Women's Health Initiative study. (Editorials).

LESSONS LEARNED FROM THE WOMEN'S HEALTH INITIATIVE STUDY

On July 9, 2002, the National Institutes of Health (NIH) dropped a bombshell. It terminated the Women's Health Initiative (WHI) study prematurely because the adverse effects of estrogen/progesterone replacement therapy outweighed the benefits. The report was posted on the Journal of the American Medical Association (JAMA) Web site that same day, and was later published. (1) This, coming shortly after the publication of the results of the Heart Estrogen/Progestin Replacement Study, (2, 3) and of another study documenting an increased risk of ovarian cancer in patients taking estrogen alone, (4) sent ripples across the medical and lay community.

About 6 million women in the United States are taking hormone replacement therapy (HRT) for a variety of reasons, ranging from relief of postmenopausal symptoms to, it was assumed, long-term health benefits. Women taking HRT need help to make a rational decision. Should they continue with their HRT, should they stop it, should they taper it down, or should they replace it with some other medication?

In an editorial last December, (5) I cautioned our readers about the lack of hard evidence to support many of the presumed beneficial effects of HRT. I emphasized that most of the studies showing beneficial effects were either retrospective, observational, or case-control studies, and that there was a paucity of prospective, randomized, placebo-controlled clinical trials to support the beneficial effects of HRT. Retrospective and observational studies are open to many biases, including the presence of some other common denominator, not known at the time of the study design. For instance, the "positive effects" on cognition may be due to the fact that more- educated women were more likely to be taking HRT than those who were less educated. Women with higher education levels are more likely to adopt healthier lifestyles than less-educated women. Thus, although on the surface it may appear that those taking HRT are physically and cognitively better than those who are not taking HRT, in fact it may not be the HRT , but the level of education that is responsible for the difference between the 2 groups. The only way to determine with any degree of certainty that HRT, rather than some other factor, is responsible for the difference between the 2 groups is to conduct prospective, randomized, placebo-controlled clinical trials. This was the raison d'etre of the WHI study. It was meant to provide the ultimate proof about whether the benefits of this therapy outweigh its adverse effects or vice versa.

The adverse-effect profile of HRT should have been anticipated. As early as 2000, the WHI study's Data and Safety Monitoring Board (DSMB) noted that, compared with those taking a placebo, women taking HRT had small increases in heart attacks, strokes, and thromboembolic events. These findings were again confirmed the following year. In May 2002, the DSMB determined that the disadvantages of HRT definitely outweigh its beneficial effects, and recommended that the study be discontinued.

Hormone replacement therapy was introduced in the pharmacopeia without rigorous evidence of efficacy and safety because of the relatively lax modus operandi of the time. Intuitively, it made sense to replace hormones that were deficient after the menopause, especially if their administration also relieved the dreaded postmenopausal symptoms. The use of HRT became established when the practice of medicine was mostly an art rather than a science. Whereas art is essentially based upon impressions and subjective and emotional experiences that often can neither be clearly defined, nor reproduced, nor accurately quantified, nor rigorously tested, science is based upon cold facts that can be quantified and reproduced and subjected to rigorous testing. Science is rapidly becoming the foundation of medicine, and evidence-based medicine is gradually permeating all aspects of medicine, including medical education.

The days of paternalistic medicine are also over. Patients now are closely involved in the decision making process. Women taking HRT placed their trust in the medical profession when they accepted HRT; it is now our responsibility to thoroughly discuss the issue with them and help them make informed decisions.

While counseling these patients, probably the most important issue is determining exactly why HRT was prescribed. In most instances, a safer and more effective medication can be prescribed, such as raloxifene or a bisphosphonate for bone demineralization, statins for lipid disorders, and aspirin for coronary heart disease and stroke prevention. Those receiving HRT to alleviate postmenopausal symptoms could taper, then discontinue, the medication. If the symptoms reapper, they could be addressed by some other means.

We also need to emphasize to our patients the exact meaning of the increased risks. A 26% increase in the risk of breast cancer sounds alarming, but it only means that if 10,000 women were taking HRT for 1 year, 8 more will develop breast cancer when compared with 10,000 women not taking HRT. (6) This is more acceptable.

We published the press release from the NIH in the August issue of the Southern Medical Journal. In this issue, we publish the views of 6 specialists on lessons learned from the WHI study and their perceptions of what clinicians should do with patients taking HRT. We also invite our readers to send us their comments for possible inclusion in the correspondence section of the Journal.

Ronald C. Hamdy, MD, FRCP, FACP 

Editor

References

(1.) Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. principal results from the women's Health Initiative randomized controlled trial. JAMA 2002; 28:321-333

(2.) Grady D, Herrington D, Blumenthal R, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 2002; 288:49-57

(3.) Hulley S, Furberg C, Barrett-Connor E, et al: Noncardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II).JAMA 2002; 288:58-66

(4.) Lacey JV, Mink PJ, Lubin JH, et al: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002; 288:34-341

(5.) Hamdy RC: Hormonal replacement therapy. South Med J 2001; 94:1141-1142

(6.) NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk, lack of overall benefit [press release]. Bethesda, Md, National institutes of Health, July 9, 2002

While it is published on the masthead of every issue of the Southern Medical Journal, it bears repeating here: The Publisher is not responsible for the authenticity of opinion or statements made by authors or in communications submitted to the Journal for publication. The author or communicant shall be held entirely responsible.

LESSONS FROM THE WOMEN'S HEALTH INITIATIVE

We sail within a vast sphere, ever drifting in uncertainty, driven from end to end. When we think to attach ourselves to any point and to fasten to it, it wavers and leaves us; and if we follow it, it eludes our grasp, slips past us, and vanishes forever. Nothing stays for us.

Blaise Pascal (1623-1662)

French scientist, philosopher

Pensees, no. 72

Uncertainty is the refuge of hope.

Henri-Frederic Amiel (1821-1881)

Swiss philosopher, poet

Journal Intime 

The estrogen/hormone replacement therapy (HRT) pendulum has been swinging for decades. In the 1950s and before, there was little interest in estrogen therapy for post-menopausal women. In the 1960s, estrogen therapy was viewed as a fountain of youth. In the 1970s, concerns arose regarding the increased risk of endometrial cancer with unopposed estrogen therapy. The 1980s saw the appearance of "estrogen evangelists," who believed that estrogen should be given to -- even forced upon -- all postmenopausal women (and perhaps added to the water supply) because of its protective effects on the cardiovascular system. (1) In the 1990s, concerns were raised about the effect of estrogen therapy on breast cancer risk, particularly when estrogen was combined with a progestin. (2, 3) The course of the pendulum was deflected by the Heart and Estrogen/Progestin Replacement Study (HERS). (4) Now the pendulum may have been stopped altogether by new results from the Women's Health Initiative (WHI). (5)

We know that estrogen is an effective agent for prevention of bone loss in recently menopausal women. Estrogen therapy has been shown to increase spinal bone mass by 5% to 10% in numerous, randomized, placebo-controlled trials. (6-10) Until about 5 years ago, I was saying and writing that estrogen is the treatment of choice for established postmenopausal osteoporosis, and I suspect that most experts in the field agreed with me at the time. This opinion was based on observational studies that suggested that estrogen use for 7 years or longer was associated with 25% to 50% fewer spine and hip fractures, (11-14) and the belief that there were significant extraskeletal benefits. In 1999, however, treatment of osteoporosis was withdrawn as an indication for estrogen therapy by the Food and Drug Administration (15) because estrogen had not been studied in the same, rigorous fashion required of newer medications used for treatment of osteoporosis.

