Current Status of Postmenopausal Hormone Therapy Mary S. Beattie, MD ABSTRACT Estrogen therapy, with or without progestins, has been widely prescribed for the treatment of menopausal symptoms. However, recent randomized trials have cast doubt on the idea that postmenopausal hormone therapy (HT) can lower the risk of certain chronic diseases, including coronary heart disease. Many retrospective and observational studies of HT had suggested that it may reduce cardiovascular morbidity and mortality. Although the placebo-controlled Postmenopausal Estrogen/Progestin Interventions trial convincingly showed HT improves lipid parameters, subsequent trials failed to disclose an associated improvement in clinical outcomes. Indeed, in the secondary prevention Heart and Estrogen/Progestin Replacement Study, HT raised cardiovascular risk over the first year of therapy, although the risk elevation reversed in subsequent years. The opposed-estrogen arm of the Women s Health Initiative also showed elevated early cardiovascular risk with HT, as well as an increased risk of thromboembolic complications. Moreover, women taking HT showed an increased rate of invasive breast cancer that became significant after 3 years. Studies suggesting HT may prevent or slow the development of dementia or Alzheimer s disease are preliminary; randomized trials are ongoing. HT may be cautiously recommended for the short-term relief of menopausal symptoms but should be limited to 3 years or less in most cases due to an increased risk of invasive breast cancer; HT poses greater clinical risks compared with potential benefit when used longer term for the primary or secondary prevention of chronic diseases. (Adv Stud Med. 2003;3(4):205-213) WOMEN S HEALTH Hormone therapy (HT) is one of the most prescribed medical regimens in the United States. Before the July 2002 publication of the opposedestrogen arm of the Women s Health Initiative (WHI), 1 which linked at least 3 years of HT to an elevated risk of invasive breast cancer, an estimated 38% of postmenopausal women in this country were taking HT. 2 In 2000, this group accounted for 46 million prescriptions for conjugated equine estrogen (CEE) and 23 million prescriptions for CEE plus medroxyprogesterone acetate (MPA). Approved indications for HT as stipulated by the US Food and Drug Administration (FDA) include the relief of menopausal symptoms and the prevention of osteoporosis. Prevention of fractures (associated with decreased bone density), vasomotor instability (hot flashes), and atro- Dr Beattie is Assistant Professor of Medicine, Division of General Internal Medicine, and Clinical Research Fellow in Women s Health, University of California, San Francisco. Dr Beattie reports having no financial or advisory relationships with corporate organizations related to this activity. Off-Label Product Discussion: The author of this article does not include information on off-label use of products. Correspondence to: Mary S. Beattie, MD, 1635 Divisadero Street, Suite 601, San Francisco, CA 94115-1793. Advanced Studies in Medicine 205
WOMEN S HEALTH phy of the urogenital epithelium are the most common reasons HT is prescribed. HT is not FDA-approved for the prevention of coronary heart disease (CHD) but has been prescribed for this reason during the past decade. Until 1998, much of the evidence regarding HT and CHD was observational. Recent evidence from randomized controlled trials has shown that HT does not decrease the risk of CHD. 1,3 SHORT-TERM HT FOR MENOPAUSAL SYMPTOMS RECENT TRIAL EVIDENCE AND CLINICAL PRACTICE Estrogen is effective for relieving hot flashes associated with menopause within several weeks. In the Table 1. Short-Term Effectiveness of Selected Treatments for Vasomotor Symptoms Therapy Effectiveness (%) Estrogen 85 Megestrol acetate 85 Progestin cream 75 SSRIs and other neurotransmitters 50 70 Provera 50 Soy 50 Placebo 35 SSRIs = selective serotonin reuptake inhibitors. Data from Rebar et al 6 ; Loprinzi et al 7 ; Leonetti et al 8 ; Elkind-Hirsch 9 ; Berendsen. 10 Table 2. Contraindications to Estrogen Therapy in Postmenopausal Women Absolute Contraindications Pregnancy Unexplained vaginal bleeding Active or chronic liver disease Cancer of the breast or endometrium Recent vascular thrombosis History of estrogen-related vascular thrombosis Relative Contraindications Hypertriglyceridemia History of thromboembolic disease Family history of breast cancer Gallbladder disease Migraine headaches early 1990s, a randomized controlled trial, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, examined the short-term effects of estrogen and estrogen/progestin on menopausal symptoms and lipids. In this multicenter trial, 875 healthy postmenopausal women aged 45 to 64 years were randomized to receive CEE, CEE plus cyclic MPA, CEE plus continuous daily MPA, CEE plus cyclic micronized progesterone, or placebo. 