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December 2002


Postmenopausal estrogen and progestin use and the risk of cardiovascular disease.

BACKGROUND: Estrogen therapy in postmenopausal women has been associated with a decreased risk of heart disease. There is little information, however, about the effect of combined estrogen and progestin therapy on the risk of cardiovascular disease. METHODS: We examined the relation between cardiovascular disease and postmenopausal hormone therapy during up to 16 years of follow-up in 59,337 women from the Nurses’ Health Study, who were 30 to 55 years of age at base line. Information on hormone use was ascertained with biennial questionnaires. From 1976 to 1992, we documented 770 cases of myocardial infarction or death from coronary disease in this group and 572 strokes. Proportional-hazards models were used to calculate relative risks and 95% confidence intervals, adjusted for confounding variables. RESULTS: We observed a marked decrease in the risk of major coronary heart disease among women who took estrogen with progestin (multivariate adjusted relative risk, 0.39; 95% confidence interval, 0.19 to 0.78) or estrogen alone (relative risk, 0.60; 95% confidence interval, 0.43 to 0.83), as compared with women who did not use hormones [corrected]. However, there was no significant association between stroke and use of combined hormones (multivariate adjusted relative risk, 1.09; 95% confidence interval, 0.66 to 1.80) or estrogen alone (relative risk, 1.27; 95% confidence interval, 0.95 to 1.69). CONCLUSIONS: The addition of progestin does not appear to attenuate the cardioprotective effects of postmenopausal estrogen therapy.

N Engl J Med 1996 Aug 15;335(7):453-61

Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study.

BACKGROUND. The effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results. METHODS. We followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses’ Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1,263 deaths from all causes. RESULTS. After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95% confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95% confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95% confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95% confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95% confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95% confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke. CONCLUSIONS. Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.

N Engl J Med 1991 Sep 12;325(11):756-62

Impact of postmenopausal hormone therapy on cardiovascular events and cancer: pooled data from clinical trials.

OBJECTIVE: To examine the incidence of cardiovascular diseases and cancer from published clinical trials that studied other outcomes of postmenopausal hormone therapy as some surveys have suggested that it may decrease the incidence of cardiovascular diseases and increase the incidence of hormone dependent cancers. DESIGN: Trials that compared hormone therapy with placebo, no therapy, or vitamins and minerals in comparable groups of postmenopausal women and reported cardiovascular or cancer outcomes were searched from the literature. SUBJECTS: 22 trials with 4,124 women were identified. In each group, the numbers of women with cardiovascular and cancer events were summed and divided by the numbers of women originally allocated to the groups. RESULTS: Data on cardiovascular events and cancer were usually given incidentally, either as a reason for dropping out of a study or in a list of adverse effects. The calculated odds ratios for women taking hormones versus those not taking hormones was 1.39 (95% confidence interval 0.48 to 3.95) for cardiovascular events without pulmonary embolus and deep vein thrombosis and 1.64 (0.55 to 4.18) with them. It is unlikely that such results would have occurred if the true odds ratio were 0.7 or less. For cancers, the numbers of reported events were too low for a useful conclusion. CONCLUSIONS: The results of these pooled data do not support the notion that postmenopausal hormone therapy prevents cardiovascular events.

BMJ 1997 Jul 19;315(7101):149-53

Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.

CONTEXT: Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized, blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20 U.S. clinical centers. PARTICIPANTS: A total of 2,763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of one year, and 75% at the end of three years. MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. RESULTS: Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year one and fewer in years four and five. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

JAMA 1998 Aug 19;280(7):605-13

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women’s Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16,608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited by 40 U.S. clinical centers in 1993 to 1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in one tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the two primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were seven more CHD events, eight more strokes, eight more PEs, and eight more invasive breast cancers, while absolute risk reductions per 10,000 person-years were six fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal U.S. women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

JAMA 2002 Jul 17;288(3):321-33

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