The antifracture benefit of HRT was recently confirmed in the HRT arm of the Will, a large, prospective, randomized, double-blind, controlled trial. (5) Good news!? In this study of more than 16,000 postmenopausal women, HRT reduced the risk of hip and clinical spine fractures by one third, the risk of all osteoporotic fractures by 23%, and the total risk of fractures by 24%. This finding is particularly remarkable in that the subjects in WHI were not selected for having osteoporosis. The WHI is a nationwide trial being conducted at 40 centers. Planning began in the 1980s. Recruitment of postmenopausal women, aged 50 to 79 years, with no competing health risks and no likely adherence or retention problems, began in 1993. The trial is scheduled to be completed in 2005. More than 161,000 women enrolled in this ambitious project. Close to 94,000 women are in an observational study because they were either ineligible for or unwilling to consent to one of the clinical trials. More than 68,000 women are participati ng in 1 of 3 interventional studies: a dietary modification study, an estrogen/hormone replacement study, and a calcium + vitamin D trial (which is nested in the other 2).

Current attention is focused on the HRT trial. This study involved more than 16,000 postmenopausal women (mean age, 63 years) who had not had hysterectomy and who agreed to be randomized to either placebo or a specific combination of HRT (conjugated equine estrogen, 0.625 mg/day, plus medroxyprogesterone acetate, 2.5 mg/day). The Data and Safety Monitoring Board (DSMB) stopped the trial early (after an average 5.2 years of follow-up rather than the planned 8.5 years) because of a statistically significant 26% increase in the risk of breast cancer, and because the overall balance of risks and benefits (global index) was unfavorable. (5) In addition to the increase in breast cancer, there was a 41 % increase in strokes, a 29% increase in heart attacks, and a 100% increase in venous thromboembolic events in women receiving HRT.

On the positive side, in addition to the reduced risk of fractures, there was a 37% reduction in colorectal cancer; however, on balance, the risks of long-term HRT were greater than the benefits. The good news that HRT reduces the risk of fracture is largely moot because of the bad news of the increased risks of breast cancer and cardiovascular disease.

But (as they say in TV infomercials) wait, there's more! In the Study of Osteoporotic Fractures, women who took HRT were more likely to have back pain, possibly because of changes in ligaments and supporting structures of the spine. (16) In post hoc analyses of data from the HERS trial, HRT was associated with worsening of urinary incontinence (17) and, in women who were not symptomatic when HRT was started, a decline in physical function and energy, and increased fatigue. (18) The hoped-for benefit of estrogen slowing the progression of Alzheimer's disease could not be shown in a well-designed and adequately powered randomized trial. (19) Thus, there are several other reasons not to give HRT to asymptomatic women for treatment of postmenopausal osteoporosis.

The HRT arm of WHI only examined a single HRT regimen (0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate daily). The results may not pertain to other forms of estrogen therapy (oral or transdermal) used with daily medroxyprogesterone acetate, to estrogen used with cyclic medroxyprogesterone acetate or other progestins, or to estrogen used alone. Does that mean that other HRT preparations are safer than the one tested in WHI? No one knows. We will probably never know.

The estrogen-only arm of WHI was not stopped by the DSMB. Does that mean the same problems that emerged with HRT do not occur with conjugated equine estrogen given without medroxyprogesterone acetate (unopposed estrogen)? Not necessarily. The estrogen-only arm of WHI is large, but with only 10,000 participants, it still may not have the statistical power to show the same effects for another year or two.

Is this another swing of the pendulum? I think not. I believe this is a paradigm shift. The conclusive evidence that HRT lacks car-dioprotective effects and appears to increase the risk of heart attacks and strokes in apparently healthy women (as well as in those with established heart disease) eliminates one of the major reasons for prescribing HRT. The increased risk of breast cancer, though small and consistent with observational data, strikes an emotional chord that is hard to overcome.

What should we be doing for our postmenopausal patients? In absolute terms, the increased risk of cardiovascular disease and breast cancer associated with HRT is relatively small, only about 1 excess case per 1,000 women per year, or, over 10 years, about 1 excess case per 100 women. The WHI did not address quality-of-life issues. I believe that women who need estrogen therapy for relief of symptoms of estrogen deficiency, such as hot flashes and vaginal dryness, should not hesitate to take estrogen or HRT, but should taper or stop HRT every few years to find out if continued treatment is needed, and that women currently taking HRT who are convinced that their quality of life is improved because of HRT should probably continue taking it.

Women who were asymptomatic when they started HRT for what we now know to be the wrong reasons, or who started HRT because of symptoms but might now be asymptomatic if HRT were stopped, should reevaluate their options. It probably makes sense for most of them to stop HRT. Should their treatment automatically be changed to something else? Not so fast! We should stop thinking of menopause as a disease. Women who stop HRT and are at risk for cardiovascular disease should consider taking medications such as hydroxymethylglutaryl co-enzyme A reductase inhibitors (statins), agents that have proven effectiveness against cardiovascular disease. Women who stop HRT and have 6steoporosis should receive medications such as raloxifene or a bisphosphonate, agents that have proven effectiveness in reducing the risk of fracture. Women who stop HRT but seem otherwise healthy do not need medication.

If, in the process of reconsidering HRT, bone status is not known, bone mineral density (BMD) testing should be done to determine if adding a pharmacologic agent is appropriate. It is less expensive to test for osteoporosis than it is to treat it. Based on BMD results, a rational decision can be made to start a preventive regimen (in a patient whose BMD is borderline-low who has risk factors), a treatment regimen (in a patient who has developed osteoporosis, despite taking HRT), or just a healthful lifestyle (in a person whose BMD is normal or borderline-low without risk factors).

As the old cigarette ad used to say, 'You've come a long way, baby." The swinging of the pendulum has stopped. We can now regroup and provide rational advice for our patients.