4 Over a 3-year follow-up period, the 4 active therapies were associated with significant improvements in profiles of low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol, and fibrinogen compared with placebo. Unopposed CEE, which had the most pronounced HDL-elevating effect, was also associated with a significantly increased risk of endometrial hyperplasia. Regarding symptoms attributed to menopause, the PEPI investigators found all of the active treatments effectively suppressed hot flashes, night sweats, and insomnia, but none significantly affected mood, depression, cognition, or sexual function. 5 HT may be an acceptable treatment for postmenopausal women without contraindications whose lives are disrupted by hot flashes, night sweats, and insomnia. Even in this group, however, other management options (pharmacologic and nonpharmacologic) exist. In a recent release of data from the WHI regarding health-related quality of life, 6,7 the estrogen-progestin HT regimen did not lead to a clinically meaningful improvement in general health, vitality, mental health, depressive symptoms, sexual satisfaction, sleep disturbance, physical functioning, and bodily pain. The latter 3 measures showed slight statistically significant improvements, but these represented an improvement of only 1% to 4% over baseline scores. Among women 50 to 54 years of age with moderate-to-severe vasomotor symptoms at baseline, estrogen and progestin improved vasomotor symptoms and resulted in a small benefit in terms of sleep disturbance but no benefit in terms of the other quality-of-life outcomes. OPTIONS FOR SHORT-TERM SYMPTOMATIC RELIEF Several options are available for women seeking relief from symptoms attributed to menopause (Table 1). Estrogen replacement with or without a progestin remains the standard treatment for the short-term relief of menopausal symptoms, with a demonstrated effectiveness of about 85% for hot flashes, night sweats, and insomnia. The symptoms improve within 206 Vol. 3, No. 4 April 2003
HORMONE THERAPY about 1 week of the start of treatment. Given the risks of HT, it is reasonable to use low doses of estrogen for the shortest period of time necessary. A dose as low as 0.3 mg daily has been shown to be effective for the relief of menopausal symptoms. 8 Megestrol acetate is nearly as effective as HT for menopausal symptoms, but side effects include bloating, headache, or nausea. 9 It is appropriate for women with breast cancer who cannot receive HT. Over-the-counter transdermal progestin cream was shown in one randomized trial to relieve hot flashes and other vasomotor symptoms, though not bone mineral loss. 10 In this 102- patient trial, improvement or complete relief of vasomotor symptoms occurred in 83% of those in the progestin cream group and in 19% of those in the placebo group (P <.001). Soy appears to be about 40% to 50% effective for relieving hot flashes at a dosage of 40 mg to 80 mg daily at least 20 times the amount normally found in the American diet. 11 Soy protein is a practical choice if that amount is to be ingested, but may be a challenge for many women. The effects of neurotransmitter reuptake inhibitors such as fluoxetine, paroxetine, and venlafaxine on menopausal symptoms have been studied in breast cancer survivors. 12 They appear to be about 50% to 70% effective in this population. Placebo is 35% to 40% effective for relief of hot flashes and menopausal symptoms. It is important in any trial that reports an agent decreases hot flashes to make sure the agent was compared with placebo. The non estrogen-based treatments for menopausal symptoms are especially appropriate for women with absolute or relative contraindications to estrogen therapy. These contraindications stem largely from the effects of estrogen on hemostatic and triglyceride biochemistry, cancer promotion, and vascular function (Table 2). Compared with short-term HT, the long-term use of HT requires a much higher degree of benefit versus risk. In women without symptoms of menopause, any drug that would be given to prolong life or prevent disease should have clear evidence of beneficial effects outweighing risks. HT FOR CARDIOVASCULAR PROTECTION: EARLY EVIDENCE Three decades ago, whether estrogen could provide cardioprotective effects was controversial. Proponents of the idea noted that heart disease was rare in premenopausal women and that estrogen produced favorable changes in the lipoprotein profile. Meanwhile, skeptics observed that oral contraceptives increase the risk of venous thrombotic, coronary, and neurovascular events and cited the negative findings from the Coronary Drug Project. 