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Estrogen Replacement and Heart Disease
Stephen Bakir, MD
, and Suzanne Oparil, MD, Birmingham, Alabama
[Clin Rev Spring:67-72, 2000. 2000 Southern Medical Association]
 

The United States has had a decline in overall mortality from cardiovascular disease (CVD) over the past 20 years, but the rate of decline has been slower in women than men. Although awareness of CVD in women has increased in this period, this has not resulted in a decline in their rate of cardiovascular death. On the contrary, as the population ages, the percentage of women increases along with the absolute number of cardiovascular deaths in women.

Cardiovascular disease, including coronary artery disease and stroke, is the leading cause of death in women. Over 500,000 women die from CVD each year. However, compared with men, the initial manifestation of CVD in women is delayed by an average of 10 years. Women in the Framingham cohort had initial myocardial infarction an average 20 years later than men, and this long delay in expression of coronary events persists today. This observation is remarkably consistent across different patient populations -- even in countries with different rates of death from CVD.

It is commonly believed that there is a link between menopause and an increased incidence of CVD, but Furman in 1968 and Tunstall-Pedoe in 1998 did not observe a sharp increase in CVD after menopause. Instead, they found a constant increase in CVD incidence in women during middle life. There was an excess of CVD mortality in men in all age groups, and this gap narrowed with age. However, this narrowing is due to a decrease in CVD death rates in men as opposed to an increase in women (Fig 3). The reasons for this trend are unclear, but there may be a survivor effect in older men.

In contrast, the data from women who undergo premature menopause -- natural and surgical -- indicate that CVD develops prematurely in these women, supporting the concept that menopause and CVD are linked. Autopsy studies have shown a clear increase in coronary disease in women after oophorectomy or premature ovarian failure. There are many possible confounding variables in these studies, including pituitary hormone increases after surgery and the antecedent disease processes that necessitated oophorectomy or caused the ovarian failure. However, the fact remains that after oophorectomy, the incidence of CVD in women is increased.

Observational studies suggest that postmenopausal hormone replacement therapy (HRT), including various estrogen preparations with or without progestin (most commonly synthetic progestin), reduce CVD risk by 35% to 50%. Studies also suggest that estrogen may slow the progression of existing coronary artery disease in postmenopausal women and limit the proliferation of vascular smooth muscle cells after vascular injury (ie, after angioplasty). These studies are supported by a large number of animal data. However, there are very few prospective, randomized controlled trials evaluating HRT and its effects on CVD in humans.

 

Determining the effects of menopause and, specifically, the loss of ovarian hormones and replacement with exogenous estrogens/progestins on CVD risk is difficult because of confounding variables: women are aging as they go through menopause, and the prevalence of more traditional CVD risk factors increases as they age. We will discuss the lines of evidence from observational studies, animals, and the few randomized, controlled trials dealing with hormones and their effects on CVD.

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Biological Plausibility

Biological  Plausibility
 

A number of biologically plausible mechanisms exist for hormone-mediated protection from CVD. The Postmenopausal Estrogen/Progestin Intervention (PEPI) trial examined the effect of estrogen replacement therapy (ERT) -- conjugated equine estrogen alone or in various combinations with medroxyprogesterone acetate (MPA) or micronized progesterone -- on cardiovascular risk factors. The PEPI trial and numerous observational studies have shown that oral estrogen therapy is associated with a 10% to 15% increase in high-density lipoprotein cholesterol (HDL-C) and a similar decrease in low-density lipoprotein cholesterol (LDL-C). The elevation in HDL-C level is due to increased production of HDL2 and apolipoprotein A-1, whereas the decrease in LDL-C is due to increased expression of hepatic LDL receptors. Oxidation of LDL-C is believed to be an inciting event in atherogenesis, and estradiol and/or other estrogens may inhibit this process. Oral conjugated estrogens are also associated with an increase in very low-density lipoprotein (VLDL), triglycerides, and apolipoprotein B levels, as well as a decreased level of Lp(a) lipoprotein. These are not large changes, however, and the effects of modest alterations in these molecules on the development of CVD are uncertain. In contrast, oral estradiol or transdermal estrogen does not undergo "first-pass" metabolism in the liver and is not associated with the same degree of lipoprotein alteration.

The beneficial effects of estrogen on lipoproteins are responsible for only a portion of the observed benefits with respect to CVD. There is evidence that estrogen also has direct effects on vascular walls. For example, estrogen treatment is associated with decreased lipid uptake and accumulation in the vessel wall. Estrogen administration also reduces the extent of atherosclerotic plaques in oophorectomized cynomolgus monkeys with diet-induced atherosclerosis. Further, in animal models and in postmenopausal women, both short-term and long-term estrogen administration reverses the pathologic vasoconstriction seen in atherosclerotic arteries in response to acetylcholine. The acetylcholine-mediated vasodilation seen in normal coronary arteries and in atherosclerotic arteries of postmenopausal women taking ERT is likely mediated by nitric oxide as an endothelial-derived relaxing factor. Estrogen use is associated with increased transcription of nitric oxide synthase and augmentation of nitric oxide release.

