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(Circulation. 1996;94:2982-2985.)
© 1996 American Heart Association, Inc.

Articles

Estrogens for Prevention of Coronary Heart Disease

Putting the Brakes on the Bandwagon

Jacques E. Rossouw, MD

the Office of Disease Prevention, National Institutes of Health, Bethesda, Md.

Correspondence to Dr Jacques E. Rossouw, Women's Health Initiative, National Institutes of Health, Federal Bldg, Room 6A09, Bethesda, MD 20892. E-mail Jacques Rossouw@NIH.GOV.

Key Words: myocardial infarction • hormones • prevention • women

	Introduction

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 
Eighty-two percent of 1383 cardiologists, internists, family doctors, and general practitioners surveyed by the National Heart, Lung, and Blood Institute (NHLBI) reported that they prescribe hormone replacement therapy (HRT). Of those who prescribe it, 93% do so for relief of menopausal symptoms and 91% for osteoporosis. These are proven and accepted indications for estrogen replacement therapy. However, 41% also prescribe it for high blood cholesterol, and 66% prescribe it for coronary heart disease. These are not proven indications and should not be accepted as such until unequivocal clinical trial data are available. Why, then, have so many medical practitioners climbed aboard the HRT bandwagon? That bandwagon is clearly rolling, as anyone who reads newspapers or magazines, watches television, or talks to colleagues can attest. The bandwagon appears to be picking up in speed and volume. The putative benefits of HRT are being trumpeted to postmenopausal women, with only transient muting for reports of possible adverse effects.

	Background

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 
A short history of HRT is instructive. The use of postmenopausal estrogens first gathered momentum during the sixties under the banner of "feminine forever." The promise to women that estrogens would hold back the ravages of time went unfulfilled, and instead they learned that they were being put at increased risk of endometrial cancer.¹ Other disturbing news emerged: estrogens increased the risk of coronary heart disease (CHD) in men, and oral contraceptives increased the risk of CHD and stroke in middle-aged women.^{2 3} Result: from the midseventies onward, estrogen use declined precipitously.⁴ Better news started emerging in the eighties: estrogens prevented bone loss, and estrogen users appeared to be at lower risk of CHD.^{5 6} When it was demonstrated that concomitant administration of progestins removed the risk of endometrial cancer, the brakes were loosened and use of postmenopausal hormones has been increasing ever since.⁷ Not even the recent reports that estrogens with or without progestins may increase the risk of breast cancer appear to have dampened the enthusiasm for its use.^{8 9}

But do we really know enough about the benefits and risks of estrogens? Are we about to repeat the mistakes of the sixties and seventies? This time, will we be brought short by an epidemic of breast cancer (arguably a far worse disease than endometrial cancer)?

The field of preventive cardiology can point to a proud tradition of evidence-based practice. The pioneering clinical trials that proved or disproved benefit of promising treatments were conducted in preventive cardiology. For example, clinical trials have led to a sophisticated understanding of the benefits and risks of treating high blood pressure and of high blood cholesterol to prevent clinical disease.^{10 11 12 13} It was not deemed sufficient to show that drugs lowered blood cholesterol; we also wanted to know that treatment lowered CHD events and did so without increasing the risk of noncoronary events. So it is doubly disturbing that many practitioners of preventive cardiology appear to be willing to accept the benefits of estrogens and to discount the potential risks, without any noteworthy clinical trial data to inform their judgment. Without such data, it is somewhat surprising that the American College of Physicians and the National Cholesterol Education Program have subscribed to the view that estrogens should be considered for the prevention of coronary disease.^{14 15}

	Evidence for Benefit

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 
The assumption that estrogens will prevent CHD is based on promising but inconclusive data from animal studies, observational studies, and studies of intermediate mechanisms. Animal studies including trials in ovariectomized nonhuman primates support the idea that estrogens may prevent atherosclerosis. Estrogens have modest or inconsistent effects on lipids in nonhuman primates, and direct effects on the vessel wall are more likely mechanisms.¹⁶ There is a burgeoning interest in the possibility that direct effects on the vessel wall may be similarly important in humans.^{17 18}

A large number of observational studies have suggested that women who are taking estrogens appear to have a lower risk of heart disease, and a few studies have also shown similar apparent risk reductions for estrogens when used in combination with progestins.^{19 20} However, all these observational studies share a fatal flaw: women who take estrogens are different from women who do not. Some of the differences have been measured, others have not. As reviewed elsewhere, women who take estrogens are on average better educated, healthier, have higher incomes, and have better access to healthcare.²¹ It is important to note that women who eventually take estrogens appear to be healthier even before starting therapy.²² These differences rather than the estrogens may account for much of the lower risk of heart disease. It is impossible to correct for all the potential biases in analyzing observational data. Furthermore, combining the results of the observational studies in meta-analyses is not helpful and may even be misleading. If there is a systematic bias in study data, then combining the data of all studies ascribes a significance level to the bias but does not illuminate the basic question.²³ Currently, we simply cannot tell from the observational studies what the real benefit of estrogens on CHD might be. The only way to obtain reliable information is through randomized controlled clinical trials, which if large enough will eliminate the possibility that differences between study groups account for the results.

