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Estrogen Plus Progestin Therapy: The Cardiovascular Risks Exceed the Benefits

Penckofer, Sue M. PhD, RN; Hackbarth, Diana PhD, RN, FAAN; Schwertz, Dorie W. PhD, RN, FAAN

The Journal of Cardiovascular Nursing: November-December 2003 - Volume 18 - Issue 5 - p 347–355
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The surprising results of the Women's Health Initiative (WHI) reported in 2002 had a profound effect on women as well as health care practitioners. The WHI was the largest, randomized clinical trial designed to determine if postmenopausal hormone use prevented cardiovascular disease as well as other age-related disorders in women. While observational studies suggested that postmenopausal use of estrogen could decrease cardiovascular risk by 40% to 50%, the WHI demonstrated that use of continuous-combined estrogen plus progestin was not cardioprotective and was even associated with increased health risks. The estrogen alone trial of the WHI is still in progress, leaving practitioners and some women still in a dilemma. This article addresses the WHI in the context of other studies and discusses possible reasons for the unexpected results.

Sue M. Penckofer, PhD, RN Professor and Associate Dean for Research, School of Nursing, Loyola University Chicago, Ill.

Diana Hackbarth, PhD, RN, FAAN Professor, Department of Health Promotion, Primary Care, Health Systems and Dietetics, School of Nursing, Loyola University Chicago, Ill.

Dorie W. Schwertz, PhD, RN, FAAN Associate Professor, Department of Medical Surgical Nursing and Pharmacology, College of Nursing, University of Illinois, Chicago, Ill.

Corresponding author Sue M. Penckofer, PhD, RN, School of Nursing, Loyola University Health System, Bld 105, Room 2840, 2160 S First Ave, Maywood, IL 60153 (e-mail: spencko@luc.edu).

Hormone replacement therapy (HRT), defined as estrogen and some form of progestogen, and estrogen replacement therapy (ERT), defined as estrogen alone, 1,* are therapies approved by the FDA for the treatment of menopausal symptoms. Menopause is associated with a loss of endogenous estrogen. Diseases such as osteoporosis and cardiovascular disease (CVD) increase in prevalence in postmenopausal women. 2 Therefore, it was reasonable to hypothesize that declining estrogen might play a role in the development of these diseases among aging women. Furthermore, since CVD is the leading cause of death among women, 3 the use of HRT/ERT for primary and secondary prevention of CVD seemed logical. However, in 1998, researchers began to question evidence that supported these assumptions. Shortly thereafter, the American Heart Association recommended that HRT should not be initiated for the secondary prevention of CVD. 4 Most recently, the findings from the Women's Health Initiative (WHI) provided evidence that HRT should not be used for the primary prevention of CVD. 5 This article will describe the findings from the WHI in the context of other studies, and what the future holds for estrogen therapy and disease prevention.

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Epidemiologic Evidence From Observational Studies

In the 1980s, researchers began to examine the relationship between estrogen and risk for heart disease using data from large prospective studies such as the Lipids Clinics Research Program, 6 the Nurses' Health Study at 10 and 20 years follow-up, 7,8 and the Leisure World Study. 9 These observational studies suggested that postmenopausal use of estrogen was associated with a 40% to 50% reduced risk of CVD. 10–12 In other words, estrogen users were almost half as likely to develop heart disease than were nonestrogen users. The major limitations of these studies included the following: (1) data on estrogen use was determined by having women recall this information or by accessing medical records, (2) women who took estrogen were initially more likely to be healthier and have better access to the healthcare system, and (3) other factors that contributed to lower heart disease risk may not have been measured or accounted for in the study.

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Studies Examining the Cardioprotective Effect of Estrogen

Since epidemiologic evidence suggested that taking estrogen was associated with a reduced risk of heart disease, studies were conducted to examine the mechanisms whereby estrogen offered cardioprotection. Several review papers have cited studies addressing beneficial cardiovascular effects such as alterations in the activation of blood monocytes, antiplatelet activity, positive effects on cardiac function and vascular resistance, and antioxidant action. 10,13 More recently, it has been suggested that estrogen may decrease the calcium content in coronary plaques and may even slow the progression of atherosclerosis. 14 Many of these studies, however, had small samples limiting the generalizability of the findings.