13,14 Two of the randomization arms in this trial of men with coronary disease included 5.0 mg or 2.5 mg of CEE per day (4 8 times the dosage typically given to women). These dosages of CEE were associated with significant increases in venous thrombotic events and no decreases in cardiac events. The controversy was revisited in the 1980s when 2 observational reports were published in the same journal showing opposite effects of estrogen on CHD in women. The Framingham Study showed an increased risk of CHD in users of estrogen, and the Nurses Health Study showed a decreased risk of CHD in users of estrogen. 15,16 The Framingham investigators found a 90% elevated risk of cardiovascular events and an excess of cerebrovascular events among women who reported using HT. The Nurses Health Study included 32 317 women who were postmen-opausal and initially free of coronary artery disease. Compared with the women who had never used HT, the women who had any history of postmenopausal HT showed a 50% reduction in relative risk of coronary events (P =.007). Those reporting that they were currently taking HT showed a 70% lower relative risk (P =.001). Both findings were independent of smoking status, obesity, oral contraceptive use, or the presence of diabetes, hypertension, or elevated cholesterol levels. Many observational cohort studies followed in the next decade, and most of these showed a decreased risk of CHD in users of HT. 17-24 For example, the Lipid Research Clinics Program Follow-up Study of 2270 women with a baseline age of 40 to 69 years found a 58% reduction in the relative risk of death due to a cardiovascular event; risk reduction over a mean of 8.5 years was associated with the noncontraceptive use of estrogen. 18 That reduction, attributed to the protective effects of elevated HDL cholesterol levels, emerged after statistical adjustments for baseline features, including preexisting cardiovascular disease. A meta-analysis of many of these observational studies published in 1998 acknowledged that they send a consistent message that HT is an effective cardioprotective agent. 25 Still, the authors cautioned that most of the known biases in those studies would tend to exaggerate estrogen s effect. The skepticism was based on the inconclusive nature of Advanced Studies in Medicine 207
WOMEN S HEALTH observational studies, not merely doubts about the risk-benefit issues. The subjects in the uncontrolled, nonrandomized observational studies were not representative of the US population of postmenopausal women. Those who choose to receive HT tend to have leaner body mass and are more likely than women who do not receive HT to be well educated, exercise, have healthier diets, and receive more frequent medical care. CARDIOVASCULAR PROTECTION IN RANDOMIZED TRIALS In the multicenter PEPI trial of 875 healthy postmenopausal women, one of the first randomized controlled trials of HT, the treatment assignments consisted of CEE, CEE plus cyclic MPA, CEE plus continuous daily MPA, CEE plus cyclic micronized progesterone, or placebo for 3 years. 4 All of the active therapies significantly elevated mean HDL cholesterol levels compared with placebo, with the most prominent increase (6 mg/dl) seen in the group that received unopposed CEE. In addition, mean LDL cholesterol levels decreased (by 15 18 mg/dl) and mean triglyceride levels increased (by 11 14 mg/dl) markedly in all activetherapy groups. Changes in systolic blood pressure and insulin levels during the trial did not vary significantly among groups. These findings, although based on prospectively defined laboratory endpoints rather than clinical outcomes, enhanced the perception that HT may reduce cardiovascular risk. RANDOMIZED TRIALS WITH CLINICAL ENDPOINTS The Heart and Estrogen/Progestin Replacement Study (HERS) was the first prospective, randomized controlled trial to examine the cardiovascular effects of HT. 3 In this secondary prevention study, 2763 postmenopausal women with established coronary Table 3. Number of CHD Events Over Time by Randomization Group in the