Nelson B. Watts, MD

University of Cincinnati Bone Health and Osteoporosis Center

222 Piedmont Ave

Suite 4300

Cincinnati, OH 45219

References

(1.) Hillner BE, Hollenberg JP, Pauker SG: Postmenopausal estrogens in prevention of osteoporosis. benefit virtually without risk if cardiovascular effects are considered. Am J Med 1986; 80:1115-1127

(2.) Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,075 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350:1047-1059

(3.) Santen RJ, Pinkerton J, McCartney C, et al: Clinical review 121. risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. J Clin Endocrinol Metab 2001; 83:16-23

(4.) Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605-613

(5.) Writing Group for the women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333

(6.) Bush TL, wells HB, James MK, et al: Effects of hormone therapy on bone mineral density. results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1996; 276:1389-1396

(7.) Genant HK, Lucas J, Weiss 8, et al: Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med 1997; 157:2609-2615

(8.) Recker RR, Davies KM, Dowd RM, et al: The effect of lowdose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women, a randomized, controlled trial. Arch Intern Med 1999; 130:897-904

(9.) Christiansen C, Riis BJ: Five years with continuous combined oestrogen/progestogen therapy. effects on calcium metabolism, lipoproteins, and bleeding pattern. Br J Obstet Gynaccol 1990; 97:1087-1092

(10.) Villareal DT, Binder EF, Williams DB, et al: Bone mineral density response to estrogen replacement in frail elderly women. a randomized controlled trial.JAMA 2001; 286:815820

(11.) Cauley JA, Seeley DG, Ensrud K, et al: Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995; 122:9-16

(12.) Ettinger B, Genant HK, Caun GE: Long-term estrogen replacement therapy prevents hone loss and fractures. Ann Intern Med 1985; 102:319-324

(13.) Paganini Hill A, Ross RK, Gerkins VR. et al: Menopausal estrogen therapy and hip fractures. Ann Intern Med 1981; 95:28-31

(14.) Weiss NS, Ure CL, Ballard JH, et al: Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 1980; 303:1195-1198

(15.) Premarin, conjugated estrogen tablets. Physicians' Desk Reference. Montvale, NJ, Medical Economics Go, 54th Ed, 2000, pp 3302-3305

(16.) Musgrave DS, Vogt MT, Nevitt MC, et al: Back problems among postmenopausal women taking estrogen replacement therapy. the study of osteoporotic fractures. Spine 2001; 26:1606-1612

(17.) Grady D, Brown JS, Vittinghoff E, et al: Postmenopausal hormones and incontinence: the Heart and Estrogen/ Progestin Replacement Study. Obstet Gynecol 2001; 97:116120

(18.) Hlatky MA, Boothroyd D, Vittinghoff E, et al for the HERS Research Group: Quality-of-life and depressive symptoms in postinenopausal women after receiving hormone therapy. results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial.JAMA 2002; 287:591-597

(19.) Mulnard RI, Cotman CW, Kawas C, et al: Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. a randomized controlled trial. JAMA 2000; 283:1007-1015

A GYNECOLOGIST'S VIEW OF HORMONE REPLACEMENT THERAPY IN LIGHT OF THE WOMEN'S HEALTH INITIATIVE

Physicians form treatment biases based, for the most part, upon the medical concerns of the population of patients they see. If a gynecologist sees predominantly early-menopausal women, approximately fifty years of age, who are otherwise healthy and without heart disease, and who are having hot flashes and dyspareunia due to vaginal dryness, that physician develops an overall impression about the utility of hormone replacement therapy (HRT) based upon experience with that population. On the other hand, if an internist or family practitioner sees more 65-year-old women who have already been through menopause and who may already have hypertension and heart disease, that physician will form a different impression as to the use and need, if any, for HRT. This bias is known as Bayesian prior probability, and explains why physicians can have markedly different views about the pros and cons of a specific medical therapy. The recent early termination of a large, prospective clinical study, testing HRT versus placebo using primary outcome measurements of coronary artery adverse events and invasive breast cancer, illustrates this well.

Hormone replacement therapy (estrogen plus progestin) is one such treatment about which professionals have different views. For many years, there have been multiple retrospective, case control/cohort, primate, and laboratory studies indicating that long-term estrogen replacement therapy (ERT) (often mixed with HRT, but mostly ERT) is associated with a lower incidence of coronary artery disease in women who did not previously have heart problems. Even from the initial retrospective report indicating a cardioprotective effect of ERT, this observation applied to the new occurrence of heart disease, not to women who already have coronary heart disease (CHD). (1) Gynecologists have never maintained that, once a woman develops coronary artery disease, estrogen therapy helps slow its progression. Over the years and with the mass of positive preventive data, however, nongyne-cologists began to prescribe HRT with some frequency to women who already had heart disease in order to see if it could, indeed, prevent progres sion. Finally, the Heart and Estrogen/Progestin Replacement Study (HERS) was conceived to test prospectively whether women who already had heart disease and whose uterus remained in place (to cause them to need the addition of progestin to the estrogen) could benefit from HRT. The HERS demonstrated a rise in CHD adverse events in the first year of the study, and a reduction in adverse events in years 3 to 5 of the study, with a 0.99 overall risk for CHD events. (2) Continued monitoring for several years after the study showed the same thing: no reduced rate of CHD adverse events in women starting HRT after a diagnosis of CHD.

The recent Women's Health Initiative (WHI) was set up to test both ERT and HRT in relatively healthy women. One part of the study tested HRT in more than 16,000 women with an in situ uterus, whose average age at entry into the study was 63 years, and about 7% of whom had previous coronary heart or vascular problems. This arm of the study was terminated recently due to an aggregate excess of adverse events. (3) The second arm of the WHI study, which is prospectively testing ERT alone in women who have had a hysterectomy, is ongoing as of this writing. We do not yet know the results, other than that monitoring limits for total adverse events have not been exceeded.

The HRT part of the study was terminated prematurely after a mean of 5.2 years of follow-up. Looking first at the adverse CHD events from that part of the study, the risk ratio was 1.29 (95% confidence interval = 1.02-1.63) for women taking HRT, which means there was a 29% increase, or a difference of 7/10,000 women-years (37 vs 30 per 10,000 person-years) of use. This translates to an excess of 7 women per 1,000 using HRT for 10 years (ie, less than a 1% excess in more than a decade of use).

It is my opinion that these increased CHD events are more likely due to the use of medroxyprogesterone acetate than to estrogen replacement. It is known that treatment with medroxyprogesterone acetate negates the positive coronary vessel dilatation that estrogens produce. (4) Additionally, studies of primates have shown that HRT/ERT needs to be started before the development of cardiovascular disease and within about 5 to 6 years of menopause in order to have its cardiovascular protective effect. (5) The same is true for maximum protection from bone loss. This is the population in which gynecologists believe HRT and ERT are most useful. To prevent these conditions, the therapy should be started as soon after menopause as possible, or at least when women are in their 50s, not for the first time when they are in their 60s.

If you read the Will HRT study carefully, you will see that the main reason it was stopped is that the incidence of breast cancer, one of the study's primary outcome measurements, exceeded the limits of monitoring. It is not clear why colon cancer and endometrial cancer were not considered primary outcomes, since the evidence of risk reduction for those cancers with ERT and HRT is well established. If the protective effect of HRT on those cancers had been included, it would have changed the decision to stop the study. The study found a risk ratio of 1.26, or a 26% increase (38 vs 30 per 10,000 person-years) of breast cancer and a reduced risk ratio (0.63) for colorectal cancer rates. Colon cancers were reduced by 37% (10 vs 16 per 10,000 person-years). Lung cancer, endometrial cancer, and, notably, total cancer rates, were not different in the HRT group versus those given placebo. In light of the result of no net increase in overall cancer rate, I do not believe the outcome of this study is reason to stop pre scribing HRT to all women.

