nichols Institute, San Juan Capistrano, Calif). This central laboratory facility participates in the Centers for Disease Control and Prevention–National Heart, Lung, and Blood Institute lipid measurement standardization program.

Lipoprotein Profile

Fasting blood samples were collected at weeks −2, 0, 12, 23, and 24 for assessment of serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and calculated low-density lipoprotein (LDL%) cholesterol. Additionally, lipoprotein(a) (Lp[a]) and apolipoproteins A-I and B (Apo A-I and Apo B) were measured at weeks 0, 12, and 23. Plasma cholesterol and triglyceride concentrations were determined with an analyzer (Hitachi 914; Boehringer Mannheim, Indianapolis, Ind) that uses enzymatic methods. The HDL cholesterol was quantified after precipitation of lower-density lipoproteins with phosphotungstate and magnesium. The LDL cholesterol level, in milligrams per deciliter, was calculated by means of the following equation: LDL cholesterol = total cholesterol-HDL cholesterol-triglycerides/5.15 This equation loses accuracy when the plasma triglyceride level exceeds 4.5 mmol/L (400 mg/dL). Accordingly, no LDL cholesterol value was calculated in cases where triglycerides were above this level. The Lp(a) concentrations were determined by means of an immunoprecipitation analysis with interpolation of sample and control concentrations to a calibration curve using 5 standards. Levels of Apo A-I and B were determined on an analyzer (Behring Nephelometer Analyzer II; Quest Nichols Institute) that assesses the turbidity resulting from specimen protein reaction with specific antisera to human Apo A-I and B, respectively.

Hemostatic Profile

Blood samples collected at weeks −2, 0, 12, and 23 were used to assess circulating levels of fibrinogen, plasminogen activator inhibitor 1 (PAI-1) antigen concentration, factor VII activity, and antithrombin III activity. Fibrinogen concentration was assessed with an automatic coagulation analyzer (model 900C; Medical Laboratory Automation, Pleasantville, NY) by means of a photo-optical clotting method. The PAI-1 concentrations were determined by color analysis of the reaction between a peroxidase enzyme substrate and the PAI-1 antigen-conjugate antibody in microtest wells (Quest Nichols Institute). Factor VII activity was determined with a clotting assay using photometric clot detection (MLA 1600; Medical Laboratory Automation). Antithrombin III activity was determined by spectrophotometry by means of a chromogenic substrate.

Carbohydrate Metabolism Profile

Blood samples collected at weeks −2, 0, 12, 23, and 24 were used for assessments of fasting glucose, insulin, and C-peptide concentrations. Hemoglobin A1c (HbA1c) was also measured in samples collected at weeks 0, 12, and 23. The serum glucose concentration was measured with an analyzer (Hitachi 914; Boehringer Mannheim) by the glucose oxidase method. The HbA1c level was measured with an analyzer (VARIANT; Bio-Rad Laboratories, Hercules, Calif) by ion-exchange high-performance liquid chromatography. Plasma insulin concentration was assessed by radioimmunoassay (Linco Scientific, St Charles, Mo). Plasma C-peptide level was measured by a radioimmunoassay using a guinea pig anti–C-peptide antiserum (Quest Nichols Institute).

Estradiol and Other Assessments

Estradiol concentration was measured in blood samples collected at weeks −4, 12, and 23. A competitive radioimmunoassay was used for the analysis of estradiol levels (Quest Nichols Institute). At weeks 0, 12, and 23, waist circumference (minimum circumference between the lower rib and iliac crest) was measured in duplicate or triplicate if the difference between the first 2 values was greater than 0.5 cm. The 2 closest values were recorded. At weeks 0, 12, and 23, subjects also completed 7-day Physical Activity Recall16 and Eating Pattern Assessment Tool17 questionnaires for evaluation of habitual physical activity and dietary patterns, respectively. On each study day, all adverse events, either observed by the investigator or spontaneously reported by the subject, were recorded and evaluated.

STATISTICAL METHODS

Statistical analyses were conducted by means of SAS (version 6.09) or Statview (version 5.0) statistical analysis packages (SAS Institute Inc, Cary, NC). Responses of cardiovascular risk markers to treatment were calculated for all subjects with evaluable data, defined as those who did not miss more than 5 doses of study medication during any 28-day cycle. Six subjects were excluded from the evaluable subset because of noncompliance. The change from baseline in LDL cholesterol concentration was defined in the study protocol as the primary outcome variable. Separate intent-to-treat analyses were also completed that included all subjects who took at least 1 dose of study medication and completed at least 1 postrandomization assessment. For these, the last observation available was carried forward to impute missing values. Response data from the evaluable and intent-to-treat samples did not differ materially; therefore, results presented are from the evaluable subset, which was defined, a priori, as the primary analysis.

The average of 2 measurements was used to define baseline (weeks −2 and 0) and end-of-treatment (weeks 23 and 24) values for total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, insulin, glucose, and C-peptide. Two samples were averaged at baseline (weeks −2 and 0) for hemostatic variables (fibrinogen, factor VII activity, PAI-1 antigen, and antithrombin III activity) and responses were calculated by subtracting the baseline value from the single value obtained at week 23. Changes from baseline to end of treatment for HbA1c, Apo A-I, Apo B, and Lp(a) were calculated from measurements taken at weeks 0 and 23.