HERS Trial HT Group Control Group Year of Follow-up (n = 1380) (n = 1383) Year 1 57 38 P =.04 Year 2 47 48 P = NS Year 3 35 41 P = NS Years 4 and 5 33 49 P = NS CHD = coronary heart disease; HERS = Heart and Estrogen/Progestin Replacement Study; NS = not significant. P =.009 for time trend. Data from Hulley et al. 3 artery disease and no history of hysterectomy were randomized to receive CEE plus MPA or placebo. The average age was 67 years, and all women were younger than 80 years. The average follow-up time was 4.1 years; 75% of the women remained on assigned therapy at the end of 3 years. Less than one half of women in the HERS trial were taking lipidlowering medications, only one third were taking beta blocking agents, and 78% were taking aspirin. Mean levels of HDL cholesterol rose, and LDL cholesterol decreased to a significant degree (by 11% and 10% respectively, P <.001 for both parameters). There were no significant differences, however, in the rates of nonfatal acute myocardial infarction (MI) or death from CHD, the primary composite endpoint, or in the rates of separate secondary endpoints that included coronary revascularization, unstable angina, congestive heart failure, and stroke. Analysis of CHD events by follow-up time disclosed a significant risk increase by the end of the first year among women taking HT (Table 3). The short-term risk elevation did not meet the predetermined criteria for stopping the trial. Subsequently, a significant time trend in the opposite direction was observed. After an elevation the first year, CHD risk started to fall such that it became lower than in the control group by years 4 and 5. A follow-up analysis of HERS found a significantly elevated risk (P =.003) of venous thromboembolic events (deep venous thrombosis or pulmonary embolism) over a mean of 4 years among women taking HT. 26 This risk was attenuated among women taking aspirin or statins. There has been considerable speculation as to the mechanisms behind the early CHD risk elevation followed by a gradual decrease in risk. Among the most intriguing are that the initiation of HT was associated with transient changes in other biochemical systems involved in the pathogenesis of CHD events, such as those responsible for inflammation or thrombogenesis; or that events during the first year of HT may have selected a population of survivors who were more resistant to CHD. HERS II was a continuation of HERS that showed there was no further decrease in CHD in users of HT after an additional 3 years. 27 At a mean follow-up time of 6.8 years, adherence to HT in the actively treated groups had declined to less than 45%, showing no persisting benefit or favorable trend. The Estrogen Replacement for Atherosclerosis (ERA) trial was a randomized placebo-controlled trial that found that estrogen therapy had no beneficial effect on plaque diameter among women with established cardiovascular disease. 28 208 Vol. 3, No. 4 April 2003
HORMONE THERAPY PRIMARY PREVENTION OF CHD Investigators for the WHI at 40 US centers randomized 16 608 postmenopausal women with an intact uterus, aged 50 to 79 years (mean age, 63 years), to receive the combination of CEE and MPA or placebo in 1 daily tablet, for a projected 8.5 years. This HT arm of the WHI was discontinued early, and results were published in July 2002. 1 Interim analyses showed progressive elevations in the risk of cardiovascular events. In women receiving active therapy, the risk threshold was exceeded for breast cancer and for a global index of overall clinical harm. The opposed-estrogen arm of the WHI was halted after a mean followup of 5.2 years. (Another WHI arm, in which 10 739 postmenopausal women without a uterus were randomized to received unopposed estrogen or placebo, is ongoing. 29 ) CHD AND OTHER RISKS IN THE WHI Table 4 shows the risks and benefits of HT found in the WHI. 1 Women taking active therapy had a 29% increased risk of CHD events, which consisted largely of an excess of nonfatal MIs, and a 41% increase in risk of stroke (P.05 vs placebo for both findings). The risks of these events over time remained elevated among actively treated women throughout the follow-up period (Figure 1). There was also a more-than-doubled risk of deep venous thrombosis and pulmonary embolism. Event curves for the endpoint of invasive breast cancer show near correspondence between the 2 treatment groups until after the third year of followup (Figure 2), a finding that appears consistent with previous observational studies. After that