Nevertheless, there are other data to support the slight increase in the incidence of breast cancer with the use of HRT/ERT (risk ratio, about 1.3), and that the risk may increase when used for more than 5 to 10 years. I think that gynecologists who have not been sure until now as to whether there is a real increase in breast cancer from HRT need to change how they counsel patients. It is wise from both a patient-care standpoint, as well as a medical/legal standpoint, to inform a woman of what appears to be increased breast cancer risks along with the other risks and benefits of taking HRT. Annual mammograms for patients treated with HRT are mandatory.

At present, studies indicate that long-term ERT produces a small increase in well-differentiated breast cancer lesions, but it also appears to reduce colon cancer almost equally. Tamoxifen use is suspected of increasing the risk of colorectal cancer, (6) and so far there is no evidence that the use of raloxifene hydrochloride reduces colorectal cancer risk to the extent that estrogen use does. Many nongynecologists are unaware of the colon cancer relationship, but they should counsel patients about it if these alternatives are used.

Based on the Journal of the American Medical Association (JAMA) article arid the report of the discontinuance of the HRT arm of the WHI study, the standard of care would be to inform menopausal women that HRT may produce a small absolute increase in adverse cardiac or vascular events in the first year or two it is used, and that it is associated with a small absolute increase in grade 1 breast cancers. We have already been informing these patients of the small but real increase in the risk of thrombophlebitis and pulmonary emboli. Informed consent, however, should also include telling patients that there appear to be long-term benefits, with reduced risk of cardiovascular disease, Alzheimer's disease, osteoporosis, colon cancer and acute macular degeneration of the eye causing blindness. If patients are symptomatic, short-term benefits of HRT include improvement in the symptoms of hot flashes, genital atrophy and dryness, and mood irritability. Therefore, the risks and benefits of HRT must be carefully weighe d for each individual woman, just as taking low-dose aspirin to prevent coronary artery events must be weighed against adverse stroke events. The physician should discuss these risks and benefits thoroughly with each woman.

I have been switching my patients who were taking HRT to combination therapy that does not include medroxyprogesterone acetate as the progestin. That is a personal preference, however, and the data are not clear. We must reevaluate the situation when the results of clinical trials using other HRT combinations are reported.

Frederick R. Jelovsek, MD

Department of Obstetrics and Gynecology 

East Tennessee State University 

P O Box 70569

Johnson City, TN 37614

References

(1.) Hammond CB, Jelovsek FR, Lee KL, et al: Effects of long-term estrogen replacement therapy. I. Metabolic effects. Am J Obstet Gynecol 1979;133:525-536

(2.) Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57

(3.) writing Group for the Women's Health Initiative investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative Randomized controlled Trial. JAMA 2002;288:321-333

(4.) Adams MR, Register TC, Golden DL, et al: Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vase Biol 1997;17:217-221

(5.) Clarkson TB: The new conundrum: do estrogens have any cardiovascular benefits? Int J Fertil Womens Med 2002;47:61-68

(6.) Rutqvist LE, Johansson H, Signomklao T, et al: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast cancer study Group. J Natl Cancer Inst 1995;87:645-651

AFTER THE WOMEN'S HEALTH INITIATIVE--WHAT TO TELL OUR PATI ENTS

The shock caused by the release of the principal results of the Women's Health Initiative (WHI) (1) is now fading, and we must come to grips with how to integrate this new information into our practices. We will be helped in the future by the WHI releasing a series of papers discussing each of its findings in more detail, and by several of the large professional societies (such as the American College of Obstetricians and Gynecologists) establishing expert committees to draw up practice guidelines incorporating the Will information.

The scope of the Will was impressive; designed to be the first prospective, randomized, controlled clinical trial of hormone replacement therapy (HRT), it aimed to recruit more than 16,000 women and do follow-up on them for 8.5 years. The next-biggest studies in women's health have involved several thousand women, lasted 4 to 5 years, and cost dramatically less. Practically, this means that the Will is not just one more study in a long line of menopause studies; rather, the Will is the only sizeable, randomized, controlled trial that has ever been done in this field. Its results will be regarded as definitive, and it is highly unlikely that any study will be done in the future to challenge or change its findings.

What are the key WHI findings? A 37% reduction in colon cancer in HRT users was found, confirming a dozen previous epidemiologic studies that uniformly found about a 40% reduction in the incidence of colon cancer in both current and past users of HRT. The Will found a 34% decrease in hip fractures among HRT users, the first study to show that HRT decreased that most important osteoporosis endpoint. A 2.11-fold increase in deep venous thromboses was observed, in the low range of the twofold to threefold increase seen in previous studies of estrogen, HRT, or selective estrogen-receptor modulator (SERM) administration. The Will was stopped prematurely when a 26% increase in invasive breast cancer achieved statistical significance. This finding was surprising, since a recent comprehensive review of previous epidemiologic studies had concluded that no convincing link between breast cancer and HRT was present.2 The big WHI surprises were the 29% increase in heart attacks and the 41% increase in strokes that were se en. For many years, epidemiologic studies indicated that HRT decreased these events by half; however, the Heart and Estrogen/Progestin Replacement Study (HERS) trial (and its extension, HERS II) was the first prospective, randomized, controlled trial of HRT and heart disease. (3,4) It examined women with established heart disease and found no benefit of HRT use. Previous epidemiologic trials of stroke patients suggested that HRT provided a benefit, but a definitive, prospective trial of the use of estrogen alone for secondary prevention, the Women's Estrogen for Stroke Trial (WEST), failed to find a benefit of hormone therapy. (5) We must conclude that much of our previous "knowledge" of HRT was erroneous, due to artifacts inherent in epidemiologic studies.

In talking to patients, the main challenge will be accurately conveying the numeric risks they face. By any standards, a 0.08% increased risk of breast cancer for each year of HRT use is extremely low. After 10 years of use, the cumulative 0.8% increase in risk is still low, but it has become a reasonable fraction of the 8% to 12% total risk of breast cancer diagnosis. Nationally, with millions of women taking HRT, many thousands will presumably have HRT-associated disease; the risk for any one woman is extremely low, however, and she may decide that the benefits she personally obtains in symptom relief outweigh this risk. Grouping all of the WHI endpoints, 30 more bad outcomes than good outcomes per 10,000 women each year were noted, a surplus risk of 0.3% yearly. After 4 years of HRT, the risk becomes 1.2%-still low, but not as discountable.

A major problem is that HRT is the only potent therapy for vasomotor symptoms and genital atrophy in menopausal women, a particularly important consideration for women with severe symptoms. Although these problems have been shown to improve when patients use some non-HRT hormones (progestins, androgens), nonhormonal prescription drugs (eg, fluoxetine, clonidine hydrochloride), and herbs (eg, black cohash), women with significant symptoms are seldom satisfied with those treatments. Similarly, some women have mood changes at menopause that are only relieved with HRT; also, HRT may help a long list of other problems (forgetfulness, cognition, libido, skin thickness, etc).

A reasonable course of action now would be to discuss this information with patients and to carefully document their being informed of these risks. Some patients will elect to quit HRT altogether. Patients taking HRT for prevention will need to reassess their treatment; few patients will get benefits from HRT that they could not get with other therapy. In addition to increased adherence to dietary/lifestyle modifications, women concerned with osteoporosis might be better served by taking SERMs (eg, raloxifene hydrochloride;) or bisphosphonates (alendronate sodium, risedronate sodium); either seems to give the same approximate fracture prevention as HRT. Some evidence indicates that raloxifene hydrochloride lowers the risk of breast cancer. (6) Women focused on heart disease and stroke prevention should similarly work on life-style, blood pressure, and lipid issues, and HRT should be dropped.