Comparability of treatment groups at baseline was assessed by analysis of variance for continuous variables and Pearson χ2 tests for nominal variables. Analysis of variance models were used to evaluate treatment effects, with changes from baseline to the end of treatment used as dependent variables. Responses were not normally distributed for some variables (triglycerides, Lp[a], and PAI-1 antigen). In these cases, rank transformations were used before analysis of variance was performed. Results tables present data from these variables as median (minimum, maximum). All other continuous response variables are presented as mean (SD). Linear contrasts were used for pairwise comparisons between treatment groups when the F ratio for the corresponding analysis of variance model was at or above the critical value for the 5% level of statistical significance.

PATIENT CHARACTERISTICS

Of the 498 women screened, 270 were found to be eligible and were randomly assigned to 1 of the 4 treatment groups. The disposition of all subjects is shown in Figure 1.

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Figure 1.

Disposition of subjects. E2 indicates 17-β estradiol; NETA, norethindrone acetate.

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Table 1 shows baseline characteristics of the evaluable sample (n = 264) according to treatment group assignment. No significant differences between treatment arms were noted with regard to race, hysterectomy or smoking status, alcohol intake, body mass index, waist circumference, systolic blood pressure, or diastolic blood pressure. The ages ranged from 42 to 70 years, with no significant differences between groups. Moreover, no significant differences between groups were observed at baseline for diet or physical activity habits as indicated by scores on the Eating Pattern Assessment Tool or the 7-day Physical Activity Recall, respectively. Scores on these questionnaires did not change significantly in any group during the trial (data not shown).

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Evaluable Sample According to Treatment Group Assignment*
SERUM LIPID AND LIPOPROTEIN PROFILE

Table 2 presents data on lipid, lipoprotein, and apolipoprotein values for each group at baseline, week 12, and end of treatment and changes from baseline to the end of treatment. In addition, median percentage changes from baseline to the end of treatment are shown in Figure 2. No significant differences between groups were observed at baseline for any aspect of the serum lipid profile.

Table Graphic Jump LocationTable 2. Serum Lipid, Lipoprotein, and Apolipoprotein Values at Baseline, Week 12, and End of Treatment and Changes From Baseline According to Treatment Group Assignment*
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Figure 2.

Median percentage difference from baseline for lipid profile. E2 indicates 17-β estradiol; E2/0.25 NETA, 17-β estradiol combined with 0.25 mg of norethindrone acetate; E2/0.5 NETA, 17-β estradiol combined with 0.5 mg of norethindrone acetate; Total C, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; Lp(a), lipoprotein(a); Apo B, apolipoprotein B; and Apo A-I, apolipoprotein A-I.

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Mean total cholesterol concentration did not change significantly from baseline to end of treatment in subjects assigned to placebo (−0.1%). The total cholesterol response associated with unopposed 17-β estradiol (−2.3%) was not significantly different from the response in the placebo group. The groups treated with 17-β estradiol plus 0.25 and 0.5 mg of norethindrone acetate showed changes in total cholesterol level of −5.6% and −9.7%, respectively. Responses in the combined HRT regimens were significantly different from placebo (P<.01) and from one another (P<.05). Only the response in the 17-β estradiol–0.5-mg norethindrone acetate group reached significance compared with unopposed 17-β estradiol (P<.001).

The LDL cholesterol level showed a small decline from baseline in the placebo group (−2.4%). Significantly larger responses were observed in the 3 active treatment groups: −10.1% (unopposed 17-β estradiol; P = .001), −10.5% (17-β estradiol with 0.25 mg of norethindrone acetate; P = .004), and −13.5% (17-β estradiol with 0.5 mg of norethindrone acetate; P = .001), which did not differ from one another.

The mean HDL cholesterol concentration showed an unexpected 8.9% increase from baseline in the placebo group. Examination of the data indicated that this increase could not be attributed to changes in physical activity, Eating Pattern Assessment Tool scores, alcohol consumption, cigarette use, plasma estradiol concentrations, or concomitant medication use. Laboratory records also offered no explanation for this finding. Fasting lipid profiles were reanalyzed in batch from archived samples for each study participant. Results from the reanalysis did not differ materially from those of the original measurements, including the increase in HDL cholesterol concentration among subjects in the placebo arm. The HDL cholesterol level increased by 13.6% in the group that received unopposed 17-β estradiol, which did not differ significantly from placebo. Smaller mean increases were observed with 17-β estradiol plus 0.25 mg of norethindrone acetate (7.1%) and 17-β estradiol plus 0.5 mg of norethindrone acetate (3.4%). Only the HDL cholesterol response in the 0.5-mg group was significantly different from placebo (P<.01). Changes from baseline in the unopposed 17-β estradiol group differed significantly (P<.01) from those of both combined HRT arms, but the responses in the combined HRT arms were not significantly different from one another.

The triglyceride concentration remained similar to baseline level among subjects taking placebo (median change of −1.0%). The group that received unopposed 17-β estradiol showed a median increase of 9.4% in triglyceride concentration, which was significantly different from placebo (P<.05). Small changes in the median triglyceride concentration were observed with 17-β estradiol plus 0.25 mg of norethindrone acetate (4.9%%) and 17-β estradiol plus 0.5 mg of norethindrone acetate (−6.1%), which were not statistically different from one another or the response in the placebo group. However, the response of the group that received 17-β estradiol plus 0.5 mg of norethindrone acetate did differ significantly from that of the unopposed 17-β estradiol group (P<.01).