point, however, the curves diverge such that the risk among actively treated women is elevated by a significant 26% by the end of the fifth year. Active therapy was associated with apparent benefits as well. Women taking opposed estrogen had a 37% decrease in risk of colorectal cancer and a 34% decrease in the risk of hip and vertebral fracture (Table 4), all significant differences. The WHI outcomes suggest that HT must be given to 237 women over 5.2 years in order for 1 CHD event to occur. Similarly, 225 women must be treated to cause 1 stroke, 105 women for 1 venous thromboembolic event, and 237 women for 1 case of invasive breast cancer. On the benefit side, 336 women must take HT to prevent 1 case of colon cancer, and 403 women must take HT to prevent 1 hip fracture. Therefore, if a clinician were to prescribe HT to generally healthy postmenopausal women, 1 at a time, treatment would be associated with at least 1 Table 4. Selected Clinical Outcomes by Randomization Assignment in the WHI Opposed-Estrogen Trial: Absolute Numbers of Patients Estrogen plus Progestin Placebo Hazard Ratio (n = 8506) (n = 8102) (Adjusted 95% CI) Mean follow-up (mo) 62.2 61.2 CHD CHD 164 122 1.29 (0.85 1.97) CHD death 33 26 1.18 (0.47 2.98) Nonfatal MI 133 96 1.32 (0.82 2.13) Stroke 127 85 1.41 (0.86 2.31) Deep venous thrombosis 115 52 2.07 (1.14 3.74) Pulmonary embolism 70 31 2.13 (0.99 4.56) Cancer Invasive breast 166 124 1.26 (0.83 1.92) Endometrial 22 25 0.83 (0.29 2.32) Colorectal 45 67 0.63 (0.32 1.24) Fractures Hip 44 62 0.66 (0.33 1.33) Vertebral 41 60 0.66 (0.32 1.34) Total 650 788 0.76 (0.63 0.92) Global index 751 623 1.15 (0.95 1.39) CI = confidence interval; CHD = coronary heart disease; MI = myocardial infarction. Adapted with permission from the Writing Group for the Women s Health Initiative Investigators. 1 Figure 1. WHI: Cumulative Hazard Rates* for CHD and Stroke Kaplan-Meier estimates of cumulative hazards for coronary heart disease (CHD) and stroke in the Women s Health Initiative (WHI) opposed-estrogen arm show a poorer outcome for actively treated women throughout the trial. *Theoretical measure of the likelihood that an individual will experience an event within a given period of time. Statistically significant based on 95% confidence interval hazard ratios. Adapted with permission from the Writing Group for the Women s Health Initiative Investigators. 1 Advanced Studies in Medicine 209
WOMEN S HEALTH serious medical condition long before any benefit was realized. The global index used in the WHI, a composite risk indicator for a range of major adverse outcomes (Table 4), indicates only 88 women would be treated before a harmful event occurred. The bottom-line message from the trial is that the risks of opposed HT as a preventive therapy in healthy postmenopausal women outweigh any likely clinical benefits. HT EFFECTS ON COGNITION AND DEMENTIA Some biochemical and physiologic studies of estrogen suggest HT has effects on neurons and cognitive function. Whether estrogen could be used to prevent cognitive decline or dementia, however, is a difficult question. Many of the studies of HT and dementia to date have been observational. In 2 meta-analyses, the authors have pooled the results of the observational studies of HT and dementia. 30,31 Observational studies can show associations but cannot show cause-effect relationships. Both metaanalyses have shown a decrease in dementia in users of HT, but the authors have been careful about recommending HT to prevent dementia. In a meta-analysis of 10 observational studies, users of HT had a 29% lower risk of dementia. 31 The study s authors noted, however, that the observational studies were heterogeneous, making it difficult to conclude that HT had an overall beneficial Figure 2. WHI: Cumulative Hazard Rates* for Invasive Breast Cancer Kaplan-Meier estimates of cumulative hazards for invasive breast cancer in the Women s Health Initiative (WHI) opposed-estrogen arm show correspondence between the groups out to 3 years, but thereafter a significantly poorer outcome for the patients taking hormone therapy. *Theoretical measure of the likelihood that an individual will experience an event within a given period of time. Statistically significant based on 95% confidence interval hazard ratios. Adapted with permission from the Writing Group for the Women s Health Initiative Investigators. 