The challenging decision, however, will come regarding women taking HRT to treat vasomotor symptoms and other symptoms of menopause, for which no truly equivalent therapies are available. Some patients will elect to continue HRT, deciding that their quality-of-life improvement outweighs the 0.3% yearly risk of a bad event. Many will try to discontinue the HRT as soon as possible after their symptoms are "over," but little, if any, evidence indicates that menopausal symptoms will be prevented or diminished by a course of HRT; rather, they will occur after HRT is stopped. Still, most women who took HRT in the past did so for a relatively brief time, usually measured in months, giving support to this approach. The efficacy of other maneuvers to minimize HRT's impact is entirely speculative but includes using estrogen-progestin medications other than those studied in the WHI, minimizing their dosages, using alternate delivery routes (patches, creams), and, in particular, adding occasional (every 2 to 4 months) pr ogestin administration to the estrogen treatment.

Ken Muse, MD

University of Kentucky 

Division of Reproductive Endocrinology

Department of Obstetrics and Gynecology

800 Rose St

Lexington, KY 40536-0084

References

(1.) Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy menopausal women, principal results from the women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333

(2.) Bush TL, Whiteman M, Flaws JA: Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001; 98:498-508

(3.) Hulley SB, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605-613

(4.) Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Follow-up Study (HERS II). JAMA 2002; 288:49-57

(5.) Viscoli CM, Brass LM, Kernan WN, et al: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345:1243-1249

(6.) Cauley JA, Norton L, Lippman ME, et al: Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treat 2001; 65:125-134

HORMONE REPLACEMENT THERAPY TO REDUCE CARDIOVASCULAR RISK: A CONCEPT WHOSE TIME HAS PASSED?

Recognition that the prevalence of cardiovascular disease is significantly lower in premenopausal women than in men of comparable age, yet approaches parity during the postmenopausal years (1) spawned hope that estrogen replacement therapy (ERT) would retard the initial development of atherosclerotic vascular disease in women and prevent its progression and complications. Estrogen replacement therapy is known to decrease low-density lipoprotein levels, increases serum high-density lipoprotein levels, and improve endothelial function. These observations, together with favorable results from small descriptive and experimental studies assessing cardiovascular risk, lent further credence to the hypothesis that ERT would prevent cardiovascular disease and its complications in postmenopausal worn en. (2-7) The possibility that ERT could favorably affect the development of atherosclerotic vascular disease, combined with its proven ability to retard the development and progression of osteoporosis, suggested that such pharmacotherapy would play a preeminent role in efforts to prevent common causes of morbidity and mortality in postmenopausal women. (2-10)

Estrogen replacement therapy, however, is not without risk. It has been shown to increase the incidence of venous thromboembolic disease, (11) increase serum triglyceride levels, (4) and increase the incidence of biliary disease. (12) Unopposed ERT has been associated with a disproportionately high incidence of endometrial cancer. (13) This has led investigators in recent years to preferentially utilize combinations of conjugated estrogens and progestin (hormone replacement therapy [HRT]) in women whose uterus was intact. In addition, concern has existed for many years that combined estrogen/progestin therapy may increase the risk of breast cancer. (14-16)

Cardiovascular disease is the leading cause of death, and osteoporosis and its complications are a common cause of morbidity in postmenopausal women. The large number of women at risk for these conditions mandates definitive assessment of the efficacy and safety of HRT if long-term therapy is to be considered.

Several large multicenter trials have evaluated the efficacy of ERT and HRT in women with established atherosclerotic vascular disease. In the Estrogen Replacement Atherosclerosis Trial, 309 postmenopausal women with angiographically proven coronary atherosclerosis were randomized to take a placebo, ERT with conjugated equine estrogens (0.625 mg orally once per day), or oral HRT with conjugated estrogens and progestin. (17) After 3.2 years of follow-up, there was no significant difference in the change in minimum luminal coronary diameter among the 3 subgroups. (17) The Postmenopausal Hormone Replacement Against Atherosclerosis Trial randomized 321 postmenopausal women with increased carotid intima-media thickness (detected using B-mode ultrasonography) to receive a placebo or 1 of 2 HRT regimens. (18, 19) All patients received 17[beta]-estradiol, 1 mg orally once per day. In addition, they were treated with gestodene, 0.025 mg orally from days 17 through 28, either every 4 weeks or every 12 weeks. (18, 19) A fter 48 months of follow-up, there was no significant difference in the progression of femoral or carotid intima-media thickness between placebo-treated patients and either subgroup treated with HRT. (18, 19) In the Women's Estrogen for Stroke Trial, 664 postmenopausal women with a recent transient ischemic attack or ischemic stroke were randomized to receive a placebo or 17[beta]-estradiol, 1 mg orally once per day. After 2.8 years of follow-up, the relative risk of nonfatal stroke in women assigned to receive 17[beta]-estradiol was 1.0. (20)

The most comprehensive studies for secondary prevention of cardiovascular disease to date are the Heart and Estrogen/Progestin Replacement Study (HERS) and its recently reported follow-up study, HERS II. (21-25) In HERS, 2,763 older postmenopausal women with established coronary heart disease were randomized to receive either a placebo or HRT with conjugated estrogens, 0.625 mg orally once per day, plus medroxyprogesterone, 2.5 mg orally once per day, and were followed up for 4.1 years. (21, 22) At the end of the follow-up period, there was no significant difference in the risk of death or coronary heart disease events. (22) During the first year of the study, however, there was a trend toward increasing risk of coronary heart disease, which was followed by a trend toward decreasing coronary heart disease risk as the duration of therapy increased. (22) Accordingly, the study was unblinded and extended to determine if the latter trend would evolve into a net benefit for use of HRT to reduce coronary heart dise ase risk (HERS II). (23) Originally intended to last 4 years, HERS II was terminated at 2.7 years because the anticipated benefit did not materialize and because it was unlikely that further treatment with HRT would produce beneficial effects. (23) The total follow-up period for HERS and HERS II combined was 6.8 years. (23) Analysis of relative hazard showed that treatment with HRT produced no significant reduction in the rates of coronary heart disease, coronary heart disease death, or nonfatal myocardial infarction compared to treatment with a placebo. (25) Similarly, HRT produced no significant reduction in the rates of coronary revascularization procedures, hospitalization for unstable angina pectoris, ischemic events, hospitalization for heart failure, sudden death, stroke or transient ischemic attacks, or peripheral arterial disease relative to treatment with a placebo. (23-26) The rate of nonfatal ventricular arrhythmias was significantly higher in patients receiving HRT than in control subjects given a placebo (relative hazard, 1.97). (23) The clinical significance of this observation is uncertain. A subgroup analysis of HERS indicated that no specific demographic or clinical subset of patients benefited from HRT. (27)