Large clinical trials are considered the “gold standard” since they provide the strongest research evidence to guide clinical practice. In this type of research, a large number of individuals are randomly assigned to either a treatment group (eg, HRT) or control group (eg, placebo), and researchers who collect data from participants are blinded to the group assignment until after data are collected. When a treatment effect is found, there is greater confidence that the results are due to the intervention rather than the characteristics of the group or preconceived ideas of the researcher.

The Postmenopausal Estrogen/Progestin Intervention Trial (PEPI) 15 was a landmark study, since it was the first clinical trial of hormone therapy (Table 1). PEPI examined intermediate outcomes known to influence risk of CVD. PEPI provided evidence that taking hormone therapy (1) improved lipid profiles and (2) was not associated with an increase in fibrinogen levels when compared to placebo. The findings from the PEPI study indirectly suggested that hormone therapy could be cardioprotective. Another important clinical finding was that taking ERT caused endometrial hyperplasia and that the addition of a progestin was needed to reduce the risk for uterine cancer in women with an intact uterus. 16 Therefore, subsequent hormone therapy trials were designed with this finding in mind. In addition, since PEPI examined intermediate outcomes, subsequent hormone trials were designed to examine the effect of replacement therapy on the occurrence of coronary heart disease (CHD), often defined as nonfatal myocardial infarction (MI) or death from CVD, as primary endpoints.

Table 1

Table 1

Table 1

Table 1

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Clinical Trials Examining Postmenopausal Hormone Use for Secondary Prevention

The Heart and Estrogen Replacement Study (HERS I) 17 was the first secondary prevention trial to determine if HRT altered the risk of cardiovascular events in women with known CHD (Table 1). An unexpected finding was that there was no significant difference in the risk for cardiac events in women taking HRT compared to women taking placebo. In addition, there was a significant time trend, indicating more cardiac events for women within the first few years of initiating HRT. A clinical recommendation from this study was that HRT should not be used for the secondary prevention of heart disease. Like PEPI, however, there were improvements in the lipid profiles of women taking HRT. Since HERS I reported decreased cardiac events in years 3 to 5 of the study, it was possible that long-term HRT might reduce future cardiac events by sustained lipid improvements. Therefore, HERS II 18 was conducted (Table 1). This was an unblinded follow-up of 2.7 additional years with women from HERS I who agreed to participate. Unfortunately, HERS II did not demonstrate a reduced risk of cardiac events in women taking HRT. The recommendation not to use HRT for secondary prevention was sustained.

Other studies for the secondary prevention of heart disease have also been conducted (Table 1). Two studies have included measurements of intermediate endpoints, such as progression of atherosclerosis and lipid improvements. The Estrogen Replacement and Atherosclerosis (ERA) Study reported no difference in angiographic data at 3 years follow-up suggesting that ERT and HRT did not alter the progression of coronary atherosclerosis, although lipid improvements were consistent with other trials. 19 The Womens' Estrogen/Progestin Lowering Hormone Atherosclerosis Regression Trial (WELLHART) is examining whether ERT and/or HRT alters the extent of atherosclerosis examined via cardiac angiogram and carotid ultrasound in postmenopausal women on lipid lowering therapy; data will be published in 2003 (F. Watcher, personal communication, January 2003).

Other secondary prevention studies (Table 1) have included the Women's Estrogen for Stroke Trial (WEST), 20 the PAPworth HRT Atherosclerosis Study (PHASE), 21 the Estrogen in Prevention of Reinfarction Trial (ESPRIT), 22 and the Women's Angiographic Vitamin and Estrogen Trial (WAVE). 23 All of these studies reported either no cardiovascular benefit or increased risk when taking hormone therapy. Findings from the Estrogen and Graft Atherosclerosis Research (EAGAR) are forthcoming. 24

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Clinical Trials Examining Postmenopausal Hormone Use for Primary Prevention

The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) examined the progression of subclinical atherosclerosis, an intermediate end point. 25 The rate of progression of carotid intima-media thickening was slower in women taking ERT as well as in those not on lipid medications (probably because they were healthier). These findings were inconsistent with previous research, and the reason for this may be that EPAT included younger women without known heart disease. The authors suggest that early intervention in the progression of atherosclerosis, especially at the start of menopause, may be the key to the prevention of CVD.