1 effect. The same group examined 4 studies of estrogen in women with Alzheimer s disease and found a possible benefit, but the studies were small, of limited length, nonrandomized, and uncontrolled. Given the known risks of estrogen therapy, the authors wrote, a recommendation to treat Alzheimer s disease or any other form of dementia with HT is premature in the absence of adequate prospective, randomized trials. One prospective, randomized multicenter trial has suggested HT may not have a role in treating dementia. In the Alzheimer s Disease Cooperative Study, 120 women with dementia who had undergone hysterectomy were randomized in a doubleblind placebo-controlled trial to unopposed CEE (0.625 mg/day or 1.25 mg/day) or to placebo. 32 Estrogen replacement at either dosage had no effect on cognitive or functional decline over 15 months. There were 4 cases of deep venous thrombosis, however, in this time period. SELECTIVE ESTROGEN RECEPTOR MODULATORS Selective estrogen receptor modulators (SERMs) exhibit tissue-specific estrogen agonist or antagonist activity. 33 Of the 2 commercially available SERMs, tamoxifen is FDA-approved for the treatment and prevention of estrogen receptor (ER) positive breast cancer, whereas raloxifene earned approval based on its documented ability to increase bone mineral density. 34 TAMOXIFEN Tamoxifen was originally approved for the treatment of metastatic breast cancer. However, the randomized Breast Cancer Prevention Trial led to the acceptance of tamoxifen as a preventive therapy for breast cancer. 35,36 In that trial, 13 388 women 35 years of age or older with an increased risk of breast cancer were randomized to receive 20 mg daily of tamoxifen or placebo for a projected 5 years. The study used well-described parameters for defining elevated risk, including age 60 years or older, 5-year predicted breast cancer risk of at least 1.66% according to the Gail algorithm for women younger than 60 years, or a history of in situ lobular carcinoma. The Gail algorithm is based on a logistic regression model incorporating a range of breast cancer risk parameters. 37 The model emphasizes age and number of relatives with a history of breast cancer but also includes parity, age at menarche, presence of atypical hyperplasia, and other variables. The trial was halted prematurely after the benefit of tamoxifen became apparent. Over 4 or more years, actively treated women showed a 49% 210 Vol. 3, No. 4 April 2003
HORMONE THERAPY decrease in the risk of invasive breast cancer (P <.001). With the participants stratified by age, the decrease in risk was 44% among women younger than 50 years, 51% for those aged 50 to 59 years, and 55% for those 60 years or older. The decrease reached 56% for women with in situ carcinoma at baseline and 86% for those with atypical hyperplasia. Tamoxifen was associated with a 50% decrease in the risk of noninvasive breast cancer over the entire population (P <.002). Not surprisingly, as a SERM, tamoxifen prevented the development of tumors that were ER positive but had no significant effect against ER-negative disease. Approximately two thirds of breast cancers are ER positive, suggesting that tamoxifen could be of significant benefit in many women with risk factors for breast cancer. Caution is appropriate, however. The Breast Cancer Prevention Trial also showed tamoxifen was associated with an elevated risk of endometrial cancer and venous thromboembolic events; 68% of actively treated women, but only 50% of the control group had hot flashes during the trial. In 2002 the US Preventive Services Task Force on Breast Cancer Prevention issued guidelines for women who were considering taking tamoxifen. 38 These guidelines noted fair evidence for harm in women at low-to-average risk of breast cancer; the risks of venous thromboembolism and other events outweighed the possible benefits. For women at high risk for breast cancer and at low risk for the potential adverse effects, however, there is fair evidence that a doctor-patient discussion of taking tamoxifen improves important health outcomes. RALOXIFENE In the most important study to clarify the clinical role of raloxifene, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a total of 7705 postmenopausal women with osteoporosis were randomized to receive either placebo or raloxifene, 60 mg or 120 mg daily for 4 years. 