Recently, the data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial were hailed in some press reports as providing definitive answers to clinical questions.²⁴ Even though this was a well-conducted randomized, controlled clinical trial, the findings did not address clinical outcomes. PEPI studied selected intermediate biological outcomes, and the results do not in any way obviate the need for the definitive trials that directly examine the effects of hormones on clinical outcomes such as heart disease and breast cancer.²⁵ Together with other recent studies,^{26 27 28} PEPI has confirmed earlier reports²⁹ that estrogens decrease LDL cholesterol (LDL-C), increase HDL cholesterol (HDL-C), and increase triglycerides. The addition of progestins blunted the estrogen-induced rise in HDL-C to varying degrees and in two other studies also blunted the rise in triglycerides.^{27 28} Among the coagulation factors there were decreases in fibrinogen in PEPI²⁴ and in the MRC trial.²⁸ Antithrombin III levels decreased and plasminogen, factor X, and factor VII (with estrogen alone) levels increased in the study by Lobo et al.²⁷ The MRC trial confirmed that activated factor VII levels rise on estrogen alone but not on combination therapy. ²⁸ The risk implications of increased postchallenge blood glucose levels for some combined estrogen and progestin regimens are uncertain, since there were no concomitant increases in postchallenge insulin levels in these studies.^{24 27} There were no effects on blood pressure or body weight.^{24 28}

Even when looked at in isolation, it is difficult to predict what the net effect of these changes would be for the outcome of CHD. Some lipid and coagulation factor changes (LDL-C, HDL-C, fibrinogen, plasminogen) could be favorable, whereas others (triglycerides, factor VII, factor X, antithrombin III) may be unfavorable. The proportion of any protective effect of estrogen mediated through any one or all of these changes is uncertain. Other potential mechanisms such as direct effects on the vessel wall may well turn out to be decisive.^{17 18} Furthermore, any cardioprotective effect for estrogens may be abrogated by the addition of progestins. From a biological perspective, progestins often counteract estrogen. Some of these opposing actions were found in recent studies. For example, the estrogen effects on HDL-C, triglycerides, and factor VII may be modified by the addition of progestins, and in some animal models the antiatherogenic effects of estrogens were abolished by the addition of progestins.^{30 31}

Importantly, none of the studies to date have directly and reliably measured the effects of these hormones on the clinical manifestations of CHD in women, and any projection of potential benefit based on the changes in surrogate biological variables is highly speculative. It would not be the first time that apparently favorable effects on intermediate biological outcomes did not translate into benefit or even harmed patients in terms of actual disease outcomes.^{32 33}

	Evidence for Harm

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 
In respect of potential harm, PEPI documented that estrogen alone in women with uterus intact led to a higher than anticipated rate of adenomatous endometrial hyperplasia with or without atypia, potentially precancerous conditions. One third of the participants in this arm of the trial had to discontinue medication for these reasons.²⁴ On this basis alone, the PEPI data should lead to a more conservative approach rather than encouraging the use of unopposed estrogens. Moreover, while PEPI confirmed that the addition of a progestin over the short term appears to avoid the development of endometrial hyperplasia, uncertainty remains as to whether endometrial cancer will be avoided over the long term.³⁴

The risk of breast cancer should not be dismissed. While the observational data suggest marginal effects for breast cancer overall, they also indicate potentially harmful trends for long-term users.^{9 19} This may be important, because what is being proposed by the estrogen enthusiasts is long-term use of these hormones. If prevention of CHD in women is the goal, then lifelong therapy after the menopause is required. Finally, most of the known modifiable risk factors for breast cancer are hormone-related (age at menarche, age at menopause, parity, obesity), and this has led to caution about hormone use among cancer experts. While progestins appear to protect against endometrial cancer, there is no indication that they will offer similar protection from breast cancer.^{8 9 19}

	Future Directions

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 
Further observational studies or trials of intermediate biological outcomes will not answer the important public health questions because of their inherent weaknesses. Will postmenopausal hormone replacement therapy reduce CHD incidence and/or will it increase the risk of breast cancer, and what is the overall benefit and risk of long-term use? To what extent do the benefits and risks apply to older women? Should most postmenopausal women be prescribed hormone replacement therapy? Only randomized trials with clinical outcomes that are of sufficient size and duration can answer these questions. Such trials are being conducted now, for example, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI). HERS is focused on the secondary prevention of CHD through the use of a combination of conjugated equine estrogens and medroxyprogesterone acetate. WHI will include women 50 to 79 years of age with and without CHD and will test conjugated equine estrogens alone and combined with medroxyprogesterone acetate. Because of its size and duration (27 500 women will be followed for an average of 9 years), WHI will also be able to discern whether estrogens increase the risk of breast cancer and thus will provide the critical data on overall benefit and risk for postmenopausal women over a wide age range.

These trials will have results around the year 2000 in the case of HERS and the year 2005 in the case of WHI. In the interim, it would seem appropriate to be conservative about prescribing estrogens except for the proven indications of managing postmenopausal symptoms (short-term treatment) and osteoporosis (long-term treatment). For the prevention of CHD, alternative and better proven treatments of risk factors exist. High LDL-C levels can be managed with diet and lipid-lowering agents, which have been shown to reduce the incidence of coronary events in men and women.³⁵ For secondary prevention lipid-lowering agents, ß-blockers, and aspirin alone or in combination are probably better choices than estrogen (although it is acknowledged that the results of a randomized trial of aspirin in women are not yet available). Even in the case of osteoporosis, alendronate (a new bisphosphonate) now offers an effective alternative to estrogen.³⁶

	Conclusions

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 
The status of estrogen as a potential preventive treatment may appear superficially similar to that of antioxidants. Expectations of benefit for antioxidants based on observational studies have not yet been borne out by clinical trials. Nevertheless, many physicians recommend and continue to take antioxidants themselves because they believe the risk of harm to be small. But estrogens are very different from antioxidants. The risk of harm may turn out to be very real. It is time to put the brakes on the hormone bandwagon while pushing ahead with the randomized trials that will provide definitive data on benefit and risk.

Received January 8, 1996; revision received February 28, 1996; accepted March 4, 1996.

	References

Top Introduction Background Evidence for Benefit Evidence for Harm Future Directions Conclusions References

 

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This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rossouw, J. E. Search for Related Content PubMed PubMed Citation Articles by Rossouw, J. E.