Over the past 20 years, we have learned that unopposed estrogen use is associated with cancer of the endometrium. This led to the addition of a progestin to estrogen replacement therapy (ie, HRT) in women with an intact uterus. There are fewer observational data in these women, but most studies have shown a beneficial effect similar to that seen with ERT. However, animal data have raised important questions concerning the effects of pro-gestins, particularly synthetic progestins such as MPA, on CVD. The addition of MPA to conjugated equine estrogen attenuated the vasodilator effect of estrogen in atherosclerotic coronary arteries of cynomolgus monkeys after acetylcholine administration. Treatment with MPA also completely blocked the estrogen-associated reduction in coronary atherosclerosis in oophorectomized monkeys.

All progestins are not alike, however, and the PEPI trial found differences in the effects of different preparations on CVD risk factors. Women in PEPI were treated with conjugated equine estrogen alone or in combination with either MPA or micronized progesterone. While all women who received estrogen had an increase in HDL-C level and a decrease in LDL-C, the HDL-C effect was more pronounced with micronized progesterone than with MPA.

Other potential benefits of ERT include effects on clotting factors. Levels of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) increase after menopause, but these increases are reversed with estrogen use. Estrogen affects prostacyclin biosynthesis by enhancing production of prostaglandin I2 and decreasing production of thromboxane A2. Platelet aggregation, as well as inflammatory cell attachment to vessel walls, is also inhibited by estrogen use. Despite these possible benefits, clinical studies have clearly associated estrogen use with an increase in venous thrombosis. The disparity between these laboratory data and clinical observations is particularly important when one considers the effects of ERT on the postmenopausal woman with established CVD; biologic plausibility alone is not sufficient to establish a protective effect of estrogen replacement in CVD.

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Evidence By Observation

Evidence By Observation
 

A large number of observational data suggest substantial cardiovascular benefit and a decrease in mortality from all causes with unopposed estrogen therapy in postmenopausal women. This reduction in risk is congruent with the data from laboratory investigations in animal models and in vitro preparations. Fewer studies have evaluated the effects of combination estrogen-progestin replacement therapy, but most have shown a 30% to 50% decrease in the risk of coronary events in postmenopausal women.

In 1991, Henderson et al found a 40% decrease in overall mortality in elderly women on long-term (>15 years) hormone therapy. This effect was predominantly seen in CVD mortality, but there was also a trend toward decreased stroke and cancer incidence in women treated with estrogen.

In the Lipid Research Clinic Follow-up Study, 2,270 hyperlipidemic, white women aged 40 to 69 years at study entry were followed for more than 8 years. Women who received estrogen had over 60% fewer CVD deaths than those who did not. This benefit remained after adjustment for age, hypertension, and smoking, and it was most pronounced in women with known CVD.

The Nurses' Health Study used dietary and health questionnaires to evaluate 59,337 women without CVD at the time of enrollment. In women taking estrogen alone, the relative risk of major coronary disease was 0.60 (95% confidence interval [CI], 0.43 to 0.83), and in those women taking estrogen with progestin, the relative risk was 0.39 (95% CI, 0.19 to 0.78) compared to women not taking hormones. Because of the small number of CVD events in the combination therapy group, the results were similar to those in women taking estrogen alone.

Not all observational evidence suggests a beneficial effect of estrogen, however. A 1997 Kaiser Permanente case-control study by Sidney et al examined postmenopausal women who were admitted for an incident myocardial infarction. They found no difference in the odds ratio of myocardial infarction between women who were current or former hormone users versus women who had never used hormones. A meta-analysis by Hemminki and McPherson in 1997 also failed to show a protective effect of postmenopausal hormone therapy with respect to cardiovascular events.

These types of retrospective, nonrandomized analyses have severe limitations, and a great deal of skepticism exists about the populations examined and the results observed. It has been proposed that the benefits of hormone replacement seen in epidemiologic studies are a result of selection bias. Women who use HRT have a better cardiovascular risk profile than those who do not: they are better educated, they engage in more leisure-time physical activity, their blood pressures are lower, and they have a better lipoprotein profile. Although the bulk of the observational data, animal data, and vascular biology findings support a protective effect of estrogen with respect to CVD, important questions remain. Prospective randomized trials can overcome many of the limitations associated with the retrospective studies listed above and will help answer many of the current questions concerning ERT, as well as point the way to new areas of investigation.
 