39-41 Active therapy increased bone mineral density in vertebrae and the femoral neck by 2% to 3%, depending on location and dosage, and reduced the risk of vertebral fracture by 40%. Women who entered the study with a history of vertebral fractures received the most benefit. Treatment with raloxifene for about 40 months in the MORE trial was associated with a 75% reduction in the risk of in situ or invasive breast cancer. Again, a significant risk reduction was found to have occurred only with respect to ER-positive tumors. There was no increase in the risk of endometrial cancer with raloxifene. However, the risk of venous thromboembolic events tripled in patients taking active therapy, and hot flashes were significantly more prevalent with raloxifene (10%) versus placebo (6%). The National Cancer Institute has launched a non placebo-controlled randomized study of the effects of the 2 SERMs on breast cancer risk, the Study of Tamoxifen and Raloxifene (STAR). At 194 North American centers, the trial will include a projected total of 22 000 postmenopausal women with in situ lobular carcinoma or elevated breast cancer risk according to Gail criteria. The 7-year STAR trial will also compare treatment effects on the risk of CHD, osteoporosis, and endometrial cancer. SERMS AND CARDIOVASCULAR RISK Both tamoxifen and raloxifene produce favorable changes in lipid parameters, 42,43 but these intermediate markers are not as clinically relevant as such outcomes as MI or CHD death. Breast cancer trials of tamoxifen have failed to show a cardiovascular risk benefit. A retrospective examination of the MORE trial showed, in a subgroup analysis, an association between raloxifene use and decreased CHD events. 41 This finding should also be interpreted with caution, because the primary intention of the MORE study was not to examine CHD events. Also, the subgroup analysis was not included in the initial data analysis plans for MORE. The subgroup that did appear to have lower CHD events on raloxifene was a subset of 1035 women with elevated baseline cardiovascular risk as determined by preexisting CHD or an elevated cardiac risk score. To examine the cardiovascular effects of raloxifene, a double-blind randomized, controlled trial, the Raloxifene Use for the Heart (RUTH) trial, will assess a wide range of CHD Table 5. Recommendations for Postmenopausal Hormone Therapy Hormone therapy ([HT] estrogen alone or estrogen plus progestin) can relieve hot flashes but has risks Do not use HT for prevention of cardiovascular disease risks outweigh benefits Discuss discontinuing HT after 1 year of therapy Aggressively try to stop HT after 3 years of therapy Selective estrogen receptor modulators should be used according to approved indications: - Prevention or treatment of breast cancer for tamoxifen - Prevention or treatment of osteoporosis for raloxifene Advanced Studies in Medicine 211
WOMEN S HEALTH outcomes in 10 101 women at 187 centers in 26 countries. 44,45 These women were randomized to receive raloxifene 60 mg daily or placebo. All participants have a documented history of CHD, peripheral artery disease, or multiple CHD risk factors. Women who have received HT within the past 6 months are excluded. The trial will be stopped after a total of 1670 women have experienced one of the primary CHD endpoints. The results from RUTH are not expected for at least 6 years. HT FOR PREVENTION: RECOMMENDATIONS HT can confer both benefit and harm in postmenopausal women (Table 5). As long-term primary or secondary preventive therapy, however, the risks of HT will usually outweigh the potential benefits. It is reasonable to discuss gradual withdrawal of HT with any postmenopausal woman currently taking this therapy. If she has been taking HT for 3 years or more (when risk of breast cancer increases), efforts to discontinue therapy should become more aggressive. The lessons learned from our investigations of HT for cardiovascular protection should be applied to our current exploration of the risks and benefits of SERMs. However promising the wider-ranging data have been, SERMs should be used according to their FDA-approved indications: tamoxifen for the treatment and prevention of breast cancer, and raloxifene for the treatment and prevention of osteoporosis. 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;288: 321-333. 2. Keating NL, Cleary PD, Rossi AS, Zaslavsky AM, Ayanian JZ. Use of hormone replacement therapy by postmenopausal women in the United States. Ann Intern Med. 1999;130:545-553. 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 PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273:199-208. 5. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol. 1998;92:982-988. 6. Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. New Engl J Med. 2003; [Published early online March 17, 2003, and will appear in the May 8, 2003 issue] 7. Grady D. Postmenopausal Hormones -- Therapy for symptoms only. New Engl J Med. 2003; [Published early online March 17, 2003, and will appear in the May 8, 2003 issue] 8. Rebar RW, Trabal J, Mortola J. Low-dose esterified estrogens (0.3 mg/day): long-term and short-term effects on menopausal symptoms and quality of life in postmenopausal women. Climacteric. 2000; 3:176-182. 9. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med. 1994;331:347-352. 10. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999; 94:225-228. 11. Elkind-Hirsch K. Effect of dietary phytoestrogens on hot flushes: can soy-based proteins substitute for traditional estrogen replacement therapy? Menopause. 2001;8:154-156. 12. Berendsen HH. The role of serotonin in hot flushes. Maturitas. 2000;36:155-164. 13. Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA. 1970;214:1303-1313. 14. Coronary Drug Project. Findings leading to discontinuation of the 2.5-mg day estrogen group. The Coronary Drug Project Research Group. JAMA. 1973;226:652-627. 15. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med. 1985; 313:1038-1043. 16. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med. 1985;313:1044-1049. 17. Wolf PH, Madans JH, Finucane FF, Higgins M, Kleinman JC. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort. Am J Obstet Gynecol. 1991;164:489-494. 18. Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation. 1987;75:1102-1109. 19. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of 212 Vol. 3, No. 4 April 2003
HORMONE THERAPY women in the Walnut Creek Study. Obstet Gynecol. 1987;70:289-293. 20. Criqui MH, Suarez L, Barrett-Connor E, McPhillips J, Wingard DL, Garland C. Postmenopausal estrogen use and mortality. Results from a prospective study in a defined, homogeneous community. Am J Epidemiol. 1988;128:606-614. 21. Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol. 1988;159:312-317. 22. Falkeborn M, Persson I, Adami HO, et al. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol. 1992;99:821-828. 23. Psaty BM, Heckbert SR, Atkins D, et al. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med. 1994;154:1333-1339. 24. Folsom AR, Mink PJ, Sellers TA, Hong CP, Zheng W, Potter JD. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Public Health. 1995;85:1128-1132. 25. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health. 1998;19:55-72. 26. 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. 27. 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). HERS Research Group. JAMA. 2002;288:49-57. 28. 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. 29. Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. JAMA. 2002; 288:366-368. 30. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA. 2001; 285:1489-1499. 31. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998;279:688-695. 32. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer s Disease Cooperative Study. JAMA. 2000;283:1007-1015. 33. Krishan V, Heath H, Bryant HU. Mechanism of action of estrogens and selective estrogen receptor modulators. Vitam Horm 2000;60:123-147. 34. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997; 337:1641-1647. 35. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90:1371-1388. 36. Wolmark N, Dunn BK. The role of tamoxifen in breast cancer prevention: issues sparked by the NSABP Breast Cancer Prevention Trial (P-1). Ann N Y Acad Sci. 2001;949:99-108. 37. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-1886. 38. Kinsinger LS, Harris R, Woolf SH, Sox HC, Lohr KN. Chemoprevention of breast cancer: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:59-69. 39. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-645. 40. Dickler MN, Norton L. The MORE trial: multiple outcomes for raloxifene evaluation breast cancer as a secondary end point: implications for prevention. Ann N Y Acad Sci. 2001;949:134-142. 41. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. The MORE Investigators. JAMA. 2002;287:847-857. 42. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998; 279:1445-1451. 43. Jordan VC. Estrogen, selective estrogen receptor modulation, and coronary heart disease: something or nothing. J Natl Cancer Inst. 2001;93:2-4. 44. Mosca L, Barrett-Connor E, Wenger NK, et al. Design and methods of the Raloxifene Use for The Heart (RUTH) study. Am J Cardiol. 2001;88:392-395. 45. Wenger NK, Barrett-Connor E, Collins P, et al. Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial. Am J Cardiol. 2002;90:1204-1210. Advanced Studies in Medicine 213