Median Lp(a) concentration increased in the placebo group (13.4%) and remained unchanged in the 3 active treatment arms. Despite the modest change in median value, the differences in response between placebo and the 17-β estradiol plus 0.25 mg (P<.05) and 17-β estradiol plus 0.5 mg (P<.05) groups reached statistical significance.

Small reductions from baseline in mean Apo B concentration were observed in the placebo (−1.6%) and unopposed 17-β estradiol (−1.1%%) groups. Changes from baseline were −5.4% and −7.7% in the 0.25-mg and 0.5-mg arms, respectively. These changes did not differ from one another, but that of the 0.5-mg group differed significantly from both placebo (P<.01) and unopposed 17-β estradiol group responses (P<.01).

Mean Apo A-I concentration declined slightly in the placebo group (−1.0%%) and increased by 8.9% in the unopposed 17-β estradiol group (P<.01 vs placebo). The change from baseline in Apo A-I level within the group that received 17-β estradiol plus 0.25 mg of norethindrone acetate (−1.1%) was similar to that in the placebo arm. 17-β Estradiol plus 0.5 mg of norethindrone acetate reduced Apo A-I level by −4.3% (P<.01 vs placebo). Responses in the 2 combined HRT groups did not differ from one another, but they did differ significantly from that of the unopposed 17-β estradiol group (P<.01).

HEMOSTATIC PROFILE

Data from baseline, week 12, and end of study and changes from baseline to the end of treatment in hemostatic variables are shown in Table 3. Median percentage changes from baseline to the end of treatment are shown in Figure 3.

Table Graphic Jump LocationTable 3. Values for Hemostatic Variables at Baseline, Week 12, and End of Treatment and Changes From Baseline According to Treatment Group Assignment*
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Figure 3.

Median percentage difference from baseline for hemostatic profile. E2 indicates 17-β estradiol; E2/0.25 NETA, 17-β estradiol combined with 0.25 mg of norethindrone acetate; E2/0.5 NETA, 17-β estradiol combined with 0.5 mg of norethindrone acetate; PAI-1, plasminogen activator inhibitor 1; and AT III, antithrombin III.

Graphic Jump Location

No significant differences in any of the hemostatic variables measured were observed between groups at baseline. A significant increase in mean fibrinogen concentration (12.4%) occurred in the placebo group during the 24-week treatment period. Smaller increases were observed in the 3 active treatment arms. The unopposed 17-β estradiol group displayed a mean change of 5.4%, which was significantly less than that of the placebo group (P<.05). The mean increase in the 17-β estradiol–0.25-mg norethindrone acetate group was 5.1%, which was near significance in comparison with the response in the placebo group (P<.07%) but did not differ from the unopposed 17-β estradiol or 17-β estradiol–0.5-mg norethindrone acetate groups. The change from baseline within the 17-β estradiol–0.5-mg norethindrone acetate arm (9.1%) did not differ significantly from any other treatment.

The PAI-1 antigen concentrations showed a median increase of 16.5% from baseline among women in the placebo group. Small declines were observed in all 3 active treatment arms, with the response in the 17-β estradiol–0.5-mg norethindrone acetate group (−7.0%) reaching statistical significance compared with placebo (P<.05).

Mean factor VII activity, expressed as a percentage of an age-adjusted normative value, did not change significantly from baseline in the placebo (−1.8%) or unopposed 17-β estradiol (1.4%) groups. The combined HRT groups showed changes from baseline in factor VII activity of −10.7% (17-β estradiol–0.25-mg norethindrone acetate) and −11.0% (17-β estradiol–0.5-mg norethindrone acetate), which were significantly different from the response in the unopposed 17-β estradiol group (P<.01 and P<.05, respectively), but not from that of the placebo arm. However, the comparison between 17-β estradiol–0.25-mg norethindrone acetate and placebo did approach significance (P<.06).

Antithrombin III activity, expressed as a percentage of an age-adjusted normative value, showed significant declines from baseline in all 4 treatment arms. The mean change among subjects in the placebo group was −9.7%. Each of the active treatment groups showed significantly larger declines vs placebo, but the responses did not differ between the unopposed 17-β estradiol (−17.0%; P<.01 vs placebo), 17-β estradiol–0.25-mg norethindrone acetate (−16.3%; P<.01 vs placebo), and 17-β estradiol–0.5-mg norethindrone acetate (−14.8%; P<.05 vs placebo) groups. Despite the marked reductions in antithrombin III activity in all active treatment groups, very few values dropped below the reference range during treatment. The number of subjects with values dropping below the reference range during treatment varied from 1 in the placebo and 17-β estradiol–0.5-mg norethindrone acetate arms to 4 in the 17-β estradiol and 17-β estradiol–0.25-mg norethindrone acetate groups.

CARBOHYDRATE METABOLISM PROFILE

Table 4 presents data on fasting glucose, HbA1c, insulin, and C-peptide values at baseline, week 12, and end of treatment and changes from baseline to end of treatment according to group assignment. No significant differences between groups were present at baseline for any of these variables. Figure 4 displays the median percentage changes from baseline.