The WHI is the largest randomized, controlled primary prevention trial to be conducted in the United States (planned duration 8.5 years). 5 Over 160,000 postmenopausal women aged 50 to 79 years have been enrolled into the clinical trial(s) (testing post-menopausal hormone use, low-fat dietary patterns, and calcium and vitamin D supplementation) or the observational study. For the hormone trials of the WHI, women with a uterus were randomized to HRT (conjugated equine estrogen (CEE) 0.625 mg/day plus continuous medroxyprogesterone acetate (MPA) of 2.5 mg/day, ie, continuous-combined therapy, Prempro) or placebo. Women without a uterus were randomized to either ERT (CEE 0.625 mg/day) or placebo. The primary outcome of the estrogen plus progestin was CHD, while hip fractures were secondary outcomes. Invasive breast cancer was designated as the primary adverse outcome. Additional outcomes included other CVDs (stroke and thromboembolism), cancers (endometrial and colon), and fractures (vertebral). 5 After a mean of 5.2 years of follow-up, a data safety monitoring board recommended stopping the HRT trial because the “test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect.” 5 (p321) These findings stunned the medical community because the risks for HRT appeared to outweigh the benefits that were necessary for a primary prevention therapy.

The findings from the combined estrogen plus progestin trial of the WHI revealed that the relative risk for CHD, as well as other diseases, was significantly greater in women taking HRT compared to those on placebo (Table 2). The assumption in the calculation of relative risk is that those who are not taking HRT have a risk of “1.” The relative risk of CHD for women taking HRT was 1.29 with a confidence interval of 1.02 to 1.63. This means that the elevated risk from taking HRT ranged from 0.02 to 0.63, which is equivalent to an increased relative risk ranging from 2% to 63%. The best estimate was 0.29 or 29% greater risk among those taking HRT compared to those taking placebo. While this percentage reflecting the increased risk for the HRT group seems high, the actual annual increased risk, or absolute risk, in the population was quite small. Regardless of treatment, women of this age group will suffer cardiac events. During a year of the WHI, on an average there were 37 CHD events, defined as nonfatal MI or CHD death, per 10,000 women in the HRT group compared to 30 events per 10,000 women in the placebo group. This means there were 7 more women per 10,000 in the HRT group who suffered cardiac events. This increased risk was evident in the first year of the study.

Table 2

Table 2

Similarly, there was a 41% increased relative risk for stroke. In terms of absolute risk, there were 8 more women per 10,000 in the HRT group who had stroke events compared to the non-HRT users. Risk of venous thromboembolism was associated with the greatest increased relative risk (111%) in HRT users. About 18 more women per 10,000 in the HRT group had venous thromboembolism (deep vein thrombosis or pulmonary embolism) than in the placebo group. Although there was a 26% increase in relative risk for invasive breast cancer in the HRT group, it was not statistically significant. However, 8 more women per 10,000 in the HRT group developed invasive breast cancer. There was a 37% decrease in the relative risk of colorectal cancer for women taking HRT. In terms of absolute risk, 6 fewer women per 10,000 who took HRT developed colon cancer. Finally, HRT was associated with a 34% decreased relative risk in hip fractures. Five fewer women per 10,000 developed hip fractures in the HRT group. In terms of overall death, there was no significant difference between groups. The conclusions from the WHI were that (1) overall health risks exceeded the benefits when taking continuous-combined CEE plus MPA (Prempro) for an average of 5.2 years, (2) the risk-benefit profile is not acceptable for the primary prevention of chronic diseases, and (3) Prempro should not be initiated or continued for the primary prevention of CHD.