The recently reported Woman's Health Initiative (WHI) was the first randomized primary prevention trial to use HRT. (28) A total of 16,608 postmenopausal women without evidence of cardiovascular disease were randomized to receive a placebo or conjugated equine estrogens (0.625 mg) plus medroxy-progesterone (2.5 mg orally once per day). (28) The planned duration of the WHI was 8.5 years, but the study was terminated after 5.2 years, due primarily to excessive global risk and risk of invasive breast cancer. (28) Analysis of hazard ratios showed that after 5.2 years, there was a 29% increase in coronary heart disease risk, including an 18% risk of coronary heart disease mortality and a 32% increase in risk of nonfatal myocardial infarction. (28) There was a 20% increase in the risk of fatal stroke and a 50% increase in the risk of nonfatal stroke in women assigned to HRT. (28) Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, was more than twice as common in women receiving HR T than in those treated with the placebo. (28) The risk of invasive breast cancer was 26% higher in the subgroup receiving HRT than in the subgroup treated with the placebo. (28) In contrast, colorectal cancer risk was reduced by 33% in women receiving HRT. (28) The risk of endometrial cancer was comparable in patients receiving the placebo and those treated with HRT. (28) Hip-fracture risk was reduced 24% in women receiving HRT. (28) Death risk was comparable between the 2 subgroups, but the global risk index was 15% higher in the HRT subgroup. (28) Translated into absolute risk and benefit, the results show that for every 10,000 women treated with HRT, 7 more will have a myocardial infarction, 8 more will have a stroke, 18 more will have venous thromboembolic disease, and 8 more will have invasive breast cancer compared with those not treated with HRT; conversely, 6 fewer women treated with HRT will have colorectal cancer and 5 fewer will have hip fractures.

The results of HERS, HERS II, and the WHI send a clear message. (22-30) Hormone replacement therapy does not provide primary or secondary prevention of cardiovascular disease in postmenopausal women, but does increase the risk of venous thromboembolism and imparts clinically important noncardiovascular risk. (22-30) Thus, HRT should not be prescribed to prevent cardiovascular disease in postmenopausal women. (22-30)

Martin A. Alpert, MD

Department of Medicine

St. John's Mercy Medical Center

621 S New Ballas Rd Suite 3019-B

St. Louis, MO 63141

References

(1.) Stampfer M, Colditz G: Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991; 20:46-63

(2.) Grady D, Rubin SM, Petitti DB, et al: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117:1016-1037

(3.) Rijpkema AH, van der Sanden AA, Ruijs AH: Effects of postmenopausal estrogen-progesterone therapy on serum lipids and lipoproteins: a review. Maturitas 1990; 12:259-285

(4.) Writing Group for the PEPI Trial: Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273:199-208

(5.) Mendelsohn M, Karas R: The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340-1801-1811

(6.) Adams MR, Kaplan JR, Manuck SB, et al: Inhibition of coronary artery atherosclerosis by 17-beta-estradiol in ovariectomized monkeys: lack of an effect of added progesterone. Arteriosclerosis 1990; 10:1051-1057

(7.) Genant HK, Baylink DJ, Gallagher JC, et al: Effect of estrone sulfate on postmenopausal bone loss. Obslet Gynecol 1990; 76:579-584

(8.) Delmas PD: Treatment of postmenopausal osteoporosis. Lancel 200:2018-2026

(9.) Weiss NS, Ure CL, Ballard JH, et al: Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 1980; 303:1195-1198

(10.) de Gerhardsson VM, London S: Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Cancer Causes Control 1992; 3:355-360

(11.) Castellsague, J, Perez G, Gaxia S, et al: Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism a review. Drug Safety 1998; 18:117-123

(12.) Coronary Drug Project Research Group: Gallbladder disease as a side effect of drugs influencing lipid metabolism. experience in the Coronary Drug Project. N Engl J Med 1977; 296:1185-1190

(13.) Grady D, Gebretsadik T, Kerlikowske K, et al: Hormone replacement therapy and endometrial cancer risk, a metaanalysis. Obslet Gynecol 1995; 85:304-313

(14.) Steinberg KA, Thacker SB, Smith SJ, et al: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991; 265:1985-1990

(15.) Bergkvist L, Adami HO, Persson I, et al: The risk of breast cancer after estrogen and estrogen-progestin replacement N Engl J Med 1989; 321:293-297

(16.) Schairer C, Lubin J, Troisi R, et al: Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:485-491

(17.) Herrington DM, Reboussin DM, Brosnihan KB, et al: Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000; 343:522-529

(18.) Angerer P, Stork S, Kothny W, et al: Effect of post-menopausal estrogen replacement on atherosclerosis in femoral arteries. Maturitas 2002; 41:51-60

(19.) Angerer P, Stork S, Kothny W, et al: Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized controlled trial. Arterioscler Thromb Vasc Biol 2001; 21:262-268

(20.) Viscoli CM, Brass LM, Kernan WN, et al: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345:1243-1249

(21.) Grady D, Applegate W, Bush TL, et al: Heart and Estrogen/Progestin Replacement Study (HERS): design, methods and baseline characteristics. Control Clin Trials 1998; 19:314-335

(22.) Hulley SB, Bittner V, Furberg C, et al: Randomized trial of estrogen plus progestin in women with coronary heart disease in postmenopatisal women. JAMA 1989; 280:605-613

(23.) Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6,8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II).JAMA 2002; 288:49-57

(24.) Simon JA, Hsia J, Cauley JA, et al: Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen/ Progestin Replacement Study (HERS). Circulation 2001; 103:638-642

(25.) Grady D, Wenger NK, Herrington D, et al: Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/Progestin Replacement Study. Ann Intern Med 2000; 132:689-696

(26.) Hulley S, Furberg C, Barrett-Connor E, et al: Non-cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II).JAMA 2002; 288:58-66

(27.) Furberg CD, Vittinghoff E, Davidson M, et al: Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study. lessons learned. Circulation 2002; 65:917-922

(28.) Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. principal results from the Women's Health Initiative Randomized Controlled Trial. JAMA 2002; 288:321-333

(29.) Pettiti DB: Hormone replacement therapy for prevention. more evidence, more pessimism. JAMA 2002; 288:99-101

(30.) Fletcher SW, Colditz GA: Failure of estrogen plus progestin therapy for prevention. JAMA 2002; 288:36-68

HORMONE REPLACEMENT THERAPY AND LIPIDS: TIME TO RECONSIDER OUR OPTIONS?