Table Graphic Jump LocationTable 4. Values for Indicators of Carbohydrate Metabolism at Baseline and End of Treatment and Changes From Baseline According to Treatment Group Assignment*
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Figure 4.

Median percentage difference from baseline for carbohydrate metabolism profile. E2 indicates 17-β estradiol; E2/0.25 NETA, 17-β estradiol combined with 0.25 mg of norethindrone acetate; E2/0.5 NETA, 17-β estradiol combined with 0.5 mg of norethindrone acetate; and HbA1c, hemoglobin A1c.

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Fasting plasma glucose levels declined in all treatment groups, with mean changes ranging from −7.8% in the placebo arm to −10.4% in the unopposed 17-β estradiol arm. Responses were not significantly different between groups. Mean HbA1c levels showed small changes from baseline ranging from 3.6% in the placebo group to −0.8% in the 17-β estradiol–0.5-mg norethindrone acetate group. The difference in HbA1c response between placebo and 17-β estradiol–0.5-mg norethindrone acetate was the only comparison to reach statistical significance (P<.01).

Mean fasting insulin levels declined slightly in all treatment arms. The placebo group showed the smallest change from baseline (−2.8%), while the unopposed 17-β estradiol group had the largest response (−18.1%). Changes in the 17-β estradiol–0.25-mg and 0.5-mg norethindrone acetate groups were −11.1% and −6.2%, respectively. The response in the placebo group was significantly different from those of the unopposed 17-β estradiol (P<.01) and 17-β estradiol–0.25-mg norethindrone acetate (P<.05) groups. The responses in the 2 combined HRT arms did not differ from one another, although there was a significant difference between the responses of the unopposed 17-β estradiol and 17-β estradiol–0.5-mg norethindrone acetate groups (P<.05).

Mean fasting C-peptide concentrations showed a slight increase from baseline in the placebo group (2.0%). The unopposed 17-β estradiol (−12.6%%) and 17-β estradiol–0.25-mg norethindrone acetate (−7.8%%) groups had significant reductions in C-peptide concentrations compared with the placebo arm (P<.01 for both). Although the responses in the 2 combined HRT arms did not differ from one another, a significant difference existed between the responses of the unopposed 17-β estradiol and 17-β estradiol–0.5-mg norethindrone acetate groups (P<.01).

ESTRADIOL

Baseline estradiol concentrations were similar in all treatment arms, with mean values ranging from 31 to 36 pmol/L (8.4 to 9.8 pg/mL) (P>.05 for all comparisons). At the end of the trial, all groups receiving hormones showed significant increases in estradiol concentration, with mean levels of 32, 291, 276, and 254 pmol/L (8.6, 79.3, 75.1, and 69.1 pg/mL) for the placebo, unopposed 17-β estradiol, 17-β estradiol–0.25-mg norethindrone acetate, and 17-β estradiol–0.5-mg norethindrone acetate groups, respectively (all P<.001 vs placebo).

ADVERSE EXPERIENCES

Significant differences between treatments were noted for several adverse experiences, including breast pain, postmenopausal bleeding, leukorrhea, hot flushes, genital pruritus, and emotional lability. The numbers of women reporting breast pain were 5, 22, 26, and 34 in the placebo, unopposed 17-β estradiol, 17-β estradiol–0.25-mg norethindrone acetate, and 17-β estradiol–0.5-mg norethindrone acetate groups, respectively. The incidence of breast pain was increased vs placebo (P<.05) in each of the groups receiving active treatment, but did not differ between the active treatment arms. As expected, postmenopausal bleeding was more common in the active treatment arms than with placebo (P<.05), occurring in 5, 16, 23, and 23 of the women in the placebo, unopposed 17-β estradiol, 17-β estradiol–0.25-mg norethindrone acetate, and 17-β estradiol–0.5-mg norethindrone acetate groups, respectively. Similarly, leukorrhea was reported by 2, 16, 11, and 14 women, respectively (all P<.05 vs placebo). Genital pruritus was most commonly reported in the unopposed 17-β estradiol group (n = 8 vs 0-3 cases in the other groups; P<.05). Hot flushes (n = 8 in the placebo group vs 0-3 in the other groups; P<.05) and emotional lability (n = 4 in the placebo group vs 0 in the other treatment groups; P<.05) were most commonly reported in the placebo group.

SERUM LIPID AND LIPOPROTEIN PROFILE

Extensive data are available from clinical trials in which interventions used to lower LDL cholesterol and Apo B levels have reduced the frequency of cardiovascular events in women and men.5,7,1820 In the present study, LDL cholesterol level was lowered by 10% to 14% from baseline in all of the groups receiving estrogen. Inclusion of norethindrone in the HRT regimen did not appear to interfere with the effects of 17-β estradiol on LDL cholesterol level. In fact, there was a nonsignificant trend toward enhanced LDL cholesterol reduction in the group receiving 17-β estradiol–0.5-mg norethindrone acetate. Unopposed 17-β estradiol, despite lowering LDL cholesterol level, had little effect on Apo B level and thus did not appear to reduce the number of circulating atherogenic lipoprotein particles. However, both groups receiving continuous combined HRT showed clinically important reductions (8%-9%) from baseline in Apo B concentration. Estrogens increase expression of hepatic LDL receptors, resulting in enhanced removal of LDL particles from the circulation.14 However, estrogens also increase the rate of very-low-density lipoprotein secretion.10 Therefore, the lack of net influence on Apo B by unopposed 17-β estradiol may reflect a reduction in LDL Apo B concentration that is offset by an increase in Apo B carried by very-low-density lipoprotein particles. Norethindrone may prevent the estrogen-induced increase in very-low-density lipoprotein secretion without altering estrogen's effect on LDL particle removal, resulting in a net decline in the circulating Apo B concentration. Other progestins, such as progesterone and 17-hydroxyprogesterone derivatives, have relatively little influence on very-low-density lipoprotein secretion and Apo B concentration.5,11,21