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Potential Reasons for Lack of Cardioprotective Effect of Replacement Therapy

Why have clinical trials of hormone therapy failed to show protection from CVD as was suggested by observational studies? Both methodologic and biologic factors have been reported as possible explanations for the difference in the findings. 11 The methodologic factors contributing to study differences include a healthy user effect, compliance bias, and incomplete capture of early clinical events in the observational studies. In these studies, women who took estrogen were more likely to be healthy and have better access to the healthcare system (healthy user effect). These women were probably compliant users because they were seeking treatment for relief of menopausal symptoms or osteoporosis and may have been more willing to take estrogen (compliance bias). In contrast, in the WHI, it was reported that for women taking estrogen plus progestin, 42% had stopped the drug some time during the study. Finally, observational studies may not have captured earlier cardiac events because of study design. For example, in the Nurses' Health Study, 7,8 data were collected at 2-year intervals. Since it has been reported that the cardiovascular events associated with HRT were greatest with the initiation of therapy (both HERS and WHI), observational studies may not have captured these early events.

The biologic factors contributing to study differences may have to do with the women's age at the initiation of hormone therapy, genetic factors, and the drug regimen used. Findings from primate studies suggest that one reason for the differences may be the “timing” of the initiation of hormone therapy. 26 In observational studies such as the Nurses' Health Study, women were younger (age ranged from 30 to 55 at enrollment), and most began hormone replacement within 2 years after menopause. 11 In most of the clinical trials (Table 1), hormone therapy was started long after menopause (63 and older). Indeed by age 65, most women have already developed advanced atherosclerotic lesions; ie, “vulnerable” plaque having a necrotic core and covered with a fibrous cap. 27 Estrogen has been shown to have effects that mitigate the development of atherosclerosis, such as inhibiting vascular smooth muscle proliferation and migration, stimulating the proliferation of vascular endothelial cells, facilitating vasodilation, inhibiting platelet activation, and decreasing expression of adhesion molecules that facilitate sticking of leukocytes to the vessel wall (which is important in the inflammatory response), and decreased calcium deposition. 13,14,28,29 In arteries with advanced atherosclerosis these protective actions of estrogen are reduced or absent. 26 In addition, most recently, HRT has been shown to increase matrix metalloproteinase-9 (MMP-9), which can degrade the fibrous cap of vulnerable plaque and cause rupture, 26,30 thereby precipitating a possible cardiac event. Therefore, HRT initiated in older postmenopausal women may increase the occurrence of negative cardiac events because of established atherosclerosis. 26

It may also be that hormone therapy is protective for some women but harmful to others depending on their genetic profile. Most of the negative cardiovascular effects of hormone therapy demonstrated in clinical trials are related to increased thrombosis. Two coagulation factor mutations, factor V Leiden (FVL) and prothrombin G20210A have been shown to interact synergistically with HRT to increase the risk of venous thromboembolism. 31 FVL causes expression of an abnormal blood protein, which results in an increased tendency toward coagulation. 31,32 Prothrombin G20210A mutation results in increased prothrombin levels. 31,33 Both of these mutations would tend to tip regulation of thrombosis toward a prothombotic state. Therefore, a genetic/drug interaction may explain why there is an early increased risk of negative events in hormone therapy clinical trials.

A major limitation of our current knowledge regarding the effect of hormone therapy on the incidence of negative cardiac events is that the largest trial, the WHI, used only one drug regimen (ie, continuous-combined CEE and MPA, Prempro) (Table 1). It is now understood that there is a complex relationship between estrogen and progesterone. Estrogen up-regulates the progesterone receptor whereas progesterone down-regulates the estrogen receptor. 34 Physiologically this makes sense relative to the menstrual cycle (early phase of the cycle is estrogen dominant and the later phase is progesterone dominant). Given the relationship between the two hormones and their receptors, it is difficult to know the effect of giving both hormones together daily. It is possible that this regimen may negate the putative benefits of estrogen.