With the onset of menopause, an adverse metabolic profile with increased susceptibility to atherogenesis has been documented. The accentuation of central fat distribution with many of the characteristics of the dysmetabolic syndrome (syndrbme X) is also evident in menopausal women. (1) Increased levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a) [Lp (a)], with less marked changes in the level of high-density lipoprotein (HDL) cholesterol, have been noted with the onset of menopause. The adverse changes in lipid levels were assumed to be largely responsible for the atherogenesis and, therefore, estrogen was considered as an alternate agent to standard lipid-lowering medication. Indeed, treatment with the combination of conjugated estrogens and a hydroxymethylglutaryl co-enzyme A reductase inhibitor (statin) was reported to have a synergistic effect on the lipid profile in postmenopausal women. (2) These well-documented, favorable lipid effects produced by hormone replacement therapy (HRT) were believed to reduce cardiovascular risk. Two recent prospective studies (3,4) have raised the possibility of adverse cardiac effects with the use of HRT. The adverse cardiovascular effects seen in these studies, despite improvement in the lipid profile, suggest that lipids are Just one factor contributing to cardiovascular risk. (3) Also, significant variation in lipid levels occur during the HRT cycle and need to be considered in study design and interpretation. (5)

The beneficial effects of oral estrogen therapy on levels of total cholesterol, LDL cholesterol, HDL cholesterol and cholesterol remnants are well documented. (6) On the other hand, it appears that transdermal estrogen delivery has fewer beneficial effects on the lipid panel, but has the potential benefit that triglyceride levels are not adversely influenced to the extent sometimes seen with oral estrogen therapy. The beneficial effects of HRT on levels of HDL cholesterol and possibly Lp(a) have been assumed to be the most likely factors resulting in cardiac benefit. (7) The beneficial lipid effects of estrogen are largely preserved when it is combined with progestin. Moreover, triglyceride levels may be lower in patients taking combination therapy versus those taking estrogen alone. In some women with basal hypertriglyceridemia, HRT may result in marked increase in triglyceride levels. Whether such elevations of triglyceride values are actually atherogenic has been debated; however, it is reasonable to assum e that marked elevation of triglyceride level does put patients at risk of acute pancreatitis. This association has been well documented with protease inhibitors. (8)

Given the concerns that have emerged with regard to HRT in both the Heart and Estrogen/Progestin Replacement Study (HERS) and Women's Health Initiative (WHI) study, do we have alternate agents with beneficial lipid effects? One such alternative group is the selective estrogen-receptor modulators (SERMs). Like conjugated estrogens, SERM therapy reduces LDL cholesterol and Lp(a) levels, though to a lesser extent than estrogen does. Tamoxifen therapy may increase triglyceride and HDL cholesterol levels, whereas treatment with raloxifene appears not to have these effects. The accentuation of hot flashes may not make these agents optimal for women with acute symptoms of menopause. In addition to the beneficial lipid effects, beneficial effects on bone and breast are present, and tamoxifen use may be associated with a reduced cardiac mortality rate. (9) Many women have also turned to phytoestrogens for their estrogen needs. The 2 classes that have been best studied include the lignans, which are found in fiber-rich foods, and isoflavones, found in soybeans. Use of phytoestrogens may reduce cardiac risk and improve the lipid profile. Their effects on Lp(a) level are currently unclear. Treatment with either SERM agents or phytoestrogens, while perhaps lacking some of the intensity of lipid changes seen with oral estrogen therapy, does have some tissue selectivity, which may be beneficial. Further study is clearly needed, however, before fully endorsing these compounds as substitutes for HRT. (10) Flaxseed, a rich source of phytoestrogens, reduces triglyceride levels and may promote cardiac health. (11)

In the latest National Cholesterol Education Program (NCEP) III guidelines, (12) treatment with estrogens is no longer a preferred method of reducing coronary artery disease risk. Clearly, until further data are available, long-term HRT for reducing lipid levels, and thereby reducing cardiac risk, is suspect. We believe that long-term HRT may be beneficial in certain penmenopausal women; unfortunately, no current data clearly identify these women. Subgroup analysis of the WHI and other forthcoming studies may lead to identification of women that may have significantly greater or reduced risks with HRT. Postmenopausal women of certain genotypes have augmented response of HDL cholesterol levels to HRT. (13)

In the meantime, and until we have clearer answers, we need to open a dialogue with our patients on this important issue and individualize treatment of lipid abnormalities. If possible, a baseline lipid profile may help narrow therapeutic options in perimenopausal women. Many women have had tangible benefits from HRT and are reluctant to discontinue this treatment. With regard to hyperlipidemia, we may need to resort to more traditional modalities such as diet, exercise, and pharmacologic intervention to achieve optimal lipid levels. Statins are effective agents in treating hyperlipidemia, and they may have additional benefits in terms of cognition and bone mass; moreover, the cardiovascular risk reduction with statin therapy appears more marked in women than in men. (14) Lipid effects are but one small part of the therapeutic equation. This equation should factor in patient preferences, symptom relief, bone and colon benefits, and risk of coronary artery disease and breast neoplasia, as well as family histor y of these illnesses. Another important point is that we may have to expand our traditional lipid profile to include apolipoprotein levels for better assessment of cardiac risk. (15) In patients who have had a hysterectomy, continuing estrogen therapy versus switching to treatment with traditional lipid-lowering drugs must be individualized. The estrogen-only arm of the WHI study continues, and will help clarify the benefits versus risk. While no clear answers have emerged with regard to the use of long-term HRT, the questions have just become clearer. Stay tuned!

Alan Peiris, MD, PhD, MRCP 

Said Iskandar, MD

Department of Medicine

Mountain Home Veterans Affairs Medical Center

East Tennessee State University

PO Box 70622

Johnson City, TN 37614-0622

Acknowledgment. We thank Patsy Ellis and Nancy Milligan of the Medical Library at Mountain Home Veterans Affairs Medical Center for their assistance.

References

(1.)Gambacciani M, Ciaponi M, Cappagli B, et al: Climacteric modifications in body weight and fat distribution. Climacteric 1999; 2:37-44

(2.) Fak AS, Erenus M, Tezcan H, et al: Effects of sinvastatin only or in combination with continuous combined hormone replacement therapy on serum lipid levels in hypercholesterolemic post-menopausal women. Eur Heart J 2000; 21:190-197

(3.) Hulley S, Grady D, Bush T, et al: 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. JAMA 1998; 280:605-613

(4.) Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333

(5.) Weintraub MS, Grosskopf I, Charach G, et al; Fluctuations of lipid and lipoprotein levels in hyperlipidemic postmenopausal women receiving hormone replacement therapy. Arch Intern Med 1998; 158:1803-1806

(6.) Sanada M, Nakagawa H, Kodama I, et al: The effect of hormone replacement therapy on metabolism of lipoprotein remnants in postmenopausal women. Maturitas 2000; 34:75-82

(7.) LaRosa JC: Women, lipoproteins, and cardiovascular disease risk. Can J Cardiot 1990; 6(suppl) 23B-29B

(8.) Krishnaswamy G, Chi DS, Kelley JL, et al: The cardiovascular and metabolic complications of HIV infection. Cardiol Rev 2000; 8:260-268

(9.) Ragaz J, Goldman A: Survival impact of adjuvant tamoxifen on competing causes of mortality in breast cancer survivors, with analysis of mortality from contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic episodes. J Clin Oncot 1998; 16:2018-2024

(10.) Merz-Demlow BE, Duncan AM, Wangen KE, et al: Soy isoflavones improve plasma lipids in normocholesterolemic, premenopausal women. Am J Clin Nutr 2000; 71:1462-1469

(11.) Albert CM, Campos H, Stampfer MJ, et al: Blood levels of long-chain n-3 fatty acids and the risks of sudden death. N Engl J Med 2002; 346:1113-1118

(12.) The National Cholesterol Education Expert Panel: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-2497