Elevated levels of triglycerides and Lp(a), as well as depressed HDL cholesterol and Apo A-I levels, are associated with increased cardiovascular risk in both sexes.2224 Moreover, the increase in relative risk of cardiovascular disease associated with hypertriglyceridemia is greater in women than men.11,14 However, direct evidence from clinical trials to show that changes in these aspects of the lipid profile influence the cardiovascular event rate is limited.25 In the present study, the increase in triglyceride levels induced by unopposed 17-β estradiol (9% increase from baseline%) was blunted by the inclusion of 0.25 mg of norethindrone acetate per day (5% increase from baseline) and prevented entirely by inclusion of 0.5 mg of norethindrone acetate (6% reduction from baseline) in the HRT regimen. Unopposed estrogen replacement raises triglyceride levels by increasing production of large, triglyceride-rich, very-low-density lipoprotein particles without producing a net increase in Apo B concentration.5,11 Observational data suggest that triglyceride elevation in the absence of increased Apo B level may not increase cardiovascular risk.23 Thus, the clinical importance of estrogen-induced hypertriglyceridemia and the ability of norethindrone to blunt or reverse this effect are of uncertain importance with regard to CHD risk.

Levels of HDL cholesterol showed an unexpected rise (9%) during the treatment period among women assigned to placebo, which could not be explained by changes in lifestyle habits, circulating estradiol concentrations, concomitant medication use, or nonnormality in the distribution of responses. Nevertheless, the mean concentration of Apo A-I, a major structural protein in HDL particles, showed a small decline from baseline (−1%) in the placebo group, suggesting that the elevation in HDL cholesterol concentration, if real, was not caused by an increase in the number of HDL particles. Increases in HDL cholesterol (14%) and Apo A-I (9%) levels were observed with unopposed 17-β estradiol. Norethindrone appears to blunt the 17-β estradiol–induced elevations in HDL cholesterol and Apo A-I levels in a dose-dependent manner.

Elevated levels of Lp(a) may increase CHD risk by enhancing both thrombogenesis and atherosclerosis.26,27 The Lp(a) concentration increased modestly (median change of 0.04 µmol/L [1.0 mg/dL] or 13%) from baseline among subjects in the placebo group but did not change in any of the active treatment arms. The finding that estrogen appeared to prevent the increase in Lp(a) observed among subjects taking placebo is consistent with results from previous studies in which reductions in Lp(a%) have been observed with ERT or HRT.12 Norethindrone did not appear to modify this effect.

The degree to which cardiovascular disease risk may be influenced by the changes in the lipoprotein profile observed in this study is difficult to predict. Reductions in LDL cholesterol and Apo B levels would be expected to be protective, especially when accompanied by a reduction of triglyceride levels. The group receiving 17-β estradiol–0.5-mg norethindrone acetate showed the largest reductions in total cholesterol, LDL cholesterol, Apo B, and triglyceride levels, suggesting that norethindrone enhanced the favorable effects of 17-β estradiol on atherogenic lipoproteins. However, norethindrone also blunted or reversed the 17-β estradiol-induced increase in HDL cholesterol and Apo A-I levels, which might be expected to partially offset the beneficial changes observed in atherogenic lipoproteins.

The data from this study suggest that the net effect of 17-β estradiol plus norethindrone on circulating lipids and lipoproteins is favorable. Studies in cholesterol-fed rabbits that have undergone ovariectomy show that 17-β estradiol reduces the accumulation of aortic cholesterol and that norethindrone does not appear to counteract this benefit.3 Indeed, trends were observed toward enhanced protection in the animals receiving continuous 17-β estradiol plus norethindrone.13 However, firm conclusions will need to await data from clinical trials assessing the influence of these therapies on direct measures of atherosclerotic burden and/or cardiovascular events.

HEMOSTATIC VARIABLES

In the Heart and Estrogen-Progestin Replacement Study, thromboembolic events were 3 times more common in women receiving HRT than placebo, an excess of 4.1 per 1000 woman-years of observation.10 This finding is consistent with data from observational studies that have also reported increased risk of thrombosis among ERT or HRT users.28,29 The thrombogenic influence of HRT may also have played a role in the early increase in cardiovascular events observed among women assigned to the HRT arm in the Heart and Estrogen-Progestin Replacement Study.10 Therefore, comparing the effects of various HRT regimens on hemostatic variables may have important implications for understanding the influence of these therapies on ischemic and thrombotic events.