Another major limitation is that the WHI and most other trials used one protocol (ie, continuous-combined daily doses of CEE and MPA, Prempro), which cannot be generalized to other protocols whereby an estrogenic drug would be given alone for a period of time, followed by the addition of progesterone for a period of time such as was used in the PEPI trial. In addition, the use of other estrogenic and progestogenic agents (eg, norethindrone acetate/ethinyl estradiol tablets, FemHRT) are being explored such as in the Women's Ischemia Syndrome Evaluation (WISE) FemHRT Ancillary Study (Dr N. B. Merz, personal communication, July 2003). Because the ERT trial of the WHI is still in progress, the cardioprotective effects of CEE given alone in women without a uterus are unknown.

Adherence to the protocol was also an issue in the WHI. It was reported that many women stopped drug therapy at some time (42% estrogen plus progestin and 38% placebo) or initiated drug therapy through their own personal clinician (6.2% estrogen plus progestin and 10.7% of placebo). It has been suggested that because of moderate adherence rates in the trial, the results reported may actually under-represent both adverse and the beneficial effects of HRT.

Finally, another limitation of the WHI and the other clinical trials was the lack of minority representation. The estrogen plus progestin trial of the WHI had the following racial/ethnic distribution: 84% White, 7% Black, 5% Hispanic, 2% Asian/Pacific Islander, 0.5% American Indian, and 1.5% unknown. This distribution was consistent or somewhat better than most of the secondary prevention trials (eg, percent of individuals in ethnic minority groups: HERS 11%, ERA 18%, WEST 16%, ESPRIT 3%). The EPAT study, which reported positive effects from unopposed ERT on subclinical atherosclerosis (Table 1), had the largest ethnic minority sample (42%). These findings suggest the need to examine the benefits and risks of different hormone preparations on larger samples of racial and ethnic groups.

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Clinical Practice Recommendations

It is important to remember that the primary indication approved by the FDA for hormone therapy has been the treatment of menopausal symptoms (eg, hot flashes and vaginal dryness). Although epidemiologic evidence was originally thought to be strong for post-menopausal use of estrogen in the prevention of heart disease, clinical trial evidence does not support these findings. Research indicates that at least the hormone agents and regimens reported in these clinical trials (Table 1) should not be used for primary or secondary prevention. Instead, established methods to lower cardiac risk in women should be used, such as controlling blood pressure and cholesterol through lifestyle and drug therapy. 35 Although there may be a need to use HRT for the treatment of menopausal symptoms, current recommendations include taking the lowest dose for the shortest period of time. 36

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Future of Postmenopausal Hormone Use in Disease Prevention

Whether HRT can be cardioprotective in younger women, at lower doses, and with different preparations, is open for investigation. Because of the potential breast cancer risk involved with long-term use and the significant cost of another large, clinical trial to examine this benefit, it is doubtful that this research will be conducted.

For this reason and others, researchers are examining designer estrogens, called selective estrogen receptor modulators (SERMs), for their effects in disease prevention. 37 For example, a study of Raloxifene for the Use in the Heart (RUTH) is currently being conducted. This clinical trial is examining 10,000 postmenopausal patients at risk for CHD to see if this drug can prevent coronary events. 38 It should be noted, however, that raloxifene does not help menopausal symptoms, and in some cases may actually exacerbate symptoms. 37

Since there are estrogen receptors in many tissues of the body, the ability to differentially stimulate or inhibit the estrogen receptor in target tissues will be important in the development of new SERMS. Further research on the effect of progesterone on receptor activity as well as the relationship between estrogen and progesterone is needed. The ideal SERM would work in the brain to prevent hot flashes and enhance memory, in the bloodstream to prevent blood clots, in the breast and reproductive track to prevent cancer, in the liver to improve the lipid profile, and in the bones to prevent osteoporosis. For now, however, the use of HRT for cardioprotection should not be advocated. Traditional strategies such as diet and exercise must continue to be recommended for the primary and secondary prevention of CVD.

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Keywords:

clinical trials; coronary heart disease; estrogen; hormone replacement therapy; Women's Health Initiative

© 2003 Lippincott Williams & Wilkins, Inc.