(13.) Herrington DM, Howard TD, Hawkins GA, et al: Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002; 346:967-974

(14.) Pedersen TR: Coronary artery disease: the Scandinavian Simvastatin Survival Study experience. Am] Cardiol 1998; 82(suppl):53T-56T

(15.) Walldius G, Jungne I, Holme I, et al: High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS Study): a prospective study. Lancet 2001; 358:2026-2033

THE RISE AND FALL OF HORMONE REPLACEMENT THERAPY: ONCOLOGISTS' VIEWS

Hormone replacement therapy (HRT) has been used for about 50 years to replenish the decrease in production of natural hormones in postmenopausal women. (1) In the United States, many postmenopausal women are routinely prescribed combined HRT consisting of estrogen plus progestin (Prempro). The use of estrogen alone was replaced by combined estrogen-progestin therapy When it Was discovered that taking estrogen alone increased the risk of uterine cancer. Therefore, progesterone was added, and an increasing percentage of women in the United States began to use the combined hormone pill in the 1980s. In addition to the short-term health benefits from acute reduction in menopausal symptoms, case-control and cohort studies suggested long-term benefits from estrogen therapy that included reduction in the risk of coronary heart disease (CHD), (2) osteoporosis, and bone fractures. (3)

The carcinogenic potential of HRT on breast epithelial tissue is not a new consideration. Population-based studies indicate that long-term use of estrogen alone as HRT does carry a significant risk of breast cancer over time. (4-6) Observational studies indicate that the risk of breast cancer may be greater with combined HRT. (7-9) Moreover, this risk may not be limited to breast epithelium alone. A separate cohort study (not a randomized, controlled trial) of 42,241 postmenopausal women, published concurrently with the Women's Health Initiative (WHI) study results, showed that women who used estrogen-only replacement therapy for 10 years or more had a significantly increased risk of ovarian cancer. (10)

Until the recent publication of the WHI study, (11) randomized trials were not available to prove or refute these observational data on the effects of estrogen and progesterone on CHD events and breast cancer risk. The role of combined HRT in the primary and secondary prevention of CHD events was uncertain when the WHI study was initiated. Observational studies have estimated a 35% to 50% reduction in CHD events with the use of estrogen alone and, less frequently, with combined HRT. Recent secondary prevention trials and observational studies have even shown that taking progestin may increase risk of CHD events in the first year of use. (12-14) Since death rates due to CHD events among women in the United States are higher than invasive breast cancer death rates, the presumed cardiovascular benefit of combined HRT was thought to outweigh any carcino genic potential. The recently published results from the WHI tell a different story. (11)

The WHI study, sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was designed to address these issues in a randomized setting in postmenopausal women taking combined HRT. The WHI is one of the largest preventive studies of its kind in the United States, focusing on the major causes of death, disability, and frailty in postmenopausal women. It is a 15-year research program with 3 main components: 1) randomized, controlled clinical trials of promising but unproven approaches to prevention; 2) an observational study to identify predictors of disease; and 3) a study of community-based approaches to developing positive health behaviors.

The WHI enrolled 16,608 healthy, ethnically diverse women, aged 50 to 79 years with an intact uterus, into this randomized, placebo-controlled primary prevention trial. Women were recruited at 40 centers in the United States between 1993 and 1998. Participants received conjugated equine estrogens (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day). Women who had previously had a hysterectomy were eligible to participate in an estrogen-only replacement therapy study. The original design of the trial was to follow up with these women until 2005. The study was closed 3 years earlier than originally planned, on the recommendation of an independent review board, because of an unacceptably higher risk of breast cancer in women receiving HRT. Invasive breast cancer, CHD, stroke, and pulmonary embolism made equal contributions to adverse events in the estrogen-progesterone arm of the study and the placebo arm. A decreased risk of colorectal cancer and fractures was observed in the HRT arm, but these benefits were overshadowed by the risks. The authors calculated that among 10,000 women over a period of 1 year, there would be 7 more CHD events, 8 more strokes, 8 more pulmonary embolisms, 8 more invasive breast cancers, 6 fewer colorectal cancers, and 5 fewer hip fractures in those receiving HRT than in those who were not. During the average follow-up time of 5.2 years, there was a 26% increase in the incidence of breast cancer in patients using HRT; data mirror results from pooled observational epidemiologic studies. The risks would have been even higher if only women who had remained compliant with HRT during the course of the study were analyzed. In the intervention arm, incidence of CHD events was increased by 22%, and rates of stroke and thromboembolisin were also increased. Death rates due to breast cancer are not reliable in this study because of the short follow-up time. The WHI results have far-reaching implications in the preventive health maintenance of postmenopausal women. The WHI study investigators r ecommend against long-term use of combined HRT in postmenopausal women. The unexpected results of the trial were that the risk of CHD events was aggravated and the risk of invasive breast cancer was higher than expected.

Although the study provided important information, answers to many other questions still remain elusive. Does the addition of progesterone increase breast cancer and cardiac risk in this population? Does the type of progesterone have a role? Would initiation of combined HRT earlier in a woman's life make a difference? Progesterone has mitogenic activity on breast epithelial tissue. (15) The addition of progestins to hormone therapy may further increase the risk of CHD events. The proatherogenic effects of progesterone may counter the positive effects of estrogens on the vascular endothelium. The beneficial effects on colorectal cancer risk are intriguing. Estrogens inhibit protein kinase C, and alter bile acid metabolism and gastrointestinal epithelial growth kinetics. The Nurses' Health Study (16) had previously shown that estrogen use may protect against colorectal cancer and large colon adenomas in postmenopausal women taking hormones. Will the use of estrogens without progestins protect the heart and redu ce the risk of colorectal cancer without significantly increasing the risk of invasive breast cancer in postmenopausal women? Results from the ongoing WHI estrogen-only study in women who have had a hysterectomy would help answer some of these questions, although the study results will not be applicable to women with an intact uterus.

The WHI is testimony to the constant need for well-conducted, adequately powered, randomized, controlled trials to support or refute clinically accepted and practiced standards of care. The WHI overturned the notion that postmenopausal, long-term combined HRT with estrogen-progestin should be part of routine, preventive health care.

The risk to a given individual is still low, but the risk to the population at large can be significant. The power of large, well-conducted clinical trials is clearly illustrated by this study, which showed the risks and benefits of such therapy and offered the clinical situations in which one would consider or not consider HRT. We believe that every major therapeutic recommendation should be backed by well-conducted, randomized controlled trials that have the statistical power and design to effectively answer a well-chosen clinical question. We should answer questions about the prevention and treatment of-all diseases by randomized controlled trials with no exceptions.

The term hormone replacement therapy had become a buzzword of wellness for women in the United States. A carefully conducted and analyzed randomized controlled trial tells us: Do not use combined HRT to prevent chronic diseases in postmenopausal women. Well-established preventive measures to reduce cardiovascular disease and osteoporosis should continue to be used.

Koyamangalath Krishnan, MD

Anand B. Karnad, MD

Division of Hematology-Oncology

Department of Internal Medicine

James H. Quillen College of Medicine

East Tennessee State University Cancer Center

Johnson City, TN 37614

References

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