In the present study, subjects in the placebo group showed changes in hemostatic variables that would favor thrombogenesis, including increases in fibrinogen, PAI-1 antigen, and Lp(a) concentrations, as well as reduced antithrombin III activity. These may be attributable to seasonal variation, since most of the subjects were enrolled during the summer months (June to August) and completed the trial during the winter (December to March). Previous investigations have demonstrated that a relative thrombogenic state is present in the winter months among subjects living in climates similar to that in Chicago.30,31 Unopposed 17-β estradiol blunted or reversed the increases observed in fibrinogen and PAI-1 levels. These effects would be expected to reduce thrombogenicity. However, unopposed 17-β estradiol appeared to depress antithrombin III activity, which may enhance the risk of thrombus formation. However, the fact that antithrombin III activity in most of the women (>94% in all groups) remained within the normal range supports the prevailing view that reduced antithrombin III activity is not a major factor responsible for the increased risk of thromboembolic events associated with ERT or HRT use.32,33 Compared with unopposed 17-β estradiol, groups receiving 17-β estradiol plus norethindrone showed less blunting of the increase in fibrinogen concentration noted in the placebo group. Norethindrone had no apparent influence on PAI-1 concentration or antithrombin III activity, but it significantly depressed factor VII activity as compared with unopposed 17-β estradiol.

Data from the Heart and Estrogen-Progestin Replacement Study suggest that HRT can produce clinically important changes in hemostasis, resulting in excess thromboembolic events. Findings from the present trial highlight the fact that HRT regimens may vary with regard to thrombogenic potential, as indicated by differential effects on some markers of hemostatic function.

CARBOHYDRATE METABOLISM PROFILE

Some significant differences, although not large, between treatments were observed for changes from baseline in indicators of carbohydrate homeostasis. Unopposed 17-β estradiol produced significant reductions in the insulin and C-peptide levels, suggesting improved insulin sensitivity.34 Insulin and C-peptide responses in the 17-β estradiol–0.25-mg norethindrone acetate group were intermediate compared with those in the unopposed 17-β estradiol and 17-β estradiol–0.5-mg norethindrone acetate groups. Norethindrone appeared to partially counteract the 17-β estradiol effects in a dose-dependent manner. A similar favorable effect of unopposed estrogen on fasting insulin and insulin resistance has been shown previously.5,35 Progestins tend to blunt the estrogen-induced improvement in insulin resistance, as was observed in the present trial. Overall, 17-β estradiol plus norethindrone did not show any detrimental effect on carbohydrate metabolism compared with placebo; in fact, the HbA1c level was reduced significantly more among subjects taking 17-β estradiol–0.5-mg norethindrone acetate than among those taking placebo. This is in accord with a previous report showing that 17-β estradiol–0.5-mg norethindrone acetate slightly reduced HbA1c level and did not cause deterioration of insulin sensitivity, measured by the euglycemic, hyperinsulinemic clamp technique, in healthy postmenopausal women.36

Postmenopausal hormone replacement affects many metabolic processes that have the potential to influence cardiovascular disease risk. Clinical trials provide evidence that HRT products may differ substantially with regard to their impact on the cardiovascular risk factor profile, depending on the specific estrogen and progestin used, as well as the dose, regimen, and route of administration. These differences may assist the medical practitioner in selecting an HRT product that is most compatible with the individual woman's cardiovascular disease risk profile. Results of the present investigation suggest that continuous combined HRT with 17-β estradiol, 1 mg, plus 0.25 to 0.50 mg of norethindrone acetate per day provides favorable changes in most of the biochemical markers of cardiovascular disease risk and has a profile distinctly different from that of unopposed 17-β estradiol, 1 mg. The overall impact on cardiovascular events of these different profiles needs to be investigated.

Accepted for publication April 28, 2000.

This research was funded by Novo Nordisk Pharmaceuticals, Inc, Princeton, NJ.

Reprints: Kevin C. Maki, PhD, Nutrition and Metabolism Research Unit, Chicago Center for Clinical Research, 515 N State St, 27th Floor, Chicago, IL 60610 (e-mail: kmaki@protocare.com).