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Randomized Trials

Randomized Trials

The recently published results from the Heart Estrogen-Progestin Replacement Study (HERS) have added to the controversy regarding ERT and cardioprotection. This was the first large-scale randomized clinical trial to test the efficacy and safety of hormone replacement on clinical CVD outcomes in postmenopausal women. The study population included 2,763 women with established coronary artery disease randomized to combination HRT (continuous conjugated equine estrogen and MPA) or placebo who were then observed for an average of 4 years. Overall, there was no significant difference between groups for the primary outcome, nonfatal myocardial infarction or coronary heart disease death, or for several secondary cardiovascular end points. There was a statistically significant time trend, with more coronary heart disease events in the treatment group than in the placebo group in year 1 and fewer in years 3 and beyond. There was an increase in the incidence of thromboembolic events (deep venous thrombosis and pulmonary emboli) in the treatment group; relative hazard was 2.89 (95% CI, 1.50 to 5.58). There was also an increase in gallbladder disease in the treatment group, with a relative hazard of 1.38 (95% CI, 1.00 to 1.92).

These results do not support instituting HRT in women with established coronary heart disease for the sole purpose of avoiding secondary events. In HERS, the question of benefit (and risk) from estrogen alone or from combined hormone replacement in primary prevention was not addressed, nor was the mechanism of the apparently biphasic effect (early detriment, later benefit) of combined hormone replacement in women with atherosclerotic disease elucidated. Answers to the first questions will come from the Women's Health Initiative (WHI), a randomized trial of estrogen and combined HRT for primary prevention, which includes 10 times as many treated women as HERS and a longer period (9 years) of treatment, and will be completed in 2005. The remaining question can be answered only by further research in both human subjects and animal models.
 

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Systemic Effects of Estrogen Replacement Therapy

Systemic Effects of Estrogen Replacement Therapy

Estrogen, with or without the addition of a progestin, is associated with a number of systemic and local effects in addition to those seen in CVD. Substantial data have come from observational studies and small clinical trials on the effects of estrogen replacement in postmenopausal women and cognition. The prospective trials are small, and data from the observational studies are conflicting. However, as with estrogen for CVD, there is biologic plausibility and preliminary evidence for a favorable effect by estrogen on cognition and dementia. Estrogen also reduces the morbidity of osteoporosis by reducing fractures, and it improves the symptoms associated with menopause.

While many benefits are associated with estrogen use, there are also adverse effects. As mentioned above, data from the HERS trial, the Nurses' Health Study, and other studies have clearly shown an increased incidence of venous thromboembolic events associated with ERT. There is also an increase in endometrial cancer with unopposed estrogen therapy, and though this risk is attenuated with the addition of a progestin, the long-term consequences of estrogen and progesterone on endometrial hyperplasia are uncertain. Breast cancer, however, is perhaps the most well-known -- and controversial -- potential adverse effect of ERT. In the Nurses' Health Study, despite an overall reduction in mortality, there was a 43% increase in the risk of breast cancer mortality in women taking hormones for more than 10 years. The Iowa Women's Health Study also found a nonsignificant trend toward increased mortality in postmenopausal women taking hormones. While these findings are not universal, most analyses have found an increased risk of breast cancer in women taking HRT, and this risk increases proportionally with the length of time on hormones. In the observational data so far, this risk has been offset by the overall benefit in total mortality (most of which is due to a decrease in CVD). The question of the risk-benefit ratio of HRT is currently being addressed in the WHI, in which three primary end points are CVD, osteoporosis, and breast cancer.

 

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Summary and Recommendations

Summary and Recommendations

The large number of data from vascular biology, animal models, observational studies, and randomized trials still leave the clinician with ambiguity about the effects of estrogen with or without a progestin for CVD. We know from HERS that there is an early risk in HRT for postmenopausal women with known CVD, and helpful data will likely come from the WHI. However, in the interim, we can neither ignore the epidemiologic data nor should we generalize the results from HERS to all women. Further clarification is needed on the effects of micronized progesterone versus MPA and their influence on CVD.

Current data support an individualized approach to HRT in postmenopausal women. There are subgroups in which estrogen currently offers more risk than benefit. However, for the majority of women, we must explain the risks and benefits as we currently understand them. The decision on whether or not to proceed with HRT should ultimately be left with the patient, with guidance and counseling from her physician.

                                                                              

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Hormone Replacement Therapy Likely Beneficial       Hormone Replacement Therapy Likely Beneficial

 

  • Women with a low HDL-C and no history of CVD.
  • Women with other CVD risk factors, but without documented CVD.
  • Women with menopausal symptoms.
  • Women at high risk for osteoporosis and fractures.

                                                                              

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                                                            Hormone Replacement Therapy Contraindicated

Hormone Replacement Therapy Contraindicated



 

  • Women with known CVD who are not currently receiving HRT.
  • Women with history of breast cancer or with a family history of breast cancer in a first-degree relative.

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