Genant  HKLucas  JWeiss  S  et al.  Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med. 1997;1572609- 2615
Link to Article
Harris  STGenant  HKBaylink  DJ  et al.  The effects of estrone (Ogen) on spinal bone density of postmenopausal women. Arch Intern Med. 1991;1511980- 1984
Link to Article
Haarbo  JSvendsen  OChristiansen  C Progestogens do not affect aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. Circ Res. 1992;701198- 1202
Link to Article
Persson  IAdami  HOBergkvist  L  et al.  Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ. 1989;298147- 151
Link to Article
The Writing Group for the PEPI Trial, Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1995;273199- 208
Link to Article
Grady  DRubin  SMPetitti  DB  et al.  Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;1171016- 1037
Link to Article
Grodstein  FStampfer  MJColditz  GA  et al.  Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;3361769- 1775
Link to Article
Psaty  BMHeckbert  SRAtkins  D  et al.  A review of the associations of estrogens and progestins with cardiovascular disease in postmenopausal women. Arch Intern Med. 1993;1531421- 1427
Link to Article
Stampfer  MJColditz  GAWillett  WC Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;2047- 63
Link to Article
Hulley  SGrady  DBush  T  et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280605- 613
Link to Article
Lobo  RAPickar  JHWild  RAWalsh  BHirvonen  E Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol. 1994;84987- 995
Walsh  BWKuller  LHWild  RA  et al.  Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;2791445- 1451
Link to Article
Alexandersen  PHaarbo  JSandholdt  IShalmi  MLawaetz  HChristiansen  C Norethindrone acetate enhances the antiatherogenic effect of 17-β estradiol. Arterioscler Thromb Vasc Biol. 1998;18902- 907
Link to Article
Walsh  BWSchiff  IRosner  BGreenberg  LRavnikar  VSacks  FM Effects of postmenopausal estrogen replacement of the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;3251196- 1204
Link to Article
Friedewald  WTLevy  RIFredrickson  DS Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18499- 502
Sallis  JFHaskell  WLWood  PD  et al.  Physical activity assessment methodology in the Five-City Project. Am J Epidemiol. 1985;12191- 106
Peters  JRQuiter  ESBrekke  ML  et al.  The Eating Patterns Assessment Tool: a simple instrument for assessing dietary fat and cholesterol intake. J Am Diet Assoc. 1994;941008- 1013
Link to Article
Lewis  SJMoye  LASacks  FM  et al.  Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range: results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med. 1998;129681- 689
Link to Article
Sacks  FMPfeffer  MAMoye  LA  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;3351001- 1009
Link to Article
Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344344
Wakatsuki  ASagara  Y Effects of continuous medroxyprogesterone acetate on lipoprotein metabolism in postmenopausal women receiving estrogen. Maturitas. 1996;2535- 44
Link to Article
Katzel  LIKrauss  RMGoldberg  AP Relations of plasma TG and HDL-C concentrations to body composition and plasma insulin levels are altered in men with small LDL particles. Arterioscler Thromb. 1994;141121- 1128
Link to Article
Lamarche  BTchernof  AMoorjani  S  et al.  Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation. 1997;9569- 75
Link to Article
Stampfer  MJKrauss  RMMa  J  et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996;276882- 888
Link to Article
Superko  HR What can we learn about dense low-density lipoprotein and lipoprotein particles from clinical trials? Curr Opin Lipidol. 1996;7363- 368
Link to Article
Adams  MRKaplan  JRManuck  SB  et al.  Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Arteriosclerosis. 1990;101051- 1057
Link to Article
Sniderman  ADPedersen  TKjekshus  J Putting low-density lipoproteins at center stage in atherogenesis. Am J Cardiol. 1997;7964- 67
Link to Article
Daly  EVessey  MPHawkins  MMCarson  JLGough  PMarsh  S Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348977- 980
Link to Article
Jick  HDerby  LEMyers  MWVasilakis  CNewton  KM Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996;348981- 983
Link to Article
Frohlich  MSund  MRuss  S  et al.  Seasonal variations of rheological and hemostatic parameters and acute-phase reactants in young, healthy subjects. Arterioscler Thromb Vasc Biol. 1997;172692- 2697
Link to Article
Stout  RWCrawford  VLMcDermott  MJRocks  MJMorris  TC Seasonal changes in haemostatic factors in young and elderly subjects. Age Ageing. 1996;25256- 258
Link to Article
Lensing  APrandoni  PPrins  MHBuller  HR Deep-vein thrombosis. Lancet. 1999;353479- 484
Link to Article
Rosendaal  FR Venous thrombosis: a multicausal disease. Lancet. 1999;3531167- 1173
Link to Article
Espeland  MAHogan  PEFineberg  SE  et al.  Effect of postmenopausal hormone therapy on glucose and insulin concentrations. Diabetes Care. 1998;211589- 1594
Link to Article
De Cleyn  KBuytaert  PCoppens  M Carbohydrate metabolism during hormonal substitution therapy. Maturitas. 1989;11235- 242
Link to Article
Kimmerle  RHeinemann  LHeise  T  et al.  Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women. Menopause. 1999;636- 42
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Disposition of subjects. E2 indicates 17-β estradiol; NETA, norethindrone acetate.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Median percentage difference from baseline for lipid profile. E2 indicates 17-β estradiol; E2/0.25 NETA, 17-β estradiol combined with 0.25 mg of norethindrone acetate; E2/0.5 NETA, 17-β estradiol combined with 0.5 mg of norethindrone acetate; Total C, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; Lp(a), lipoprotein(a); Apo B, apolipoprotein B; and Apo A-I, apolipoprotein A-I.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Median percentage difference from baseline for hemostatic profile. E2 indicates 17-β estradiol; E2/0.25 NETA, 17-β estradiol combined with 0.25 mg of norethindrone acetate; E2/0.5 NETA, 17-β estradiol combined with 0.5 mg of norethindrone acetate; PAI-1, plasminogen activator inhibitor 1; and AT III, antithrombin III.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Median percentage difference from baseline for carbohydrate metabolism profile. E2 indicates 17-β estradiol; E2/0.25 NETA, 17-β estradiol combined with 0.25 mg of norethindrone acetate; E2/0.5 NETA, 17-β estradiol combined with 0.5 mg of norethindrone acetate; and HbA1c, hemoglobin A1c.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Evaluable Sample According to Treatment Group Assignment*
Table Graphic Jump LocationTable 2. Serum Lipid, Lipoprotein, and Apolipoprotein Values at Baseline, Week 12, and End of Treatment and Changes From Baseline According to Treatment Group Assignment*
Table Graphic Jump LocationTable 3. Values for Hemostatic Variables at Baseline, Week 12, and End of Treatment and Changes From Baseline According to Treatment Group Assignment*
Table Graphic Jump LocationTable 4. Values for Indicators of Carbohydrate Metabolism at Baseline and End of Treatment and Changes From Baseline According to Treatment Group Assignment*

References

Genant  HKLucas  JWeiss  S  et al.  Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med. 1997;1572609- 2615
Link to Article
Harris  STGenant  HKBaylink  DJ  et al.  The effects of estrone (Ogen) on spinal bone density of postmenopausal women. Arch Intern Med. 1991;1511980- 1984
Link to Article
Haarbo  JSvendsen  OChristiansen  C Progestogens do not affect aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. Circ Res. 1992;701198- 1202
Link to Article
Persson  IAdami  HOBergkvist  L  et al.  Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ. 1989;298147- 151
Link to Article
The Writing Group for the PEPI Trial, Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1995;273199- 208
Link to Article
Grady  DRubin  SMPetitti  DB  et al.  Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;1171016- 1037
Link to Article
Grodstein  FStampfer  MJColditz  GA  et al.  Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;3361769- 1775
Link to Article
Psaty  BMHeckbert  SRAtkins  D  et al.  A review of the associations of estrogens and progestins with cardiovascular disease in postmenopausal women. Arch Intern Med. 1993;1531421- 1427
Link to Article
Stampfer  MJColditz  GAWillett  WC Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;2047- 63
Link to Article
Hulley  SGrady  DBush  T  et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280605- 613
Link to Article
Lobo  RAPickar  JHWild  RAWalsh  BHirvonen  E Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol. 1994;84987- 995
Walsh  BWKuller  LHWild  RA  et al.  Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;2791445- 1451
Link to Article
Alexandersen  PHaarbo  JSandholdt  IShalmi  MLawaetz  HChristiansen  C Norethindrone acetate enhances the antiatherogenic effect of 17-β estradiol. Arterioscler Thromb Vasc Biol. 1998;18902- 907
Link to Article
Walsh  BWSchiff  IRosner  BGreenberg  LRavnikar  VSacks  FM Effects of postmenopausal estrogen replacement of the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;3251196- 1204
Link to Article
Friedewald  WTLevy  RIFredrickson  DS Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18499- 502
Sallis  JFHaskell  WLWood  PD  et al.  Physical activity assessment methodology in the Five-City Project. Am J Epidemiol. 1985;12191- 106
Peters  JRQuiter  ESBrekke  ML  et al.  The Eating Patterns Assessment Tool: a simple instrument for assessing dietary fat and cholesterol intake. J Am Diet Assoc. 1994;941008- 1013
Link to Article
Lewis  SJMoye  LASacks  FM  et al.  Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range: results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med. 1998;129681- 689
Link to Article
Sacks  FMPfeffer  MAMoye  LA  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;3351001- 1009
Link to Article
Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344344
Wakatsuki  ASagara  Y Effects of continuous medroxyprogesterone acetate on lipoprotein metabolism in postmenopausal women receiving estrogen. Maturitas. 1996;2535- 44
Link to Article
Katzel  LIKrauss  RMGoldberg  AP Relations of plasma TG and HDL-C concentrations to body composition and plasma insulin levels are altered in men with small LDL particles. Arterioscler Thromb. 1994;141121- 1128
Link to Article
Lamarche  BTchernof  AMoorjani  S  et al.  Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation. 1997;9569- 75
Link to Article
Stampfer  MJKrauss  RMMa  J  et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996;276882- 888
Link to Article
Superko  HR What can we learn about dense low-density lipoprotein and lipoprotein particles from clinical trials? Curr Opin Lipidol. 1996;7363- 368
Link to Article
Adams  MRKaplan  JRManuck  SB  et al.  Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Arteriosclerosis. 1990;101051- 1057
Link to Article
Sniderman  ADPedersen  TKjekshus  J Putting low-density lipoproteins at center stage in atherogenesis. Am J Cardiol. 1997;7964- 67
Link to Article
Daly  EVessey  MPHawkins  MMCarson  JLGough  PMarsh  S Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348977- 980
Link to Article
Jick  HDerby  LEMyers  MWVasilakis  CNewton  KM Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996;348981- 983
Link to Article
Frohlich  MSund  MRuss  S  et al.  Seasonal variations of rheological and hemostatic parameters and acute-phase reactants in young, healthy subjects. Arterioscler Thromb Vasc Biol. 1997;172692- 2697
Link to Article
Stout  RWCrawford  VLMcDermott  MJRocks  MJMorris  TC Seasonal changes in haemostatic factors in young and elderly subjects. Age Ageing. 1996;25256- 258
Link to Article
Lensing  APrandoni  PPrins  MHBuller  HR Deep-vein thrombosis. Lancet. 1999;353479- 484
Link to Article
Rosendaal  FR Venous thrombosis: a multicausal disease. Lancet. 1999;3531167- 1173
Link to Article
Espeland  MAHogan  PEFineberg  SE  et al.  Effect of postmenopausal hormone therapy on glucose and insulin concentrations. Diabetes Care. 1998;211589- 1594
Link to Article
De Cleyn  KBuytaert  PCoppens  M Carbohydrate metabolism during hormonal substitution therapy. Maturitas. 1989;11235- 242
Link to Article
Kimmerle  RHeinemann  LHeise  T  et al.  Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women. Menopause. 1999;636- 42
Link to Article

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